|
1
|
Zhang J, Zou Z, He Y, Filipczak N, Yalamarty SSK, Li X, Torchilin VP. Hybrid micellar preparations for co-delivery of PARP-1 siRNA and quercetin for cataract treatment. J Control Release 2025; 382:113700. [PMID: 40189052 DOI: 10.1016/j.jconrel.2025.113700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 04/01/2025] [Accepted: 04/03/2025] [Indexed: 04/11/2025]
Abstract
Cataract remains a major cause of ocular blindness. Cyclic Arg-Gly-Asp-d-Phe-Lys (RGD) peptide was introduced to the surface of self-assembled hybrid micelles for the co-delivery of poly (ADP-ribose) polymerase 1 (PARP-1) small-interfering RNA (siRNA) and quercetin (Q/siP-c-M). Q/siP-c-M exhibited uniform particle size distribution, good dispersibility, high encapsulation efficiency, and strong stability for siRNA and quercetin. Q/siP-c-M significantly improved the transcorneal co-delivery of siRNA and quercetin to the deeper cornea and led to greater drug accumulation. In addition, Q/siP-c-M significantly increased the activity of catalase and the content of adenosine triphosphate (ATP), reduced the expression of PARP-1 protein, and effectively prevented lipid peroxidation in the lens. Among selenite-induced cataract rats, the Q/siP-c-M-treated rats produced higher levels of ATP and catalase, as well as lower levels of malondialdehyde and PARP-1 protein expression compared with those in the model group. Administration of quercetin further resulted in a decrease in neutrophil extracellular trap formation and downregulation of gene expression of related proteins and pro-inflammatory cytokines. These observations indicated that quercetin has the potential to serve as a therapeutic for alleviating an excessive inflammatory reaction characterized by an overabundance of neutrophil extracellular traps in the eyes. Therefore, this study highlights the potential of Q/siP-c-M against cataract development through the regulation of the immune response by regulating inflammatory conditions. Furthermore, Q/siP-c-M may offer benefits in terms of apoptosis attenuation for lens epithelial cells.
Collapse
Affiliation(s)
- Jing Zhang
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Key Laboratory of Modern Preparation of TCM, Ministry of Education, State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, Jiangxi, China; China Resources Jiangzhong Pharmaceutical Group Co., Ltd., Nanchang 330004, Jiangxi, China
| | - Zhilin Zou
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Key Laboratory of Modern Preparation of TCM, Ministry of Education, State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, Jiangxi, China
| | - Yao He
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Key Laboratory of Modern Preparation of TCM, Ministry of Education, State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, Jiangxi, China
| | - Nina Filipczak
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston 02115, MA, USA
| | | | - Xiang Li
- National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Key Laboratory of Modern Preparation of TCM, Ministry of Education, State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, Jiangxi, China.
| | - Vladimir P Torchilin
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston 02115, MA, USA
| |
Collapse
|
|
2
|
Xiong B, Zhang Y, Liu S, Liao S, Zhou Z, He Q, Zhou Y. NOX Family: Regulators of Reactive Oxygen Species Balance in Tumor Cells. FASEB J 2025; 39:e70565. [PMID: 40266050 PMCID: PMC12017260 DOI: 10.1096/fj.202500238rrr] [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: 01/23/2025] [Revised: 04/09/2025] [Accepted: 04/14/2025] [Indexed: 04/24/2025]
Abstract
Cancer cells are capable of surviving, proliferating, and invading or migrating within hypoxic environments by regulating various adaptive mechanisms. Due to the activation of oncogenes and the inactivation of tumor suppressor genes, and relative deficiencies in oxygen and nutrients, cancer cells demonstrate elevated production of reactive oxygen species (ROS), primarily sourced from NADPH oxidases (NOX family). A key aspect of the reorientation of tumor cell metabolism is the combating of cellular oxidative stress through the promotion of antioxidant molecule synthesis to counteract ROS production. Given that most cancers experience hypoxia and that NOX is closely linked to numerous redox-dependent signaling pathways, the expression and function of NOX are altered in various malignancies. Therefore, this review summarizes the characteristics of NOX family members, their influence on tumor proliferation, invasion, and migration, the role of NOX in promoting tumor angiogenesis, the impact of NOX on the function of immune cells within the tumor microenvironment, and the potential of targeting NOX in tumor therapy. This aims to offer a fresh viewpoint on a comprehensive understanding of the functions of NOX family members.
Collapse
Affiliation(s)
- Bin Xiong
- Department of Radiation OncologyThe Affiliated Cancer Hospital of Xiangya School of Medicine Central South University/Hunan Cancer HospitalChangshaHunanChina
- Cancer Research Institute, Basic School of MedicineCentral South UniversityChangshaHunanChina
| | - Yang Zhang
- Cancer Research Institute, Basic School of MedicineCentral South UniversityChangshaHunanChina
| | - Siyi Liu
- Cancer Research Institute, Basic School of MedicineCentral South UniversityChangshaHunanChina
| | - Shan Liao
- Department of PathologyThe Third Xiangya Hospital of Central South UniversityChangshaHunanChina
| | - Zihua Zhou
- Department of OncologyLoudi Central HospitalLoudiHunanChina
| | - Qian He
- Department of Radiation OncologyThe Affiliated Cancer Hospital of Xiangya School of Medicine Central South University/Hunan Cancer HospitalChangshaHunanChina
| | - Yanhong Zhou
- Cancer Research Institute, Basic School of MedicineCentral South UniversityChangshaHunanChina
| |
Collapse
|
|
3
|
Zhang G, Zhang Y, Wang B, Xu H, Xie D, Guo Z. miR-605-3p may affect caerulein-induced ductal cell injury and pyroptosis in acute pancreatitis by targeting the DUOX2/NLRP3/NF-κB pathway. PeerJ 2024; 12:e17874. [PMID: 39224819 PMCID: PMC11368084 DOI: 10.7717/peerj.17874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 07/16/2024] [Indexed: 09/04/2024] Open
Abstract
Acute pancreatitis (AP) is a sudden-onset disease of the digestive system caused by abnormal activation of pancreatic enzymes. Dual oxidase 2 (DUOX2) has been found to be elevated in the progression of a variety of inflammatory diseases. Therefore, we analyzed the specific roles of DUOX2 in AP development. Blood samples were collected from of AP patients and healthy people, and the caerulein- stimulated human pancreatic duct cells (H6C7) were utilized to establish an AP cell model. Cell growth and apoptosis were measured using an MTT assay and TUNEL staining. Additionally, RT-qPCR and western blot assays were conducted to assess the RNA and protein expressions of the cells. ELISA kits were used to determine TNF-α, IL-6, IL-8, and IL-1β levels. The interaction between DUOX2 and miR-605-3p was predicted using the Targetscan database and confirmed by dual-luciferase report assay. We found that DUOX2 increased while miR-605-3p decreased in the blood of AP patients and caerulein-stimulated H6C7 cells. DUOX2 was targeted by miR-605-3p. Furthermore, DUOX2 knockdown or miR-605-3p overexpression promoted cell viability, decreased the TNF-α, IL-6, IL-8, and IL-1β levels, and inhibited apoptosis rate in caerulein-stimulated H6C7 cells. DUOX2 knockdown or miR-605-3p overexpression also increased the Bcl-2 protein levels and down-regulated Bax, cleaved-caspase-1, NLRP3 and p-p65. Interestingly, DUOX2 overexpression reversed the miR-605-3p mimic function in the caerulein-treated H6C7 cells. In conclusion, our research demonstrated that DUOX2 knockdown relieved the injury and inflammation in caerulein-stimulated H6C7 cells.
Collapse
Affiliation(s)
- Gai Zhang
- Department of Emergency Internal Medicine, The First Affiliated Hospital of Wannan Medical College Yijishan Hospital, Wuhu, Anhui, China
| | - Yuanyuan Zhang
- Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Bing Wang
- Department of Emergency Surgery, The First Affiliated Hospital of Wannan Medical College Yijishan Hospital, Wuhu, Anhui, China
| | - Hao Xu
- Department of Emergency Internal Medicine, The First Affiliated Hospital of Wannan Medical College Yijishan Hospital, Wuhu, Anhui, China
| | - Donghui Xie
- Department of Emergency Internal Medicine, The First Affiliated Hospital of Wannan Medical College Yijishan Hospital, Wuhu, Anhui, China
| | - Zhenli Guo
- Department of Oncology, First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China
| |
Collapse
|
|
4
|
Bi YW, Li LS, Ru N, Zhang B, Lei X. Nicotinamide adenine dinucleotide phosphate oxidase in pancreatic diseases: Mechanisms and future perspectives. World J Gastroenterol 2024; 30:429-439. [PMID: 38414585 PMCID: PMC10895600 DOI: 10.3748/wjg.v30.i5.429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/17/2023] [Accepted: 01/12/2024] [Indexed: 01/31/2024] Open
Abstract
Pancreatitis and pancreatic cancer (PC) stand as the most worrisome ailments affecting the pancreas. Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases, yet their true nature continues to elude their grasp. Within this realm, oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC. Excessive accumulation of reactive oxygen species (ROS) can cause oxidative stress, and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides (NOX). NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells, activate pancreatic stellate cells, and mediate macrophage polarization. Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis, creating an oxidative microenvironment that can cause abnormal apoptosis, epithelial to mesenchymal transition and genomic instability. Therefore, understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases. In this review, we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders, aiming to provide novel insights into understanding the mechanisms underlying these diseases.
Collapse
Affiliation(s)
- Ya-Wei Bi
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Long-Song Li
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Nan Ru
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Bo Zhang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Xiao Lei
- Department of Radiation Oncology, Chinese PLA General Hospital, Beijing 100853, China
| |
Collapse
|
|
5
|
Abstract
PURPOSE OF REVIEW Oxidative stress plays a central role in cataract pathogenesis, a leading cause of global blindness. This review delves into the role of oxidative stress in cataract development and key biomarkers - glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) - to clarify their functions and potential applications in predictive diagnostics and therapies. RECENT FINDINGS Antioxidants serve as pivotal markers in cataract pathogenesis. GSH affects the central lens due to factors such as enzyme depletion and altered connexin expression, impairing GSH diffusion. Age-related oxidative stress may hinder GSH transport via connexin channels or an internal microcirculation system. N-acetylcysteine, a GSH precursor, shows promise in mitigating lens opacity when applied topically. Additionally, SOD, particularly SOD1, correlates with increased cataract development and gel formulations have exhibited protective effects against posterior subscapular cataracts. Lastly, markers of lipid peroxidation, MDA and 4-HNE, have been shown to reflect disease severity. Studies suggest a potential link between 4-HNE and connexin channel modification, possibly contributing to reduced GSH levels. SUMMARY Oxidative stress is a significant contributor to cataract development, underscoring the importance of antioxidants in diagnosis and treatment. Notably, GSH depletion, SOD decline, and lipid peroxidation markers are pivotal factors in cataract pathogenesis, offering promising avenues for both diagnosis and therapeutic intervention.
Collapse
Affiliation(s)
- Bryanna Lee
- Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California, San Diego, California, USA
| | | | | |
Collapse
|
|
6
|
Lopez-Blazquez C, Lacalle-Gonzalez C, Sanz-Criado L, Ochieng’ Otieno M, Garcia-Foncillas J, Martinez-Useros J. Iron-Dependent Cell Death: A New Treatment Approach against Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2023; 24:14979. [PMID: 37834426 PMCID: PMC10573128 DOI: 10.3390/ijms241914979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/02/2023] [Accepted: 10/05/2023] [Indexed: 10/15/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating tumor type where a very high proportion of people diagnosed end up dying from cancer. Surgical resection is an option for only about 20% of patients, where the 5-year survival increase ranges from 10 to 25%. In addition to surgical resection, there are adjuvant chemotherapy schemes, such as FOLFIRINOX (a mix of Irinotecan, oxaliplatin, 5-Fluorouraci and leucovorin) or gemcitabine-based treatment. These last two drugs have been compared in the NAPOLI-3 clinical trial, and the NALIRIFOX arm was found to have a higher overall survival (OS) (11.1 months vs. 9.2 months). Despite these exciting improvements, PDAC still has no effective treatment. An interesting approach would be to drive ferroptosis in PDAC cells. A non-apoptotic reactive oxygen species (ROS)-dependent cell death, ferroptosis was first described by Dixon et al. in 2012. ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell's antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. In this review, we point out ferroptosis as an approach to consider in PDAC and propose that altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC.
Collapse
Affiliation(s)
- Carlos Lopez-Blazquez
- Translational Oncology Division, OncoHealth Institute, Health Research Institute—Fundación Jimenéz Diaz, Fundación Jimenéz Díaz University Hospital/Universidad Autónoma de Madrid (IIS-FJD/UAM), 28040 Madrid, Spain; (C.L.-B.); (L.S.-C.)
| | - Carlos Lacalle-Gonzalez
- Department of Medical Oncology, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain;
| | - Lara Sanz-Criado
- Translational Oncology Division, OncoHealth Institute, Health Research Institute—Fundación Jimenéz Diaz, Fundación Jimenéz Díaz University Hospital/Universidad Autónoma de Madrid (IIS-FJD/UAM), 28040 Madrid, Spain; (C.L.-B.); (L.S.-C.)
| | - Michael Ochieng’ Otieno
- Translational Oncology Division, OncoHealth Institute, Health Research Institute—Fundación Jimenéz Diaz, Fundación Jimenéz Díaz University Hospital/Universidad Autónoma de Madrid (IIS-FJD/UAM), 28040 Madrid, Spain; (C.L.-B.); (L.S.-C.)
| | - Jesus Garcia-Foncillas
- Department of Medical Oncology, Fundación Jiménez Díaz University Hospital, 28040 Madrid, Spain;
| | - Javier Martinez-Useros
- Translational Oncology Division, OncoHealth Institute, Health Research Institute—Fundación Jimenéz Diaz, Fundación Jimenéz Díaz University Hospital/Universidad Autónoma de Madrid (IIS-FJD/UAM), 28040 Madrid, Spain; (C.L.-B.); (L.S.-C.)
- Area of Physiology, Department of Basic Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain
| |
Collapse
|
|
7
|
Wang SL, Wu Y, Konaté M, Lu J, Mallick D, Antony S, Meitzler JL, Jiang G, Dahan I, Juhasz A, Diebold B, Roy K, Doroshow JH. Exogenous DNA enhances DUOX2 expression and function in human pancreatic cancer cells by activating the cGAS-STING signaling pathway. Free Radic Biol Med 2023; 205:262-274. [PMID: 37330147 PMCID: PMC10527782 DOI: 10.1016/j.freeradbiomed.2023.06.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 05/27/2023] [Accepted: 06/14/2023] [Indexed: 06/19/2023]
Abstract
Pro-inflammatory cytokines upregulate the expression of the H2O2-producing NADPH oxidase dual oxidase 2 (DUOX2)2 which, when elevated, adversely affects survival from pancreatic ductal adenocarcinoma (PDAC). Because the cGAS-STING pathway is known to initiate pro-inflammatory cytokine expression following uptake of exogenous DNA, we examined whether activation of cGAS-STING could play a role in the generation of reactive oxygen species by PDAC cells. Here, we found that a variety of exogenous DNA species markedly increased the production of cGAMP, the phosphorylation of TBK1 and IRF3, and the translocation of phosphorylated IRF3 into the nucleus, leading to a significant, IRF3-dependent enhancement of DUOX2 expression, and a significant flux of H2O2 in PDAC cells. However, unlike the canonical cGAS-STING pathway, DNA-related DUOX2 upregulation was not mediated by NF-κB. Although exogenous IFN-β significantly increased Stat1/2-associated DUOX2 expression, intracellular IFN-β signaling that followed cGAMP or DNA exposure did not itself increase DUOX2 levels. Finally, DUOX2 upregulation subsequent to cGAS-STING activation was accompanied by the enhanced, normoxic expression of HIF-1α and VEGF-A as well as DNA double strand cleavage, suggesting that cGAS-STING signaling may support the development of an oxidative, pro-angiogenic microenvironment that could contribute to the inflammation-related genetic instability of pancreatic cancer.
Collapse
Affiliation(s)
- Stephen L Wang
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Yongzhong Wu
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Mariam Konaté
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Jiamo Lu
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - David Mallick
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Smitha Antony
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Jennifer L Meitzler
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Guojian Jiang
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Iris Dahan
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Agnes Juhasz
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Becky Diebold
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Krishnendu Roy
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - James H Doroshow
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA; Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
8
|
Ngum JA, Tatang FJ, Toumeni MH, Nguengo SN, Simo USF, Mezajou CF, Kameni C, Ngongang NN, Tchinda MF, Dongho Dongmo FF, Akami M, Ngane Ngono AR, Tamgue O. An overview of natural products that modulate the expression of non-coding RNAs involved in oxidative stress and inflammation-associated disorders. Front Pharmacol 2023; 14:1144836. [PMID: 37168992 PMCID: PMC10165025 DOI: 10.3389/fphar.2023.1144836] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 03/24/2023] [Indexed: 05/13/2023] Open
Abstract
Oxidative stress is a state in which oxidants are produced in excess in the body's tissues and cells, resulting in a biological imbalance amid the generation of reactive oxygen and nitrogen species (RONS) from redox reactions. In case of insufficient antioxidants to balance, the immune system triggers signaling cascades to mount inflammatory responses. Oxidative stress can have deleterious effects on major macromolecules such as lipids, proteins, and nucleic acids, hence, Oxidative stress and inflammation are among the multiple factors contributing to the etiology of several disorders such as diabetes, cancers, and cardiovascular diseases. Non-coding RNAs (ncRNAs) which were once referred to as dark matter have been found to function as key regulators of gene expression through different mechanisms. They have dynamic roles in the onset and development of inflammatory and oxidative stress-related diseases, therefore, are potential targets for the control of those diseases. One way of controlling those diseases is through the use of natural products, a rich source of antioxidants that have drawn attention with several studies showing their involvement in combating chronic diseases given their enormous gains, low side effects, and toxicity. In this review, we highlighted the natural products that have been reported to target ncRNAs as mediators of their biological effects on oxidative stress and several inflammation-associated disorders. Those natural products include Baicalein, Tanshinone IIA, Geniposide, Carvacrol/Thymol, Triptolide, Oleacein, Curcumin, Resveratrol, Solarmargine, Allicin, aqueous extract or pulp of Açai, Quercetin, and Genistein. We also draw attention to some other compounds including Zanthoxylum bungeanum, Canna genus rhizome, Fuzi-ganjiang herb pair, Aronia melanocarpa, Peppermint, and Gingerol that are effective against oxidative stress and inflammation-related disorders, however, have no known effect on ncRNAs. Lastly, we touched on the many ncRNAs that were found to play a role in oxidative stress and inflammation-related disorders but have not yet been investigated as targets of a natural product. Shedding more light into these two last points of shadow will be of great interest in the valorization of natural compounds in the control and therapy of oxidative stress- and inflammation-associated disorders.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Ousman Tamgue
- Department of Biochemistry, Faculty of Sciences, University of Douala, Douala, Cameroon
| |
Collapse
|
|
9
|
Cagle LA, Linderholm AL, Franzi LM, Last JA, Simon SI, Kenyon NJ, Harper RW. Early mechanisms of neutrophil activation and transmigration in acute lung injury. Front Physiol 2022; 13:1059686. [PMID: 36620212 PMCID: PMC9811384 DOI: 10.3389/fphys.2022.1059686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Introduction:Neutrophil transmigration is multifactorial and primarily driven by selectins and β2-integrins (CD11b/CD18), whose expression are dependent on the underlying stimulus. Ventilator-induced lung injury (VILI) results in a predominantly CD18-independent mechanism of neutrophil recruitment, while direct endotoxin-induced lung injury results from a CD18-dependent mechanism. We previously observed that lack of NADPH oxidases DUOX1 and DUOX2 resulted in reduced neutrophil influx in a VILI model of lung injury but had no influence on neutrophil influx after LPS exposure. Based on these observations, we hypothesized that DUOX1/DUOX2 are an important component of CD18-independent mechanisms of neutrophil recruitment in the lung. Methods:We exposed Duoxa -/- (KO) mice and Duoxa +/+ (WT) mice to either an intratracheal exposure of lipopolysaccharide (LPS/endotoxin)-or high tidal volume ventilation and compared expression of neutrophil markers between groups. WT mice (129S6/SvEvTac) were obtained from Taconic Biosciences (One Discovery Drive Suite 304; Rensselaer, NY 1244) and were allowed to acclimatize for one week prior to study enrollment. KO mice were generated as previously described [Grasberger 2012] and bred in-house on a 129S6 background. We provided positive-pressure ventilation at a tidal volume of 10 ml/kg with 2 cmH20 positive end-expiratory pressure (PEEP). Mice were assigned to groups consisting of KO (n = 5) and WT (n = 5) in each group and divided into non-ventilated, positive-pressure ventilation, or LPS IT exposure groups. Positive-pressure ventilation was instituted for 4-h using a FlexiVent (Flexiware 8.1, Scireq, Montreal, QC, Canada). Lipopolysaccharide (Salmonella enterica serotype tryphimurium L6143, Millipore Sigma) was administered via an intratracheal (IT) route at a dose of 0.1 mg/kg. Mice were humanely euthanized at 4-h post-injection consistent with the UC Davis IAUCAC-approved protocol. Results:As previously observed, neutrophilic influx into the airways was significantly impaired in the Duoxa -/- (KO) mice after VILI, but not after LPS exposure. LPS-induced lung injury resulted in upregulation of CD11b+ neutrophils and shedding of CD62L and CD162 regardless of DUOX expression, whereas VILI resulted in upregulation of CD49+ neutrophils in the Duoxa +/+ (WT) mice but not the Duoxa -/- (KO) mice. Conclusion:Our data suggest DUOX is required for CD18-independent mechanisms of neutrophil recruitment in the lung induced by acute lung injury, but not for canonical CD18depedent mechanisms after LPS exposure.
Collapse
Affiliation(s)
- L. A. Cagle
- University of California Lung Center, University of California, Davis, Davis, CA, United States
| | - A. L. Linderholm
- University of California Lung Center, University of California, Davis, Davis, CA, United States,Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Sacramento, Sacramento, CA, United States,Department of Veterans Affairs, Northern California Healthcare System, Mather, CA, United States
| | - L. M. Franzi
- University of California Lung Center, University of California, Davis, Davis, CA, United States
| | - J. A. Last
- University of California Lung Center, University of California, Davis, Davis, CA, United States
| | - S. I. Simon
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - N. J. Kenyon
- University of California Lung Center, University of California, Davis, Davis, CA, United States,Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Sacramento, Sacramento, CA, United States,Department of Veterans Affairs, Northern California Healthcare System, Mather, CA, United States
| | - R. W. Harper
- University of California Lung Center, University of California, Davis, Davis, CA, United States,Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Sacramento, Sacramento, CA, United States,Department of Veterans Affairs, Northern California Healthcare System, Mather, CA, United States,*Correspondence: R. W. Harper,
| |
Collapse
|
|
10
|
Endotoxin contamination alters macrophage-cancer cell interaction and therapeutic efficacy in pre-clinical 3D in vitro models. BIOMATERIALS ADVANCES 2022; 144:213220. [PMID: 36476713 DOI: 10.1016/j.bioadv.2022.213220] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/26/2022] [Accepted: 11/22/2022] [Indexed: 11/27/2022]
Abstract
The rapid developments in biofabrication, in particular 3D bioprinting, in the recent years have facilitated the need for novel biomaterials that aim to replicate the target tissue in great detail. The presence of endotoxins in these biomaterials is often an overlooked problem. In pre-clinical 3D in vitro models, endotoxins can have significant influence on cell behavior and credibility of the model. In this study we demonstrate the effects of high levels of endotoxins in commercially-available gelatin on the macrophage-cancer cell crosstalk in a 3D bioprinted co-culture model. First, it is demonstrated that, while presenting the same mechanical and structural stimuli, high levels of endotoxin can have significant influence on the metabolic activity of macrophages and cancer cells. Furthermore, this study shows that high endotoxin contamination causes a strong inflammatory reaction in macrophages and significantly inhibits the effects of a paracrine macrophage-cancer cell co-culture. At last, it is demonstrated that the differences in endotoxin levels can drastically alter the efficacy of novel macrophage modulating immunotherapies, AS1517499 and 3-methyladenine. Altogether, this study shows that endotoxin contamination in biomaterials can significantly alter intra- and intercellular communication and thereby drug efficacy, which might lead to misinterpretation of the potency and safety of the tested compounds.
Collapse
|
|
11
|
Du L, Zhang J, Zhang X, Li C, Wang Q, Meng G, Kan X, Zhang J, Jia Y. Oxypeucedanin relieves LPS-induced acute lung injury by inhibiting the inflammation and maintaining the integrity of the lung air-blood barrier. Aging (Albany NY) 2022; 14:6626-6641. [PMID: 35985771 PMCID: PMC9467393 DOI: 10.18632/aging.204235] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/21/2022] [Indexed: 11/25/2022]
Abstract
Introduction: Acute lung injury (ALI) is commonly accompanied by a severe inflammatory reaction process, and effectively managing inflammatory reactions is an important therapeutic approach for alleviating ALI. Macrophages play an important role in the inflammatory response, and this role is proinflammatory in the early stages of inflammation and anti-inflammatory in the late stages. Oxypeucedanin is a natural product with a wide range of pharmacological functions. This study aimed to determine the effect of oxypeucedanin on lipopolysaccharide (LPS)-induced ALI. Methods and Results: In this study, the following experiments were performed based on LPS-induced models in vivo and in vitro. Using myeloperoxidase activity measurement, ELISA, qRT-PCR, and Western blotting, we found that oxypeucedanin modulated the activity of myeloperoxidase and decreased the expression levels of inflammatory mediators such as TNF-α, IL-6, IL-1β, MPO, COX-2 and iNOS in LPS-induced inflammation models. Meanwhile, oxypeucedanin inhibited the activation of PI3K/AKT and its downstream NF-κB and MAPK signaling pathways. In addition, oxypeucedanin significantly decreased the pulmonary vascular permeability, which was induced by LPSs, and the enhanced expression of tight junction proteins (Occludin and Claudin 3). Conclusions: In conclusion, this study demonstrated that the anti-inflammatory mechanism of oxypeucedanin is associated with the inhibition of the activation of PI3K/AKT/NF-κB and MAPK signaling pathways and the maintenance of the integrity of the lung air-blood barrier.
Collapse
Affiliation(s)
- Li Du
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jinrong Zhang
- Department of Pathogeny Biology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Xiyue Zhang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Chunyan Li
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Qi Wang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Guangping Meng
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xingchi Kan
- Department of Theoretic Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Jie Zhang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yuxi Jia
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin, China.,Application Demonstration Center of Precision Medicine Molecular Diagnosis, The Second Hospital of Jilin University, Changchun, Jilin, China
| |
Collapse
|
|
12
|
Pal S, Haldar C, Verma R. Melatonin attenuates LPS-induced ovarian toxicity via modulation of SIRT-1, PI3K/pAkt, pErk1/2 and NFĸB/COX-2 expressions. Toxicol Appl Pharmacol 2022; 451:116173. [PMID: 35878799 DOI: 10.1016/j.taap.2022.116173] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/04/2022] [Accepted: 07/18/2022] [Indexed: 10/17/2022]
Abstract
The association between inflammation and metabolic disturbances leads to various female pathophysiological conditions. Bacterial lipopolysaccharide (LPS), found in the outer membrane of gram-negative bacteria, elicits an oxidative and inflammatory response that profoundly interferes with female reproductive health. We investigated the ameliorative action of melatonin on LPS-induced ovarian pathophysiology in golden hamsters, Mesocricetus auratus. Hamsters were administered with exogenous melatonin (5 mg/kg BW) and LPS (100 μg/kg BW) intraperitoneally for 7 days. LPS treatment impaired ovarian folliculogenesis as evident by histoarchitecture (elevated number of atretic follicles, reduced number of growing follicles and corpus luteum) and steroidogenesis (decreased aromatase/ERα, estradiol and progesterone). On the other hand, LPS administration also perturbed thyroid hormone (T3 and T4) homeostasis, ovarian melatonin receptor (MT-1) expression, antioxidant potential (SOD and catalase) and concomitantly elevated nitro-oxidative stress (decreased SOD, catalase and elevated CRP, TNFα and nitrate/nitrite level) and inflammatory load (NFĸB and COX-2) which culminated into ovarian follicular apoptosis (elevated caspase-3). LPS also disrupted metabolic homeostasis as indicated by hyperinsulinemia with a simultaneous decrease in ovarian IR/GLUT-4 and glucose content. Moreover, LPS treatment decreased expressions of key markers of ovarian physiology (SIRT-1, pErk1/2, PI3K and pAkt). Melatonin co-treatment with LPS improve these detrimental changes proposing melatonin as a potent therapeutic candidate against ovarian dysfunction induced by endotoxin.
Collapse
Affiliation(s)
- Sriparna Pal
- Reproduction and Molecular Biology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, U.P., India.
| | - Chandana Haldar
- Reproduction and Molecular Biology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, U.P., India.
| | - Rakesh Verma
- Reproduction and Molecular Biology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi 221005, U.P., India.
| |
Collapse
|
|
13
|
Lee CG, Park C, Hwang S, Hong JE, Jo M, Eom M, Lee Y, Rhee KJ. Pulsed Electromagnetic Field (PEMF) Treatment Reduces Lipopolysaccharide-Induced Septic Shock in Mice. Int J Mol Sci 2022; 23:ijms23105661. [PMID: 35628471 PMCID: PMC9147061 DOI: 10.3390/ijms23105661] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/14/2022] [Accepted: 05/17/2022] [Indexed: 12/04/2022] Open
Abstract
Despite advances in medicine, mortality due to sepsis has not decreased. Pulsed electromagnetic field (PEMF) therapy is emerging as an alternative treatment in many inflammation-related diseases. However, there are few studies on the application of PEMF therapy to sepsis. In the current study, we examined the effect of PEMF therapy on a mouse model of lipopolysaccharide (LPS)-induced septic shock. Mice injected with LPS and treated with PEMF showed higher survival rates compared with the LPS group. The increased survival was correlated with decreased levels of pro-inflammatory cytokine mRNA expression and lower serum nitric oxide levels and nitric oxide synthase 2 mRNA expression in the liver compared with the LPS group. In the PEMF + LPS group, there was less organ damage in the liver, lungs, spleen, and kidneys compared to the LPS group. To identify potential gene targets of PEMF treatment, microarray analysis was performed, and the results showed that 136 genes were up-regulated, and 267 genes were down-regulated in the PEMF + LPS group compared to the LPS group. These results suggest that PEMF treatment can dramatically decrease septic shock through the reduction of pro-inflammatory cytokine gene expression. In a clinical setting, PEMF may provide a beneficial effect for patients with bacteria-induced sepsis and reduce septic shock-induced mortality.
Collapse
Affiliation(s)
- Chang-Gun Lee
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University MIRAE Campus, Wonju 26493, Korea; (C.-G.L.); (C.P.); (S.H.); (J.-E.H.); (M.J.)
- Department of Medical Genetics, School of Medicine, Ajou University, Suwon 16499, Korea
| | - Chanoh Park
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University MIRAE Campus, Wonju 26493, Korea; (C.-G.L.); (C.P.); (S.H.); (J.-E.H.); (M.J.)
| | - Soonjae Hwang
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University MIRAE Campus, Wonju 26493, Korea; (C.-G.L.); (C.P.); (S.H.); (J.-E.H.); (M.J.)
- Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, GAIST, College of Medicine, Gachon University, Incheon 21999, Korea
| | - Ju-Eun Hong
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University MIRAE Campus, Wonju 26493, Korea; (C.-G.L.); (C.P.); (S.H.); (J.-E.H.); (M.J.)
| | - Minjeong Jo
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University MIRAE Campus, Wonju 26493, Korea; (C.-G.L.); (C.P.); (S.H.); (J.-E.H.); (M.J.)
| | - Minseob Eom
- Department of Pathology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea;
| | - Yongheum Lee
- Department of Biomedical Engineering, College of Software and Digital Healthcare Convergence, Yonsei University MIRAE Campus, Wonju 26493, Korea
- Correspondence: (Y.L.); (K.-J.R.); Tel.: +82-33-760-2863 (Y.L.); +82-33-760-2445 (K.-J.R.); Fax: +82-33-760-2561 (Y.L.); +82-33-760-2195 (K.-J.R.)
| | - Ki-Jong Rhee
- Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University MIRAE Campus, Wonju 26493, Korea; (C.-G.L.); (C.P.); (S.H.); (J.-E.H.); (M.J.)
- Correspondence: (Y.L.); (K.-J.R.); Tel.: +82-33-760-2863 (Y.L.); +82-33-760-2445 (K.-J.R.); Fax: +82-33-760-2561 (Y.L.); +82-33-760-2195 (K.-J.R.)
| |
Collapse
|
|
14
|
Morale MG, Tamura RE, Cintra R, Araújo NM, Villa LL. TLR4 and SARM1 modulate survival and chemoresistance in an HPV-positive cervical cancer cell line. Sci Rep 2022; 12:6714. [PMID: 35468924 PMCID: PMC9039070 DOI: 10.1038/s41598-022-09980-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/25/2022] [Indexed: 11/25/2022] Open
Abstract
Human Papillomavirus is responsible for a wide range of mucosal lesions and tumors. The immune system participate in tumorigenesis in different ways. For example, signaling pathways triggered by Toll-like receptors (TLR) play a role in chemotherapy resistance in several tumor types and are candidates for contributing to the development of HPV-induced tumors. Here, we studied the receptor TLR4 and the adaptor molecule SARM1 in HeLa cells, an HPV-positive cervical cancer cell line. Knocking out of these genes individually proved to be important for maintaining cell viability and proliferation. TLR4 knock out cells were more sensitive to cisplatin treatment, which was illustrated by an increased frequency of apoptotic cells. Furthermore, TLR4 and SARM1 modulated ROS production, which was induced by cell death in response to cisplatin. In conclusion, TLR4 and SARM1 are important for therapy resistance and cervical cancer cell viability and may be relevant clinical targets.
Collapse
|
|
15
|
Bi Y, Lei X, Chai N, Linghu E. NOX4: a potential therapeutic target for pancreatic cancer and its mechanism. J Transl Med 2021; 19:515. [PMID: 34930338 PMCID: PMC8686284 DOI: 10.1186/s12967-021-03182-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/03/2021] [Indexed: 12/18/2022] Open
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is one of the seven isoforms of NOX family, which is upregulated in pancreatic cancer cell, mouse model of pancreatic cancer and human pancreatic cancer tissue. NOX4 is a constitutively active enzyme that primarily produces hydrogen peroxide, which exhibits completely different properties from other subtypes of NOX family. More importantly, recent studies illuminate that NOX4 promotes pancreatic cancer occurrence and development in different ways. This review summarizes the potential roles and its mechanism of NOX4 in pancreatic cancer and explores NOX4 as the potential therapeutic target in pancreatic cancer.
Collapse
Affiliation(s)
- Yawei Bi
- Department of Gastroenterology and Hepatology, The First Medical Center of PLA General Hospital, Beijing, 100853, China
| | - Xiao Lei
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, 100859, China
| | - Ningli Chai
- Department of Gastroenterology and Hepatology, The First Medical Center of PLA General Hospital, Beijing, 100853, China.
| | - Enqiang Linghu
- Department of Gastroenterology and Hepatology, The First Medical Center of PLA General Hospital, Beijing, 100853, China.
| |
Collapse
|
|
16
|
Ren Y, Jiang W, Luo C, Zhang X, Huang M. Atractylenolide III Ameliorates TNBS-Induced Intestinal Inflammation in Mice by Reducing Oxidative Stress and Regulating Intestinal Flora. Chem Biodivers 2021; 18:e2001001. [PMID: 34156157 DOI: 10.1002/cbdv.202001001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 06/03/2021] [Indexed: 12/16/2022]
Abstract
The present study aimed to explore the therapeutic effects of the main active ingredients of Atractylodes macrocephala on the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced mouse colitis model. TNBS-induced colitis was established in mice, which were treated with 8-β-Hydroxyasterolide (Atractylenolide III) for 14 days. The body weight of the mice in the middle and high dose groups of Atractylenolide III was increased compared with that of the model group. The disease activity index score was significantly reduced. The activity levels of myeloperoxidase were significantly decreased following increase in the dosage of Atractylenolide III, as determined by histological analysis. Moreover, Atractylenolide III downregulated the expression levels of the inflammatory factors interleukin-1β and tumor necrosis factor-α, and greatly suppressed the levels of the pro-oxidant markers, reactive oxygen species and malondialdehyde, while enhancing the expression levels of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase. The protein expression levels of formyl peptide receptor 1 (FPR1) and nuclear respiratory factor 2 (Nrf2) were upregulated in the colonic tissues of TNBS-treated mice. This effect was effectively reversed by Atractylenolide III treatment. In vivo studies indicated that TNBS alone induced a decrease in the abundance of lactobacilli and in the biodiversity of the colon. In conclusion, the present study suggested that Atractylenolide III attenuated TNBS-induced acute colitis by regulating oxidative stress via the FPR1 and Nrf2 pathways and by affecting the development of intestinal flora.
Collapse
Affiliation(s)
- Yan Ren
- College of Pharmaceutical Science, Guizhou University, Guiyang, 550025, P. R. China
| | - Wenwen Jiang
- College of Pharmaceutical Science, Guizhou University, Guiyang, 550025, P. R. China
| | - Chunli Luo
- College of Agriculture, Guizhou University, Guiyang, 550025, P. R. China
| | - Xiaohan Zhang
- College of Pharmaceutical Science, Guizhou University, Guiyang, 550025, P. R. China
| | - Mingjin Huang
- College of Agriculture, Guizhou University, Guiyang, 550025, P. R. China
| |
Collapse
|
|
17
|
DUOX2 As a Potential Prognostic Marker which Promotes Cell Motility and Proliferation in Pancreatic Cancer. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6530298. [PMID: 33748270 PMCID: PMC7943273 DOI: 10.1155/2021/6530298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 12/04/2020] [Accepted: 01/18/2021] [Indexed: 12/25/2022]
Abstract
DUOX2 has been reported to highly express in several types of cancers. However, the prognostic significance and the biological function of DUOX2 expression with pancreatic cancer (PC) still remain unclear. The present study is aimed at investigating whether DUOX2 could act as a novel biomarker of prognosis and evaluating its effect on PC cell progression. The mRNA and protein expression of DUOX2 in PC cells and tissues were assessed by quantitative real-time PCR (RT-qPCR) and immunohistochemistry. The effect of DUOX2 expression on PC cell motility and proliferation was evaluated in vitro. The correlation between DUOX2 mRNA expression and clinicopathological features and its prognostic significance were analyzed according to the Gene Expression Profiling Interactive Analysis (GEPIA) website based on The Cancer Genome Atlas (TCGA) and the GTEx databases combined with our clinical information. According to bioinformatics analysis, we forecasted the upstream transcription factors (TFs) and microRNA (miRNA) regulatory mechanism of DUOX2 in PC. The expression of DUOX2 at transcriptional and protein level was dramatically increased in PC specimens when compared to adjacent nontumor specimens. Functionally, DUOX2 knockdown inhibited cell motility and proliferation activities. Our clinical data revealed that the patients had better postoperative overall survival (OS) with lower expression of DUOX2, which is consistent with GEPIA data. Multivariate analysis revealed that high DUOX2 expression was considered as an independent prognostic indicator for OS (P = 0.031). Based on Cistrome database, the top 5 TFs of each positively and negatively association with DUOX2 were predicted. hsa-miR-5193 and hsa-miR-1343-3p targeting DUOX2 were forecasted from TargetScan, miRDB, and DIANA-TarBase databases, which were negatively correlated with OS (P = 0.043 and P = 0.0088, respectively) and DUOX2 expression (P = 0.0093 and P = 0.0032, respectively) in PC from TCGA data. These findings suggest that DUOX2 acts as a promising predictive biomarker and an oncogene in PC, which could be a therapeutic target for PC.
Collapse
|
|
18
|
Salehi B, Quispe C, Sharifi-Rad J, Giri L, Suyal R, Jugran AK, Zucca P, Rescigno A, Peddio S, Bobiş O, Moise AR, Leyva-Gómez G, Del Prado-Audelo ML, Cortes H, Iriti M, Martorell M, Cruz-Martins N, Kumar M, Zam W. Antioxidant potential of family Cucurbitaceae with special emphasis on Cucurbita genus: A key to alleviate oxidative stress-mediated disorders. Phytother Res 2021; 35:3533-3557. [PMID: 33590924 DOI: 10.1002/ptr.7045] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 12/28/2020] [Accepted: 01/25/2021] [Indexed: 12/24/2022]
Abstract
Oxidative stress is the imbalance between reactive oxygen species (ROS) production, and accumulation and the ability of a biological system to clear these reactive products. This imbalance leads to cell and tissue damage causing several disorders in human body, such as neurodegeneration, metabolic problems, cardiovascular diseases, and cancer. Cucurbitaceae family consists of about 100 genera and 1,000 species of plants including mostly tropical, annual or perennial, monoecious, and dioecious herbs. The plants from Cucurbita species are rich sources of phytochemicals and act as a rich source of antioxidants. The most important phytochemicals present in the cucurbits are cucurbitacins, saponins, carotenoids, phytosterols, and polyphenols. These bioactive phyto-constituents are responsible for the pharmacological effects including antioxidant, antitumor, antidiabetic, hepatoprotective, antimicrobial, anti-obesity, diuretic, anti-ulcer activity, and antigenotoxic. A wide number of in vitro and in vivo studies have ascribed these health-promoting effects of Cucurbita genus. Results of clinical trials suggest that Cucurbita provides health benefits for diabetic patients, patients with benign prostate hyperplasia, infertile women, postmenopausal women, and stress urinary incontinence in women. The intend of the present review is to focus on the protective role of Cucurbita spp. phytochemicals on oxidative stress-related disorders on the basis of preclinical and human studies. The review will also give insights on the in vitro and in vivo antioxidant potential of the Cucurbitaceae family as a whole.
Collapse
Affiliation(s)
- Bahare Salehi
- Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Cristina Quispe
- Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
| | - Lalit Giri
- G.B. Pant National Institute of Himalayan Environment & Sustainable Development, Almora, Uttarakhand, India
| | - Renu Suyal
- G.B. Pant National Institute of Himalayan Environment & Sustainable Development, Almora, Uttarakhand, India
| | - Arun K Jugran
- G.B. Pant National Institute of Himalayan Environment & Sustainable Development, Srinagar, Uttarakhand, India
| | - Paolo Zucca
- Department of Biomedical Sciences, University of Cagliari - Cagliari, University Campus, Monserrato, Italy
| | - Antonio Rescigno
- Department of Biomedical Sciences, University of Cagliari - Cagliari, University Campus, Monserrato, Italy
| | - Stefania Peddio
- Department of Biomedical Sciences, University of Cagliari - Cagliari, University Campus, Monserrato, Italy
| | - Otilia Bobiş
- Life Science Institute, Apiculture and Sericulture Department, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania
| | - Adela Ramona Moise
- Life Science Institute, Apiculture and Sericulture Department, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca, Romania
| | - Gerardo Leyva-Gómez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - María L Del Prado-Audelo
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Hernán Cortes
- Laboratorio de Medicina Genómica, Departamento de Genética, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Ciudad de México, Mexico
| | - Marcello Iriti
- Department of Agricultural and Environmental Sciences, Milan State University, Milan, Italy
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, Concepción, Chile.,Universidad de Concepción, Unidad de Desarrollo Tecnológico, UDT, Concepción, Chile
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, Porto, Portugal.,Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.,Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Porto, Portugal
| | - Manoj Kumar
- Chemical and Biochemical Processing Division, ICAR - Central Institute for Research on Cotton Technology, Mumbai, India
| | - Wissam Zam
- Faculty of Pharmacy, Department of Analytical and Food Chemistry, Al-Wadi International University, Homs, Syria
| |
Collapse
|
|
19
|
Yang L, Chen Y, Liu Y, Xing Y, Miao C, Zhao Y, Chang X, Zhang Q. The Role of Oxidative Stress and Natural Antioxidants in Ovarian Aging. Front Pharmacol 2021; 11:617843. [PMID: 33569007 PMCID: PMC7869110 DOI: 10.3389/fphar.2020.617843] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/15/2020] [Indexed: 12/17/2022] Open
Abstract
The ovarian system comprises vital organs in females and is of great significance for the maintenance of reproductive potential and endocrine stability. Although complex pathogenesis undoubtedly contributes to ovarian aging, increasing attention is being paid to the extensive influence of oxidative stress. However, the role of oxidative stress in ovarian aging is yet to be fully elucidated. Exploring oxidative stress-related processes might be a promising strategy against ovarian aging. In this review, compelling evidence is shown that oxidative stress plays a role in the etiology of ovarian aging and promotes the development of other ovarian aging-related etiologies, including telomere shortening, mitochondrial dysfunction, apoptosis, and inflammation. In addition, some natural antioxidants such as quercetin, resveratrol, and curcumin have a protective role in the ovaries through multiple mechanisms. These findings raise the prospect of oxidative stress modulator-natural antioxidants as therapeutic interventions for delaying ovarian aging.
Collapse
Affiliation(s)
- Liuqing Yang
- Guangxing Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Yun Chen
- Guangxing Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Yan Liu
- The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yu Xing
- Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Chenyun Miao
- Guangxing Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Ying Zhao
- Guangxing Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiangwei Chang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Qin Zhang
- Guangxing Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
| |
Collapse
|
|
20
|
NOX2-Derived Reactive Oxygen Species in Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7095902. [PMID: 33312338 PMCID: PMC7721506 DOI: 10.1155/2020/7095902] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 10/21/2019] [Indexed: 12/16/2022]
Abstract
The formation of reactive oxygen species (ROS) by the myeloid cell NADPH oxidase NOX2 is critical for the destruction of engulfed microorganisms. However, recent studies imply that ROS, formed by NOX2+ myeloid cells in the malignant microenvironment, exert multiple actions of relevance to the growth and spread of neoplastic cells. By generating ROS, tumor-infiltrating myeloid cells and NOX2+ leukemic myeloid cells may thus (i) compromise the function and viability of adjacent cytotoxic lymphocytes, including natural killer (NK) cells and T cells, (ii) oxidize DNA to trigger cancer-promoting somatic mutations, and (iii) affect the redox balance in cancer cells to control their proliferation and survival. Here, we discuss the impact of NOX2-derived ROS for tumorigenesis, tumor progression, regulation of antitumor immunity, and metastasis. We propose that NOX2 may be a targetable immune checkpoint in cancer.
Collapse
|
|
21
|
Sun J, Wang L, Yang W, Wang L, Fu Q, Song L. IgIT-Mediated Signaling Inhibits the Antimicrobial Immune Response in Oyster Hemocytes. THE JOURNAL OF IMMUNOLOGY 2020; 205:2402-2413. [PMID: 32989090 DOI: 10.4049/jimmunol.2000294] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/27/2020] [Indexed: 12/23/2022]
Abstract
The long-term evolutionary interaction between the host and symbiotic microbes determines their cooperative relationship. It is well known that the symbiotic microbes have evolved various mechanisms to either benefit or exploit the mammalian host immune system to maintain homeostasis. However, the strategies employed by the symbiotic microbes to overcome host immune responses in invertebrates are still not clear. In the current study, the hemolymph microbes in oyster Crassostrea gigas were found to be able to directly bind an oyster Ig superfamily member (IgSF) (designated as CgIgIT) to inhibit the immune responses of hemocytes. The mRNA transcripts of CgIgIT in hemocytes increased significantly after the stimulation with hemolymph microbes. CgIgIT was found to be located on the hemocyte membrane and it was able to directly bind the hemolymph microbes and polysaccharides via its three Ig domains and recruited the protein tyrosine phosphatase CgSHP2 through its ITIM. The recruited CgSHP2 inhibited the activities of CgERK, CgP38 and CgJNK proteins to reduce the productions of dual oxidase 2 (CgDuox2) and defensin 2 (CgDef2), which eventually protected the hemolymph microbes from CgDuox2/CgDef2-mediated elimination. Collectively, the results suggest that the oyster IgIT-SHP2 signaling pathway can recognize bacteria capable of residing in oyster hemolymph and inhibit innate immune responses, which contributes to the maintenance, colonization, and survival of hemolymph microbes.
Collapse
Affiliation(s)
- Jiejie Sun
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian 116023, China.,Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China
| | - Lingling Wang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian 116023, China.,Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China.,Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China; and.,Dalian Key Laboratory of Aquatic Animal Disease Control, Dalian Ocean University, Dalian 116023, China
| | - Wenwen Yang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian 116023, China.,Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China
| | - Liyan Wang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian 116023, China.,Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China
| | - Qiang Fu
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian 116023, China.,Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian 116023, China; .,Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China.,Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China; and
| |
Collapse
|
|
22
|
Abstract
Significance: The primary function of NADPH oxidases (NOX1-5 and dual oxidases DUOX1/2) is to produce reactive oxygen species (ROS). If inadequately regulated, NOX-associated ROS can promote oxidative stress, aberrant signaling, and genomic instability. Correspondingly, NOX isoforms are known to be overexpressed in multiple malignancies, thus constituting potential therapeutic targets in cancer. Recent Advances: Multiple genetic studies aimed at suppressing the expression of NOX proteins in cellular and animal models of cancer have provided support for the notion that NOXs play a pro-tumorigenic role. Further, large drug screens and rational design efforts have yielded inhibitor compounds, such as the diphenylene iodonium (DPI) analog series developed by our group, with increased selectivity and potency over "first generation" NOX inhibitors such as apocynin and DPI. Critical Issues: The precise role of NOX enzymes in tumor biology remains poorly defined. The tumorigenic properties of NOXs vary with cancer type, and precise tools, such as selective inhibitors, are needed to deconvolute NOX contribution to cancer development. Most NOX inhibitors developed to date are unspecific, and/or their mechanistic and pharmacological characteristics are not well defined. A lack of high-resolution crystal structures for NOX functional domains has hindered the development of potent and selective inhibitors. Future Directions: In-depth studies of NOX interactions with the tumor microenvironment (e.g., cytokines, cell-surface antigens) will help identify new approaches for NOX inhibition in cancer.
Collapse
Affiliation(s)
- Mariam M Konaté
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Smitha Antony
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - James H Doroshow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland, USA.,Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| |
Collapse
|
|
23
|
The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of "inflame-aging". Inflamm Res 2020; 69:825-839. [PMID: 32529477 PMCID: PMC7289226 DOI: 10.1007/s00011-020-01372-8] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/31/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023] Open
Abstract
Purpose Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely, ample evidences have been shown that the severity of COVID-19 infections varies widely from children (asymptomatic), adults (mild infection), as well as elderly adults (deadly critical). It has proven that COVID-19 infection in some elderly critical adults leads to a cytokine storm, which is characterized by severe systemic elevation of several pro-inflammatory cytokines. Then, a cytokine storm can induce edematous, ARDS, pneumonia, as well as multiple organ failure in aged patients. It is far from clear till now why cytokine storm induces in only COVID-19 elderly patients, and not in young patients. However, it seems that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, which is characterized by “inflamm-aging”. It is highly likely that “inflamm-aging” is correlated to increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection. Methods A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for COVID-19, Coronavirus, SARS-CoV-2, senescent cell, cytokine storm, inflame-aging, ACE2 receptor, autophagy, and Vitamin D. Electronic database searches combined and duplicates were removed. Results The aim of the present review was to summarize experimental data and clinical observations that linked the pathophysiology mechanisms of “inflamm-aging”, mild-grade inflammation, and cytokine storm in some elderly adults with severe COVID-19 infection.
Collapse
|
|
24
|
de Faria CC, Fortunato RS. The role of dual oxidases in physiology and cancer. Genet Mol Biol 2020; 43:e20190096. [PMID: 32453337 PMCID: PMC7265977 DOI: 10.1590/1678-4685/gmb-2019-0096] [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: 03/20/2019] [Accepted: 01/24/2020] [Indexed: 01/17/2023] Open
Abstract
NOX/DUOX enzymes are transmembrane proteins that carry electrons through biological membranes generating reactive oxygen species. The NOX family is composed of seven members, which are NOX1 to NOX5 and DUOX1 and 2. DUOX enzymes were initially called thyroid oxidases, based on their high expression level in the thyroid tissue. However, DUOX expression has been documented in several extrathyroid tissues, mostly at the apical membrane of the salivary glands, the airways, and the intestinal tract, revealing additional cellular functions associated with DUOX-related H2O2 generation. In this review, we will briefly summarize the current knowledge regarding DUOX structure and physiological functions, as well as their possible role in cancer biology.
Collapse
Affiliation(s)
- Caroline Coelho de Faria
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas
Filho, Rio de Janeiro, RJ, Brazil
| | - Rodrigo Soares Fortunato
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas
Filho, Rio de Janeiro, RJ, Brazil
| |
Collapse
|
|
25
|
Lu J, Jiang G, Wu Y, Antony S, Meitzler JL, Juhasz A, Liu H, Roy K, Makhlouf H, Chuaqui R, Butcher D, Konaté MM, Doroshow JH. NADPH oxidase 1 is highly expressed in human large and small bowel cancers. PLoS One 2020; 15:e0233208. [PMID: 32428030 PMCID: PMC7237001 DOI: 10.1371/journal.pone.0233208] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 04/30/2020] [Indexed: 12/21/2022] Open
Abstract
To facilitate functional investigation of the role of NADPH oxidase 1 (NOX1) and associated reactive oxygen species in cancer cell signaling, we report herein the development and characterization of a novel mouse monoclonal antibody that specifically recognizes the C-terminal region of the NOX1 protein. The antibody was validated in stable NOX1 overexpression and knockout systems, and demonstrates wide applicability for Western blot analysis, confocal microscopy, flow cytometry, and immunohistochemistry. We employed our NOX1 antibody to characterize NOX1 expression in a panel of 30 human colorectal cancer cell lines, and correlated protein expression with NOX1 mRNA expression and superoxide production in a subset of these cells. Although a significant correlation between oncogenic RAS status and NOX1 mRNA levels could not be demonstrated in colon cancer cell lines, RAS mutational status did correlate with NOX1 expression in human colon cancer surgical specimens. Immunohistochemical analysis of a comprehensive set of tissue microarrays comprising over 1,200 formalin-fixed, paraffin-embedded tissue cores from human epithelial tumors and inflammatory disease confirmed that NOX1 is overexpressed in human colon and small intestinal adenocarcinomas, as well as adenomatous polyps, compared to adjacent, uninvolved intestinal mucosae. In contradistinction to prior studies, we did not find evidence of NOX1 overexpression at the protein level in tumors versus histologically normal tissues in prostate, lung, ovarian, or breast carcinomas. This study constitutes the most comprehensive histopathological characterization of NOX1 to date in cellular models of colon cancer and in normal and malignant human tissues using a thoroughly evaluated monoclonal antibody. It also further establishes NOX1 as a clinically relevant therapeutic target in colorectal and small intestinal cancer.
Collapse
Affiliation(s)
- Jiamo Lu
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Guojian Jiang
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Yongzhong Wu
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Smitha Antony
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Jennifer L. Meitzler
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Agnes Juhasz
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Han Liu
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Krishnendu Roy
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Hala Makhlouf
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Rodrigo Chuaqui
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Donna Butcher
- Pathology/Histotechnology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America
| | - Mariam M. Konaté
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, United States of America
| | - James H. Doroshow
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, United States of America
| |
Collapse
|
|
26
|
Ahmad A, Ahsan H. Biomarkers of inflammation and oxidative stress in ophthalmic disorders. J Immunoassay Immunochem 2020; 41:257-271. [PMID: 32046582 DOI: 10.1080/15321819.2020.1726774] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The review article focuses on free radicals and oxidative stress involved in ophthalmological diseases such as retinopathy, cataract, glaucoma, etc. Oxidative stress is considered as a key factor involved in the pathology of many chronic diseases including ophthalmic complication and inflammatory process. Oxidative stress and inflammation are closely related pathophysiological processes and are simultaneously found in many pathological conditions. The free radicals produced oxidize cellular components such as lipids and phospholipids leading to lipid peroxidation and trigger the onset of retinopathy. Cataract is a significant cause of visual disability and it is proposed that the high incidence is related to oxidative stress induced by continued intraocular penetration of light and consequent photochemical generation of free radical oxidants. Glaucoma is the leading cause of irreversible blindness and comprises a group of diseases characterized by progressive optic nerve degeneration. Oxidative injury and altered antioxidant defense mechanisms in glaucoma appear to play a role in the pathophysiology of glaucomatous neurodegeneration that is characterized by death of retinal ganglion cells. The UVB radiations through this way may cause a number of diseases like photo-keratitis, pterygium, damage to epithelium, edema, and corneal cell apoptosis.Abbreviations: ROS: reactive oxygen species; RNS: reactive nitrogen species; O2.: superoxide anion; H2O2: hydrogen peroxide;. OH: hydroxyl radicals; ONOO-, ONO2-: peroxynitrite; NO: nitric oxide; IOP: intraocular pressure; RGC: retinal ganglion cells. WHO: World Health Organization; IAPB: International Agency for the Prevention of Blindness.
Collapse
Affiliation(s)
- Anas Ahmad
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, India.,Department of Nano-Therapeutics, Institute of Nano Science and Technology, Habitat Centre, Mohali, India
| | - Haseeb Ahsan
- Faculty of Dentistry, Department of Biochemistry, Jamia Millia Islamia, New Delhi, India
| |
Collapse
|
|
27
|
Ali SS, Ahsan H, Zia MK, Siddiqui T, Khan FH. Understanding oxidants and antioxidants: Classical team with new players. J Food Biochem 2020; 44:e13145. [PMID: 31960481 DOI: 10.1111/jfbc.13145] [Citation(s) in RCA: 243] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 11/25/2019] [Accepted: 12/28/2019] [Indexed: 12/15/2022]
Abstract
The free radical oxidants such as reactive oxygen species, reactive nitrogen species, and reactive sulfur species are produced inside cells through various metabolic processes. The body is equipped with an antioxidant defense system that guards against oxidative damage caused by these reactive oxidants and plays a major role in protecting cells from oxidative stress and damage. Antioxidants such as glutathione (GSH), thioredoxin, ascorbic acid and enzymes, for example, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) counter the oxidative stress and protect lipids, proteins, and DNA. Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids are also natural antioxidants present in foods. There is increasing demand and availability of designer foods fortified with antioxidants and probiotics that may be important in human health. The review article presents a brief overview of oxidants and antioxidant systems inside the human body including the role of probiotics and inflammation. PRACTICAL APPLICATIONS: Antioxidants such as GSH, thioredoxin, ascorbic acid, etc. and protective enzymes, for example, SOD, GPx, CAT, etc. counter oxidative stress and protect cellular biomolecules. Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids, phospholipids, and sterols are natural antioxidants found in consumed foods. They play a major role in scavenging free radical and non-radical oxidants, and protect cells from oxidative stress and damage. The importance of antioxidants can be understood from the fact that oxidative damage is now associated with a variety of diseases including cancer, neurodegeneration, diabetes, etc. Several approaches to improve human health and achieve longevity use dietary antioxidants as formulation in diet and fortified foods. Antioxidants also maintain freshness and prolonging the shelf life of food products. The fortified or designer foods that are added with antioxidant nutrients and the use of microorganisms as probiotics are increasingly available in the market as health foods and supplements.
Collapse
Affiliation(s)
- Syed Saqib Ali
- Faculty of Life Sciences, Department of Biochemistry, Aligarh Muslim University, Aligarh, India
| | - Haseeb Ahsan
- Faculty of Dentistry, Department of Biochemistry, Jamia Millia Islamia, New Delhi, India
| | - Mohammad Khalid Zia
- Faculty of Life Sciences, Department of Biochemistry, Aligarh Muslim University, Aligarh, India
| | - Tooba Siddiqui
- Faculty of Life Sciences, Department of Biochemistry, Aligarh Muslim University, Aligarh, India
| | - Fahim Halim Khan
- Faculty of Life Sciences, Department of Biochemistry, Aligarh Muslim University, Aligarh, India
| |
Collapse
|
|
28
|
Wu Y, Konaté MM, Lu J, Makhlouf H, Chuaqui R, Antony S, Meitzler JL, Difilippantonio MJ, Liu H, Juhasz A, Jiang G, Dahan I, Roy K, Doroshow JH. IL-4 and IL-17A Cooperatively Promote Hydrogen Peroxide Production, Oxidative DNA Damage, and Upregulation of Dual Oxidase 2 in Human Colon and Pancreatic Cancer Cells. THE JOURNAL OF IMMUNOLOGY 2019; 203:2532-2544. [PMID: 31548328 DOI: 10.4049/jimmunol.1800469] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 08/27/2019] [Indexed: 01/05/2023]
Abstract
Dual oxidase 2 (DUOX2) generates H2O2 that plays a critical role in both host defense and chronic inflammation. Previously, we demonstrated that the proinflammatory mediators IFN-γ and LPS enhance expression of DUOX2 and its maturation factor DUOXA2 through STAT1- and NF-κB‒mediated signaling in human pancreatic cancer cells. Using a panel of colon and pancreatic cancer cell lines, we now report the induction of DUOX2/DUOXA2 mRNA and protein expression by the TH2 cytokine IL-4. IL-4 activated STAT6 signaling that, when silenced, significantly decreased induction of DUOX2. Furthermore, the TH17 cytokine IL-17A combined synergistically with IL-4 to increase DUOX2 expression in both colon and pancreatic cancer cells mediated, at least in part, by signaling through NF-κB. The upregulation of DUOX2 was associated with a significant increase in the production of extracellular H2O2 and DNA damage-as indicated by the accumulation of 8-oxo-dG and γH2AX-which was suppressed by the NADPH oxidase inhibitor diphenylene iodonium and a DUOX2-specific small interfering RNA. The clinical relevance of these experiments is suggested by immunohistochemical, microarray, and quantitative RT-PCR studies of human colon and pancreatic tumors demonstrating significantly higher DUOX2, IL-4R, and IL-17RA expression in tumors than in adjacent normal tissues; in pancreatic adenocarcinoma, increased DUOX2 expression is adversely associated with overall patient survival. These data suggest a functional association between DUOX2-mediated H2O2 production and induced DNA damage in gastrointestinal malignancies.
Collapse
Affiliation(s)
- Yongzhong Wu
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Mariam M Konaté
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Jiamo Lu
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Hala Makhlouf
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Rodrigo Chuaqui
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Smitha Antony
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Jennifer L Meitzler
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Michael J Difilippantonio
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Han Liu
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Agnes Juhasz
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Guojian Jiang
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
| | - Iris Dahan
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Krishnendu Roy
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - James H Doroshow
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and .,Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| |
Collapse
|
|
29
|
Purohit V, Simeone DM, Lyssiotis CA. Metabolic Regulation of Redox Balance in Cancer. Cancers (Basel) 2019; 11:cancers11070955. [PMID: 31288436 PMCID: PMC6678865 DOI: 10.3390/cancers11070955] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/01/2019] [Accepted: 07/02/2019] [Indexed: 12/13/2022] Open
Abstract
Reactive oxygen species (ROS) are chemically active free radicals produced by partial reduction of oxygen that can activate discrete signaling pathways or disrupt redox homeostasis depending on their concentration. ROS interacts with biomolecules, including DNA, and can cause mutations that can transform normal cells into cancer cells. Furthermore, certain cancer-causing mutations trigger alterations in cellular metabolism that can increase ROS production, resulting in genomic instability, additional DNA mutations, and tumor evolution. To prevent excess ROS-mediated toxicity, cancer-causing mutations concurrently activate pathways that manage this oxidative burden. Hence, an understanding of the metabolic pathways that regulate ROS levels is imperative for devising therapies that target tumor cells. In this review, we summarize the dual role of metabolism as a generator and inhibitor of ROS in cancer and discuss current strategies to target the ROS axis.
Collapse
Affiliation(s)
- Vinee Purohit
- Perlmutter Cancer Center, New York University, New York, NY 10016, USA
| | - Diane M Simeone
- Perlmutter Cancer Center, New York University, New York, NY 10016, USA
- Department of Surgery, New York University, New York, NY 10016, USA
- Department of Pathology, New York University, New York, NY 10016, USA
| | - Costas A Lyssiotis
- Departments of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
- Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
| |
Collapse
|
|
30
|
Dose dependent acute toxicity of abrin in Balb/c mice after intraperitoneal administration. Toxicon 2019; 167:49-59. [PMID: 31185238 DOI: 10.1016/j.toxicon.2019.06.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 05/30/2019] [Accepted: 06/03/2019] [Indexed: 12/12/2022]
Abstract
Abrin toxin is one of the most potent and deadly plant toxin obtained from the seeds of Abrus precatorious. It is more toxic than ricin which is classified as Schedule 1 agent by OPCW and Category B bioterrorism agent by Centre for Disease Control (CDC). Dose dependent acute toxicity of abrin is still a matter of investigation. The present study was carried out to assess the toxicity of abrin from sub lethal to supralethal doses (0.5X, 1X, 2X and 5XLD50) after intraperitoneal administration. After 8 and 24h of abrin exposure, hematological, biochemical, inflammatory and oxidative stress associated parameters were analyzed. Liver histology was also done to analyze the effect of abrin. Abrin exerts its toxicity in a dose and time dependent manner. Increases in neutrophil counts, lipid peroxidation with decreased lymphocyte counts, are the initiating factor irrespective of time and dose. At higher doses of abrin there was a decrease in hemoglobin level and RBC count which is reflected by increased levels of serum ammonia and bilirubin. Neutrophil infiltration in the liver and lipid peroxidation cause liver toxicity (increased production of ALT and ALP); oxidative stress (depletion of GSH and total antioxidant status); inflammation (increased production of TNF-α and IFN-γ). Further, at higher doses of abrin, intensity of oxidative stress, inflammation and liver toxicity are more pronounced which may have been maintained by the self-sustaining loop of toxicity leading to death of the animals.
Collapse
|
|
31
|
Ding H, Ci X, Cheng H, Yu Q, Li D. Chicoric acid alleviates lipopolysaccharide-induced acute lung injury in mice through anti-inflammatory and anti-oxidant activities. Int Immunopharmacol 2019; 66:169-176. [DOI: 10.1016/j.intimp.2018.10.042] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 10/16/2018] [Accepted: 10/30/2018] [Indexed: 12/21/2022]
|
|
32
|
Lee MT, Lin WC, Lee TT. Potential crosstalk of oxidative stress and immune response in poultry through phytochemicals - A review. ASIAN-AUSTRALASIAN JOURNAL OF ANIMAL SCIENCES 2018; 32:309-319. [PMID: 30381743 PMCID: PMC6409470 DOI: 10.5713/ajas.18.0538] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 09/28/2018] [Indexed: 12/14/2022]
Abstract
Phytochemicals which exist in various plants and fungi are non-nutritive compounds that exert numerous beneficial bioactive actions for animals. In recent years following the restriction of antibiotics, phytochemicals have been regarded as a primal selection when dealing with the challenges during the producing process in the poultry industry. The selected fast-growing broiler breed was more fragile when confronting the stressors in their growing environments. The disruption of oxidative balance that impairs the production performance in birds may somehow be linked to the immune system since oxidative stress and inflammatory damage are multi-stage processes. This review firstly discusses the individual influence of oxidative stress and inflammation on the poultry industry. Next, studies related to the application of phytochemicals or botanical compounds with the significance of their antioxidant and immunomodulatory abilities are reviewed. Furthermore, we bring up nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor kappa B (NF-κB) for they are respectively the key transcription factors involved in oxidative stress and inflammation for elucidating the underlying signal transduction pathways. Finally, by the discussion about several reports using phytochemicals to regulate these transcription factors leading to the improvement of oxidative status, heme oxygenase-1 gene is found crucial for Nrf2-mediated NF-κB inhibition.
Collapse
Affiliation(s)
- M T Lee
- Department of Animal Science, National Chung Hsing University, Taichung 402, Taiwan
| | - W C Lin
- Department of Animal Science, National Chung Hsing University, Taichung 402, Taiwan
| | - T T Lee
- Department of Animal Science, National Chung Hsing University, Taichung 402, Taiwan.,The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan
| |
Collapse
|
|
33
|
Zhang Y, Yue D, Cheng L, Huang A, Tong N, Cheng P. Vitamin A-coupled liposomes carrying TLR4-silencing shRNA induce apoptosis of pancreatic stellate cells and resolution of pancreatic fibrosis. J Mol Med (Berl) 2018; 96:445-458. [PMID: 29589070 DOI: 10.1007/s00109-018-1629-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Revised: 02/05/2018] [Accepted: 02/12/2018] [Indexed: 02/05/2023]
Abstract
UNLABELLED Chronic pancreatitis leads to irreversible damage in pancreatic endocrine and exocrine functions. However, there is no clinically available antifibrotic drug. Pancreatic stellate cells (PSCs) can be activated by Toll-like receptor 4 (TLR4) responses to its ligands and they contribute to the formation of pancreatic fibrosis. Silencing the expression of TLR4 in PSCs by RNAi may be a novel therapeutic strategy for the treatment of pancreatic fibrosis. In addition, PSCs have a remarkable capacity for vitamin A uptake most likely through cellular retinol binding protein (CRBP). In our study, to ensure the efficient delivery of RNAi therapeutic agents to PSCs, VitA-coupled liposomes (VA-lips) were used as drug carriers to deliver plasmids expressing TLR4-specific short hairpin RNA (shRNA) to treat pancreatic fibrosis. Our study demonstrated that silencing the expression of TLR4 could induce mitochondrial apoptosis in aPSCs and might be an effective therapeutic strategy for the treatment of pancreatic fibrosis. KEY MESSAGES VA-lip-shRNA-TLR4 recovers pancreatic tissue damage. VA-lip-shRNA-TLR4 resolution of pancreatic fibrosis. VA-lip-shRNA-TLR4 accelerates ECM degradation and inhibits ECM synthesis. Silencing TLR4 induces aPSCs mitochondrial apoptosis. Silencing TLR4 inhibits the activation of NF-κB.
Collapse
Affiliation(s)
- Yuwei Zhang
- Department of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No.37 Guo Xue Xiang, Chengdu, 610041, China
| | - Dan Yue
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No.17 Section 3 People's South Road, Chengdu, 610041, China
| | - Liuliu Cheng
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No.17 Section 3 People's South Road, Chengdu, 610041, China
| | - Anliang Huang
- Department of Pathology, West China Second Hospital, Sichuan University, No.20 Section 3 People's South Road, Chengdu, 610041, China
| | - Nanwei Tong
- Department of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No.37 Guo Xue Xiang, Chengdu, 610041, China
| | - Ping Cheng
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, No.17 Section 3 People's South Road, Chengdu, 610041, China.
| |
Collapse
|
|
34
|
Antony S, Jiang G, Wu Y, Meitzler JL, Makhlouf HR, Haines DC, Butcher D, Hoon DS, Ji J, Zhang Y, Juhasz A, Lu J, Liu H, Dahan I, Konate M, Roy KK, Doroshow JH. NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates normoxic HIF-1α and p27 Kip1 expression in malignant melanoma and other human tumors. Mol Carcinog 2017; 56:2643-2662. [PMID: 28762556 PMCID: PMC5675809 DOI: 10.1002/mc.22708] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 07/19/2017] [Accepted: 07/28/2017] [Indexed: 12/14/2022]
Abstract
NADPH oxidase 5 (NOX5) generated reactive oxygen species (ROS) have been implicated in signaling cascades that regulate cancer cell proliferation. To evaluate and validate NOX5 expression in human tumors, we screened a broad range of tissue microarrays (TMAs), and report substantial overexpression of NOX5 in malignant melanoma and cancers of the prostate, breast, and ovary. In human UACC-257 melanoma cells that possesses high levels of functional endogenous NOX5, overexpression of NOX5 resulted in enhanced cell growth, increased numbers of BrdU positive cells, and increased γ-H2AX levels. Additionally, NOX5-overexpressing (stable and inducible) UACC-257 cells demonstrated increased normoxic HIF-1α expression and decreased p27Kip1 expression. Similarly, increased normoxic HIF-1α expression and decreased p27Kip1 expression were observed in stable NOX5-overexpressing clones of KARPAS 299 human lymphoma cells and in the human prostate cancer cell line, PC-3. Conversely, knockdown of endogenous NOX5 in UACC-257 cells resulted in decreased cell growth, decreased HIF-1α expression, and increased p27Kip1 expression. Likewise, in an additional human melanoma cell line, WM852, and in PC-3 cells, transient knockdown of endogenous NOX5 resulted in increased p27Kip1 and decreased HIF-1α expression. Knockdown of endogenous NOX5 in UACC-257 cells resulted in decreased Akt and GSK3β phosphorylation, signaling pathways known to modulate p27Kip1 levels. In summary, our findings suggest that NOX5 expression in human UACC-257 melanoma cells could contribute to cell proliferation due, in part, to the generation of high local concentrations of extracellular ROS that modulate multiple pathways that regulate HIF-1α and networks that signal through Akt/GSK3β/p27Kip1 .
Collapse
Affiliation(s)
- Smitha Antony
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMaryland
| | - Guojian Jiang
- Developmental Therapeutics Branch, Center for Cancer ResearchNational Cancer InstituteBethesdaMaryland
| | - Yongzhong Wu
- Developmental Therapeutics Branch, Center for Cancer ResearchNational Cancer InstituteBethesdaMaryland
| | - Jennifer L. Meitzler
- Developmental Therapeutics Branch, Center for Cancer ResearchNational Cancer InstituteBethesdaMaryland
| | - Hala R. Makhlouf
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMaryland
| | - Diana C. Haines
- Pathology/Histotechnology Laboratory, Leidos Inc./Frederick National Laboratory for Cancer ResearchNational Cancer InstituteFrederickMaryland
| | - Donna Butcher
- Pathology/Histotechnology Laboratory, Leidos Inc./Frederick National Laboratory for Cancer ResearchNational Cancer InstituteFrederickMaryland
| | - Dave S. Hoon
- Department of Molecular OncologyJohn Wayne Cancer InstituteSanta MonicaCalifornia
| | - Jiuping Ji
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMaryland
| | - Yiping Zhang
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMaryland
| | - Agnes Juhasz
- Developmental Therapeutics Branch, Center for Cancer ResearchNational Cancer InstituteBethesdaMaryland
| | - Jiamo Lu
- Developmental Therapeutics Branch, Center for Cancer ResearchNational Cancer InstituteBethesdaMaryland
| | - Han Liu
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMaryland
| | - Iris Dahan
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMaryland
| | - Mariam Konate
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMaryland
| | - Krishnendu K. Roy
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMaryland
| | - James H. Doroshow
- Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaMaryland
- Developmental Therapeutics Branch, Center for Cancer ResearchNational Cancer InstituteBethesdaMaryland
| |
Collapse
|
|
35
|
Liu Q, Lv H, Wen Z, Ci X, Peng L. Isoliquiritigenin Activates Nuclear Factor Erythroid-2 Related Factor 2 to Suppress the NOD-Like Receptor Protein 3 Inflammasome and Inhibits the NF-κB Pathway in Macrophages and in Acute Lung Injury. Front Immunol 2017; 8:1518. [PMID: 29163554 PMCID: PMC5677786 DOI: 10.3389/fimmu.2017.01518] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 10/26/2017] [Indexed: 01/11/2023] Open
Abstract
Among the cellular response mechanisms, the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway is considered a survival pathway that alleviates oxidative injury, while both the NOD-like receptor protein 3 (NLRP3) and NF-κB pathways are pro-inflammatory pathways that cause damage to cells. These pathways are implicated in the development and resolution of acute lung injury (ALI). Isoliquiritigenin (ISL), a flavonoid from the liquorice compound, is suggested to be a regulator of the above pathways, but the mechanisms of how the NLRP3/NF-κB pathway interacts with Nrf2 and its protective effects in ALI remain unknown. In the present study, ISL inhibited reactive oxygen species (ROS) generation and cytotoxicity induced by t-BHP and pro-inflammatory enzymes production induced by LPS in RAW 264.7 cells. Such cytoprotective effects coincided with the induction of AMP-activated protein kinase (AMPK)/Nrf2/antioxidant response element (ARE) signaling and the suppression of the NLRP3 and NF-κB pathways. Consistent with these findings, ISL treatment significantly alleviated lung injury in LPS-induced ALI mice, which was reflected by reductions in histopathological changes, pulmonary edema, and protein leakage. At the same time, the increased levels of inflammatory cell exudation and pro-inflammatory mediators, the enhanced production of ROS, myeloperoxidase, and malondialdehyde, and the depleted expression of GSH and superoxide dismutase induced by LPS were ameliorated by ISL. Furthermore, ISL notably activated AMPK/Nrf2/ARE signaling and inhibited LPS-induced NLRP3 and NF-κB activation in the lung. Moreover, although inhibition of the LPS-induced histopathological changes and ROS production were attenuated in Nrf2-deficient mice, the repression of the NLRP3 and NF-κB pathways by ISL was Nrf2-dependent and Nrf2-independent, respectively. In conclusion, our results are the first to highlight the beneficial role and relevant mechanisms of ISL in LPS-induced ALI and provide novel insight into its application.
Collapse
Affiliation(s)
- Qinmei Liu
- Department of Respiration, The First Hospital of Jilin University, Changchun, China
| | - Hongming Lv
- Department of Respiration, The First Hospital of Jilin University, Changchun, China
| | - Zhongmei Wen
- Department of Respiration, The First Hospital of Jilin University, Changchun, China
| | - Xinxin Ci
- Department of Respiration, The First Hospital of Jilin University, Changchun, China
| | - Liping Peng
- Department of Respiration, The First Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
36
|
Little AC, Sulovari A, Danyal K, Heppner DE, Seward DJ, van der Vliet A. Paradoxical roles of dual oxidases in cancer biology. Free Radic Biol Med 2017; 110:117-132. [PMID: 28578013 PMCID: PMC5535817 DOI: 10.1016/j.freeradbiomed.2017.05.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 05/26/2017] [Accepted: 05/30/2017] [Indexed: 02/06/2023]
Abstract
Dysregulated oxidative metabolism is a well-recognized aspect of cancer biology, and many therapeutic strategies are based on targeting cancers by altering cellular redox pathways. The NADPH oxidases (NOXes) present an important enzymatic source of biological oxidants, and the expression and activation of several NOX isoforms are frequently dysregulated in many cancers. Cell-based studies have demonstrated a role for several NOX isozymes in controlling cell proliferation and/or cell migration, further supporting a potential contributing role for NOX in promoting cancer. While various NOX isoforms are often upregulated in cancers, paradoxical recent findings indicate that dual oxidases (DUOXes), normally prominently expressed in epithelial lineages, are frequently suppressed in epithelial-derived cancers by epigenetic mechanisms, although the functional relevance of such DUOX silencing has remained unclear. This review will briefly summarize our current understanding regarding the importance of reactive oxygen species (ROS) and NOXes in cancer biology, and focus on recent observations indicating the unique and seemingly opposing roles of DUOX enzymes in cancer biology. We will discuss current knowledge regarding the functional properties of DUOX, and recent studies highlighting mechanistic consequences of DUOX1 loss in lung cancer, and its consequences for tumor invasiveness and current anticancer therapy. Finally, we will also discuss potentially unique roles for the DUOX maturation factors. Overall, a better understanding of mechanisms that regulate DUOX and the functional consequences of DUOX silencing in cancer may offer valuable new diagnostic insights and novel therapeutic opportunities.
Collapse
Affiliation(s)
- Andrew C Little
- Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT 05405, United States; Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, VT 05405, United States
| | - Arvis Sulovari
- Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, VT 05405, United States; Department of Microbiology and Molecular Genetics, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT 05405, United States
| | - Karamatullah Danyal
- Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT 05405, United States
| | - David E Heppner
- Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT 05405, United States
| | - David J Seward
- Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT 05405, United States
| | - Albert van der Vliet
- Department of Pathology and Laboratory Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, VT 05405, United States; Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont, Burlington, VT 05405, United States.
| |
Collapse
|
|
37
|
The receptor for advanced glycation end products: A fuel to pancreatic cancer. Semin Cancer Biol 2017; 49:37-43. [PMID: 28811077 DOI: 10.1016/j.semcancer.2017.07.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/23/2017] [Accepted: 07/31/2017] [Indexed: 12/27/2022]
Abstract
The receptor for advanced glycation end products (RAGEs) was first illustrated in the year 1992. RAGE is a single-transmembrane and multi-ligand component of the immunoglobulin protein super family. The engagement of RAGE turns out to an establishment of numerous intracellular signalling mechanisms resulting in the progression and perpetuation of many types of cancer including, the pancreatic cancer. The present review primarily focuses on the multi-ligand activation of RAGEs leading to the downstream signalling cascade activation. The kick start of the RAGEs activation leads to the several anomalies and includes multiple types of cancers. The RAGE expression correlates well with the survival of pancreatic cancer cells leading to the myeloid response. RAGEs assist in the tumourogenesis which enhance and thrive to its fullest in the stressed tumour microenvironment. An improved perceptive of its involvement in pancreatic cancer may offer novel targets for tumour supervision and risk measurement.
Collapse
|
|
38
|
Beyer K, Partecke LI, Roetz F, Fluhr H, Weiss FU, Heidecke CD, von Bernstorff W. LPS promotes resistance to TRAIL-induced apoptosis in pancreatic cancer. Infect Agent Cancer 2017; 12:30. [PMID: 28572836 PMCID: PMC5450120 DOI: 10.1186/s13027-017-0139-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 05/16/2017] [Indexed: 12/29/2022] Open
Abstract
Background Though TRAIL has been hailed as a promising drug for tumour treatment, it has been observed that many tumour cells have developed escape mechanisms against TRAIL-induced apoptosis. As a receptor of LPS, TLR 4, which is expressed on a variety of cancer cells, can be associated with TRAIL-resistance of tumour cells and tumour progression as well as with the generation of an anti-tumour immune response. Methods In this study, the sensitivity to TRAIL-induced apoptosis as well as the influence of LPS-co-stimulation on the cell viability of the pancreatic cancer cell lines PANC-1, BxPC-3 and COLO 357 was examined by FACS analyses and a cell viability assay. Subsequently, the expression of TRAIL-receptors was detected via FACS analyses. Levels of osteoprotegerin (OPG) were also determined using an enzyme-linked immunosorbent assay. Results PANC-1 cells were shown to be resistant to TRAIL-induced apoptosis. This was accompanied by significantly increased osteoprotegerin levels and a significantly decreased expression of DR4. In contrast, TRAIL significantly induced apoptosis in COLO 357 cells and to a lesser degree in BxPC-3 cells. Co-stimulation of COLO 357 as well as BxPC-3 cells combining TRAIL and LPS resulted in a significant decrease in TRAIL-induced apoptosis. In COLO 357 cells TRAIL-stimulation decreased the levels of OPG thereby not altering the expression of the TRAIL-receptors 1–4 resulting in a high susceptibility to TRAIL-induced apoptosis. Co-stimulation with LPS and TRAIL completely reversed the effect of TRAIL on OPG levels reaching a 2-fold increase beyond the level of non-stimulated cells resulting in a lower susceptibility to apoptosis. In BxPC-3, TRAIL stimulation decreased the expression of DR4 and significantly increased the decoy receptors TRAIL-R3 and TRAIL-R4 leading to a decrease in TRAIL-induced apoptosis. OPG levels remained unchanged. Co-stimulation with TRAIL and LPS further enhanced the changes in TRAIL-receptor-expression promoting apoptosis resistance. Conclusions Here it has been shown that TRAIL-resistance in pancreatic cancer cells can be mediated by the inflammatory molecule LPS as well as by different expression patterns of functional and non-functional TRAIL-receptors.
Collapse
Affiliation(s)
- Katharina Beyer
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany.,Department of General, Visceral and Vascular Surgery, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Lars Ivo Partecke
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Felicitas Roetz
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Herbert Fluhr
- Department of Medicine A, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Frank Ulrich Weiss
- Department of Obstetrics and Gynaecology, Universitätsklinikum Heidelberg, Heidelberg, Germany
| | - Claus-Dieter Heidecke
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Wolfram von Bernstorff
- Department of General, Visceral, Thoracic and Vascular Surgery, Universitätsmedizin Greifswald, Greifswald, Germany
| |
Collapse
|
|
39
|
NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017. [PMID: 28626501 PMCID: PMC5463201 DOI: 10.1155/2017/9420539] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
NADPH oxidases (NOX) are reactive oxygen species- (ROS-) generating enzymes regulating numerous redox-dependent signaling pathways. NOX are important regulators of cell differentiation, growth, and proliferation and of mechanisms, important for a wide range of processes from embryonic development, through tissue regeneration to the development and spread of cancer. In this review, we discuss the roles of NOX and NOX-derived ROS in the functioning of stem cells and cancer stem cells and in selected aspects of cancer cell physiology. Understanding the functions and complex activities of NOX is important for the application of stem cells in tissue engineering, regenerative medicine, and development of new therapies toward invasive forms of cancers.
Collapse
|
|
40
|
Hibiya S, Tsuchiya K, Hayashi R, Fukushima K, Horita N, Watanabe S, Shirasaki T, Nishimura R, Kimura N, Nishimura T, Gotoh N, Oshima S, Okamoto R, Nakamura T, Watanabe M. Long-term Inflammation Transforms Intestinal Epithelial Cells of Colonic Organoids. J Crohns Colitis 2017; 11:621-630. [PMID: 28453760 DOI: 10.1093/ecco-jcc/jjw186] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 10/07/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS Patients with ulcerative colitis [UC] are at an increased risk of developing colitis-associated cancer [CAC], suggesting that continuous inflammation in the colon promotes the transformation of colonic epithelial cells. However, the mechanisms underlying cell transformation in UC remain unknown. We therefore aimed to investigate the effect of long-term inflammation on intestinal epithelial cells [IECs] using organoid culture. METHODS IECs were isolated from mouse colon, and were cultured according to a method for a three-dimensional [3D] organoid culture. To mimic chronic inflammation, a mixture of cytokines and bacterial components were added to the medium for over a year. Cell signal intensity was assessed by 3D immunofluorescence. Cell transformation was assessed by microarray with gene set enrichment analysis. RESULTS Stimulation with cytokines resulted in a significant induction of target genes for the nuclear factor [NF]-κB pathway in colonic organoids. Following 60 weeks of continuous stimulation, cell differentiation was suppressed. Continuous stimulation also resulted in significant amplification of NF-κB signalling. Amplified NF-κB signalling by long-term stimulation remained in colonic organoids even 11 weeks after the removal of all cytokines. Some genes were specifically upregulated only in colonic organoids after the removal all cytokines following long-term stimulation. CONCLUSIONS Colonic organoids stimulated with cytokines for a prolonged period were established as in vitro model to assess long-term epithelial responses to inflammatory cytokines. Chronic inflammation led to sustained NF-κB signalling activation in colonic organoids, resulting in cell transformation that might be related to the carcinogenesis of CAC in UC.
Collapse
Affiliation(s)
- Shuji Hibiya
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ryohei Hayashi
- Department of Endoscopy and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keita Fukushima
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Nobukatsu Horita
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Sho Watanabe
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tomoaki Shirasaki
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ryu Nishimura
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Natsuko Kimura
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Tatsunori Nishimura
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Noriko Gotoh
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Shigeru Oshima
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Center for Stem Cell and Regenerative Medicine, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tetsuya Nakamura
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Advanced Therapeutics for Gastrointestinal Diseases, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Mamoru Watanabe
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| |
Collapse
|
|
41
|
Gong Y, Xiang XJ, Feng M, Chen J, Fang ZL, Xiong JP. CUL4A promotes cell invasion in gastric cancer by activating the NF-κB signaling pathway. Biologics 2017; 11:45-53. [PMID: 28442889 PMCID: PMC5395274 DOI: 10.2147/btt.s127650] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cullin 4A (CUL4A) overexpression has been reported to be involved in the carcinogenesis and progression of many malignant tumors. However, the role of CUL4A in the progression of gastric cancer (GC) remains unclear. In this study, we explored whether and how CUL4A regulates proinflammatory signaling to promote GC cell invasion. Our results showed that knockdown of CUL4A inhibited GC cell migration and invasion induced by lipopolysaccharide (LPS) stimulation. We also found that both CUL4A and nuclear factor-kappa B (NF-κB) protein expressions were enhanced by LPS stimulation in HGC27 GC cell lines. Furthermore, knockdown of CUL4A decreased the protein expression of NF-κB and mRNA expression of the downstream genes of the NF-κB pathway, such as matrix metalloproteinase (MMP) 2, MMP9, and interleukin-8. Our immunohistochemistry analysis on 50 GC tissue samples also revealed that CUL4A positively correlated with NF-κB expression. Taken together, our findings suggest that CUL4A may promote GC cell invasion by regulating the NF-κB signaling pathway and could be considered as a potential therapeutic target in patients with GC.
Collapse
Affiliation(s)
- Yu Gong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Xiao-Jun Xiang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Miao Feng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Jun Chen
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Zi-Ling Fang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Jian-Ping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
| |
Collapse
|
|
42
|
Durand N, Storz P. Targeting reactive oxygen species in development and progression of pancreatic cancer. Expert Rev Anticancer Ther 2016; 17:19-31. [PMID: 27841037 DOI: 10.1080/14737140.2017.1261017] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDA) is characterized by expression of oncogenic KRas which drives all aspects of tumorigenesis. Oncogenic KRas induces the formation of reactive oxygen species (ROS) which have been implicated in initiation and progression of PDA. To facilitate tumor promoting levels and to avoid oncogene-induced senescence or cytotoxicity, ROS homeostasis in PDA cells is balanced by additional up-regulation of antioxidant systems. Areas covered: We examine the sources of ROS in PDA, the mechanisms by which ROS homeostasis is maintained, and the biological consequences of ROS in PDA. Additionally, we discuss the potential mechanisms for targeting ROS homoeostasis as a point of therapeutic intervention. An extensive review of the relevant literature as it relates to the topic was conducted using PubMed. Expert commentary: Even though oncogenic mutations in the KRAS gene have been detected in over 95% of human pancreatic adenocarcinoma, targeting its gene product, KRas, has been difficult. The dependency of PDA cells on balancing ROS homeostasis could be an angle for new prevention or treatment strategies. These include use of antioxidants to prevent formation or progression of precancerous lesions, or methods to increase ROS in tumor cells to toxic levels.
Collapse
Affiliation(s)
- Nisha Durand
- a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA
| | - Peter Storz
- a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA
| |
Collapse
|
|
43
|
Wu Y, Meitzler JL, Antony S, Juhasz A, Lu J, Jiang G, Liu H, Hollingshead M, Haines DC, Butcher D, Panter MS, Roy K, Doroshow JH. Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H2O2-induced, ERK-associated up-regulation of HIF-1α and VEGF-A. Oncotarget 2016; 7:68412-68433. [PMID: 27637085 PMCID: PMC5340089 DOI: 10.18632/oncotarget.12032] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 09/01/2016] [Indexed: 12/18/2022] Open
Abstract
Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokine IFN-γ increased DUOX2 expression (but not other NADPH oxidases) leading to long-lived H2O2 production. To elucidate the pathophysiology of DUOX2-mediated H2O2 formation in the pancreas further, we demonstrate here that IFN-γ-treated BxPC-3 and CFPAC-1 pancreatic cancer cells (known to increase DUOX2 expression) produce significant levels of intracellular oxidants and extracellular H2O2 which correlate with concomitant up-regulation of VEGF-A and HIF-1α transcription. These changes are not observed in the PANC-1 line that does not increase DUOX2 expression following IFN-γ treatment. DUOX2 knockdown with short interfering RNA significantly decreased IFN-γ-induced VEGF-A or HIF-1α up-regulation, as did treatment of pancreatic cancer cells with the NADPH oxidase inhibitor diphenylene iodonium, the multifunctional reduced thiol N-acetylcysteine, and the polyethylene glycol-modified form of the hydrogen peroxide detoxifying enzyme catalase. Increased DUOX2-related VEGF-A expression appears to result from reactive oxygen-mediated activation of ERK signaling that is responsible for AP-1-related transcriptional effects on the VEGF-A promoter. To clarify the relevance of these observations in vivo, we demonstrate that many human pre-malignant pancreatic intraepithelial neoplasms and frank pancreatic cancers express substantial levels of DUOX protein compared to histologically normal pancreatic tissues, and that expression of both DUOX2 and VEGF-A mRNAs is significantly increased in surgically-resected pancreatic cancers compared to the adjacent normal pancreas.
Collapse
Affiliation(s)
- Yongzhong Wu
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | | | - Smitha Antony
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Agnes Juhasz
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Jiamo Lu
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Guojian Jiang
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Han Liu
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
| | - Melinda Hollingshead
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
| | - Diana C. Haines
- Pathology/Histotechnology Laboratory, Leidos, Inc./Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Donna Butcher
- Pathology/Histotechnology Laboratory, Leidos, Inc./Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Michaela S. Panter
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
| | - Krishnendu Roy
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
| | - James H. Doroshow
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
| |
Collapse
|
|
44
|
Fernández A, Pupo A, Mena-Ulecia K, Gonzalez C. Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives. Mol Pharmacol 2016; 90:385-402. [PMID: 27260771 DOI: 10.1124/mol.116.103804] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Accepted: 06/02/2016] [Indexed: 12/23/2022] Open
Abstract
The pharmacological modulation of the immunosuppressive tumor microenvironment has emerged as a relevant component for cancer therapy. Several approaches aiming to deplete innate and adaptive suppressive populations, to circumvent the impairment in antigen presentation, and to ultimately increase the frequency of activated tumor-specific T cells are currently being explored. In this review, we address the potentiality of targeting the voltage-gated proton channel, Hv1, as a novel strategy to modulate the tumor microenvironment. The function of Hv1 in immune cells such as macrophages, neutrophils, dendritic cells, and T cells has been associated with the maintenance of NADPH oxidase activity and the generation of reactive oxygen species, which are required for the host defense against pathogens. We discuss evidence suggesting that the Hv1 proton channel could also be important for the function of these cells within the tumor microenvironment. Furthermore, as summarized here, tumor cells express Hv1 as a primary mechanism to extrude the increased amount of protons generated metabolically, thus maintaining physiologic values for the intracellular pH. Therefore, because this channel might be relevant for both tumor cells and immune cells supporting tumor growth, the pharmacological inhibition of Hv1 could be an innovative approach for cancer therapy. With that focus, we analyzed the available compounds that inhibit Hv1, highlighted the need to develop better drugs suitable for patients, and commented on the future perspectives of targeting Hv1 in the context of cancer therapy.
Collapse
Affiliation(s)
- Audry Fernández
- Interdisciplinary Center for Neurosciences of Valparaíso, Faculty of Sciences, University of Valparaíso, Chile
| | - Amaury Pupo
- Interdisciplinary Center for Neurosciences of Valparaíso, Faculty of Sciences, University of Valparaíso, Chile
| | - Karel Mena-Ulecia
- Interdisciplinary Center for Neurosciences of Valparaíso, Faculty of Sciences, University of Valparaíso, Chile
| | - Carlos Gonzalez
- Interdisciplinary Center for Neurosciences of Valparaíso, Faculty of Sciences, University of Valparaíso, Chile
| |
Collapse
|
|
45
|
Han M, Zhang T, Yang L, Wang Z, Ruan J, Chang X. Association between NADPH oxidase (NOX) and lung cancer: a systematic review and meta-analysis. J Thorac Dis 2016; 8:1704-11. [PMID: 27499960 DOI: 10.21037/jtd.2016.06.31] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Lung cancer is a leading cause of death worldwide. Considerable studies have reported that NADPH oxidase (NOX) expression or activity may play an important role in the tumorigenesis of lung cancer. However, the results are inconsistent. Thus, a systematic review and meta-analysis were conducted in this study. METHODS A systematic search of electronic databases was performed. Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3). The pooled Hedges's g with 95% confidence intervals (95% CIs) or rate ratio with 95% CIs was adopted to assess the effect size. Fixed or random effect model was separately used based on the heterogeneity between the studies. RESULTS A total of ten eligible studies were included in the current systematic review and overall meta-analysis showed that NOX/DUOX activity and mRNA were significantly in favor of lung cancer (Hedges's g =1.216, P=0.034). Suppression of NOX function by pharmacologic inhibitor or expression by siRNA resulted in significant inhibition of lung cancer cell invasion and migration in in vitro experiments (Hedges's g =2.422, P<0.001) and lung cancer formation in vivo studies (rate ratio =0.366, P=0.002). CONCLUSIONS Findings of this systematic review indicate that NOX activity and expression is associated with tumorigenesis of lung cancer and inhibition of NOX function or mRNA expression significantly blocks lung cancer formation and invasion. Suppressing NOX up-regulation or interfering NOX function in tumor microenvironment may be one important approach to prevent oxidative-stress-related carcinogenesis in the lung.
Collapse
Affiliation(s)
- Ming Han
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Tianhui Zhang
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Lei Yang
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Zitong Wang
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Junzhong Ruan
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Xiujun Chang
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| |
Collapse
|
|
46
|
Neutrophil elastase enhances IL-12p40 production by lipopolysaccharide-stimulated macrophages via transactivation of the PAR-2/EGFR/TLR4 signaling pathway. Blood Cells Mol Dis 2016; 59:1-7. [PMID: 27282560 DOI: 10.1016/j.bcmd.2016.03.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Revised: 03/17/2016] [Accepted: 03/20/2016] [Indexed: 12/25/2022]
Abstract
Proteinase-activated receptor 2 (PAR-2) and toll-like receptor 4 (TLR4) are involved in innate immune responses and signaling cross-talk between these receptor molecules has the potential to augment an ongoing inflammatory response. The aim of this study was to evaluate the possible cooperative influence of PAR-2 and TLR4 on IL-12p40 production by macrophages after stimulation with lipopolysaccharide (LPS). During culture, GM-CSF upregulated PAR-2 expression by macrophages in a time-dependent manner. Stimulation with LPS enhanced IL-12p40 production by macrophages in a concentration-dependent manner. While human neutrophil elastase (HNE) did not induce IL-12p40 production, pretreatment of macrophages with HNE synergistically increased the IL-12p40 protein level after LPS exposure. Silencing of TLR4 with small interfering RNA blunted the synergistic enhancement of IL-12p40 by HNE combined with LPS. Silencing of β-arrestin 2, p22phox, or ERK1/2 also inhibited an increase of IL-12p40. Interestingly, transfection of macrophages with small interfering RNA duplexes for DUOX-2, EGFR, TLR4, or TRAF6 significantly blunted the increase of IL-12p40 in response to treatment with HNE plus LPS. U73122 and Rottlerin also inhibited the increased production of IL-12p40. In conclusion, HNE is involved in transactivation of TLR4 through activation of DUOX-2/EGFR and synergistically enhances IL-12p40 production by macrophages stimulated with LPS.
Collapse
|
|
47
|
Does the Interdependence between Oxidative Stress and Inflammation Explain the Antioxidant Paradox? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:5698931. [PMID: 26881031 PMCID: PMC4736408 DOI: 10.1155/2016/5698931] [Citation(s) in RCA: 717] [Impact Index Per Article: 79.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 10/29/2015] [Accepted: 11/19/2015] [Indexed: 12/13/2022]
Abstract
Oxidative stress has been implicated in many chronic diseases. However, antioxidant trials are so far largely unsuccessful as a preventive or curative measure. Chronic low-grade inflammatory process, on the other hand, plays a central role in the pathogenesis of a number of chronic diseases. Oxidative stress and inflammation are closely related pathophysiological processes, one of which can be easily induced by another. Thus, both processes are simultaneously found in many pathological conditions. Therefore, the failure of antioxidant trials might result from failure to select appropriate agents that specifically target both inflammation and oxidative stress or failure to use both antioxidants and anti-inflammatory agents simultaneously or use of nonselective agents that block some of the oxidative and/or inflammatory pathways but exaggerate the others. To examine whether the interdependence between oxidative stress and inflammation can explain the antioxidant paradox we discussed in the present review the basic aspects of oxidative stress and inflammation and their relationship and dependence.
Collapse
|
|
48
|
Li J, Lan T, Zhang C, Zeng C, Hou J, Yang Z, Zhang M, Liu J, Liu B. Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalings promotes proliferation and survival of non-small cell lung cancer cells. Oncotarget 2015; 6:1031-48. [PMID: 25504436 PMCID: PMC4359215 DOI: 10.18632/oncotarget.2671] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 11/02/2014] [Indexed: 12/14/2022] Open
Abstract
Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer. Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC). In our recent study, we confirmed that NADPH oxidase 4 (NOX4), an important source of reactive oxygen species (ROS) production in NSCLC cells, promotes malignant progression of NSCLC. However, whether the crosstalk of NOX4 and IL-6 signalings exists in NSCLC remains undentified. In this study, we show that NOX4 expression is positively correlated with IL-6 expression in NSCLC tissues. Exogenous IL-6 treatment significantly enhances NOX4/ROS/Akt signaling in NSCLC cells. NOX4 also enhances IL-6 production and activates IL-6/STAT3 signaling in NSCLC cells. Specifically, NOX4 is confirmed to functionally interplay with IL-6 to promote NSCLC cell proliferation and survival. The in vivo results were similar to those obtained in vitro. These data indicate a novel NOX4-dependent link among IL-6 in the NSCLC microenvironment, oxidative stress in NSCLC cells and autocrined IL-6 in NSCLC cells. NOX4/Akt and IL-6/STAT3 signalings can reciprocally and positively regulate each other, leading to enhanced NSCLC cell proliferation and survival. Therefore, NOX4 may serve as a promising target against NSCLC alone with IL-6 signaling.
Collapse
Affiliation(s)
- Juan Li
- Clinical Pharmacy Department, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Tian Lan
- Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Cuixiang Zhang
- Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 110300, China.,Beijing Key Laboratory of Pharmacology of Chinese Materia Medica, Beijing 110300, China
| | - Cheng Zeng
- Clinical Pharmacy Department, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jincai Hou
- Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 110300, China.,Beijing Key Laboratory of Pharmacology of Chinese Materia Medica, Beijing 110300, China
| | - Zhicheng Yang
- Department of Pharmacology, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Min Zhang
- Department of Health Statistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jianxun Liu
- Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 110300, China.,Beijing Key Laboratory of Pharmacology of Chinese Materia Medica, Beijing 110300, China
| | - Bing Liu
- Clinical Pharmacy Department, Guangdong Pharmaceutical University, Guangzhou 510006, China
| |
Collapse
|
|
49
|
Abstract
The mechanism by which reactive oxygen species (ROS) are produced by tumour cells remained incompletely understood until the discovery over the last 15 years of the family of NADPH oxidases (NOXs 1–5 and dual oxidases DUOX1/2) which are structural homologues of gp91phox, the major membrane-bound component of the respiratory burst oxidase of leucocytes. Knowledge of the roles of the NOX isoforms in cancer is rapidly expanding. Recent evidence suggests that both NOX1 and DUOX2 species produce ROS in the gastrointestinal tract as a result of chronic inflammatory stress; cytokine induction (by interferon-γ, tumour necrosis factor α, and interleukins IL-4 and IL-13) of NOX1 and DUOX2 may contribute to the development of colorectal and pancreatic carcinomas in patients with inflammatory bowel disease and chronic pancreatitis, respectively. NOX4 expression is increased in pre-malignant fibrotic states which may lead to carcinomas of the lung and liver. NOX5 is highly expressed in malignant melanomas, prostate cancer and Barrett's oesophagus-associated adenocarcinomas, and in the last it is related to chronic gastro-oesophageal reflux and inflammation. Over-expression of functional NOX proteins in many tissues helps to explain tissue injury and DNA damage from ROS that accompany pre-malignant conditions, as well as elucidating the potential mechanisms of NOX-related damage that contribute to both the initiation and the progression of a wide range of solid and haematopoietic malignancies.
Collapse
|
|
50
|
Sommer F, Bäckhed F. The gut microbiota engages different signaling pathways to induce Duox2 expression in the ileum and colon epithelium. Mucosal Immunol 2015; 8:372-9. [PMID: 25160818 DOI: 10.1038/mi.2014.74] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 07/15/2014] [Indexed: 02/04/2023]
Abstract
The epithelium is a first line of defense against microorganisms in the gut. Reactive oxygen species (ROS) have an important role in controlling the normal gut microbiota and pathogenic bacteria. Dual oxidase 2 (DUOX2) is an important source of hydrogen peroxide in the small and large intestine, and the gut microbiota induces Duox2 expression. Here, we investigated the microbial regulation of Duox2 expression. We found that Duox2 was expressed by intestinal epithelial cells mainly in the tip of the epithelium. Duox2 expression was strongly induced by the presence of a normal microbiota in mice, but not when germ-free mice were colonized with various commensal bacteria. Duox2 expression was more rapidly induced by the gut microbiota in the colon than in the ileum. Furthermore, we showed that regulation of Duox2 expression in the ileum involved TIR-domain-containing adaptor protein including interferon-β (TRIF) and canonical nuclear factor-κB p50/p65 signaling, whereas regulation of Duox2 expression in the colon involved MyD88 and the p38 pathway. Collectively, these data indicate that the gut microbiota uses two distinct signaling pathways to induce Duox2 expression in the ileum and colon epithelium.
Collapse
Affiliation(s)
- F Sommer
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - F Bäckhed
- 1] The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden [2] Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|