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Mei J, Tian HX, Zhang XY, Chen YS, Wang LY, Zhang Z, Zhang YL, Rong DC, Zeng J, Dong M, Gao Y, Yin JY, Wu HJ, Wang PY, Zhang W. Heme oxygenase 1 (HO-1) is a drug target for reversing cisplatin resistance in non-small cell lung cancer. J Adv Res 2025:S2090-1232(25)00347-9. [PMID: 40389113 DOI: 10.1016/j.jare.2025.05.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/22/2025] [Accepted: 05/12/2025] [Indexed: 05/21/2025] Open
Abstract
INTRODUCTION Platinum-based drugs, the most widely used chemotherapeutic drugs in clinical oncology, have long faced the problem of drug resistance, which is urgently in need of resolution. Identifying biomarkers of drug resistance may help reduce platinum resistance and improve therapeutic efficacy. OBJECTIVES This study aims to identify potential biomarkers associated with the development of cisplatin resistance in non-small cell lung cancer (NSCLC) and explore mechanisms to overcome chemoresistance. METHODS NSCLC cisplatin resistance cell lines were constructed, and transcriptome sequencing was performed. Results were validated using Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Molecular docking, proteomics sequencing, and in vitro and in vivo experiments were conducted to evaluate the role of Heme Oxygenase 1 (HO-1) in cisplatin resistance. RESULTS NSCLC cisplatin resistance cell lines, GEO and TCGA data identified HMOX1, downstream of Nrf2, as a key drug resistance gene induced by cisplatin. Activation of the Nrf2/HO-1 pathway was found to induce ferroptosis resistance, a critical mechanism of cisplatin resistance. Candidate compounds SB 202190 and Nordihydroguaiaretic acid (NDGA) effectively reactivated ferroptosis by inhibiting HO-1, thereby increasing cisplatin sensitivity. CONCLUSION The Nrf2/HO-1 pathway is a significant contributor to cisplatin resistance in NSCLC. Targeting HO-1 with SB 202190 and NDGA presents a promising strategy to overcome resistance and improve chemotherapy outcomes.
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Affiliation(s)
- Jie Mei
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China; Central Laboratory of Hunan Cancer Hospital, Central South University, Changsha 410013, People's Republic of China; FuRong Laboratory, Changsha 410078 Hunan, People's Republic of China; Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Hui-Xiang Tian
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China
| | - Xiao-Ye Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China; Central Laboratory of Hunan Cancer Hospital, Central South University, Changsha 410013, People's Republic of China
| | - Yuan-Shen Chen
- The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, People's Republic of China
| | - Lei-Yun Wang
- Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Zhao Zhang
- Central South University Xiangya Medical School, Changsha 410013, People's Republic of China
| | - Yu-Long Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China
| | - Ding-Chao Rong
- Department of Orthopedics, The First Affiliated Hospital of Shaoyang University, Shaoyang 422000, People's Republic of China
| | - Jun Zeng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Min Dong
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, People's Republic of China
| | - Yang Gao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China.
| | - Hai-Jun Wu
- Department of Oncology, Xiangya Hospital of Central South University, Changsha 410008, People's Republic of China.
| | - Peng-Yuan Wang
- Oujiang Laboratory, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou 325000, People's Republic of China.
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics and National Clinical Research Center for Geriatric Disorders, Engineering Research Center of Applied Technology of Pharmacogenomics (Ministry of Education, China), Key Laboratory of Pharmacomicrobiomics of Hunan Province, Central South University, Changsha 410078, People's Republic of China; Central Laboratory of Hunan Cancer Hospital, Central South University, Changsha 410013, People's Republic of China; FuRong Laboratory, Changsha 410078 Hunan, People's Republic of China; The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, People's Republic of China.
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Andersen BB, Greisen S, Stengaard-Pedersen K, Junker P, Hørslev-Petersen K, Hetland ML, Østergaard M, Ørnbjerg LM, Hvid M, Deleuran B, Nielsen MA. Plasma haem oxygenase-1 may represent a first-in-class biomarker of oxidative stress in rheumatoid arthritis. Scand J Rheumatol 2025; 54:153-157. [PMID: 39287051 DOI: 10.1080/03009742.2024.2392364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 08/12/2024] [Indexed: 09/19/2024]
Abstract
OBJECTIVES This study explores the early identification of rheumatoid arthritis (RA) patients at elevated risk of progression. Haem-oxygenase-1 (HO-1) is a marker of oxidative stress in inflammation. Here, we investigate HO-1 as a biomarker of oxidative stress and its association with clinical disease activity and radiographic progression in RA. METHOD Baseline HO-1 was measured sequentially in plasma samples from patients with early rheumatoid arthritis (eRA) (n = 80). Disease Activity Score based on 28-joint count-C-reactive protein, Clinical Disease Activity Index, and total Sharp score were used to evaluate the disease course serially over 2 years. Paired plasma and synovial fluid samples were examined for HO-1 in active established rheumatoid arthritis (esRA) (n = 20). Plasma from healthy control subjects was also included (n = 35). RESULTS Plasma HO-1 levels were increased in eRA {1373 pg/mL [interquartile range (IQR) 1110-2050]} and esRA [2034 pg/mL (IQR 1630-2923)] compared with controls [1064 pg/mL (IQR 869.5-1378)]. HO-1 plasma levels decreased with treatment. Baseline HO-1 correlated with disease activity and radiographic progression. A strong, linear correlation was found between synovial and plasma HO-1 levels (r = 0.75, p < 0.001). CONCLUSION In eRA, plasma levels of HO-1 were increased and correlated with disease and radiographic progression. A baseline measurement of plasma HO-1 levels demonstrated superior performance to currently used clinical and serological disease markers in the prediction of radiographic progression. Plasma HO-1 may function as a first-in-class biomarker of synovial oxidative stress in RA.
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Affiliation(s)
- B B Andersen
- Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark
| | - S Greisen
- Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark
- Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
| | | | - P Junker
- Department of Rheumatology, Odense University Hospital, Odense, Denmark
| | - K Hørslev-Petersen
- Danish Hospital for the Rheumatic Diseases, University of Southern Denmark, Odense, Denmark
| | - M Lund Hetland
- Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - M Østergaard
- Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - L Midtbøll Ørnbjerg
- Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - M Hvid
- Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - B Deleuran
- Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark
- Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
| | - M A Nielsen
- Department of Biomedicine, Health, Aarhus University, Aarhus, Denmark
- Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Internal Medicine, Horsens Regional Hospital, Horsens, Denmark
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Ouyang X, Wang J, Qiu X, Hu D, Cui J. Current developments of pharmacotherapy targeting heme oxygenase 1 in cancer (Review). Int J Oncol 2025; 66:26. [PMID: 39981901 DOI: 10.3892/ijo.2025.5732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 01/16/2025] [Indexed: 02/22/2025] Open
Abstract
Malignant tumors are non-communicable diseases that impact human health and quality of life. Identifying and targeting the underlying genetic drivers is a challenge. Heme oxygenase-1 (HO-1), a stress-inducible enzyme also known as heat shock protein 32, plays a crucial role in maintaining cellular homeostasis. It mitigates oxidative stress-induced damage and exhibits anti-apoptotic properties. HO-1 is expressed in a wide range of malignancies and is associated with tumor growth. However, the precise role of HO-1 in tumor development remains controversial. Drugs, both naturally occurring and chemically synthesized, can inhibit tumor growth by modulating HO-1 expression in cancer cells. The present review aimed to discuss biological functions of HO-1 pharmacological therapies targeting HO-1.
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Affiliation(s)
- Xiaohu Ouyang
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jingbo Wang
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xiaoyuan Qiu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Desheng Hu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jing Cui
- Health Management Center, Hubei Provincial Hospital of Integrated Chinese & Western Medicine, Wuhan, Hubei 430015, P.R. China
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Salloom RJ, Sahtout DZ, Ahmad IM, Abdalla MY. Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment. Transl Oncol 2025; 54:102339. [PMID: 40037158 PMCID: PMC11925535 DOI: 10.1016/j.tranon.2025.102339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/24/2025] [Accepted: 02/27/2025] [Indexed: 03/06/2025] Open
Abstract
Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, highlighting the need for novel therapeutic strategies. Our study investigates the therapeutic potential of targeting the heme degradation pathway through heme oxygenase-1 (HO-1) inhibition in PC. Using both in vitro and in vivo models, we explored the effects of combining HO-1 inhibition with chemotherapy, represented by docetaxel (Doc), on tumor growth and immune infiltration. In vitro experiments demonstrated that HO-1 inhibition, as well as HO-1 knockout (KO), significantly reduced tumor cell proliferation and enhanced chemosensitivity in RM-1 cells. Additionally, U937 cells co-cultured with HO-1 KO cells shifted cell polarization toward an M1 phenotype. In vivo, the combined treatment of the HO-1 inhibitor, tin protoporphyrin (SnPP), with Doc significantly enhanced anti-tumor efficacy in mouse models compared to chemotherapy or SnPP alone. This combination therapy not only reduced Ki67 expression and increased CC3 expression in tumor tissues but also shifted macrophage polarization toward an M1 phenotype and enhanced CD4+ and CD8+ T cells infiltration, indicating an augmented immune response. Further investigation using macrophage-specific HO-1 knockout mice revealed a direct role of HO-1 inhibition in driving macrophage polarization, confirming its involvement in promoting the shift toward an M1 phenotype. Although this response was significant, it was more robust with systemic HO-1 inhibition. Our findings indicate that HO-1 inhibition can potentiate the effects of chemotherapy, offering a promising avenue for improving PC treatment outcomes.
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Affiliation(s)
| | | | - Iman M Ahmad
- Department of Clinical, Diagnostics, and Therapeutic Sciences, University of Nebraska Medical Center, Omaha, NE, USA
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Fatima R, Soni P, Sharma M, Prasher P, Kaverikana R, Mangalpady SS, Sharifi-Rad J, Calina D. Fisetin as a chemoprotective and chemotherapeutic agent: mechanistic insights and future directions in cancer therapy. Med Oncol 2025; 42:104. [PMID: 40074915 DOI: 10.1007/s12032-025-02664-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/04/2025] [Indexed: 03/14/2025]
Abstract
Cancer remains a leading cause of mortality globally, characterized by the uncontrolled proliferation of abnormal cells, invasion of healthy tissues, and potential metastasis. Natural compounds have become a focus in cancer research due to their potential therapeutic roles. Among these, fisetin, a dietary flavonoid, demonstrates notable anti-cancer properties through various molecular mechanisms. This review evaluates the chemoprotective and chemotherapeutic potential of fisetin, focusing on its mechanisms of action against cancer and its capacity to enhance cancer treatment. A systematic literature search was conducted across PubMed, Web of Science, and Scopus databases using keywords related to fisetin and cancer. The review synthesizes findings from in vitro and in vivo studies examining fisetin's effects on signaling pathways, apoptosis induction, oxidative stress modulation, and synergistic potential with chemotherapeutic agents. Fisetin has shown the ability to suppress tumor growth and metastasis by modulating critical signaling pathways, including PI3K/Akt/mTOR, NF-κB, and MAPK. It induces apoptosis in cancer cells through mitochondrial and endoplasmic reticulum stress responses and demonstrates antioxidative properties by reducing reactive oxygen species. Additionally, fisetin enhances the efficacy of conventional chemotherapies, indicating its role as a potential adjuvant in cancer treatment. Fisetin presents a promising natural compound with diverse anti-cancer effects, impacting cell cycle arrest, apoptosis, and oxidative stress pathways. Further clinical studies are warranted to fully elucidate its therapeutic potential and to optimize its delivery for improved bioavailability in cancer patients.
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Affiliation(s)
- Rabab Fatima
- Department of Chemistry, UPES, Dehradun, 248007, India
| | - Priyal Soni
- Amity Institute of Pharmacy, Amity University, Lucknow, 226010, India
| | - Mousmee Sharma
- Department of Chemistry, Uttaranchal University, Dehradun, 248007, India
| | | | - Rajesh Kaverikana
- Department of Pharmacology, Nitte (Deemed to Be University), NGSM Institute of Pharmaceuticals, Mangaluru, India
| | | | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, Ecuador.
- Centro de Estudios Tecnológicos y Universitarios del Golfo, Veracruz, Mexico.
- Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
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Consoli V, Sorrenti V, Gulisano M, Spampinato M, Vanella L. Navigating heme pathways: the breach of heme oxygenase and hemin in breast cancer. Mol Cell Biochem 2025; 480:1495-1518. [PMID: 39287890 PMCID: PMC11842487 DOI: 10.1007/s11010-024-05119-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 09/07/2024] [Indexed: 09/19/2024]
Abstract
Breast cancer remains a significant global health challenge, with diverse subtypes and complex molecular mechanisms underlying its development and progression. This review comprehensively examines recent advances in breast cancer research, with a focus on classification, molecular pathways, and the role of heme oxygenases (HO), heme metabolism implications, and therapeutic innovations. The classification of breast cancer subtypes based on molecular profiling has significantly improved diagnosis and treatment strategies, allowing for tailored approaches to patient care. Molecular studies have elucidated key signaling pathways and biomarkers implicated in breast cancer pathogenesis, shedding light on potential targets for therapeutic intervention. Notably, emerging evidence suggests a critical role for heme oxygenases, particularly HO-1, in breast cancer progression and therapeutic resistance, highlighting the importance of understanding heme metabolism in cancer biology. Furthermore, this review highlights recent advances in breast cancer therapy, including targeted therapies, immunotherapy, and novel drug delivery systems. Understanding the complex interplay between breast cancer subtypes, molecular pathways, and innovative therapeutic approaches is essential for improving patient outcomes and developing more effective treatment strategies in the fight against breast cancer.
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Affiliation(s)
- Valeria Consoli
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
- CERNUT - Research Centre on Nutraceuticals and Health Products, University of Catania, 95125, Catania, Italy
| | - Valeria Sorrenti
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
- CERNUT - Research Centre on Nutraceuticals and Health Products, University of Catania, 95125, Catania, Italy
| | - Maria Gulisano
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
| | - Mariarita Spampinato
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy
| | - Luca Vanella
- Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy.
- CERNUT - Research Centre on Nutraceuticals and Health Products, University of Catania, 95125, Catania, Italy.
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Li L, Lu X, He Q, Shu C, Walter ERH, Wang L, Long NJ, Jiang L. NADPH-Independent Fluorescent Probe for Live-Cell Imaging of Heme Oxygenase-1. ACS Sens 2025; 10:499-506. [PMID: 39745434 PMCID: PMC11773557 DOI: 10.1021/acssensors.4c02978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/05/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025]
Abstract
Heme oxygenase-1 (HO-1) catalyzes heme degradation on the consumption of NADPH and molecular oxygen. As an inducible enzyme, HO-1 is highly induced in various disease states, including cancer. Currently, two fluorescent probes for HO-1 have been designed based on the catalytic activity of HO-1, in which the probes serve as a substrate, so NADPH is required to enable the detection. Probes functioning in a NADPH-dependent way may influence other NADPH-consuming pathways, as all these pathways share a common NADPH pool. Here, we report the peptide-based fluorescent probe NBD-P5 as a simple alternative approach for HO-1 sensing. The designed probe NBD-P5 functions independently of the catalytic activity of HO-1, therefore enabling fast and sensitive detection of HO-1 with no requirements of other substances, including NADPH and biliverdin reductase. Moreover, it overcomes the need for a large substrate amount and long incubation time during the detection. NBD-P5 can be quickly taken up by cells, demonstrates an excellent colocalization with the endoplasmic reticulum (where HO-1 is mainly located), and is shown to be reliable in reporting changes in HO-1 levels in live cells. This work provides a simple alternative approach for designing HO-1 fluorescent probes, and we expect it will act as a practical tool for further studying HO-1 biology.
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Affiliation(s)
- Liang Li
- Hubei
Key Laboratory of Genetic Regulation & Integrative Biology, Key
Laboratory of Pesticide and Chemical Biology of Ministry of Education,
School of Life Sciences, Central China Normal
University, Wuhan 430079, China
| | - Xuanyi Lu
- Hubei
Key Laboratory of Genetic Regulation & Integrative Biology, Key
Laboratory of Pesticide and Chemical Biology of Ministry of Education,
School of Life Sciences, Central China Normal
University, Wuhan 430079, China
| | - Qiyuan He
- Hubei
Key Laboratory of Genetic Regulation & Integrative Biology, Key
Laboratory of Pesticide and Chemical Biology of Ministry of Education,
School of Life Sciences, Central China Normal
University, Wuhan 430079, China
| | - Chao Shu
- State
Key Laboratory of Green Pesticide, College of Chemistry, Central China Normal University, Wuhan 430079, China
| | - Edward R. H. Walter
- Department
of Chemistry, Imperial College London, MSRH Building, White City Campus, London W12 0BZ, U.K.
| | - Lin Wang
- Institute
of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou 215028, China
| | - Nicholas J. Long
- Department
of Chemistry, Imperial College London, MSRH Building, White City Campus, London W12 0BZ, U.K.
| | - Lijun Jiang
- Hubei
Key Laboratory of Genetic Regulation & Integrative Biology, Key
Laboratory of Pesticide and Chemical Biology of Ministry of Education,
School of Life Sciences, Central China Normal
University, Wuhan 430079, China
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Kumar A, Kaushal A, Verma PK, Gupta MK, Chandra G, Kumar U, Yadav AK, Kumar D. An insight into recent developments in imidazole based heterocyclic compounds as anticancer agents: Synthesis, SARs, and mechanism of actions. Eur J Med Chem 2024; 280:116896. [PMID: 39366252 DOI: 10.1016/j.ejmech.2024.116896] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 10/06/2024]
Abstract
Among all non-communicable diseases, cancer is ranked as the second most common cause of death and is rising constantly. While cancer treatments mainly include radiation therapy, chemotherapy, and surgery; chemotherapy is considered the most commonly employed and effective treatment. Most of the chemotherapeutic agents are azoles based compounds and imidazole is one such insightful azole. The anticancer properties of imidazole-based compounds have been thoroughly explored in recent years and all monosubstituted, disubstituted, trisubstituted, and tetrasubstituted imidazoles have been explored for their anticancer activities. Along with these compounds, other imidazole-based compounds like 1,3-dihydro-2H-imidazole-2-thiones, imidazolones, and poly imidazole compounds have also been explored for their anticancer activities. The activities of these compounds are heavily influenced by their structural resemblance to combretastatin 4A and ABI (2-aryl-4-benzoyl-imidazole). The lead compounds were highly active on breast, gastric, colon, ovarian, cervical, bone marrow, melanoma, prostate, lung, leukemic, neuroblastoma, liver, Ehrlich, melanoma, and pancreatic cancers. The targets of these leads like tubulin, heme oxygenases, VEGF, tyrosine kinases, EGFR, and others have also been explored. The exploration of the anticancer potential of substituted imidazole compounds is the main topic of this review including synthesis, SAR, and mechanism.
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Affiliation(s)
- Arun Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173 229, India
| | - Anjali Kaushal
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173 229, India; Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Parul University, Vadodara, Gujarat, 391760, India
| | - Prabhakar K Verma
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, India
| | - Manoj K Gupta
- Department of Chemistry, Central University of Haryana, Mahendergarh, Haryana, 123031, India
| | - Girish Chandra
- Department of Chemistry, School of Physical and Chemical Sciences, Central University of South Bihar, Gaya, Bihar, 824236, India
| | - Umesh Kumar
- Catalysis and Bioinorganic Research Lab, Department of Chemistry, Deshbandhu College, University of Delhi, New Delhi, 110019, India
| | - Ashok K Yadav
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
| | - Deepak Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173 229, India.
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Wang W, Li J, Pan C, Wang D, Dong J. miR-328-3p suppresses hepatocellular carcinoma progression by regulating HMOX1 expression. Discov Oncol 2024; 15:735. [PMID: 39617834 PMCID: PMC11609136 DOI: 10.1007/s12672-024-01610-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 11/19/2024] [Indexed: 01/03/2025] Open
Abstract
INTRODUCTION Most oncogenic genes contribute to cancer progression, but their role and regulatory mechanisms are not yet fully understood in hepatocellular carcinoma (HCC). This study aimed to explore the role of miR-328-3p and the regulatory relationship between miR-328-3p and HMOX1 in HCC. METHODS We utilized Cox and LASSO regression to identify a panel of oncogenic genes associated with hepatocellular carcinoma (HCC) progression within the TCGA-LIHC cohort and the GSE104580 dataset. The expression levels of the hub gene, HMOX1, were assessed in HCC cell lines using qPCR. The functional roles of miR-328-3p and HMOX1 were evaluated through a series of in vitro assays, including CCK-8 for proliferation, colony formation, wound healing, and Transwell assays for migration and invasion. The direct interaction between miR-328-3p and HMOX1 was explored using a luciferase reporter assay, Western blot (WB) for protein expression analysis, and functional assays to determine the impact on cell proliferation and migration. RESULTS Eight candidate genes (BIRC5, TNSF4, SPP1, HMOX1, ADM, RBP2, IGF1, and LECT2) were screen out. The hub gene HMOX1 among had high expression level in HCC cell lines. High HMOX1 expressing cell line had significantly increased proliferation and migration capacities. Moreover, HMOX1 was identified as a target of miR-328-3p, which regulated the HMOX1 expression in qPCR and WB assays. High miR-328-3p expressing HCC cell had diminished capacities for proliferation and migration. However, concurrent upregulation of HMOX1 expression resulted in enhanced proliferative and migratory abilities in these cells. CONCLUSION Our study has advanced our understanding of the roles of miR-328-3p and HMOX1 in HCC, demonstrating the inhibitory effect of miR-328-3p on the oncogenic activity of HMOX1. Hence, these results revealed the function of miR-328-3p and a novel mechanistic pathway for HCC and suggested the potential therapeutic targeting of miR-328-3p and HMOX1 for HCC intervention strategies.
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Affiliation(s)
- Weixing Wang
- Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Jiaotong University, Shanghai, 201600, China
| | - Jun Li
- Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Jiaotong University, Shanghai, 201600, China
| | - Changjun Pan
- Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Jiaotong University, Shanghai, 201600, China
| | - Deguo Wang
- Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Jiaotong University, Shanghai, 201600, China.
| | - Jian Dong
- Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Jiaotong University, Shanghai, 201600, China.
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Li N, Hao L, Li S, Deng J, Yu F, Zhang J, Nie A, Hu X. The NRF-2/HO-1 Signaling Pathway: A Promising Therapeutic Target for Metabolic Dysfunction-Associated Steatotic Liver Disease. J Inflamm Res 2024; 17:8061-8083. [PMID: 39512865 PMCID: PMC11542495 DOI: 10.2147/jir.s490418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 10/18/2024] [Indexed: 11/15/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver disorder with a rising prevalence. It begins with lipid accumulation in hepatocytes and gradually progresses to Metabolic-associated steatohepatitis (MASH), fibrosis, cirrhosis, and potentially hepatocellular carcinoma (HCC). The pathophysiology of MASLD is complex and involves multiple factors, with oxidative stress playing a crucial role. Oxidative stress drives the progression of MASLD by causing cellular damage, inflammatory responses, and fibrosis, making it a key pathogenic mechanism. The Nuclear Factor Erythroid 2-Related Factor 2 / Heme Oxygenase-1 (Nrf2/HO-1) signaling axis provides robust multi-organ protection against a spectrum of endogenous and exogenous insults, particularly oxidative stress. It plays a pivotal role in mediating antioxidant, anti-inflammatory, and anti-apoptotic responses. Many studies indicate that activating the Nrf2/HO-1 signaling pathway can significantly mitigate the progression of MASLD. This article examines the role of the Nrf2/HO-1 signaling pathway in MASLD and highlights natural compounds that protect against MASLD by targeting Nrf2/HO-1 activation. The findings indicate that the Nrf2/HO-1 signaling pathway holds great promise as a therapeutic target for MASLD.
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Affiliation(s)
- Na Li
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Liyuan Hao
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Shenghao Li
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Jiali Deng
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Fei Yu
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Junli Zhang
- Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, People's Republic of China
| | - Aiyu Nie
- Department of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
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11
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Consonni FM, Incerti M, Bertolotti M, Ballerini G, Garlatti V, Sica A. Heme catabolism and heme oxygenase-1-expressing myeloid cells in pathophysiology. Front Immunol 2024; 15:1433113. [PMID: 39611159 PMCID: PMC11604077 DOI: 10.3389/fimmu.2024.1433113] [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: 05/15/2024] [Accepted: 10/01/2024] [Indexed: 11/30/2024] Open
Abstract
Although the pathological significance of myeloid cell heterogeneity is still poorly understood, new evidence indicates that distinct macrophage subsets are characterized by specific metabolic programs that influence disease onset and progression. Within this scenario, distinct subsets of macrophages, endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), play critical roles in physiologic and pathological conditions. Of relevance, the substrates of HO-1 activity are the heme groups that derive from cellular catabolism and are converted into carbon monoxide (CO), biliverdin and Fe2+, which together elicit anti-apoptotic, anti-inflammatory activities and control oxidative damage. While high levels of expression of HO-1 enzyme by specialized macrophage populations (erythrophagocytes) guarantee the physiological disposal of senescent red blood cells (i.e. erythrocateresis), the action of HO-1 takes on pathological significance in various diseases, and abnormal CO metabolism has been observed in cancer, hematological diseases, hypertension, heart failure, inflammation, sepsis, neurodegeneration. Modulation of heme catabolism and CO production is therefore a feasible therapeutic opportunity in various diseases. In this review we discuss the role of HO-1 in different pathological contexts (i.e. cancer, infections, cardiovascular, immune-mediated and neurodegenerative diseases) and highlight new therapeutic perspectives on the modulation of the enzymatic activity of HO-1.
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Affiliation(s)
- Francesca Maria Consonni
- Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Martina Incerti
- Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Milena Bertolotti
- Navita S.r.l., University of Eastern Piedmont A. Avogadro, Novara, Italy
| | - Giulia Ballerini
- Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Valentina Garlatti
- Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Antonio Sica
- Department of Pharmaceutical Sciences, University of Piemonte Orientale “A. Avogadro”, Novara, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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12
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Chu C, Xu H, Liu C, Wei X, Li L, Wang R, Cui W, Zhang G, Liu C, Wang K, An L, He F. Cytotoxicity and inhibitory potential of CUDC-101 in non-small cell lung cancer cells with rare EGFR L861Q mutation. Curr Res Toxicol 2024; 7:100194. [PMID: 39524037 PMCID: PMC11546682 DOI: 10.1016/j.crtox.2024.100194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 09/11/2024] [Accepted: 09/13/2024] [Indexed: 11/16/2024] Open
Abstract
The epidermal growth factor receptor (EGFR) represents an effective target for the treatment of non-small cell lung cancer. In the treatment of classical EGFR mutations, EGFR tyrosine kinase inhibitors have achieved desirable clinical efficacy. However, the effectiveness of tyrosine kinase inhibitors (TKIs) against the L861Q mutation has not been fully established. In this study, the four cell lines containing the L861Q mutation were constructed by CRISPR and the anti-tumour effects of CUDC-101 on them were investigated in vitro by various chemosensitivity methods, with afatinib serving as a positive control. The results demonstrated that CUDC-101 inhibited the proliferation and clonogenic capacity on the four cells through the ERK or AKT pathways, decreased the mitochondrial membrane potential of the cells, blocked the cell cycle and promoted apoptosis. Our findings suggest that CUDC-101 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation L861Q.
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Affiliation(s)
- Chunhong Chu
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
- Institutes of Traditional Chinese Medicine, School of Pharmacy, Henan University, Kaifeng 475000, Henan, China
| | - Huixia Xu
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
| | - Chenxue Liu
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
| | - Xiangkai Wei
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
| | - Lanxin Li
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
| | - Rui Wang
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
| | - Wenrui Cui
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
| | - Guoliang Zhang
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
- Institutes of Traditional Chinese Medicine, School of Pharmacy, Henan University, Kaifeng 475000, Henan, China
| | - Chenyang Liu
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
| | - Ke Wang
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
| | - Lei An
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
- Institutes of Traditional Chinese Medicine, School of Pharmacy, Henan University, Kaifeng 475000, Henan, China
| | - Fei He
- Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng 475000, China
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13
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Leal AS, Liby KT. The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice. Int J Mol Sci 2024; 25:9985. [PMID: 39337472 PMCID: PMC11432103 DOI: 10.3390/ijms25189985] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/10/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
In pancreatic cancer, the tumor microenvironment (TME) accounts for up to 90% of the tumor mass. Pancreatitis, characterized by the increased infiltration of macrophages into the pancreas, is a known risk factor for pancreatic cancer. The NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor regulates responses to oxidative stress and can promote cancer and chemoresistance. NRF2 also attenuates inflammation through the regulation of macrophage-specific genes. Heme oxygenase 1 (HO-1) is expressed by anti-inflammatory macrophages to degrade heme, and its expression is dependent on NRF2 translocation to the nucleus. In macrophages stimulated with conditioned media from pancreatic cancer cells, HO-1 protein levels increased, which correlated with higher NRF2 expression in the nuclear fraction. Significant differences in macrophage infiltration and HO-1 expression were detected in LSL-KrasG12D/+; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice and wildtype mice with pancreatitis. Since epigenetic modulation is a mechanism used by tumors to regulate the TME, using small molecules as epigenetic modulators to activate immune recognition is therapeutically desirable. When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis.
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Affiliation(s)
- Ana S. Leal
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Karen T. Liby
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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14
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Shrestha J, Limbu KR, Chhetri RB, Paudel KR, Hansbro PM, Oh YS, Baek DJ, Ki SH, Park EY. Antioxidant genes in cancer and metabolic diseases: Focusing on Nrf2, Sestrin, and heme oxygenase 1. Int J Biol Sci 2024; 20:4888-4907. [PMID: 39309448 PMCID: PMC11414382 DOI: 10.7150/ijbs.98846] [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: 05/24/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024] Open
Abstract
Reactive oxygen species are involved in the pathogenesis of cancers and metabolic diseases, including diabetes, obesity, and fatty liver disease. Thus, inhibiting the generation of free radicals is a promising strategy to control the onset of metabolic diseases and cancer progression. Various synthetic drugs and natural product-derived compounds that exhibit antioxidant activity have been reported to have a protective effect against a range of metabolic diseases and cancer. This review highlights the development and aggravation of cancer and metabolic diseases due to the imbalance between pro-oxidants and endogenous antioxidant molecules. In addition, we discuss the function of proteins that regulate the production of reactive oxygen species as a strategy to treat metabolic diseases. In particular, we summarize the role of proteins such as nuclear factor-like 2, Sestrin, and heme oxygenase-1, which regulate the expression of various antioxidant genes in metabolic diseases and cancer. We have included recent literature to discuss the latest research on identifying novel signals of antioxidant genes that can control metabolic diseases and cancer.
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Affiliation(s)
- Jitendra Shrestha
- College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
- Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
| | - Khem Raj Limbu
- College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
| | | | - Keshav Raj Paudel
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sci., Sydney, NSW 2007, Australia
| | - Philip M. Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sci., Sydney, NSW 2007, Australia
| | - Yoon Sin Oh
- Department of Food and Nutrition, Eulji University, Seongnam 13135, Republic of Korea
| | - Dong Jae Baek
- College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Sung-Hwan Ki
- College of Pharmacy, Chosun University, Gwangju 61451, Republic of Korea
| | - Eun-Young Park
- College of Pharmacy, Mokpo National University, Jeonnam 58554, Republic of Korea
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15
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Ore A, Angelastro JM, Giulivi C. Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases. Brain Sci 2024; 14:899. [PMID: 39335395 PMCID: PMC11429837 DOI: 10.3390/brainsci14090899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 08/31/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.
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Affiliation(s)
- Adaleiz Ore
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
- Department of Chemical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - James M. Angelastro
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
| | - Cecilia Giulivi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
- University of California Medical Investigations of Neurodevelopmental Disorders Institute (MIND Institute), University of California Health, Sacramento, CA 95817, USA
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16
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Kaplan Ö, Gökşen Tosun N. Molecular pathway of anticancer effect of next-generation HSP90 inhibitors XL-888 and Debio0932 in neuroblastoma cell line. Med Oncol 2024; 41:194. [PMID: 38958814 PMCID: PMC11222184 DOI: 10.1007/s12032-024-02428-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 06/13/2024] [Indexed: 07/04/2024]
Abstract
Neuroblastoma is a common nervous system tumor in childhood, and current treatments are not adequate. HSP90 is a molecular chaperone protein that plays a critical role in the regulation of cancer-related proteins. HSP90 inhibition may exert anticancer effects by targeting cancer-related processes such as tumor growth, cell proliferation, metastasis, and apoptosis. Therefore, HSP90 inhibition is a promising strategy in the treatment of various types of cancer, and the development of next-generation inhibitors could potentially lead to more effective and safer treatments. XL-888 and Debio0932 is a next-generation HSP90 inhibitor and can inhibit the correct folding and stabilization of client proteins that cancer-associated HSP90 helps to fold correctly. In this study, we aimed to investigate the comprehensive molecular pathways of the anticancer activity of XL-888 and Debio0932 in human neuroblastoma cells SH-SY5Y. The cytotoxic effects of XL-888 and Debio0932 on the neuroblastoma cell line SH-SY5Y cells were evaluated by MTT assay. Then, the effect of these HSP90 inhibitors on the expression of important genes in cancer was revealed by Quantitative Real Time Polymerase Chain Reaction (qRT-PCR) method. The qRT-PCR data were evaluated using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) biological process tools. Finally, the effect of HSP90 inhibitors on HSP27, HSP70 and HSP90 protein expression was investigated by Western blotting analysis. The results revealed that XL-888 and Debio0932 had a role in regulating many cancer-related pathways such as migration, invasion, metastasis, angiogenesis, and apoptosis in SH-SY5Y cells. In conclusion, it shows that HSP90 inhibitors can be considered as a promising candidate in the treatment of neuroblastoma and resistance to chemotherapy.
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Affiliation(s)
- Özlem Kaplan
- Department of Genetics and Bioengineering, Rafet Kayış Faculty of Engineering, Alanya Alaaddin Keykubat University, Antalya, Türkiye.
| | - Nazan Gökşen Tosun
- Department of Medical Services and Techniques, Tokat Gaziosmanpaşa University, Tokat Vocational School of Health Services, Tokat, Türkiye.
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17
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D’Amico AG, Maugeri G, Vanella L, Consoli V, Sorrenti V, Bruno F, Federico C, Fallica AN, Pittalà V, D’Agata V. Novel Acetamide-Based HO-1 Inhibitor Counteracts Glioblastoma Progression by Interfering with the Hypoxic-Angiogenic Pathway. Int J Mol Sci 2024; 25:5389. [PMID: 38791428 PMCID: PMC11121434 DOI: 10.3390/ijms25105389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/06/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Glioblastoma multiforme (GBM) represents the deadliest tumor among brain cancers. It is a solid tumor characterized by uncontrolled cell proliferation generating the hypoxic niches in the cancer core. By inducing the transcription of hypoxic inducible factor (HIF), hypoxia triggers many signaling cascades responsible for cancer progression and aggressiveness, including enhanced expression of vascular endothelial growth factor (VEGF) or antioxidant enzymes, such as heme oxygenase-1 (HO-1). The present work aimed to investigate the link between HO-1 expression and the hypoxic microenvironment of GBM by culturing two human glioblastoma cell lines (U87MG and A172) in the presence of a hypoxic mimetic agent, deferoxamine (DFX). By targeting hypoxia-induced HO-1, we have tested the effect of a novel acetamide-based HO-1 inhibitor (VP18/58) on GBM progression. Results have demonstrated that hypoxic conditions induced upregulation and nuclear expression of HO-1 in a cell-dependent manner related to malignant phenotype. Moreover, our data demonstrated that the HO-1 inhibitor counteracted GBM progression by modulating the HIFα/HO-1/VEGF signaling cascade in cancer cells bearing more malignant phenotypes.
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Affiliation(s)
- Agata Grazia D’Amico
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.G.D.); (V.C.); (V.S.); (V.P.)
| | - Grazia Maugeri
- Department of Biomedical and Biotechnological Sciences, Section of Anatomy, Histology and Movement Sciences, University of Catania, 95100 Catania, Italy
| | - Luca Vanella
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.G.D.); (V.C.); (V.S.); (V.P.)
| | - Valeria Consoli
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.G.D.); (V.C.); (V.S.); (V.P.)
| | - Valeria Sorrenti
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.G.D.); (V.C.); (V.S.); (V.P.)
| | - Francesca Bruno
- Department of Biological, Geological and Environmental Sciences, Section of Animal Biology, University of Catania, 95123 Catania, Italy (C.F.)
| | - Concetta Federico
- Department of Biological, Geological and Environmental Sciences, Section of Animal Biology, University of Catania, 95123 Catania, Italy (C.F.)
| | - Antonino Nicolò Fallica
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.G.D.); (V.C.); (V.S.); (V.P.)
| | - Valeria Pittalà
- Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy; (A.G.D.); (V.C.); (V.S.); (V.P.)
- Department of Molecular Medicine, College of Medicine and Medical Sciences, Princess Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama 329, Bahrain
| | - Velia D’Agata
- Department of Biomedical and Biotechnological Sciences, Section of Anatomy, Histology and Movement Sciences, University of Catania, 95100 Catania, Italy
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18
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Estarreja J, Caldeira G, Silva I, Mendes P, Mateus V. The Pharmacological Effect of Hemin in Inflammatory-Related Diseases: A Systematic Review. Biomedicines 2024; 12:898. [PMID: 38672251 PMCID: PMC11048114 DOI: 10.3390/biomedicines12040898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/08/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Hemin is clinically used in acute attacks of porphyria; however, recent evidence has also highlighted its capability to stimulate the heme oxygenase enzyme, being associated with cytoprotective, antioxidant, and anti-inflammatory effects. Indeed, current preclinical evidence emphasizes the potential anti-inflammatory role of hemin through its use in animal models of disease. Nevertheless, there is no consensus about the underlying mechanism(s) and the most optimal therapeutic regimens. Therefore, this review aims to summarize, analyze, and discuss the current preclinical evidence concerning the pharmacological effect of hemin. METHODS Following the application of the search expression and the retrieval of the articles, only nonclinical studies in vivo written in English were considered, where the potential anti-inflammatory effect of hemin was evaluated. RESULTS Forty-nine articles were included according to the eligibility criteria established. The results obtained show the preference of using 30 to 50 mg/kg of hemin, administered intraperitoneally, in both acute and chronic contexts. This drug demonstrates significant anti-inflammatory and antioxidant activities considering its capacity for reducing the expression of proinflammatory and oxidative markers. CONCLUSIONS This review highlighted the significant anti-inflammatory and antioxidant effects of hemin, providing a clearer vision for the medical community about the use of this drug in several human diseases.
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Affiliation(s)
- João Estarreja
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
| | - Gonçalo Caldeira
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
| | - Inês Silva
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal
| | - Priscila Mendes
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
| | - Vanessa Mateus
- H&TRC—Health and Technology Research Center, ESTeSL—Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; (J.E.); (G.C.); (I.S.); (P.M.)
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal
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19
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Wang T, Hu L, Li R, Ren H, Li S, Sun Q, Ding X, Li Y, Wang C, Li L. Hyperoside inhibits EHV-8 infection via alleviating oxidative stress and IFN production through activating JNK/Keap1/Nrf2/HO-1 signaling pathways. J Virol 2024; 98:e0015924. [PMID: 38499512 PMCID: PMC11019850 DOI: 10.1128/jvi.00159-24] [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: 01/26/2024] [Accepted: 02/29/2024] [Indexed: 03/20/2024] Open
Abstract
Equine herpesvirus type 8 (EHV-8) causes abortion and respiratory disease in horses and donkeys, leading to serious economic losses in the global equine industry. Currently, there is no effective vaccine or drug against EHV-8 infection, underscoring the need for a novel antiviral drug to prevent EHV-8-induced latent infection and decrease the pathogenicity of this virus. The present study demonstrated that hyperoside can exert antiviral effects against EHV-8 infection in RK-13 (rabbit kidney cells), MDBK (Madin-Darby bovine kidney), and NBL-6 cells (E. Derm cells). Mechanistic investigations revealed that hyperoside induces heme oxygenase-1 expression by activating the c-Jun N-terminal kinase/nuclear factor erythroid-2-related factor 2/Kelch-like ECH-associated protein 1 axis, alleviating oxidative stress and triggering a downstream antiviral interferon response. Accordingly, hyperoside inhibits EHV-8 infection. Meanwhile, hyperoside can also mitigate EHV-8-induced injury in the lungs of infected mice. These results indicate that hyperoside may serve as a novel antiviral agent against EHV-8 infection.IMPORTANCEHyperoside has been reported to suppress viral infections, including herpesvirus, hepatitis B virus, infectious bronchitis virus, and severe acute respiratory syndrome coronavirus 2 infection. However, its mechanism of action against equine herpesvirus type 8 (EHV-8) is currently unknown. Here, we demonstrated that hyperoside significantly inhibits EHV-8 adsorption and internalization in susceptible cells. This process induces HO-1 expression via c-Jun N-terminal kinase/nuclear factor erythroid-2-related factor 2/Kelch-like ECH-associated protein 1 axis activation, alleviating oxidative stress and triggering an antiviral interferon response. These findings indicate that hyperoside could be very effective as a drug against EHV-8.
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Affiliation(s)
- Tongtong Wang
- College of Agronomy, Liaocheng University, Liaocheng, China
| | - Leyu Hu
- College of Agronomy, Liaocheng University, Liaocheng, China
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
| | - Ruibo Li
- College of Agronomy, Liaocheng University, Liaocheng, China
| | - Huiying Ren
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China
| | - Shuwen Li
- College of Agronomy, Liaocheng University, Liaocheng, China
| | - Qi Sun
- College of Agronomy, Liaocheng University, Liaocheng, China
| | - Xiangdan Ding
- College of Agronomy, Liaocheng University, Liaocheng, China
| | - Yubao Li
- College of Agronomy, Liaocheng University, Liaocheng, China
| | - Changfa Wang
- College of Agronomy, Liaocheng University, Liaocheng, China
| | - Liangliang Li
- College of Agronomy, Liaocheng University, Liaocheng, China
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20
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Singhabahu R, Kodagoda Gamage SM, Gopalan V. Pathological significance of heme oxygenase-1 as a potential tumor promoter in heme-induced colorectal carcinogenesis. CANCER PATHOGENESIS AND THERAPY 2024; 2:65-73. [PMID: 38601482 PMCID: PMC11002664 DOI: 10.1016/j.cpt.2023.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/01/2023] [Accepted: 04/06/2023] [Indexed: 04/12/2024]
Abstract
The significance of the heme-metabolizing enzyme heme oxygenase-1 (HMOX1) in the pathogenesis of colorectal cancer (CRC) has not been fully explored. HMOX1 cytoprotection is imperative to limit oxidative stress. However, its roles in preventing carcinogenesis in response to high levels of heme are not thoroughly understood. This study reviews various mechanisms associated with the paradoxical role of HMOX1, which is advantageous for tumor growth, refractoriness, and survival of cancer cells amid oxidative stress in heme-induced CRC. The alternate role of HMOX1 promotes cell proliferation and metastasis through immune modulation and angiogenesis. Inhibiting HMOX1 has been found to reverse tumor promotion. Thus, HMOX1 acts as a conditional tumor promoter in CRC pathogenesis.
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Affiliation(s)
- Rachitha Singhabahu
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland 4222, Australia
| | - Sujani M. Kodagoda Gamage
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland 4222, Australia
- Faculty of Health Sciences and Medicine, Bond University, Robina 4226, Australia
| | - Vinod Gopalan
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, Queensland 4222, Australia
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21
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Fan J, Chen B, Luo Q, Li J, Huang Y, Zhu M, Chen Z, Li J, Wang J, Liu L, Wei Q, Cao D. Potential molecular biomarkers for the diagnosis and prognosis of bladder cancer. Biomed Pharmacother 2024; 173:116312. [PMID: 38417288 DOI: 10.1016/j.biopha.2024.116312] [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: 12/18/2023] [Revised: 02/07/2024] [Accepted: 02/17/2024] [Indexed: 03/01/2024] Open
Abstract
Bladder cancer (BC) is a common malignant tumor of urinary system, which can be divided into muscle-invasive BC (MIBC) and nonmuscle-invasive BC (NMIBC). The number of BC patients has been gradually increasing currently. At present, bladder tumours are diagnosed and followed-up using a combination of cystoscopic examination, cytology and histology. However, the detection of early grade tumors, which is much easier to treat effectively than advanced stage disease, is still insufficient. It frequently recurs and can progress when not expeditiously diagnosed and monitored following initial therapy for NMIBC. Treatment strategies are totally different for different stage diseases. Therefore, it is of great practical significance to study new biomarkers for diagnosis and prognosis. In this review, we summarize the current state of biomarker development in BC diagnosis and prognosis prediction. We retrospectively analyse eight diagnostic biomarkers and eight prognostic biomarkers, in which CK, P53, PPARγ, PTEN and ncRNA are emphasized for discussion. Eight molecular subtype systems are also identified. Clinical translation of biomarkers for diagnosis, prognosis, monitoring and treatment will hopefully improve outcomes for patients. These potential biomarkers provide an opportunity to diagnose tumors earlier and with greater accuracy, and help identify those patients most at risk of disease recurrence.
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Affiliation(s)
- Junping Fan
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China; West China School of Medicine, Sichuan University, Chengdu, China
| | - Bo Chen
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China; West China School of Medicine, Sichuan University, Chengdu, China
| | - Qiuping Luo
- Out-patient Department, West China Hospital, Sichuan University, Chengdu, China
| | - Jinze Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China; West China School of Medicine, Sichuan University, Chengdu, China
| | - Yin Huang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China; West China School of Medicine, Sichuan University, Chengdu, China
| | - Mengli Zhu
- Research Core Facility, West China Hospital, Sichuan University, Chengdu, China
| | - Zeyu Chen
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China; West China School of Medicine, Sichuan University, Chengdu, China
| | - Jin Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China; West China School of Medicine, Sichuan University, Chengdu, China
| | - Jia Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Liangren Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Qiang Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
| | - Dehong Cao
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
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22
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Wei Q, Zhang YH. Flavonoids with Anti-Angiogenesis Function in Cancer. Molecules 2024; 29:1570. [PMID: 38611849 PMCID: PMC11013936 DOI: 10.3390/molecules29071570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 03/23/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
The formation of new blood vessels, known as angiogenesis, significantly impacts the development of multiple types of cancer. Consequently, researchers have focused on targeting this process to prevent and treat numerous disorders. However, most existing anti-angiogenic treatments rely on synthetic compounds and humanized monoclonal antibodies, often expensive or toxic, restricting patient access to these therapies. Hence, the pursuit of discovering new, affordable, less toxic, and efficient anti-angiogenic compounds is imperative. Numerous studies propose that natural plant-derived products exhibit these sought-after characteristics. The objective of this review is to delve into the anti-angiogenic properties exhibited by naturally derived flavonoids from plants, along with their underlying molecular mechanisms of action. Additionally, we summarize the structure, classification, and the relationship between flavonoids with their signaling pathways in plants as anti-angiogenic agents, including main HIF-1α/VEGF/VEGFR2/PI3K/AKT, Wnt/β-catenin, JNK1/STAT3, and MAPK/AP-1 pathways. Nonetheless, further research and innovative approaches are required to enhance their bioavailability for clinical application.
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Affiliation(s)
- Qiang Wei
- School of Medicine, Anhui Xinhua University, 555 Wangjiang West Road, Hefei 230088, China;
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23
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Raptania CN, Zakia S, Fahira AI, Amalia R. Article review: Brazilin as potential anticancer agent. Front Pharmacol 2024; 15:1355533. [PMID: 38515856 PMCID: PMC10955326 DOI: 10.3389/fphar.2024.1355533] [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: 12/14/2023] [Accepted: 02/14/2024] [Indexed: 03/23/2024] Open
Abstract
Brazilin is the main compound in Caesalpinia sappan and Haematoxylum braziletto, which is identified as a homoisoflavonoid based on its molecular structure. These plants are traditionally used as an anti-inflammatory to treat fever, hemorrhage, rheumatism, skin problems, diabetes, and cardiovascular diseases. Recently, brazilin has increased its interest in cancer studies. Several findings have shown that brazilin has cytotoxic effects on colorectal cancer, breast cancer, lung cancer, multiple myeloma, osteosarcoma, cervical cancer, bladder carcinoma, also other cancers, along with numerous facts about its possible mechanisms that will be discussed. Besides its flavonoid content, brazilin is able to chelate metal ions. A study has proved that brazilin could be used as an antituberculosis agent based on its ability to chelate iron. This possible iron-chelating of brazilin and all the studies discussed in this review will lead us to the statement that, in the future, brazilin has the potency to be a chemo-preventive and anticancer agent. The article review aimed to determine the brazilin mechanism and pathogenesis of cancer.
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Affiliation(s)
- Callista Najla Raptania
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia
| | - Syifa Zakia
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia
| | - Alistia Ilmiah Fahira
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia
- Laboratory of Cell and Molecular Biology, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia
| | - Riezki Amalia
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia
- Laboratory of Cell and Molecular Biology, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia
- Center of Excellence in Pharmaceutical Care Innovation, Universitas Padjadjaran, Bandung, Indonesia
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Li W, Shen MY, Liu RB, Zhang JY, Li RY, Wang GG. Deletion of protein kinase C θ attenuates hepatic ischemia/reperfusion injury and further elucidates its mechanism in pathophysiology. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:1323-1330. [PMID: 39229579 PMCID: PMC11366945 DOI: 10.22038/ijbms.2024.77365.16730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 04/06/2024] [Indexed: 09/05/2024]
Abstract
Objectives Hepatic ischemia-reperfusion (HIR) is a severe process in pathophysiology that occurs clinically in hepatectomy, and hepatic transplantations. The present study aimed to investigate the effect of PKC θ deletion against HIR injury and elucidate its mechanism in pathophysiology. Materials and Methods HIR injury was induced in wild-type and PKC θ deletion mice treated with or without heme. The ALT and AST levels were determined to evaluate liver function. HIR injury was observed via histological examination. Oxidative stress and inflammatory response markers, and their signaling pathways were detected. Results The study found that PKC θ knockout decreased serum AST and ALT levels when compared to the WT mice. Furthermore, heme treatment significantly reduced the ALT and AST levels of the PKC θ deletion mice compared with the untreated PKC θ deletion mice. PKC θ deletion markedly elevated superoxide dismutase activity in the liver tissue, reduced malondialdehyde content in the tissue, and the serum TNF-α and IL-6 levels compared with the WT mice. Heme treatment was observed to elevate the activity of SOD and reduced MDA content and serum of TNF-α and IL 6 in the PKC θ deletion animals. Meanwhile, heme treatment increased HO-1 and Nrf 2 protein expression, and reduced the levels of TLR4, phosphorylated NF-κB, and IKB-α. Conclusion These findings suggested that PKC θ deletion ameliorates HIR, and heme treatment further improves HIR, which is related to regulation of PKC θ deletion on Nrf 2/HO-1 and TLR4/NF-κB/IKB α pathway.
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Affiliation(s)
- Wei Li
- Department of Pathophysiology, Wannan Medical College, Wuhu, China
| | - Meng-Yuan Shen
- School of Medical Imaging, Wannan Medical College, Wuhu, China
| | - Ruo-Bing Liu
- School of Clinical Medicine, Wannan Medical College, Wuhu, China
| | - Jun-Yang Zhang
- School of Medical Imaging, Wannan Medical College, Wuhu, China
| | - Rong-Yu Li
- Department of Immunology, Wannan Medical College, Wuhu, China
| | - Guo-Guang Wang
- Department of Pathophysiology, Wannan Medical College, Wuhu, China
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Alipanah-Moghadam R, Khodaei M, Aghamohammadi V, Malekzadeh V, Afrouz M, Nemati A, Zahedian H. Andrographolide induced heme oxygenase-1 expression in MSC-like cells isolated from rat bone marrow exposed to environmental stress. Biochem Biophys Res Commun 2023; 687:149212. [PMID: 37944470 DOI: 10.1016/j.bbrc.2023.149212] [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: 08/12/2023] [Revised: 10/29/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND AND OBJECTIVES Mesenchymal stem cells (MSC-like cells) are the most important stem cells that are used in transplantation clinically in various applications. The survival rate of MSC-like cells is strongly reduced due to adverse conditions in the microenvironment of transplantation, including environmental stress. Heme oxygenase-1 (HO-1) is a member of the heat shock protein, as well as a stress-induced enzyme, present throughout the body. The present study was conducted to investigate the effect of andrographolide, an active derivative from andrographolide paniculate, on HO-1 expression in mesenchymal stem cells derived from rat bone marrow. MATERIALS AND METHODS The rat bone marrow-derived mesenchymal stem cells (BMSC-like cells) were extracted and proliferated in several passages. The identity of MSC-like cells was confirmed by morphological observations and differential tests. The flow cytometry method was used to verify the MSC-specific markers. Isolated MSC-like cells were treated with different concentrations of andrographolide and then exposed to environmental stress. Cell viability was assessed using the MTT colorimetric assay. A real-time PCR technique was employed to evaluate the expression level of HO-1 in the treated MSC-like cells. RESULTS Isolated MSC-like cells demonstrated fibroblast-like morphology. These cells in different culture mediums differentiated into osteocytes and adipocytes and were identified using alizarin red and oil red staining, respectively. As well, MSC-like cells were verified by the detection of CD105 surface antigen and the absence of CD14 and CD45 antigens. The results of the MTT assay showed that the pre-treatment of MSC-like cells with andrographolide concentration independently increased the viability and resistance of these cells to environmental stress caused by hydrogen peroxide and serum deprivation (SD). Real-time PCR findings indicated a significant increase in HO-1 gene expression in the andrographolide-receiving groups (p < 0.01). CONCLUSION Our results suggest that andrographolide creates a promising strategy for enhancing the quality of cell therapy by increasing the resistance of MSC-like cells to environmental stress and inducing the expression of HO-1.
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Affiliation(s)
- Reza Alipanah-Moghadam
- Department of Clinical Biochemistry, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Maryam Khodaei
- Department of Clinical Biochemistry, Ardabil University of Medical Sciences, Ardabil, Iran.
| | | | - Vadoud Malekzadeh
- Department of Anatomical Sciences, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - Mehdi Afrouz
- Department of Plant Production and Genetics, University of Mohaghegh Ardabili, Iran.
| | - Ali Nemati
- Department of Clinical Biochemistry, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Hoda Zahedian
- Department of Deutsch-Sprachen, Volkshochschule, Gütersloh, Germany
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26
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Estarreja J, Caldeira G, Silva I, Mendes P, Mateus V. The Pharmacological Effect of Hemin in Inflammatory-Related Diseases: Protocol for a Systematic Review. JMIR Res Protoc 2023; 12:e48368. [PMID: 37971806 PMCID: PMC10690530 DOI: 10.2196/48368] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/28/2023] [Accepted: 08/10/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Hemin is a commonly used drug in the treatment of acute attacks of porphyria, due to its capability of restoring normal levels of hemoproteins and respiratory pigments. In addition, this drug has demonstrated the capacity to induce the heme oxygenase (HO) enzyme. At the moment, there are 3 known HO isoenzymes in mammals: HO-1, HO-2, and HO-3. The first of these shows cytoprotective, antioxidant, and anti-inflammatory effects. Currently, medicines used in inflammatory disorders have increased toxicity, especially over longer time frames, which highlights the need to investigate new, safer options. Indeed, the current nonclinical evidence demonstrates the potential that hemin has a significant anti-inflammatory effect in several animal models of inflammation-related diseases, such as experimental colitis, without significant side effects. However, the underlying mechanism(s) are still not fully understood. In addition, past nonclinical studies have applied different therapeutic regimens, making it relatively difficult to understand which is optimal. According to the literature, there is a lack of review articles discussing this topic, highlighting the need for a summary and analysis of the available preclinical evidence to elucidate the abovementioned issues. Therefore, a qualitative synthesis of the current evidence is essential for the research and medical communities. OBJECTIVE This systematic review aims to summarize and analyze currently available nonclinical data to ascertain the potential anti-inflammatory effect of hemin in animal models. METHODS Throughout the development of this protocol, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The comprehensive search strategy will be carried out in MEDLINE (PubMed), Web of Science, and Scopus without any filters associated with publication date. Only in vivo, nonclinical studies that evaluated the potential anti-inflammatory effect of hemin will be included. The evaluated outcomes will be the observed clinical signs, inflammatory and other biochemical markers, and macroscopic and microscopic evaluations. To analyze the potential risk of bias, we will use the risk of bias tool developed by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE). RESULTS Currently, it is not possible to disclose any results since the project is still in initial steps. More specifically, we are currently engaged in the identification of eligible articles through the application of the inclusion and exclusion criteria. The work was initiated in April 2023, and it is expected to be finished at the end of 2023. CONCLUSIONS Concerning the major gap in the literature regarding the underlying mechanism(s) and treatment-related properties, this systematic review will be essential to clearly summarize and critically analyze the nonclinical data available, promoting a clearer vision of the potential anti-inflammatory effect of hemin. TRIAL REGISTRATION PROSPERO CRD42023406160; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=406160. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/48368.
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Affiliation(s)
- João Estarreja
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
| | - Gonçalo Caldeira
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
| | - Inês Silva
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
| | - Priscila Mendes
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
| | - Vanessa Mateus
- H&TRC-Health and Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
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27
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Sun WC, Lin CL, Lee TH, Chang CH, Ong AZ, Yeh YH, Yu CL, Chen GW, Hsieh YH, Wang SW. Critical role of heme oxygenase-1 in chaetoglobosin A by triggering reactive oxygen species mediated mitochondrial apoptosis in colorectal cancer. Free Radic Biol Med 2023; 208:833-845. [PMID: 37776916 DOI: 10.1016/j.freeradbiomed.2023.09.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/21/2023] [Accepted: 09/23/2023] [Indexed: 10/02/2023]
Abstract
The incidence rate of colorectal cancer (CRC) has been increasing and poses severe threats to human health worldwide and developing effective treatment strategies remains an urgent task. In this study, Chaetoglobosin A (ChA), an endophytic fungal metabolite from the medicinal herb-derived fungus Chaetomium globosum Km1126, was identified as a potent and selective antitumor agent in human CRC. ChA induced growth inhibition of CRC cells in a concentration-dependent manner but did not impair the viability of normal colon cells. ChA triggered mitochondrial intrinsic and caspase-dependent apoptotic cell death. In addition, apoptosis antibody array analysis revealed that expression of Heme oxygenase-1 (HO-1) was significantly increased by ChA. Inhibition of HO-1 increased the sensitivity of CRC cells to ChA, suggesting HO-1 may play a protective role in ChA-mediated cell death. ChA induced cell apoptosis via the induction of reactive oxygen species (ROS) and ROS scavenger (NAC) prevented ChA-induced cell death, mitochondrial dysfunction, and HO-1 activation. ChA promoted the activation of c-Jun N-terminal kinase (JNK), and co-administration of JNK inhibitor or siRNA markedly reversed ChA-mediated apoptosis. ChA significantly decreased the tumor growth without eliciting any organ toxicity or affecting the body weight of the CRC xenograft mice. This is the first study to demonstrate that ChA exhibits promising anti-cancer properties against human CRC both in vitro and in vivo. ChA is a potential therapeutic agent worthy of further development in clinical trials for cancer treatment.
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Affiliation(s)
- Wen-Chun Sun
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan; Division of Colon and Rectal Surgery, Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan
| | - Chia-Liang Lin
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan
| | - Tzong-Huei Lee
- Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan
| | - Chia-Hao Chang
- Institute of Fisheries Science, National Taiwan University, Taipei, Taiwan
| | - Ann-Zhi Ong
- Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan
| | - Yen-Hsiu Yeh
- Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chen-Lin Yu
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan
| | - Guang-Wei Chen
- Department of Chinese Medicine, MacKay Memorial Hospital, Taipei, Taiwan
| | - Yi-Hsien Hsieh
- Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, Taichung City, Taiwan.
| | - Shih-Wei Wang
- Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City, Taiwan; Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
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28
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Mancuso C. Biliverdin as a disease-modifying agent: An integrated viewpoint. Free Radic Biol Med 2023; 207:133-143. [PMID: 37459935 DOI: 10.1016/j.freeradbiomed.2023.07.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/27/2023] [Accepted: 07/14/2023] [Indexed: 07/24/2023]
Abstract
Biliverdin is one of the three by-products of heme oxygenase (HO) activity, the others being ferrous iron and carbon monoxide. Under physiological conditions, once formed in the cell, BV is reduced to bilirubin (BR) by the biliverdin reductase (BVR). However, if BVR is inhibited by either genetic variants, as occurs in the Inuit ethnicity, or dioxin intoxication, BV accumulates in cells giving rise to a clinical syndrome known as green jaundice. Preclinical studies have demonstrated that BV not only has a direct antioxidant effect by scavenging free radicals, but also targets many signal transduction pathways, such as BVR, soluble guanylyl cyclase, and the aryl hydrocarbon receptor. Through these direct and indirect mechanisms, BV has shown beneficial roles in ischemia/reperfusion-related diseases, inflammatory diseases, graft-versus-host disease, viral infections and cancer. Unfortunately, no clinical data are available to confirm these potential therapeutic effects and the kinetics of exogenous BV in humans is unknown. These limitations have so far excluded the possibility of transforming BV from a mere by-product of heme degradation into a disease-modifying agent. A closer collaboration between basic and clinical researchers would be advantageous to overcome these issues and promote translational research on BV in free radical-induced diseases.
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Affiliation(s)
- Cesare Mancuso
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica Del Sacro Cuore, Largo F. Vito, 1, 00168, Rome, Italy.
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29
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Ben-Eltriki M, Gayle EJ, Walker N, Deb S. Pharmacological Significance of Heme Oxygenase 1 in Prostate Cancer. Curr Issues Mol Biol 2023; 45:4301-4316. [PMID: 37232742 DOI: 10.3390/cimb45050273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/09/2023] [Accepted: 05/11/2023] [Indexed: 05/27/2023] Open
Abstract
Heme oxygenase 1 (HO-1) is a detoxifying antioxidant microsomal enzyme that regulates inflammation, apoptosis, cell proliferation, and angiogenesis in prostate cancer (PCa). This makes HO-1 a promising target for therapeutic prevention and treatment due to its anti-inflammatory properties and ability to control redox homeostasis. Clinical evidence highlights the possible correlation between HO-1 expression and PCa growth, aggressiveness, metastasized tumors, resistance to therapy, and poor clinical outcomes. Interestingly, studies have reported anticancer benefits mediated by both HO-1 induction and inhibition in PCa models. Contrasting evidence exists on the role of HO-1 in PCa progression and possible treatment targets. Herein, we provide an overview of available evidence on the clinical significance of HO-1 signaling in PCa. It appears that the beneficial effects of HO-1 induction or inhibition are dependent on whether it is a normal versus malignant cell as well as the intensity (major vs. minor) of the increase in HO-1 enzymatic activity. The current literature evidence indicates that HO-1 has dual effects in PCa. The amount of cellular iron and reactive oxygen species (ROS) can determine the role of HO-1 in PCa. A major increase in ROS enforces HO-1 to a protective role. HO-1 overexpression may provide cryoprotection to normal cells against oxidative stress via suppressing the expression of proinflammatory genes, and thus offer therapeutic prevention. In contrast, a moderate increase in ROS can lead to the perpetrator role of HO-1, which is associated with PCa progression and metastasis. HO-1 inhibition by xenobiotics in DNA-damaged cells tilts the balance to promote apoptosis and inhibit PCa proliferation and metastasis. Overall, the totality of the evidence revealed that HO-1 may play a dual role in the therapeutic prevention and treatment of PCa.
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Affiliation(s)
- Mohamed Ben-Eltriki
- Department of Pharmacology and Therapeutics, Clinical Pharmacology Lab, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0T6, Canada
- Cochrane Hypertension Review Group, Therapeutic Initiative, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Erysa J Gayle
- College of Biomedical Sciences, Larkin University, 18301 N. Miami Avenue, Miami, FL 33169, USA
| | - Noah Walker
- College of Biomedical Sciences, Larkin University, 18301 N. Miami Avenue, Miami, FL 33169, USA
| | - Subrata Deb
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA
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30
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Abdel-Hamid HA, Marey H, Ibrahim MFG. Hemin protects against cell stress induced by estrogen and progesterone in rat mammary glands via modulation of Nrf2/HO-1 and NF-κB pathways. Cell Stress Chaperones 2023; 28:289-301. [PMID: 36930344 PMCID: PMC10167073 DOI: 10.1007/s12192-023-01337-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/19/2023] [Accepted: 03/08/2023] [Indexed: 03/18/2023] Open
Abstract
Mammary gland hyperplasia is one of the risk factors for breast cancer. Till date, there is no study that has addressed the effect of hemin in this condition. Thus, this study was designed to evaluate the effect of the heme oxygenase 1 (HO-1) inducer (hemin) and its inhibitor (zinc protoporphyrin-IX) (ZnPP-IX) on mammary gland hyperplasia (MGH) induced by estrogen and progesterone in adult albino rats. Forty adult female albino rats were divided into the control group, MGH group, MGH + Hemin group, and MGH + Hemin + ZnPP-IX group. Serum levels of estradiol and progesterone were measured. Breast tissues were taken for estimation of oxidative, inflammatory, and apoptotic markers. Mammary gland histology was performed, and expression of Ki-67, Beclin, and P53 in breast tissue was also measured. Estrogen and progesterone administration induced hyperplasia of cells lining the ducts of the breast tissues associated with increased diameter and height of the nipples as well as increased oxidative stress markers, inflammatory markers, antiapoptotic markers, and cell autophagy. Hemin administration during induction of MGH can reverse all the affected parameters. Then, these effects were abolished by ZnPP-IX administration. We concluded that hemin administration can antagonize the cell stress induced by estrogen and progesterone and protect against the development of mammary gland hyperplasia via modulation of Nrf2/HO-1 and NF-κB pathways.
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Affiliation(s)
- Heba A. Abdel-Hamid
- Department of Medical Physiology, Faculty of Medicine, Minia University, Minia, 61111 Egypt
- Department of Medical Physiology, Faculty of Medicine, Al-Baha University, Al Baha, Saudi Arabia
| | - Heba Marey
- Department of Medical Biochemistry, Faculty of Medicine, Minia University, Minia, 61111 Egypt
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Cytotoxic and Antioxidant Activity of Hypericum perforatum L. Extracts against Human Melanoma Cells from Different Stages of Cancer Progression, Cultured under Normoxia and Hypoxia. Molecules 2023; 28:molecules28031509. [PMID: 36771178 PMCID: PMC9921514 DOI: 10.3390/molecules28031509] [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: 12/31/2022] [Revised: 01/26/2023] [Accepted: 01/28/2023] [Indexed: 02/09/2023] Open
Abstract
Oxidative stress and the hypoxic microenvironment play a key role in the progression of human melanoma, one of the most aggressive skin cancers. The aim of our study was to evaluate the effect of Hypericum perforatum extracts of different origins (both commercially available (HpEx2) and laboratory-prepared from wild grown (HpEx12) and in vitro cultured (HpEx13) plants) and hyperforin salt on WM115 primary and WM266-4 lymph node metastatic human melanoma cells cultured under normoxic and hypoxic conditions. The polyphenol content, radical scavenging activity, and hyperforin concentration were determined in the extracts, while cell viability, apoptosis, ROS production, and expression of NRF2 and HO-1, important oxidative stress-related factors, were analyzed after 24 h of cell stimulation with HpExs and hyperforin salt. We found that cytotoxic, pro-apoptotic and antioxidant effects depend on the extract composition, the stage of melanoma progression, and the oxygen level. Hyperforin salt showed lower activity than H. perforatum extracts. Our study for the first time showed that the anticancer activity of H. perforatum extracts differs in normoxia and hypoxia. Importantly, the composition of extracts of various origins, including in vitro cultured, resulting in their unique properties, may be important in the selection of plants for therapeutic application.
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Xu J, Zhu K, Wang Y, Chen J. The dual role and mutual dependence of heme/HO-1/Bach1 axis in the carcinogenic and anti-carcinogenic intersection. J Cancer Res Clin Oncol 2023; 149:483-501. [PMID: 36310300 DOI: 10.1007/s00432-022-04447-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
INTRODUCTION In physiological concentrations, heme is nontoxic to the cell and is essential for cell survival and proliferation. Increasing intracellular heme concentrations beyond normal levels, however, will lead to carcinogenesis and facilitate the survival of tumor cells. Simultaneously, heme in an abnormally high quantity is also a potent inducer of tumor cell death, contributing to its ability to generate oxidative stress on the cells by boosting oxidative phosphorylation and suppressing tumors through ferroptosis. During tumorigenesis and progression, therefore, heme works as a double-edged sword. Heme oxygenase 1 (HO-1) is the rate-limiting enzyme in heme catabolism, which converts heme into physiologically active catabolites of carbon monoxide (CO), biliverdin, and ferrous iron (Fe2+). HO-1 maintains redox equilibrium in healthy cells and functions as a carcinogenesis inhibitor. It is widely recognized that HO-1 is involved in the adaptive response to cellular stress and the anti-inflammation effect. Notably, its expression level in cancer cells corresponds with tumor growth, aggressiveness, metastasis, and angiogenesis. Besides, heme-binding transcription factor BTB and CNC homology 1 (Bach1) play a critical regulatory role in heme homeostasis, oxidative stress and senescence, cell cycle, angiogenesis, immune cell differentiation, and autoimmune disorders. Moreover, it was found that Bach1 influences cancer cells' metabolism and metastatic capacity. Bach1 controls heme level by adjusting HO-1 expression, establishing a negative feedback loop. MATERIALS AND METHODS Herein, the authors review recent studies on heme, HO-1, and Bach1 in cancer. Specifically, they cover the following areas: (1) the carcinogenic and anticarcinogenic aspects of heme; (2) the carcinogenic and anticarcinogenic aspects of HO-1; (3) the carcinogenic and anticarcinogenic aspects of Bach1; (4) the interactions of the heme/HO-1/Bach1 axis involved in tumor progression. CONCLUSION This review summarized the literature about the dual role of the heme/HO-1/Bach1 axis and their mutual dependence in the carcinogenesis and anti-carcinogenesis intersection.
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Affiliation(s)
- Jinjing Xu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China.,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China
| | | | - Yali Wang
- Jiangsu Huai'an Maternity and Children Hospital, Huai'an, 223001, China
| | - Jing Chen
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China. .,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, China. .,College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China.
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To Explore the Inhibitory Mechanism of Quercetin in Thyroid Papillary Carcinoma through Network Pharmacology and Experiments. DISEASE MARKERS 2022; 2022:9541080. [PMID: 36510497 PMCID: PMC9741536 DOI: 10.1155/2022/9541080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/29/2022] [Accepted: 10/12/2022] [Indexed: 12/07/2022]
Abstract
Quercetin, a flavonoid with anti-inflammatory and anticancer properties, is expected to be an innovative anticancer therapeutic agent for papillary thyroid carcinoma (PTC). However, the downstream signaling pathways that mediate quercetin-dependent anticancer properties remain to be deciphered. Herein, potential targets of quercetin were screened with several bioinformatic avenues including PharmMapper, Gene Expression Omnibus (GEO) database, protein-protein interaction (PPI) network, and molecular docking. Besides, western blot, CCK-8 transwell analysis of migration and invasion, flow cytometric analysis, and colony formation assays were performed to investigate the underlying mechanism. We found four core nodes (MMP9, JUN, SPP1, and HMOX1) by constructing a PPI network with 23 common targets. Through functional enrichment analysis, we confirmed that the above four target genes are enriched in the TNF, PI3K-AKT, and NF-κB signaling pathways, which are involved in the inflammatory microenvironment and inhibit the development and progression of tumors. Furthermore, molecular docking results demonstrated that quercetin shows strong binding efficiency with the proteins encoded by these 4 key proteins. Finally, quercetin displayed strong antitumor efficacy in PTC cell lines. In this research, we demonstrated the application of network pharmacology in evaluating the mechanisms of action and molecular targets of quercetin, which regulates a variety of proteins and signaling pathways in PTC. These data might explain the mechanism underlying the anticancer effects of quercetin in PTC.
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Shi MY, Liu L, Yang FY. Strategies to improve the effect of mesenchymal stem cell therapy on inflammatory bowel disease. World J Stem Cells 2022; 14:684-699. [PMID: 36188115 PMCID: PMC9516464 DOI: 10.4252/wjsc.v14.i9.684] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/07/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis and is an idiopathic, chronic inflammatory disease of the colonic mucosa. The occurrence of IBD, causes irreversible damage to the colon and increases the risk of carcinoma. The routine clinical treatment of IBD includes drug treatment, endoscopic treatment and surgery. The vast majority of patients are treated with drugs and biological agents, but the complete cure of IBD is difficult. Mesenchymal stem cells (MSCs) have become a new type of cell therapy for the treatment of IBD due to their immunomodulatory and nutritional functions, which have been confirmed in many clinical trials. This review discusses some potential mechanisms of MSCs in the treatment of IBD, summarizes the experimental results, and provides new insights to enhance the therapeutic effects of MSCs in future applications.
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Affiliation(s)
- Meng-Yue Shi
- School of Medicine, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Fu-Yuan Yang
- Health Science Center, Yangtze University, Jingzhou 434020, Hubei Province, China
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Hormesis and Oxidative Distress: Pathophysiology of Reactive Oxygen Species and the Open Question of Antioxidant Modulation and Supplementation. Antioxidants (Basel) 2022; 11:antiox11081613. [PMID: 36009331 PMCID: PMC9405171 DOI: 10.3390/antiox11081613] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/14/2022] [Accepted: 08/17/2022] [Indexed: 11/24/2022] Open
Abstract
Alterations of redox homeostasis leads to a condition of resilience known as hormesis that is due to the activation of redox-sensitive pathways stimulating cell proliferation, growth, differentiation, and angiogenesis. Instead, supraphysiological production of reactive oxygen species (ROS) exceeds antioxidant defence and leads to oxidative distress. This condition induces damage to biomolecules and is responsible or co-responsible for the onset of several chronic pathologies. Thus, a dietary antioxidant supplementation has been proposed in order to prevent aging, cardiovascular and degenerative diseases as well as carcinogenesis. However, this approach has failed to demonstrate efficacy, often leading to harmful side effects, in particular in patients affected by cancer. In this latter case, an approach based on endogenous antioxidant depletion, leading to ROS overproduction, has shown an interesting potential for enhancing susceptibility of patients to anticancer therapies. Therefore, a deep investigation of molecular pathways involved in redox balance is crucial in order to identify new molecular targets useful for the development of more effective therapeutic approaches. The review herein provides an overview of the pathophysiological role of ROS and focuses the attention on positive and negative aspects of antioxidant modulation with the intent to find new insights for a successful clinical application.
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Han L, Li L, Wu G. Induction of ferroptosis by carnosic acid-mediated inactivation of Nrf2/HO-1 potentiates cisplatin responsiveness in OSCC cells. Mol Cell Probes 2022; 64:101821. [PMID: 35490795 DOI: 10.1016/j.mcp.2022.101821] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 12/18/2022]
Abstract
Oral squamous cell carcinoma (OSCC) represents an increasing problem in the global public health due to the high incidence and worsening prognosis. Traditional chemotherapy extends the limited benefit for OSCC patients because of acquired drug resistance. Carnosic acid is an important polyphenol and has attracted more interesting based on the indispensable role in the progression of several cancers. Nevertheless, its roles in OSCC remain elusive. In this study, carnosic acid dose-dependently inhibited OSCC cell viability while preserving normal oral keratinocytes. Importantly, carnosic acid application sensitized cisplatin-resistant CAL27-DDP and SCC9-DDP cells to cisplatin by decreasing cell viability and increasing cell death. Noticeably, SCC9-DDP and CAL27-DDP cells exhibited lower ferroptosis relative to the parental cells evident by the higher intracellular GSH levels and lower ROS and lipid peroxidation in cisplatin-resistant cells. Treatment with carnosic acid induced ferroptosis in cisplatin-resistant OSCC cells; however, this suppression was reversed following the application of ferroptosis antagonist liproxstatin-1 (Lip-1), indicating the involvement of ferroptosis for carnosic acid-mediated cisplatin resistance. Furthermore, compared with parental cells, stronger activation of the Nrf2/HO-1/xCT signaling was observed in cisplatin-resistant cells, which was inhibited by carnosic acid. Of interest, reactivating the Nrf2 signaling reversed carnosic acid-evoked ferroptosis in cisplatin-resistant cells and ultimately attenuated carnosic acid-mediated cell sensitivity to cisplatin. Together, the current findings highlight that carnosic acid may re-sensitize cisplatin-resistant cells to cisplatin by inducing ferroptosis, which involves the inactivation of Nrf2/HO-1/xCT pathway. Hence, this research may support a promising therapeutic approach to overcome chemoresistance in OSCC.
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Affiliation(s)
- Lu Han
- Department of Stomatology, Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222000, Jiangsu, PR China
| | - Lei Li
- Department of Stomatology, Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222000, Jiangsu, PR China
| | - Geng Wu
- Department of Stomatology, Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, 222000, Jiangsu, PR China.
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Chang LC, Fan CW, Tseng WK, Chen JR, Hua CC. The tumor/normal tissue ratio of Keap1 protein is a predictor for lymphovascular invasion in colorectal cancer: A correlation study between the Nrf2 and KRas pathways. Biomarkers 2022; 27:701-707. [PMID: 35830714 DOI: 10.1080/1354750x.2022.2102211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
PURPOSE: Oxidative stress has impacts on the KRas and Nrf2/Keap1 pathways, which have multiple interactions with each other and play important roles in colorectal cancer (CRC). This study investigated the expressions of proteins in the KRas and Nrf2/Keap1 pathways and their associations with clinicopathological features in CRC.METHODS: The protein levels of Nrf2, Keap1, Bach1, p62, HO1, KRas, Erk, Raf1 and PI3K in both the tumor and normal tissues of 60 CRC subjects were determined by Western blot and their T/N (tumor/normal tissue) ratios were correlated with clinicopathological features.RESULTS: The T/N ratios of proteins in the KRas and Nrf2/Keap1 pathways had correlation patterns and proximity profiles in cluster dendrograms different in CRC with different status of lymphovascular invasion (LVI) or lymph node/distant metastases. The Keap1 protein T/N ratio was a significant predictor (odd ratio: 2.24; 95% confidence interval: 1.26 - 4.38) of LVI, which in turn predicted metastases (11.0; 3.49 - 39.8).CONCLUSION: The interactions between the KRas and Nrf2/Keap1 pathways may be affected differently by LVI and metastases, and the protein T/N ratio of Keap1 may be helpful for predicting LVI in CRC.
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Affiliation(s)
- Liang-Che Chang
- Department of Pathology, Chang Gung Memorial Hospital, Keelung and Chang Gung university, Keelung, Republic of China
| | - Chung-Wei Fan
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Keelung and Chang Gung university Keelung, Republic of China
| | - Wen-Ko Tseng
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Keelung and Chang Gung university Keelung, Republic of China
| | - Jim-Ray Chen
- Department of Pathology, Chang Gung Memorial Hospital, Keelung and Chang Gung university, Keelung, Republic of China
| | - Chung-Ching Hua
- Division of Pulmonary, Critical Care and Sleep Medicine, Chang Gung Memorial Hospital, Keelung and Chang Gung university Keelung, Republic of China
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HO-1 Limits the Efficacy of Vemurafenib/PLX4032 in BRAF V600E Mutated Melanoma Cells Adapted to Physiological Normoxia or Hypoxia. Antioxidants (Basel) 2022; 11:antiox11061171. [PMID: 35740068 PMCID: PMC9219655 DOI: 10.3390/antiox11061171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/08/2022] [Accepted: 06/10/2022] [Indexed: 02/04/2023] Open
Abstract
Induction of heme oxygenase 1 (HO-1) favors immune-escape in BRAFV600 melanoma cells treated with Vemurafenib/PLX4032 under standard cell culture conditions. However, the oxygen tension under standard culture conditions (~18 kPa O2) is significantly higher than the physiological oxygen levels encountered in vivo. In addition, cancer cells in vivo are often modified by hypoxia. In this study, MeOV-1 primary melanoma cells bearing the BRAFV600E mutation, were adapted to either 5 kPa O2 (physiological normoxia) or 1 kPa O2 (hypoxia) and then exposed to 10 μM PLX4032. PLX4032 abolished ERK phosphorylation, reduced Bach1 expression and increased HO-1 levels independent of pericellular O2 tension. Moreover, cell viability was significantly reduced further in cells exposed to PLX4032 plus Tin mesoporphyrin IX, a HO-1 inhibitor. Notably, our findings provide the first evidence that HO-1 inhibition in combination with PLX4032 under physiological oxygen tension and hypoxia restores and increases the expression of the NK ligands ULBP3 and B7H6 compared to cells exposed to PLX4032 alone. Interestingly, although silencing NRF2 prevented PLX4032 induction of HO-1, other NRF2 targeted genes were unaffected, highlighting a pivotal role of HO-1 in melanoma resistance and immune escape. The present findings may enhance translation and highlight the potential of the HO-1 inhibitors in the therapy of BRAFV600 melanomas.
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Paradox Role of Oxidative Stress in Cancer: State of the Art. Antioxidants (Basel) 2022; 11:antiox11051027. [PMID: 35624891 PMCID: PMC9138152 DOI: 10.3390/antiox11051027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 05/18/2022] [Indexed: 02/01/2023] Open
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Xi X, Li Z, Liu H, Chen S, Liu D. Nrf2 Activation Is Involved in Cyclic Mechanical Stress-Stimulated Osteogenic Differentiation in Periodontal Ligament Stem Cells via PI3K/Akt Signaling and HO1-SOD2 Interaction. Front Cell Dev Biol 2022; 9:816000. [PMID: 35071244 PMCID: PMC8770743 DOI: 10.3389/fcell.2021.816000] [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: 11/16/2021] [Accepted: 12/15/2021] [Indexed: 12/22/2022] Open
Abstract
Nuclear factor erythroid-2-related factor-2 (Nrf2), the major transcriptional regulator in antioxidant response and cellular defense, had the vital effect on regulating osteogenic differentiation. Our previous study revealed that Nrf2 activation was involved in cyclic mechanical stress-stimulated osteogenic differentiation in the human periodontal ligament stem cells (PDLSCs). However, the mechanisms of Nrf2 underlying this process remained unclear. The goal of the study was to explore the mechanisms of Nrf2 in PDLSCs during cyclic mechanical stress-stimulated osteogenic differentiation via the tandem mass tag (TMT)-based liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis. And we applied tert-Butylhydroquinone (t-BHQ), the Nrf2 activator, to the orthodontic rats and detected the expression levels of the osteogenesis markers by immunohistochemistry (IHC) staining. Our results showed that Nrf2 activation in PDLSCs was involved in cyclic mechanical stress-stimulated osteogenic differentiation via phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt) pathway. The protein-protein interaction between Akt and Nrf2 was detected. And the protein-protein interaction between heme oxygenase 1 (HO1) and superoxide dismutase 2 (SOD2), the downstream antioxidants of Nrf2, was associated with cyclic mechanical stress-stimulated osteogenic differentiation. T-BHQ enhanced the expression levels of the osteogenesis markers in orthodontic rats. Nrf2 might possess the potential to be a feasible molecular target in orthodontics.
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Affiliation(s)
- Xun Xi
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Zixuan Li
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Hong Liu
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Shuai Chen
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Dongxu Liu
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
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Zeng X, Yu J, Zeng T, Liu Y, Li B. 3'-daidzein sulfonate protects myocardial cells from hypoxic-ischemic injury via the NRF2/HO-1 signaling pathway. J Thorac Dis 2022; 13:6897-6910. [PMID: 35070374 PMCID: PMC8743394 DOI: 10.21037/jtd-21-1909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/17/2021] [Indexed: 12/11/2022]
Abstract
Background Myocardial infarction (MI) has a high mortality and disability rate and greatly affects human health. This study sought to explore the therapeutic effect and molecular mechanism of 3'-daidzein sulfonate (DSS) on MI. Methods A rat MI model was established and low and high doses of DSS were administered to the rats. An in vitro oxygen glucose deprivation model was used to verify the treatment role and mechanism of DSS. The establishment of the rat MI model was confirmed by electrocardiogram. The tissue changes were detected by HE, Masson’s trichrome, TUNEL and TTC staining. Cell viability was detected by CCK-8. The viable and dead cells were detected by Calcein-AM/PI. Apoptotic cells, ROS and JC-1 were detected by flow cytometry apoptosis. The level of proteins was detected by western blotting. MDA, SOD and GSH were detected by ELISA. Results The results of Hematoxylin and eosin, TUNEL, and Masson staining showed that the myocardial tissue of the MI group was repaired by DSS. The serum levels of cardiac troponin I (CTnI), lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and malondialdehyde (MDA) were decreased by DSS, while the serum levels of superoxide dismutase and glutathione were promoted by DSS. The treatment of DSS activated the Nuclear Factor Erythroid 2-Related Factor 2 (NRF-2)/Heme Oxygenase 1 (HO-1) pathway and inhibited the caspase-3 apoptosis pathway. The in vitro experiment showed that DSS greatly restored cell viability and reduced cell apoptosis. DSS also greatly inhibited mitochondrial membrane potential depolarization, reactive oxygen species production, and oxidative stress. The application of the NRF-2 inhibitor, C29H25N3O4S (ML385), greatly inhibited the treatment role of DSS and the NRF-2/HO-1 pathway, and activated the caspase-3 apoptosis pathway. Conclusions In conclusion, this study first identified the beneficial role of DSS in MI. DSS protected myocardial cells by activating the NRF-2/HO-1 pathway and inhibiting cell apoptosis. DSS could be used as a novel drug in the treatment of MI.
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Affiliation(s)
- Xueliang Zeng
- Department of pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Junjian Yu
- Cardiovascular and Thoracic Surgery Department 2, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Taohui Zeng
- Department of pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yuan Liu
- Department of pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Bei Li
- Department of pharmacy, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
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Magnolol Triggers Caspase-Mediated Apoptotic Cell Death in Human Oral Cancer Cells through JNK1/2 and p38 Pathways. Biomedicines 2021; 9:biomedicines9101295. [PMID: 34680412 PMCID: PMC8533260 DOI: 10.3390/biomedicines9101295] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/10/2021] [Accepted: 09/18/2021] [Indexed: 12/16/2022] Open
Abstract
Magnolol is a natural compound extracted from Chinese herbal medicine and can induce apoptosis in numerous types of cancer cells. However, the molecular mechanisms of magnolol in oral cancer are still unclear. In this study, we investigated the anti-cancer effects and underlying mechanisms of magnolol in human oral cancer cell lines. Our results exhibited that magnolol inhibited the cell proliferation via inducing the sub-G1 phase and cell apoptosis of HSC-3 and SCC-9 cells. The human apoptosis array and Western blot assay showed that magnolol increased the expression of cleaved caspase-3 proteins and heme oxygenase-1 (HO-1). Moreover, we proved that magnolol induces apoptosis in oral cancer cell lines via the c-Jun N-terminal kinase (JNK)1/2 and p38 pathways. Overall, the current study supports the role for magnolol as a therapeutic approach for oral cancer through JNK1/2- and p38-mediated caspase activation.
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Nobiletin Attenuates Pathological Cardiac Remodeling after Myocardial Infarction via Activating PPAR γ and PGC1 α. PPAR Res 2021; 2021:9947656. [PMID: 34422028 PMCID: PMC8373512 DOI: 10.1155/2021/9947656] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/02/2021] [Accepted: 07/24/2021] [Indexed: 12/15/2022] Open
Abstract
Materials and Methods C57BL/6 mice were treated with coronary artery ligation to generate an MI model, followed by treatment for 3 weeks with NOB (50 mg/kg/d) or vehicle (50 mg/kg/d), with or without the peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor T0070907 (1 mg/kg/d). Cardiac function (echocardiography, survival rate, Evans blue, and triphenyl tetrazolium chloride staining), fibrosis (Masson's trichrome staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot (WB)), hypertrophy (haematoxylin-eosin staining, wheat germ agglutinin staining, and qRT-PCR), and apoptosis (WB and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining) were evaluated. Hypoxia-induced apoptosis (TUNEL, WB) and phenylephrine- (PE-) induced pathological hypertrophy (immunofluorescence staining, qRT-PCR) models were established in primary neonatal rat ventricular myocytes (NRVMs). The effects of NOB with or without T0070907 were examined for the expression of PPARγ and PPARγ coactivator 1α (PGC1α) by WB in mice and NRVMs. The potential downstream effectors of PPARγ were further analyzed by WB in mice. Results Following MI in mice, NOB intervention enhanced cardiac function across three predominant dimensions of pathological cardiac remodeling, which reflected in decreasing cardiac fibrosis, apoptosis, and hypertrophy decompensation. NOB intervention also alleviated apoptosis and hypertrophy in NRVMs. NOB intervention upregulated PPARγ and PGC1α in vivo and in vitro. Furthermore, the PPARγ inhibitor abolished the protective effects of NOB against pathological cardiac remodeling during the progression from MI to CHF. The potential downstream effectors of PPARγ were nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1). Conclusions Our findings suggested that NOB alleviates pathological cardiac remodeling after MI via PPARγ and PGC1α upregulation.
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Wang T, Ashrafi A, Modareszadeh P, Deese AR, Chacon Castro MDC, Alemi PS, Zhang L. An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases. Cancers (Basel) 2021; 13:4142. [PMID: 34439295 PMCID: PMC8393563 DOI: 10.3390/cancers13164142] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/08/2021] [Accepted: 08/13/2021] [Indexed: 12/28/2022] Open
Abstract
Heme is an essential prosthetic group in proteins and enzymes involved in oxygen utilization and metabolism. Heme also plays versatile and fascinating roles in regulating fundamental biological processes, ranging from aerobic respiration to drug metabolism. Increasing experimental and epidemiological data have shown that altered heme homeostasis accelerates the development and progression of common diseases, including various cancers, diabetes, vascular diseases, and Alzheimer's disease. The effects of heme on the pathogenesis of these diseases may be mediated via its action on various cellular signaling and regulatory proteins, as well as its function in cellular bioenergetics, specifically, oxidative phosphorylation (OXPHOS). Elevated heme levels in cancer cells intensify OXPHOS, leading to higher ATP generation and fueling tumorigenic functions. In contrast, lowered heme levels in neurons may reduce OXPHOS, leading to defects in bioenergetics and causing neurological deficits. Further, heme has been shown to modulate the activities of diverse cellular proteins influencing disease pathogenesis. These include BTB and CNC homology 1 (BACH1), tumor suppressor P53 protein, progesterone receptor membrane component 1 protein (PGRMC1), cystathionine-β-synthase (CBS), soluble guanylate cyclase (sGC), and nitric oxide synthases (NOS). This review provides an in-depth analysis of heme function in influencing diverse molecular and cellular processes germane to disease pathogenesis and the modes by which heme modulates the activities of cellular proteins involved in the development of cancer and other common diseases.
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Affiliation(s)
| | | | | | | | | | | | - Li Zhang
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA; (T.W.); (A.A.); (P.M.); (A.R.D.); (M.D.C.C.C.); (P.S.A.)
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Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity. Molecules 2021; 26:molecules26133860. [PMID: 34202711 PMCID: PMC8270315 DOI: 10.3390/molecules26133860] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/17/2021] [Accepted: 06/22/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1–4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.
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