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Faleti OD, Alsaadawe M, Long J, Luo Q, Hu L, Zhang Y, Deng S, Wu G, Fang W, He M, Lyu X. Dimethyl fumarate abrogates hepatocellular carcinoma growth by inhibiting Nrf2/Bcl-xL axis and enhances sorafenib's efficacy. Sci Rep 2025; 15:16724. [PMID: 40369009 DOI: 10.1038/s41598-025-00832-7] [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: 01/15/2025] [Accepted: 04/30/2025] [Indexed: 05/16/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by poor prognosis and remains a leading cause of cancer mortality worldwide. Advanced HCC is managed with several first-line therapies, including tyrosine kinase inhibitors (TKI) and immunotherapy (mAb-PD-1 and mAb-VEGF). However, the efficacy of HCC therapeutics is often short-lived. Recent studies have demonstrated that the activation of the Nrf2-Bcl-xL pathway contributes to poor prognosis in a subset of HCC patients. Here, we found that dimethyl fumarate (DMF), a drug used for treating psoriasis and multiple sclerosis, regulates the Nrf2-Bcl-xL signaling axis to inhibit HCC growth in a mice xenograft model. Mechanistically, the downregulation of the Nrf2-Bcl-xL axis led to mitochondria stress and apoptosis in vitro and in vivo. Enforced Nrf2 or Bcl-xL expression in HCC cells markedly reversed the antitumor effects of DMF in HCC cells. Importantly, DMF enhanced sorafenib's antitumor effects. Collectively, our results demonstrate new mechanism insights into the antitumor effects of DMF and that Nrf2-targeted therapy might improve HCC treatment outcomes.
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Affiliation(s)
- Oluwasijibomi Damola Faleti
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510630, China
- Department of Biomedical Sciences, City University of Hong Kong, HKSAR, Kowloon, 999077, China
| | - Moyed Alsaadawe
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510630, China
- Cancer Center, TCM-Integrated Hospital, Southern Medical University, Guangzhou, 510630, China
| | - Jingyi Long
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510630, China
| | - Qingshuang Luo
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510630, China
| | - Longtai Hu
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510630, China
| | - Yuanbin Zhang
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510630, China
| | - Simin Deng
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China
| | - Gongfa Wu
- Department of Pathology, The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511300, Guangdong, China
| | - Weiyi Fang
- Cancer Center, TCM-Integrated Hospital, Southern Medical University, Guangzhou, 510630, China.
| | - Mingliang He
- Department of Biomedical Sciences, City University of Hong Kong, HKSAR, Kowloon, 999077, China.
- Biotechology Center, CityU Shenzhen Research Institute, Nanshan, Shenzhen, 518000, China.
| | - Xiaoming Lyu
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, China.
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510630, China.
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Dangi K, Kumar V, Mittal D, Yadav P, Malik M, Verma AK. Nanotherapeutics induced redox resetting of oxidative and nitrosative stress: targeting glutathione-depletion in cancer. Nanomedicine (Lond) 2025; 20:955-965. [PMID: 40192277 PMCID: PMC12051575 DOI: 10.1080/17435889.2025.2489918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 04/03/2025] [Indexed: 05/02/2025] Open
Abstract
Cancer cells display a distinctive defense mechanism against any exogenous moieties that renders all treatments inefficient. Glutathione, a thiol tripeptide plays a paradoxical role in cancer as intracellular glutathione (GSH) are voracious scavengers of free radicals produced by chemotherapy, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Cancer cells show Warburg effect, wherein the intracellular GSH levels are exceptionally enhanced to overcome the oxidative stress created by ROS/RNS production or by the other free radicals generated as side products of intracellular redox reactions. Therefore, redox resetting is essential to maintain the redox homeostasis for cell survival and their proliferation and trigger escalation of GSH levels. Nanotherapeutics have facilitated the targeted delivery of GSH-depleting agents in combination with radiotherapy, chemotherapy, and novel therapeutic interventions including chemodynamic therapy (CDT), photodynamic therapy (PDT), ferroptosis induction, sonodynamic therapy (SDT), and immunotherapy are being explored. This review aims to compile the strategic role of GSH in cancer cells, the importance of nanotherapeutics for GSH depletion in cancer to target numerous forms of programmed cell death (PCD), including apoptosis, ferroptosis, necroptosis, and autophagy.
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Affiliation(s)
- Kapil Dangi
- Nano-Biotech Lab, Kirori Mal College, University of Delhi, Delhi, India
- Department of Zoology, Deshbandhu College, University of Delhi, Delhi, India
| | - Vijay Kumar
- Nano-Biotech Lab, Kirori Mal College, University of Delhi, Delhi, India
- Department of Anatomy, School of Medicine, University of Galway, Galway, Ireland
| | - Disha Mittal
- Nano-Biotech Lab, Kirori Mal College, University of Delhi, Delhi, India
- Department of Life Sciences, School of Biosciences and Technology, Galgotias University, Greater Noida, India
| | - Pooja Yadav
- Nano-Biotech Lab, Kirori Mal College, University of Delhi, Delhi, India
| | - Mansi Malik
- Nano-Biotech Lab, Kirori Mal College, University of Delhi, Delhi, India
| | - Anita Kamra Verma
- Nano-Biotech Lab, Kirori Mal College, University of Delhi, Delhi, India
- Delhi School of Public Health, Institution of Eminence, University of Delhi, Delhi, India
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Myo Myo Tint K, Wei X, Wang P, Liu GL, Zhang M, Chi ZM, Chi Z. Biotechnological application of Aureobasidium spp. as a promising chassis for biosynthesis of ornithine-urea cycle-derived bioproducts. Crit Rev Biotechnol 2025; 45:591-605. [PMID: 39161061 DOI: 10.1080/07388551.2024.2382954] [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: 08/17/2023] [Revised: 02/12/2024] [Accepted: 07/03/2024] [Indexed: 08/21/2024]
Abstract
The ornithine-urea cycle (OUC) in fungal cells has biotechnological importance and many physiological functions and is closely related to the acetyl glutamate cycle (AGC). Fumarate can be released from argininosuccinate under the catalysis of argininosuccinate lyase in OUC which is regulated by the Ca2+ signaling pathway and over 93.9 ± 0.8 g/L fumarate can be yielded by the engineered strain of Aureobasidium pullulans var. aubasidani in the presence of CaCO3. Furthermore, 2.1 ± 0.02 mg of L-ornithine (L-Orn)/mg of the protein also can be synthesized via OUC by the engineered strains of Aureobasidum melanogenum. Fumarate can be transformed into many drugs and amino acids and L-Orn can be converted into siderophores (1.7 g/L), putrescine (33.4 g/L) and L-piperazic acid (L-Piz) (3.0 g/L), by different recombinant strains of A. melanogenum. All the fumarate, L-Orn, siderophore, putrescine and L-Piz have many applications. As the yeast-like fungi and the promising chassis, Aureobasidium spp, have many advantages over any other fungal strains. Further genetic manipulation and bioengineering will enhance the biosynthesis of fumarate and L-Orn and their derivates.
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Affiliation(s)
- Khin Myo Myo Tint
- College of Marine Life Sciences, Ocean University of China, Qingdao, China
| | - Xin Wei
- College of Marine Life Sciences, Ocean University of China, Qingdao, China
| | - Peng Wang
- College of Marine Life Sciences, Ocean University of China, Qingdao, China
| | - Guang-Lei Liu
- College of Marine Life Sciences, Ocean University of China, Qingdao, China
| | - Mei Zhang
- College of Marine Life Sciences, Ocean University of China, Qingdao, China
| | - Zhen-Ming Chi
- College of Marine Life Sciences, Ocean University of China, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, Shandong, China
| | - Zhe Chi
- College of Marine Life Sciences, Ocean University of China, Qingdao, China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, Shandong, China
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Jia F, Yang J, Wang Y, Liu J, Zhou X. Proteomics and Metabolomics Study on the Responses of Sertoli Cells Infected With Brucella and Its bvfA-Deletion Strains. Proteomics Clin Appl 2025; 19:e202300231. [PMID: 39512196 DOI: 10.1002/prca.202300231] [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: 12/11/2023] [Revised: 09/16/2024] [Accepted: 10/10/2024] [Indexed: 11/15/2024]
Abstract
OBJECTIVE To investigate the potential effects of BvfA in reproductive system damage caused by Brucella. METHODS Brucella intracellular multiplication ability was determined by a gentamicin protection assay; the LDH method was used to determine the lethal effect of Brucella on TM4 cells. Afterward, Label-free proteomics and LC-MS/MS metabolomics assays were combined to reveal differential abundant proteins and metabolites of TM4 cells infected with bvfA-deletion strains and parental strains. Finally, PRM mass spectrometry and western blot analysis were carried out to confirm differential expression of proteins. RESULTS This report demonstrated that bvfA-deletion strains failed to invade TM4 cells and reconstitution of invasion when a strain with gene bvfA was reintroduced to the deletion strain in 3 h. The bvfA-deletion exhibited weakened intracellular multiplication compared with parental strains in TM4 cells in 12 h; however, the death rate of TM4 cells infected with bvfA-deletion strains was higher than that of TM4 cells infected with parental strains. Combined proteomics and metabolomics analyses revealed that the differential abundant proteins and metabolites in TM4 cells infected with bvfA-deletion and parental strains mainly involved the mineral absorption-related pathway, NADH:ubiquinone oxidoreductase subunit-related mitochondrial respiratory signaling pathway, and sphingolipid signaling pathway of TM4 cells. These three signaling pathways were involved in expression changes of TRPM6/7, STEAP1, Gnaq, Trp53, Pbk, Tns2, Akt2, and the NADH:ubiquinone oxidoreductase subunit, as well as content changes of l-Valine, l-Isoleucine, l-Methionine, PC, PE DG, and SM metabolites. SIGNIFICANCE These results indicated that BvfA of Brucella abortus S19 affected the above proteins and metabolites in TM4 cells.
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Affiliation(s)
- Fang Jia
- Key Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Ningxia University, Yinchuan, Ningxia, China
- Inner Mongolia Key Laboratory of Molecular Biology, School of Basic Medical Sciences, Inner Mongolia Medical University, Hohhot, China
| | - Jiangliu Yang
- Key Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Ningxia University, Yinchuan, Ningxia, China
| | - Yujiong Wang
- Key Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Ningxia University, Yinchuan, Ningxia, China
| | - Jun Liu
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin, China
| | - Xuezhang Zhou
- Key Laboratory of the Ministry of Education for the Conservation and Utilization of Special Biological Resources of Western China, Ningxia University, Yinchuan, Ningxia, China
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Li L, Xu T, Qi X. Balanced regulation of ROS production and inflammasome activation in preventing early development of colorectal cancer. Immunol Rev 2025; 329:e13417. [PMID: 39523732 DOI: 10.1111/imr.13417] [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] [Indexed: 11/16/2024]
Abstract
Reactive oxygen species (ROS) production and inflammasome activation are the key components of the innate immune response to microbial infection and sterile insults. ROS are at the intersection of inflammation and immunity during cancer development. Balanced regulation of ROS production and inflammasome activation serves as the central hub of innate immunity, determining whether a cell will survive or undergo cell death. However, the mechanisms underlying this balanced regulation remain unclear. Mitochondria and NADPH oxidases are the two major sources of ROS production. Recently, NCF4, a component of the NADPH oxidase complex that primarily contributes to ROS generation in phagocytes, was reported to balance ROS production and inflammasome activation in macrophages. The phosphorylation and puncta distribution of NCF4 shifts from the membrane-bound NADPH complex to the perinuclear region, promoting ASC speck formation and inflammasome activation, which triggers downstream IL-18-IFN-γ signaling to prevent the progression of colorectal cancer (CRC). Here, we review ROS signaling and inflammasome activation studies in colitis-associated CRC and propose that NCF4 acts as a ROS sensor that balances ROS production and inflammasome activation. In addition, NCF4 is a susceptibility gene for Crohn's disease (CD) and CRC. We discuss the evidence demonstrating NCF4's crucial role in facilitating cell-cell contact between immune cells and intestinal cells, and mediating the paracrine effects of inflammatory cytokines and ROS. This coordination of the signaling network helps create a robust immune microenvironment that effectively prevents epithelial cell mutagenesis and tumorigenesis during the early stage of colitis-associated CRC.
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Affiliation(s)
- Longjun Li
- Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Tao Xu
- Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaopeng Qi
- Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- State Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, Shandong, China
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Yao Y, Shan T, Li X. HucMSCs can alleviate abnormal vasculogenesis induced by high glucose through the MAPK signaling pathway. iScience 2024; 27:111354. [PMID: 39640585 PMCID: PMC11618028 DOI: 10.1016/j.isci.2024.111354] [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: 06/17/2024] [Revised: 08/27/2024] [Accepted: 11/06/2024] [Indexed: 12/07/2024] Open
Abstract
Vascular complications caused by diabetes mellitus contribute a major threat to increased disability and mortality of diabetic patients, which are characterized by damaged endothelial cells and angiogenesis. Human umbilical cord-derived mesenchymal stem cells (hucMSCs) have been demonstrated to alleviate endothelial cell damage and improve angiogenesis. However, these investigations overlooked the pivotal role of vasculogenesis. In this study, we utilized blood vessel organoids (BVOs) to investigate the impact of high glucose on vasculogenesis and subsequent angiogenesis. We found that BVOs in the vascular lineage induction stage were more sensitive to high glucose and more susceptible to affect endothelial cell differentiation and function. Moreover, hucMSCs can alleviate the high glucose-induced inhibition of endothelial cell differentiation and dysfunction through MAPK signaling pathway downregulation, with the MAPK activator dimethyl fumarate further illustrating the results. Thereby, we demonstrated that high glucose can lead to abnormal vasculogenesis and impact subsequent angiogenesis, and hucMSCs can alleviate this effect.
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Affiliation(s)
- Yang Yao
- Department of Anesthesiology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266011, China
- Research Center of Translational Medicine, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China
| | - Tiantian Shan
- Research Center of Translational Medicine, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xiaoying Li
- Research Center of Translational Medicine, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China
- Department of Emergency, Jinan Central Hospital, Jinan 250013, China
- Department of Emergency, Central Hospital Affiliated Shandong First Medical University, Jinan 250013, China
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Hu L, Liu Y, Yuan Z, Guo H, Duan R, Ke P, Meng Y, Tian X, Xiao F. Glucose-6-phosphate dehydrogenase alleviates epileptic seizures by repressing reactive oxygen species production to promote signal transducer and activator of transcription 1-mediated N-methyl-d-aspartic acid receptors inhibition. Redox Biol 2024; 74:103236. [PMID: 38875958 PMCID: PMC11225908 DOI: 10.1016/j.redox.2024.103236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/07/2024] [Accepted: 06/07/2024] [Indexed: 06/16/2024] Open
Abstract
The pathogenesis of epilepsy remains unclear; however, a prevailing hypothesis suggests that the primary underlying cause is an imbalance between neuronal excitability and inhibition. Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway, which is primarily involved in deoxynucleic acid synthesis and antioxidant defense mechanisms and exhibits increased expression during the chronic phase of epilepsy, predominantly colocalizing with neurons. G6PD overexpression significantly reduces the frequency and duration of spontaneous recurrent seizures. Furthermore, G6PD overexpression enhances signal transducer and activator of transcription 1 (STAT1) expression, thus influencing N-methyl-d-aspartic acid receptors expression, and subsequently affecting seizure activity. Importantly, the regulation of STAT1 by G6PD appears to be mediated primarily through reactive oxygen species signaling pathways. Collectively, our findings highlight the pivotal role of G6PD in modulating epileptogenesis, and suggest its potential as a therapeutic target for epilepsy.
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Affiliation(s)
- Liqin Hu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China
| | - Yan Liu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China
| | - Ziwei Yuan
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China
| | - Haokun Guo
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China
| | - Ran Duan
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China
| | - Pingyang Ke
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China
| | - Yuan Meng
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China
| | - Xin Tian
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
| | - Fei Xiao
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China; Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
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Shokeen K, Baroi MK, Chahar M, Das D, Saini H, Kumar S. Arginyltransferase 1 (ATE1)-mediated proteasomal degradation of viral haemagglutinin protein: a unique host defence mechanism. J Gen Virol 2024; 105. [PMID: 39207120 DOI: 10.1099/jgv.0.002020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Abstract
The extensive protein production in virus-infected cells can disrupt protein homeostasis and activate various proteolytic pathways. These pathways utilize post-translational modifications (PTMs) to drive the ubiquitin-mediated proteasomal degradation of surplus proteins. Protein arginylation is the least explored PTM facilitated by arginyltransferase 1 (ATE1) enzyme. Several studies have provided evidence supporting its importance in multiple physiological processes, including ageing, stress, nerve regeneration, actin formation and embryo development. However, its function in viral pathogenesis is still unexplored. The present work utilizes Newcastle disease virus (NDV) as a model to establish the role of the ATE1 enzyme and its activity in pathogenesis. Our data indicate a rise in levels of N-arginylated cellular proteins in the infected cells. Here, we also explore the haemagglutinin-neuraminidase (HN) protein of NDV as a presumable target for arginylation. The data indicate that the administration of Arg amplifies the arginylation process, resulting in reduced stability of the HN protein. ATE1 enzyme activity inhibition and gene expression knockdown studies were also conducted to analyse modulation in HN protein levels, which further substantiated the findings. Moreover, we also observed Arg addition and probable ubiquitin modification to the HN protein, indicating engagement of the proteasomal degradation machinery. Lastly, we concluded that the enhanced levels of the ATE1 enzyme could transfer the Arg residue to the N-terminus of the HN protein, ultimately driving its proteasomal degradation.
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Affiliation(s)
- Kamal Shokeen
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
| | - Malay Kumar Baroi
- Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, India
| | - Manjeet Chahar
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak, India
| | - Debapratim Das
- Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, India
| | - Harimohan Saini
- Centre for Medical Biotechnology, Maharshi Dayanand University, Rohtak, India
| | - Sachin Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
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Yan L, Shi J, Zhu J. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions. Discov Oncol 2024; 15:294. [PMID: 39031216 PMCID: PMC11265098 DOI: 10.1007/s12672-024-01163-1] [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: 05/27/2024] [Accepted: 07/15/2024] [Indexed: 07/22/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.
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Affiliation(s)
- Lei Yan
- Medical Department, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jia Shi
- Department of Obstetrics and Gynecology, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jiazuo Zhu
- Department of Oncology, Xuancheng City Central Hospital, No. 117 Tong Road, Xuancheng, Anhui, China.
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Ye S, Hu X, Sun S, Su B, Cai J, Jiang J. Oridonin promotes RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress signaling pathway JNK/Nrf2/HO-1. Eur J Pharmacol 2024; 974:176620. [PMID: 38685305 DOI: 10.1016/j.ejphar.2024.176620] [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: 11/22/2023] [Revised: 04/20/2024] [Accepted: 04/25/2024] [Indexed: 05/02/2024]
Abstract
The incidence and mortality of breast cancer, the most common malignant tumor among women in the world, are increasing year by year, which greatly threatens women's health. Ferroptosis is an iron and lipid reactive oxygen species (ROS)-dependent process, a novel form of cell death that is distinct from apoptosis and is closely related to the progression of breast cancer. Inducing the occurrence of ferroptosis in tumor cells can effectively block its malignant progress in vivo. Oridonin (ORI), the primary active ingredient extracted from the Chinese herbal medicine Rabdosia rubescens, has been shown to cause glutathione depletion and directly inhibit glutathione peroxidase 4 induced cell death by ferroptosis, but its mechanism of action in breast cancer remains inadequately elucidated. Therefore, we further investigated whether ORI could promote RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress pathway JNK/Nrf2/HO-1. In our study, we assessed cell survival of RSL3 and ORI treatment by MTT assay, and found that co-treatment with RSL3 and ORI inhibited cell proliferation, as evidenced by the cloning assay. To investigate the ability of ORI to promote RSL3-induced ferroptosis in breast cancer cells, we measured levels of ROS, malondialdehyde, glutathione, superoxide dismutase, and Fe2+ content. Lipid peroxidation, ROS, and mitochondrial membrane potential levels induced by co-treatment of ORI with RSL3 were reversed by ferrostatin-1, further confirming that the cell death induced by RSL3 and ORI was ferroptosis rather than other programmed cell death modes. Moreover, RSL3 and ORI co-treatment regulated the JNK/Nrf2/HO-1 axis, as demonstrated by western blotting and target activator validation. Our results showed that ORI could enhance the inhibitory effect of RSL3 on breast cancer cells viability via the induction of ferroptosis. Mechanistically, it potentiated RSL3-induced ferroptosis in breast cancer cells by activating the JNK/Nrf2/HO-1 axis. This study provides a theoretical basis for the application of ORI based on the mechanism of ferroptosis, and provides potential natural drug candidates for cancer prevention and treatment.
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Affiliation(s)
- Shiying Ye
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
| | - Xiangyan Hu
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Shaowei Sun
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Bo Su
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jiye Cai
- Department of Chemistry, Jinan University, Guangzhou 510632, China
| | - Jinhuan Jiang
- Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
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11
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Collongues N, Durand-Dubief F, Lebrun-Frenay C, Audoin B, Ayrignac X, Bensa C, Bigaut K, Bourre B, Carra-Dallière C, Ciron J, Defer G, Kwiatkowski A, Leray E, Maillart E, Marignier R, Mathey G, Morel N, Thouvenot E, Zéphir H, Boucher J, Boutière C, Branger P, Da Silva A, Demortière S, Guillaume M, Hebant B, Januel E, Kerbrat A, Manchon E, Moisset X, Montcuquet A, Pierret C, Pique J, Poupart J, Prunis C, Roux T, Schmitt P, Androdias G, Cohen M. Cancer and multiple sclerosis: 2023 recommendations from the French Multiple Sclerosis Society. Mult Scler 2024; 30:899-924. [PMID: 38357870 DOI: 10.1177/13524585231223880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
BACKGROUND Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk. OBJECTIVE To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS). METHODS The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal. RESULTS Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations. CONCLUSION These recommendations propose a strategic approach to managing cancer risk in PwMS.
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Affiliation(s)
- Nicolas Collongues
- Department of Neurology, University Hospital of Strasbourg, Strasbourg, France
- Center for Clinical Investigation, INSERM U1434, Strasbourg, France
- Biopathology of Myelin, Neuroprotection and Therapeutic Strategy, INSERM U1119, Strasbourg, France
- Department of Pharmacology, Addictology, Toxicology, and Therapeutics, Strasbourg University, Strasbourg, France
| | - Françoise Durand-Dubief
- Service de Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer, Bron, France
| | - Christine Lebrun-Frenay
- Department of Neurology, CHU Nice, Nice, France
- Université Côte d'Azur, UMR2CA-URRIS, Nice, France
| | - Bertrand Audoin
- Department of Neurology, CRMBM, APHM, Aix-Marseille University, Marseille, France
| | - Xavier Ayrignac
- Department of Neurology, Montpellier University Hospital, Montpellier, France
- University of Montpellier, Montpellier, France
- INM, INSERM, Montpellier, France
| | - Caroline Bensa
- Department of Neurology, Hôpital Fondation Adolphe de Rothschild, Paris, France
| | - Kévin Bigaut
- Department of Neurology, University Hospital of Strasbourg, Strasbourg, France
- Biopathology of Myelin, Neuroprotection and Therapeutic Strategy, INSERM U1119, Strasbourg, France
| | | | | | - Jonathan Ciron
- CHU de Toulouse, CRC-SEP, Department of Neurology, Toulouse, France
- Université Toulouse III, Infinity, INSERM UMR1291-CNRS UMR5051, Toulouse, France
| | - Gilles Defer
- Department of Neurology, Caen University Hospital, Caen, France
| | - Arnaud Kwiatkowski
- Department of Neurology, Lille Catholic University, Lille Catholic Hospitals, Lille, France
| | - Emmanuelle Leray
- Université de Rennes, EHESP, CNRS, INSERM, ARENES-UMR 6051, RSMS-U1309, Rennes, France
| | | | - Romain Marignier
- Service de Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer, Bron, France
| | - Guillaume Mathey
- Department of Neurology, Nancy University Hospital, Nancy, France
| | - Nathalie Morel
- Service de Neurologie, Centre Hospitalier Annecy Genevois, Epagny-Metz-Tessy, France
| | - Eric Thouvenot
- Service de Neurologie, CHU de Nîmes, Nîmes, France
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Hélène Zéphir
- University of Lille, INSERM U1172, CHU de Lille, Lille, France
| | - Julie Boucher
- Department of Neurology, CHU de Lille, Lille, France
| | - Clémence Boutière
- Department of Neurology, University Hospital of Marseille, Marseille, France
| | - Pierre Branger
- Service de Neurologie, CHU de Caen Normandie, Caen, France
| | - Angélique Da Silva
- Breast Cancer Unit, Centre François Baclesse, Institut Normand du Sein, Caen, France
| | - Sarah Demortière
- Department of Neurology, CRMBM, APHM, Aix-Marseille University, Marseille, France
| | | | | | - Edouard Januel
- Sorbonne Université, Paris, France/Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Paris, France
- Département de Neurologie, Hôpital Pitié Salpêtrière, AP-HP, Paris, France
| | - Anne Kerbrat
- Service de Neurologie, CHU de Rennes, France
- EMPENN U1228, INSERM-INRIA, Rennes, France
| | - Eric Manchon
- Service de Neurologie, Centre Hospitalier de Gonesse, Gonesse, France
| | - Xavier Moisset
- Université Clermont Auvergne, CHU Clermont-Ferrand, INSERM, Neuro-Dol, Clermont-Ferrand, France
| | | | - Chloé Pierret
- Université de Rennes, EHESP, CNRS, INSERM, ARENES-UMR 6051, RSMS U-1309, Rennes, France
| | - Julie Pique
- Service de Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer, Bron, France
| | - Julien Poupart
- Department of Neurology and U995-LIRIC-Lille Inflammation Research International Center, INSERM, University of Lille, CHU Lille, Lille, France
| | - Chloé Prunis
- Department of Neurology, Nancy University Hospital, Nancy, France
| | - Thomas Roux
- Hôpital La Pitié-Salpêtrière, Service de Neurologie, Paris, France
- CRC-SEP Paris. Centre des maladies inflammatoires rares du cerveau et de la moelle de l'enfant et de l'adulte (Mircem)
| | | | - Géraldine Androdias
- Service de Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Service de Neurologie, Hôpital Neurologique Pierre Wertheimer, Bron, France
- Clinique de la Sauvegarde-Ramsay Santé, Lyon, France
| | - Mikael Cohen
- Department of Neurology, CHU Nice, Nice, France/Université Côte d'Azur, UMR2CA-URRIS, Nice, France
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12
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Cen Y, Li F, Li Y, Zhang K, Riaz F, Zhao K, Wei P, Pan F. Dimethyl fumarate alleviates allergic asthma by strengthening the Nrf2 signaling pathway in regulatory T cells. Front Immunol 2024; 15:1375340. [PMID: 38711519 PMCID: PMC11070462 DOI: 10.3389/fimmu.2024.1375340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/08/2024] [Indexed: 05/08/2024] Open
Abstract
Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.
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Affiliation(s)
- Yanhong Cen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Otolaryngology, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Fangfang Li
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yikui Li
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Kaimin Zhang
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Farooq Riaz
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Kuaile Zhao
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Ping Wei
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Otolaryngology, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Fan Pan
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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13
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Yang S, Hu C, Chen X, Tang Y, Li J, Yang H, Yang Y, Ying B, Xiao X, Li SZ, Gu L, Zhu Y. Crosstalk between metabolism and cell death in tumorigenesis. Mol Cancer 2024; 23:71. [PMID: 38575922 PMCID: PMC10993426 DOI: 10.1186/s12943-024-01977-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 03/02/2024] [Indexed: 04/06/2024] Open
Abstract
It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer cells constantly encounter the limits of insufficient oxygen and nutrient supplies. To satisfy their growth needs and resist adverse environmental events, tumor cells modify the metabolic pathways to produce both extra energies and substances required for rapid growth. Realizing the metabolic characters special for tumor cells will be helpful for eliminating them during therapy. Cell death is a hot topic of long-term study and targeting cell death is one of the most effective ways to repress tumor growth. Many studies have successfully demonstrated that metabolism is inextricably linked to cell death of cancer cells. Here we summarize the recently identified metabolic characters that specifically impact on different types of cell deaths and discuss their roles in tumorigenesis.
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Affiliation(s)
- Shichao Yang
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China
| | - Caden Hu
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China
| | - Xiaomei Chen
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China
| | - Yi Tang
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, P. R. China
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, P. R. China
| | - Juanjuan Li
- Department of breast and thyroid surgery, Renmin hospital of Wuhan University, Wuhan, 430060, P. R. China
| | - Hanqing Yang
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China
| | - Yi Yang
- Institute of Pathology and Southwest Cancer Center, The First Affiliated Hospital, Key Laboratory of Tumor Immunopathology, Third Military Medical University (Army Medical University, Ministry of Education of China, Chongqing, 400038, P. R. China
| | - Binwu Ying
- Department of Laboratory Medicine/Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, P. R. China.
| | - Xue Xiao
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, P. R. China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, P. R. China.
| | - Shang-Ze Li
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China.
| | - Li Gu
- Department of Laboratory Medicine/Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, P. R. China.
| | - Yahui Zhu
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China.
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14
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Shokeen K, Kumar S. Newcastle disease virus regulates its replication by instigating oxidative stress-driven Sirtuin 7 production. J Gen Virol 2024; 105. [PMID: 38376490 DOI: 10.1099/jgv.0.001961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2024] Open
Abstract
Reactive oxygen species (ROS) accumulation inside the cells instigates oxidative stress, activating stress-responsive genes. The viral strategies for promoting stressful conditions and utilizing the induced host proteins to enhance their replication remain elusive. The present work investigates the impact of oxidative stress responses on Newcastle disease virus (NDV) pathogenesis. Here, we show that the progression of NDV infection varies with intracellular ROS levels. Additionally, the results demonstrate that NDV infection modulates the expression of oxidative stress-responsive genes, majorly sirtuin 7 (SIRT7), a NAD+-dependent deacetylase. The modulation of SIRT7 protein, both through overexpression and knockdown, significantly impacts the replication dynamics of NDV in DF-1 cells. The activation of SIRT7 is found to be associated with the positive regulation of cellular protein deacetylation. Lastly, the results suggested that NDV-driven SIRT7 alters NAD+ metabolism in vitro and in ovo. We concluded that the elevated expression of NDV-mediated SIRT7 protein with enhanced activity metabolizes the NAD+ to deacetylase the host proteins, thus contributing to high virus replication.
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Affiliation(s)
- Kamal Shokeen
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
| | - Sachin Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
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15
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Alwithenani A, Taha Z, Thomson M, Chen A, Wong B, Arulanandam R, Diallo JS. Unlocking the potential of dimethyl fumarate: enhancing oncolytic HSV-1 efficacy for wider cancer applications. Front Immunol 2023; 14:1332929. [PMID: 38169670 PMCID: PMC10758402 DOI: 10.3389/fimmu.2023.1332929] [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: 11/03/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024] Open
Abstract
Immunotherapy and specifically oncolytic virotherapy has emerged as a promising option for cancer patients, with oncolytic herpes simplex virus-1 (oHSV-1) expressing granulocyte macrophage colony stimulating factor being the first OV to be approved by the FDA for treatment of melanoma. However, not all cancers are sensitive and responsive to oncolytic viruses (OVs). Our group has demonstrated that fumaric and maleic acid esters (FMAEs) are very effective in sensitizing cancer cells to OV infection. Of note, these FMAEs include dimethyl fumarate (DMF, also known as Tecfidera®), an approved treatment for multiple sclerosis and psoriasis. This study aimed to assess the efficacy of DMF in combination with oncolytic HSV-1 in preclinical cancer models. We demonstrate herewith that pre-treatment with DMF or other FMAEs leads to a significant increase in viral growth of oHSV-1 in several cancer cell lines, including melanoma, while decreasing cell viability. Additionally, DMF was able to enhance ex vivo oHSV-1 infection of mouse-derived tumor cores as well as human patient tumor samples but not normal tissue. We further reveal that the increased viral spread and oncolysis of the combination therapy occurs via inhibition of type I IFN production and response. Finally, we demonstrate that DMF in combination with oHSV-1 can improve therapeutic outcomes in aggressive syngeneic murine cancer models. In sum, this study demonstrates the synergistic potential of two approved therapies for clinical evaluation in cancer patients.
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Affiliation(s)
- Akram Alwithenani
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, ON, Canada
- Department of Clinical Laboratory Science, Faculty of Applied Medical Science, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Zaid Taha
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, ON, Canada
| | - Max Thomson
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Andrew Chen
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Boaz Wong
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, ON, Canada
| | - Rozanne Arulanandam
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Jean-Simon Diallo
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, ON, Canada
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16
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Chen XY, Dong YC, Yu YY, Jiang M, Bu WJ, Li P, Sun ZJ, Dong DL. Anthelmintic nitazoxanide protects against experimental pulmonary fibrosis. Br J Pharmacol 2023; 180:3008-3023. [PMID: 37428102 DOI: 10.1111/bph.16190] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 06/02/2023] [Accepted: 07/03/2023] [Indexed: 07/11/2023] Open
Abstract
BACKGROUND AND PURPOSE Nitazoxanide is a therapeutic anthelmintic drug. Our previous studies found that nitazoxanide and its metabolite tizoxanide activated adenosine 5'-monophosphate-activated protein kinase (AMPK) and inhibited signal transducer and activator of transcription 3 (STAT3) signals. As AMPK activation and/or STAT3 inhibition are targets for treating pulmonary fibrosis, we hypothesized that nitazoxanide would be effective in experimental pulmonary fibrosis. EXPERIMENTAL APPROACH The mitochondrial oxygen consumption rate of cells was measured by using the high-resolution respirometry system Oxygraph-2K. The mitochondrial membrane potential of cells was evaluated by tetramethyl rhodamine methyl ester (TMRM) staining. The target protein levels were measured by using western blotting. The mice pulmonary fibrosis model was established through intratracheal instillation of bleomycin. The examination of the lung tissues changes were carried out using haematoxylin and eosin (H&E), and Masson staining. KEY RESULTS Nitazoxanide and tizoxanide activated AMPK and inhibited STAT3 signalling in human lung fibroblast cells (MRC-5 cells). Nitazoxanide and tizoxanide inhibited transforming growth factor-β1 (TGF-β1)-induced proliferation and migration of MRC-5 cells, collagen-I and α-smooth muscle cell actin (α-SMA) expression, and collagen-I secretion from MRC-5 cells. Nitazoxanide and tizoxanide inhibited epithelial-mesenchymal transition (EMT) and inhibited TGF-β1-induced Smad2/3 activation in mouse lung epithelial cells (MLE-12 cells). Oral administration of nitazoxanide reduced the bleomycin-induced mice pulmonary fibrosis and, in the established bleomycin-induced mice, pulmonary fibrosis. Delayed nitazoxanide treatment attenuated the fibrosis progression. CONCLUSIONS AND IMPLICATIONS Nitazoxanide improves the bleomycin-induced pulmonary fibrosis in mice, suggesting a potential application of nitazoxanide for pulmonary fibrosis treatment in the clinic.
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Affiliation(s)
- Xu-Yang Chen
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yan-Chao Dong
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Yuan-Yuan Yu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Man Jiang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Wen-Jie Bu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Ping Li
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Zhi-Jie Sun
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - De-Li Dong
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
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17
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Bosco-Lévy P, Boutmy E, Guiard E, Foch C, Lassalle R, Favary C, Sabidó M, Blin P. Risk of cancer with immunosuppressants compared to immunomodulators in multiple sclerosis: A nested case-control study within the French nationwide claims database. Pharmacoepidemiol Drug Saf 2023; 32:1421-1430. [PMID: 37555380 DOI: 10.1002/pds.5669] [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: 09/13/2022] [Revised: 06/22/2023] [Accepted: 07/11/2023] [Indexed: 08/10/2023]
Abstract
PURPOSE The objective was to compare the risk of malignancies in real-world settings between exclusive immunosuppressant (IS) and immunomodulator (IM) use in multiple sclerosis (MS). METHODS A nested case-control study was designed within a new-user cohort of all patients with MS who initiated a first IM or IS between 2008 and 2014, and without cancer history, using the information of the SNDS nationwide French claims database. Incident cancer cases were matched with up to six controls on year of birth, sex, initiation date, and disease risk score of cancer. A conditional logistic regression (odds ratio [95% confidence interval]) was used to compare exclusive IS versus IM use during follow-up and according to three use durations. RESULTS From 28 720 newly treated patients with MS, 407 incident cancers were observed during the follow-up with 2324 matched controls. A significant increase in cancer risk was observed for IS compared with IM (1.36 [1.05, 1.77]), with similar increases for the first 2 years of use but not for ≥2 years (1.06 [0.65, 1.75]). Similar increase was also observed for IS with indications other than MS (1.37 [1.04, 1.81]) but not for IS indicated only in MS (1.03 [0.45, 2.34]). CONCLUSIONS Compared with IM, a 37% increase in cancer risk was observed for IS with indications other than MS and used for a short duration (≤2 years) but not for IS indicated only in MS. The absence of risk for prolonged exposure of IS with indications other than MS is not in favor of a causal relation with these drugs.
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Affiliation(s)
- Pauline Bosco-Lévy
- INSERM CIC-P 1401, Bordeaux PharmacoEpi, Université de Bordeaux, Bordeaux, France
| | | | - Estelle Guiard
- INSERM CIC-P 1401, Bordeaux PharmacoEpi, Université de Bordeaux, Bordeaux, France
| | | | - Régis Lassalle
- INSERM CIC-P 1401, Bordeaux PharmacoEpi, Université de Bordeaux, Bordeaux, France
| | - Clélia Favary
- INSERM CIC-P 1401, Bordeaux PharmacoEpi, Université de Bordeaux, Bordeaux, France
| | | | - Patrick Blin
- INSERM CIC-P 1401, Bordeaux PharmacoEpi, Université de Bordeaux, Bordeaux, France
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18
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Ma D, Wang X, Liu J, Cui Y, Luo S, Wang F. The development of necroptosis: what we can learn. Cell Stress Chaperones 2023; 28:969-987. [PMID: 37995025 PMCID: PMC10746674 DOI: 10.1007/s12192-023-01390-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 08/03/2023] [Accepted: 10/17/2023] [Indexed: 11/24/2023] Open
Abstract
Necroptosis is a new type of programmed cell death discovered in recent years, playing an important role in various diseases. Since it was conceptualized in 2005, research on necroptosis has developed rapidly. However, few bibliometric analyses have provided a comprehensive overview of the field. This study aimed to employ a bibliometric analysis to assess necroptosis research's current status and hotspot, highlight landmark findings, and orientate future research. A total of 3993 publications from the WoSCC were collected for this study. Multiple tools were used for bibliometric analysis and data visualization, including an online website, VOSviewer, CiteSpace, and HistCite. Publications related to necroptosis have increased significantly annually, especially in the last 5 years. Globally, the USA and Harvard University are the most outstanding countries and institutions in this field, respectively. The academic groups managed by Peter Vandenabeele and Junying Yuan both have permanent and intensive research on necroptosis. Cell Death and Differentiation is the most vital journal in this field. The molecular mechanisms of necroptosis and its role in disease are the focus of current research, while the crosstalk between programmed cell death is an emerging direction in the field. The "reactive oxygen species", "innate immunity", and "programmed cell death" may be potential research hotspots. Our results present a comprehensive knowledge map and explore research trends. Researchers and funding agencies on necroptosis can obtain helpful references from our study.
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Affiliation(s)
- Dongbin Ma
- Department of Neurosurgery, Chengdu Fifth People's Hospital, Chengdu, China
| | - Xuan Wang
- Department of Obstetrics, Sichuan Provincial Maternity and Child Health Care Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Jia Liu
- Department of Neurosurgery, Chengdu Fifth People's Hospital, Chengdu, China
| | - Yang Cui
- Department of Neurosurgery, Hebei Yanda Hospital, Langfang, China
| | - Shuang Luo
- Department of Neurosurgery, Chengdu Fifth People's Hospital, Chengdu, China
| | - Fanchen Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
- Department of Graduate School, Tianjin Medical University, Tianjin, China.
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19
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Guo X, Guo Y, Li J, Liu Q, Wu H. Arginine Expedites Erastin-Induced Ferroptosis through Fumarate. Int J Mol Sci 2023; 24:14595. [PMID: 37834044 PMCID: PMC10572513 DOI: 10.3390/ijms241914595] [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: 07/31/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 10/15/2023] Open
Abstract
Ferroptosis is a newly characterized form of programmed cell death. The fundamental biochemical feature of ferroptosis is the lethal accumulation of iron-catalyzed lipid peroxidation. It has gradually been recognized that ferroptosis is implicated in the pathogenesis of a variety of human diseases. Increasing evidence has shed light on ferroptosis regulation by amino acid metabolism. Herein, we report that arginine deprivation potently inhibits erastin-induced ferroptosis, but not RSL3-induced ferroptosis, in several types of mammalian cells. Arginine presence reduces the intracellular glutathione (GSH) level by sustaining the biosynthesis of fumarate, which functions as a reactive α,β-unsaturated electrophilic metabolite and covalently binds to GSH to generate succinicGSH. siRNA-mediated knockdown of argininosuccinate lyase, the critical urea cycle enzyme directly catalyzing the biosynthesis of fumarate, significantly decreases cellular fumarate and thus relieves erastin-induced ferroptosis in the presence of arginine. Furthermore, fumarate is decreased during erastin exposure, suggesting that a protective mechanism exists to decelerate GSH depletion in response to pro-ferroptotic insult. Collectively, this study reveals the ferroptosis regulation by the arginine metabolism and expands the biochemical functionalities of arginine.
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Affiliation(s)
- Xinxin Guo
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (X.G.); (Y.G.); (J.L.); (Q.L.)
- Hubei Hongshan Laboratory, Wuhan 430070, China
| | - Yubo Guo
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (X.G.); (Y.G.); (J.L.); (Q.L.)
- Hubei Hongshan Laboratory, Wuhan 430070, China
| | - Jiahuan Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (X.G.); (Y.G.); (J.L.); (Q.L.)
- Hubei Hongshan Laboratory, Wuhan 430070, China
| | - Qian Liu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (X.G.); (Y.G.); (J.L.); (Q.L.)
- Hubei Hongshan Laboratory, Wuhan 430070, China
| | - Hao Wu
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (X.G.); (Y.G.); (J.L.); (Q.L.)
- Hubei Hongshan Laboratory, Wuhan 430070, China
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20
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Wang X, Zhou Y, Ning L, Chen J, Chen H, Li X. Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer. Cell Death Dis 2023; 14:588. [PMID: 37666806 PMCID: PMC10477278 DOI: 10.1038/s41419-023-06114-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 08/17/2023] [Accepted: 08/24/2023] [Indexed: 09/06/2023]
Abstract
Annexin A10 (ANXA10) belongs to a family of membrane-bound calcium-dependent phospholipid-binding proteins, but its precise function remains unclear. Further research is required to understand its role in sessile serrated lesions (SSL) and colorectal cancer (CRC). We conducted transcriptome sequencing on pairs of SSL and corresponding normal control (NC) samples. Bioinformatic methods were utilized to assess ANXA10 expression in CRC. We knocked down and overexpressed ANXA10 in CRC cells to examine its effects on cell malignant ability. The effect of ANXA10 on lung metastasis of xenograft tumor cells in nude mice was also assessed. Furthermore, we used quantitative polymerase chain reaction, western blotting, and flow cytometry for reactive oxygen species (ROS), lipid ROS, and intracellular Fe2+ to measure ferroptosis. Immunoblotting and Immunofluorescence staining were used to detect autophagy. We found that ANXA10 was significantly overexpressed in SSL compared to NC. ANXA10 was also highly expressed in BRAF mutant CRCs and was associated with poor prognosis. ANXA10 knockdown reduced the survival, proliferation, and migration ability of CRC cells. Knockdown of ANXA10 inhibited lung metastasis of CRC cells in mice. ANXA10 knockdown increased transferrin receptor (TFRC) protein levels and led to downregulation of GSH/GSSG, increased Fe2+, MDA concentration, and ROS and lipid ROS in cells. Knockdown of ANXA10 inhibited TFRC degradation and was accompanied by an accumulation of autophagic flux and an increase in SQSTM1. Finally, Fer-1 rescued the migration and viability of ANXA10 knockdown cell lines. In brief, the knockdown of ANXA10 induces cellular ferroptosis by inhibiting autophagy-mediated TFRC degradation, thereby inhibiting CRC progression. This study reveals the mechanism of ANXA10 in ferroptosis, suggesting that it may serve as a potential therapeutic target for CRC of the serrated pathway.
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Affiliation(s)
- Xinyuan Wang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yujie Zhou
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lijun Ning
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinnan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huimin Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaobo Li
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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21
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Zhu X, Li S. Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300824. [PMID: 37436087 PMCID: PMC10502844 DOI: 10.1002/advs.202300824] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 06/29/2023] [Indexed: 07/13/2023]
Abstract
In recent years, the incidence of gastrointestinal cancers is increasing, particularly in the younger population. Effective treatment is crucial for improving patients' survival outcomes. Programmed cell death, regulated by various genes, plays a fundamental role in the growth and development of organisms. It is also critical for maintaining tissue and organ homeostasis and takes part in multiple pathological processes. In addition to apoptosis, there are other types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, which can induce severe inflammatory responses. Notably, besides apoptosis, ferroptosis, necroptosis, and pyroptosis also contribute to the occurrence and development of gastrointestinal cancers. This review aims to provide a comprehensive summary on the biological roles and molecular mechanisms of ferroptosis, necroptosis, and pyroptosis, as well as their regulators in gastrointestinal cancers and hope to open up new paths for tumor targeted therapy in the near future.
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Affiliation(s)
- Xudong Zhu
- Department of General SurgeryCancer Hospital of Dalian University of TechnologyCancer Hospital of China Medical UniversityLiaoning Cancer Hospital and InstituteShenyangLiaoning Province110042China
| | - Shenglong Li
- Second Ward of Bone and Soft Tissue Tumor SurgeryCancer Hospital of Dalian University of TechnologyCancer Hospital of China Medical UniversityLiaoning Cancer Hospital and InstituteShenyangLiaoning Province110042China
- The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with EngineeringShenyangLiaoning Province110042China
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22
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Manai F, Zanoletti L, Arfini D, Micco SGD, Gjyzeli A, Comincini S, Amadio M. Dimethyl Fumarate and Intestine: From Main Suspect to Potential Ally against Gut Disorders. Int J Mol Sci 2023; 24:9912. [PMID: 37373057 DOI: 10.3390/ijms24129912] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/04/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Dimethyl fumarate (DMF) is a well-characterized molecule that exhibits immuno-modulatory, anti-inflammatory, and antioxidant properties and that is currently approved for the treatment of psoriasis and multiple sclerosis. Due to its Nrf2-dependent and independent mechanisms of action, DMF has a therapeutic potential much broader than expected. In this comprehensive review, we discuss the state-of-the-art and future perspectives regarding the potential repurposing of DMF in the context of chronic inflammatory diseases of the intestine, such as inflammatory bowel disorders (i.e., Crohn's disease and ulcerative colitis) and celiac disease. DMF's mechanisms of action, as well as an exhaustive analysis of the in vitro/in vivo evidence of its beneficial effects on the intestine and the gut microbiota, together with observational studies on multiple sclerosis patients, are here reported. Based on the collected evidence, we highlight the new potential applications of this molecule in the context of inflammatory and immune-mediated intestinal diseases.
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Affiliation(s)
- Federico Manai
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Lisa Zanoletti
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
- Department of Chronic Diseases and Metabolism (CHROMETA), Katholieke Universiteit Leuven, 3000 Leuven, Belgium
| | - Davide Arfini
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Simone Giorgio De Micco
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Arolda Gjyzeli
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Sergio Comincini
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Marialaura Amadio
- Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy
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23
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Chu X, Zhang J, Li Y, Yuan K, Wang X, Gui X, Sun Y, Geng C, Ju W, Xu M, Li Z, Zeng L, Xu K, Qiao J. Dimethyl fumarate possesses antiplatelet and antithrombotic properties. Int Immunopharmacol 2023; 120:110381. [PMID: 37245302 DOI: 10.1016/j.intimp.2023.110381] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 05/10/2023] [Accepted: 05/22/2023] [Indexed: 05/30/2023]
Abstract
BACKGROUND Dimethyl fumarate (DMF) is a methyl ester of fumaric acid and has been approved for treating multiple sclerosis (MS) and psoriasis due to anti-inflammatory effect. There is a close association between platelets and the pathogenesis of MS. Whether DMF affects platelet function remains unclear. Our study intends to evaluate DMF's effect on platelet function. METHODS Washed human platelets were treated with different concentrations of DMF (0, 50, 100 and 200 μM) at 37 °C for 1 h followed by analysis of platelet aggregation, granules release, receptors expression, spreading and clot retraction. In addition, mice received intraperitoneal injection of DMF (15 mg/kg) to assess tail bleeding time, arterial and venous thrombosis. RESULTS DMF significantly inhibited platelet aggregation and the release of dense/alpha granules in response to collagen-related peptide (CRP) or thrombin stimulation dose-dependently without altering the expression of platelet receptors αIIbβ3, GPIbα, and GPVI. In addition, DMF-treated platelets presented significantly reduced spreading on collagen or fibrinogen and thrombin-mediated clot retraction along with the decreased phosphorylation of c-Src and PLCγ2. Moreover, administration of DMF into mice significantly prolonged the tail bleeding time and impaired arterial and venous thrombus formation. Furthermore, DMF reduced the generation of intracellular reactive oxygen species and calcium mobilization, and inhibited NF-κB activation and the phosphorylation of ERK1/2, p38 and AKT. CONCLUSION DMF inhibits platelet function and arterial/venous thrombus formation. Considering the presence of thrombotic events in MS, our study indicates that DMF treatment for patients with MS might obtain both anti-inflammatory and anti-thrombotic benefits.
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Affiliation(s)
- Xiang Chu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Jie Zhang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Yingying Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Ke Yuan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Xue Wang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Xiang Gui
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Yueyue Sun
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Chaonan Geng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Wen Ju
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Mengdi Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Zhenyu Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Lingyu Zeng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China
| | - Jianlin Qiao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China; Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou, China.
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24
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Yang G, Li H, Dong Z, Deng K, Lu Y. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis. Open Med (Wars) 2023; 18:20230708. [PMID: 37251542 PMCID: PMC10224614 DOI: 10.1515/med-2023-0708] [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: 08/18/2022] [Revised: 03/24/2023] [Accepted: 04/17/2023] [Indexed: 05/31/2023] Open
Abstract
The chemokine, C-X-C motif chemokine ligand 12 (CXCL12) and its G-protein-coupled receptor (GPCR) and C-X-C chemokine receptor type 4 (CXCR4), are closely associated with promoting hepatocellular carcinoma (HCC) chemotaxis and metastasis. The binding of CXCL12 and CXCR4 depends on the heterotrimeric Gi proteins to regulate actin polymerisation and mobility in HCC. Although the role of GPCR/Gi signalling in carcinogenesis migration has been intensively studied, the detailed mechanism remains largely unknown. In this study, a small interfering RNA technique was used to knock down the Nucleophosmin 1 (NPM1) gene expression. Through the chemotaxis and invasion assays, wound healing, proliferation, filamentous-actin, immunofluorescence, immunohistochemical assays, and co-immunoprecipitation assays, we investigated the specific biological role and underlying mechanisms of the NPM1 in HCC. Additionally, dimethyl fumarate (DMF), a fumaric acid ester, was used to inhibit the HCC cell chemokines and metastasis by regulating ELMO1 and NPM1. Therefore, this study reported that NPM1 gene expression was upregulated in the HCC tissues and cell lines. The NPM1 knockdown significantly inhibited the proliferation, migration, and chemotaxis of the HepG2 cells in vitro. Further mechanistic studies suggested that the NPM1 interacts with ELMO1 and the CXCL12/CXCR4 pathway activates NPM1-dependent regulation of the ELMO1 localisation. Furthermore, the DMF significantly inhibited tumour metastasis induced by the NPM1/ELMO1 signalling pathway, as observed in in vitro cell functional experiments. These data suggested that as a potentially novel therapeutic approach, the simultaneous targeting of NPM1 and ELMO1 could effectively be used to treat HCC.
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Affiliation(s)
- Gangqi Yang
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550001, China
- General Surgery Department and Neurology Department, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Beijing100053, China
- Comprehensive Liver Cancer Center, 5th Medical Center of the PLA General Hospital, Beijing100039, China
- Guangdong Key Laboratory of Epigenetics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Hongyan Li
- General Surgery Department and Neurology Department, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Beijing100053, China
| | - Zheng Dong
- Comprehensive Liver Cancer Center, 5th Medical Center of the PLA General Hospital, Beijing100039, China
| | - Kai Deng
- The First Affiliated Hospital of Chongqing Medical College, Chongqing400016, China
| | - Yinying Lu
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550001, China
- Comprehensive Liver Cancer Center, 5th Medical Center of the PLA General Hospital, Beijing100039, China
- Guangdong Key Laboratory of Epigenetics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong 518055, China
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25
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Ma MH, Li FF, Li WF, Zhao H, Jiang M, Yu YY, Dong YC, Zhang YX, Li P, Bu WJ, Sun ZJ, Dong DL. Repurposing nitazoxanide as a novel anti-atherosclerotic drug based on mitochondrial uncoupling mechanisms. Br J Pharmacol 2023; 180:62-79. [PMID: 36082580 DOI: 10.1111/bph.15949] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 08/03/2022] [Accepted: 08/28/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND PURPOSE The anthelmintic drug nitazoxanide has a mitochondrial uncoupling effect. Mitochondrial uncouplers have been proven to inhibit smooth muscle cell proliferation and migration, inhibit NLRP3 inflammasome activation of macrophages and improve dyslipidaemia. Therefore, we aimed to demonstrate that nitazoxanide would protect against atherosclerosis. EXPERIMENTAL APPROACH The mitochondrial oxygen consumption of cells was measured by using the high-resolution respirometry system, Oxygraph-2K. The proliferation and migration of A10 cells were measured by using Edu immunofluorescence staining, wound-induced migration and the Boyden chamber assay. Protein levels were measured by using the western blot technique. ApoE (-/-) mice were fed with a Western diet to establish an atherosclerotic model in vivo. KEY RESULTS The in vitro experiments showed that nitazoxanide and tizoxanide had a mitochondrial uncoupling effect and activated cellular AMPK. Nitazoxanide and tizoxanide inhibited serum- and PDGF-induced proliferation and migration of A10 cells. Nitazoxanide and tizoxanide inhibited NLRP3 inflammasome activation in RAW264.7 macrophages, the mechanism by which involved the AMPK/IκBα/NF-κB pathway. Nitazoxanide and tizoxanide also induced autophagy in A10 cells and RAW264.7 macrophages. The in vivo experiments demonstrated that oral administration of nitazoxanide reduced the increase in serum IL-1β and IL-6 levels and suppressed atherosclerosis in Western diet-fed ApoE (-/-) mice. CONCLUSION AND IMPLICATIONS Nitazoxanide inhibits the formation of atherosclerotic plaques in ApoE (-/-) mice fed on a Western diet. In view of nitazoxanide being an antiprotozoal drug already approved by the FDA, we propose it as a novel anti-atherosclerotic drug with clinical translational potential.
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Affiliation(s)
- Ming-Hui Ma
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Feng-Feng Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Wen-Feng Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Hui Zhao
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Man Jiang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Yuan-Yuan Yu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Yan-Chao Dong
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Yi-Xin Zhang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Ping Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Wen-Jie Bu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China
| | - Zhi-Jie Sun
- Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China
| | - De-Li Dong
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China.,Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China
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Zhu J, Ma R, Li G. Drug repurposing: Clemastine fumarate and neurodegeneration. Biomed Pharmacother 2023; 157:113904. [PMID: 36370521 DOI: 10.1016/j.biopha.2022.113904] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 10/13/2022] [Accepted: 10/19/2022] [Indexed: 11/10/2022] Open
Abstract
Neurodegenerative diseases have been a weighty problem in elder people who might be stricken with motor or/and cognition defects with lower life quality urging for effective treatment. Drugs are costly from development to market, so that drug repurposing, exploration of existing drugs for novel therapeutic purposes, becomes a wise and popular strategy to raise new treatment options. Clemastine fumarate, different from anti-allergic effect as H1 histamine antagonist, was screened and identified as promising drug for remyelination and autophagy enhancement. Surprisingly, fumarate salt also has similar effect. Hence, whether clemastine fumarate would make a protective impact on neurodegenerative diseases and what contribution fumarate probably makes are intriguing to us. In this review, we summarize the potential mechanism surrounding clemastine fumarate in current literature, and try to distinguish independent or synergistic effect between clemastine and fumarate, aiming to find worthwhile research direction for neurodegeneration diseases.
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Affiliation(s)
- Jiahui Zhu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Rong Ma
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Gang Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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27
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Zhang T, Wang Y, Inuzuka H, Wei W. Necroptosis pathways in tumorigenesis. Semin Cancer Biol 2022; 86:32-40. [PMID: 35908574 PMCID: PMC11010659 DOI: 10.1016/j.semcancer.2022.07.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/13/2022] [Accepted: 07/27/2022] [Indexed: 01/27/2023]
Abstract
Necroptosis is a caspase-independent form of programmed cell death executed by the receptor interacting protein kinase 1 (RIPK1)-RIPK3-mixed lineage kinase domain-like protein (MLKL) signaling cascade, deregulation of which can cause various human diseases including cancer. Escape from programmed cell death is a hallmark of cancer, leading to uncontrolled growth and drug resistance. Therefore, it is crucial to further understand whether necroptosis plays a key role in therapeutic resistance. In this review, we summarize the recent findings of the link between necroptosis and cancer, and discuss that targeting necroptosis is a new strategy to overcome apoptosis resistance in tumor therapy.
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Affiliation(s)
- Tao Zhang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Yingnan Wang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310006, China
| | - Hiroyuki Inuzuka
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Kalyanaraman B. NAC, NAC, Knockin' on Heaven's door: Interpreting the mechanism of action of N-acetylcysteine in tumor and immune cells. Redox Biol 2022; 57:102497. [PMID: 36242913 PMCID: PMC9563555 DOI: 10.1016/j.redox.2022.102497] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/05/2022] [Indexed: 11/17/2022] Open
Abstract
N-acetylcysteine (NAC) has been used as a direct scavenger of reactive oxygen species (hydrogen peroxide, in particular) and an antioxidant in cancer biology and immuno-oncology. NAC is the antioxidant drug most frequently employed in studies using tumor cells, immune cells, and preclinical mouse xenografts. Most studies use redox-active fluorescent probes such as dichlorodihydrofluorescein, hydroethidine, mitochondria-targeted hydroethidine, and proprietary kit-based probes (i.e., CellROX Green and CellROX Red) for intracellular detection of superoxide or hydrogen peroxide. Inhibition of fluorescence by NAC was used as a key experimental observation to support the formation of reactive oxygen species and redox mechanisms proposed for ferroptosis, tumor metastasis, and redox signaling in the tumor microenvironment. Reactive oxygen species such as superoxide and hydrogen peroxide stimulate or abrogate tumor cells and immune cells depending on multiple factors. Understanding the mechanism of antioxidants is crucial for interpretation of the results. Because neither NAC nor the fluorescent probes indicated above react directly with hydrogen peroxide, it is critically important to reinterpret the results to advance our understanding of the mechanism of action of NAC and shed additional mechanistic insight on redox-regulated signaling in tumor biology. To this end, this review is focused on how NAC could affect multiple pathways in cancer cells, including iron signaling, ferroptosis, and the glutathione-dependent antioxidant and redox signaling mechanism, and how NAC could inhibit oxidation of the fluorescent probes through multiple mechanisms.
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Affiliation(s)
- Balaraman Kalyanaraman
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, USA.
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Chaouhan HS, Vinod C, Mahapatra N, Yu SH, Wang IK, Chen KB, Yu TM, Li CY. Necroptosis: A Pathogenic Negotiator in Human Diseases. Int J Mol Sci 2022; 23:12714. [PMID: 36361505 PMCID: PMC9655262 DOI: 10.3390/ijms232112714] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/25/2022] Open
Abstract
Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.
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Affiliation(s)
- Hitesh Singh Chaouhan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
| | - Ch Vinod
- Department of Biological Sciences, School of Applied Sciences, KIIT University, Bhubaneshwar 751024, India
| | - Nikita Mahapatra
- Department of Biological Sciences, School of Applied Sciences, KIIT University, Bhubaneshwar 751024, India
| | - Shao-Hua Yu
- Department of Emergency Medicine, China Medical University Hospital, Taichung 40402, Taiwan
| | - I-Kuan Wang
- School of Medicine, China Medical University, Taichung 40402, Taiwan
- Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan
| | - Kuen-Bao Chen
- Department of Anesthesiology, China Medical University Hospital, Taichung 40402, Taiwan
| | - Tung-Min Yu
- School of Medicine, China Medical University, Taichung 40402, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40402, Taiwan
| | - Chi-Yuan Li
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
- School of Medicine, China Medical University, Taichung 40402, Taiwan
- Department of Anesthesiology, China Medical University Hospital, Taichung 40402, Taiwan
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Shiau JP, Chuang YT, Tang JY, Yang KH, Chang FR, Hou MF, Yen CY, Chang HW. The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products. Antioxidants (Basel) 2022; 11:1845. [PMID: 36139919 PMCID: PMC9495789 DOI: 10.3390/antiox11091845] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 01/10/2023] Open
Abstract
Oxidative stress and AKT serine-threonine kinase (AKT) are responsible for regulating several cell functions of cancer cells. Several natural products modulate both oxidative stress and AKT for anticancer effects. However, the impact of natural product-modulating oxidative stress and AKT on cell functions lacks systemic understanding. Notably, the contribution of regulating cell functions by AKT downstream effectors is not yet well integrated. This review explores the role of oxidative stress and AKT pathway (AKT/AKT effectors) on ten cell functions, including apoptosis, autophagy, endoplasmic reticulum stress, mitochondrial morphogenesis, ferroptosis, necroptosis, DNA damage response, senescence, migration, and cell-cycle progression. The impact of oxidative stress and AKT are connected to these cell functions through cell function mediators. Moreover, the AKT effectors related to cell functions are integrated. Based on this rationale, natural products with the modulating abilities for oxidative stress and AKT pathway exhibit the potential to regulate these cell functions, but some were rarely reported, particularly for AKT effectors. This review sheds light on understanding the roles of oxidative stress and AKT pathway in regulating cell functions, providing future directions for natural products in cancer treatment.
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Affiliation(s)
- Jun-Ping Shiau
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan or
| | - Ya-Ting Chuang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jen-Yang Tang
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaoshiung Medical University, Kaohsiung 80708, Taiwan
| | - Kun-Han Yang
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Fang-Rong Chang
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Feng Hou
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan or
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ching-Yu Yen
- Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Tainan 71004, Taiwan
- School of Dentistry, Taipei Medical University, Taipei 11031, Taiwan
| | - Hsueh-Wei Chang
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Wang Y, Zhang Z, Sun W, Zhang J, Xu Q, Zhou X, Mao L. Ferroptosis in colorectal cancer: Potential mechanisms and effective therapeutic targets. Biomed Pharmacother 2022; 153:113524. [PMID: 36076606 DOI: 10.1016/j.biopha.2022.113524] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 01/17/2023] Open
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The regulation of necroptosis and perspectives for the development of new drugs preventing ischemic/reperfusion of cardiac injury. Apoptosis 2022; 27:697-719. [DOI: 10.1007/s10495-022-01760-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2022] [Indexed: 12/11/2022]
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Shafizadeh M, Jangholi E, Maroufi SF, Rostami M, Bereimipour A, Majidi S, Mohebi N, Khoshnevisan A. Effects of Dimethyl Fumarate on the Karnofsky Performance Status and Serum S100β Level in Newly Glioblastoma Patients: A Randomized, Phase-II, Placebo, Triple Blinded, Controlled Trial: Effect of DMF On the Serum S100β Level and KPS Score of GBM Patients. Galen Med J 2022; 10:1-10. [PMID: 36340958 PMCID: PMC9616682 DOI: 10.31661/gmj.v11i.1897] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Indexed: 09/26/2023] Open
Abstract
Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy with a low survival without extra logistics. Currently, there is no definitive chemotherapy among the studied options. This study aims to evaluate the neuroprotective effects of dimethyl fumarate (DMF) on surgical brain injuries in patients treated for GBM. Materials and Methods: This randomized, phase II, placebo, triple-blinded, controlled trial was performed on 36 patients with a diagnosis of GBM. All the patients received DMF (240 mg, three-times per day) or placebo (with the same shape and administration route) one week before surgery. Also, patients in both groups after the operation received standard treatments (radiotherapy plus chemotherapy). In addition, Kanofsky's performance status (KPS) score was evaluated at baseline and one month later. Also, serum S100β was measured 48 hours before and after surgery. Results: There was no significant difference among DMF and control groups with regard to age, gender, and the extent of resections (P˃0.05). The most adverse event in both groups was a headache. Although the serum S100β level was not markedly changed after surgery, the mean KPS in the DMF group was higher than in the control group after surgery. Conclusion: The DMF could be a possible good regime for the treatment of GBM; however, questions are raised regarding its efficacy and application for the addition to standard treatment.
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Affiliation(s)
- Milad Shafizadeh
- Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ehsan Jangholi
- Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Rostami
- Spine Center of Excellence, Yas hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Bereimipour
- Department of Stem Cells and Developmental Biology at Cell Science Research Centre, Royan Institute, Tehran, Iran
- Faculty of Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Shahram Majidi
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Niayesh Mohebi
- Department of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Khoshnevisan
- Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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Rosin Derivative IDOAMP Inhibits Prostate Cancer Growth via Activating RIPK1/RIPK3/MLKL Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9325973. [PMID: 35965682 PMCID: PMC9371855 DOI: 10.1155/2022/9325973] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/25/2022] [Indexed: 12/05/2022]
Abstract
Rosin derivatives such as dehydroabietic acid and dehydroabietic amine belonging to diterpenoids have similar structure with androgen that inhibited the occurrence and development of prostate cancer. In this study, the effects and possible mechanism of the rosin derivative IDOAMP on prostate cancer were investigated. Our results showed that IDOAMP effectively inhibited cell viabilities of LNCaP, PC3, and DU145 prostate cells. After the treatment with IDOAMP, the levels of cleaved-PARP, LC3BII/I, and HMGB1 were increased, whereas the expression of GPX4 was decreased. Interestingly, cell viability was reversed by the supplements of necrostatin-1 and necrosulfonamide. Meanwhile, the IDOAMP downregulated the expression of human Aurora kinase A that was overexpressed in prostate cancer. In addition, co-IP results showed that IDOAMP inhibited the binding of Aurora kinase A to the receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3. However, the binding of RIPK1 to FADD, RIPK3, or MLKL was significantly promoted. Further studies showed that the phosphorylation levels of RIPK1, RIPK, and MLKL were increased in a concentration-dependent manner. In in vivo model, IDOAMP reduced the tumor volumes and weights. In conclusion, IDOAMP directly inhibited Aurora kinase A and promoted the RIPK1/RIPK3/MLKL necrosome activation to inhibit the prostate cancer.
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Rupp T, Debasly S, Genest L, Froget G, Castagné V. Therapeutic Potential of Fingolimod and Dimethyl Fumarate in Non-Small Cell Lung Cancer Preclinical Models. Int J Mol Sci 2022; 23:ijms23158192. [PMID: 35897763 PMCID: PMC9330228 DOI: 10.3390/ijms23158192] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/22/2022] [Accepted: 07/24/2022] [Indexed: 01/27/2023] Open
Abstract
New therapies are required for patients with non-small cell lung cancer (NSCLC) for which the current standards of care poorly affect the patient prognosis of this aggressive cancer subtype. In this preclinical study, we aim to investigate the efficacy of Fingolimod, a described inhibitor of sphingosine-1-phosphate (S1P)/S1P receptors axis, and Dimethyl Fumarate (DMF), a methyl ester of fumaric acid, both already approved as immunomodulators in auto-immune diseases with additional expected anti-cancer effects. The impact of both drugs was analyzed with in vitro cell survival analysis and in vivo graft models using mouse and human NSCLC cells implanted in immunocompetent or immunodeficient mice, respectively. We demonstrated that Fingolimod and DMF repressed tumor progression without apparent adverse effects in vivo in three preclinical mouse NSCLC models. In vitro, Fingolimod did not affect either the tumor proliferation or the cytotoxicity, although DMF reduced tumor cell proliferation. These results suggest that Fingolimod and DMF affected tumor progression through different cellular mechanisms within the tumor microenvironment. Fingolimod and DMF might uncover potential therapeutic opportunities in NSCLC.
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Affiliation(s)
- Tristan Rupp
- Porsolt SAS, ZA de Glatigné, 53940 Le Genest-Saint-Isle, France; (S.D.); (L.G.); (G.F.); (V.C.)
- Correspondence: or ; Tel.: +33-(0)2-43-69-36-07
| | - Solène Debasly
- Porsolt SAS, ZA de Glatigné, 53940 Le Genest-Saint-Isle, France; (S.D.); (L.G.); (G.F.); (V.C.)
- CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Université de Reims-Champagne-Ardenne, Campus Moulin de la Housse, 51687 Reims, France
| | - Laurie Genest
- Porsolt SAS, ZA de Glatigné, 53940 Le Genest-Saint-Isle, France; (S.D.); (L.G.); (G.F.); (V.C.)
| | - Guillaume Froget
- Porsolt SAS, ZA de Glatigné, 53940 Le Genest-Saint-Isle, France; (S.D.); (L.G.); (G.F.); (V.C.)
| | - Vincent Castagné
- Porsolt SAS, ZA de Glatigné, 53940 Le Genest-Saint-Isle, France; (S.D.); (L.G.); (G.F.); (V.C.)
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Li P, Zhang L, Guo Z, Kang Q, Chen C, Liu X, Ma Q, Zhang J, Hu Y, Wang T. Epimedium koreanum Nakai-Induced Liver Injury-A Mechanistic Study Using Untargeted Metabolomics. Front Pharmacol 2022; 13:934057. [PMID: 35910368 PMCID: PMC9326364 DOI: 10.3389/fphar.2022.934057] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Epimedii Folium is widely used worldwide as an herbal supplement, and the risk of its induced liver damage has emerged in recent years. Our preliminary study has found that, among several Epimedii Folium species specified in the Chinese Pharmacopoeia, Epimedium koreanum Nakai has a more severe propensity for hepatotoxicity. However, the mechanism of hepatotoxicity of Epimedium koreanum Nakai is still unclear. In this study, untargeted metabolomics was performed to analyze the serum and liver tissue to explore the mechanism of hepatotoxicity of Epimedium koreanum Nakai. The results of experiments in vivo showed that, after 28 days of exposure to Epimedium koreanum Nakai ethanol extract (EEE), the liver weight, levels of AST, ALP, TBIL, etc. in serum of rats in the EEE group were significantly increased, as well as severe cytoplasmic vacuolation appeared in the liver tissue, which suggested that EEE has significant hepatotoxicity. Subsequently, the results of metabolomics revealed significant changes in the metabolic profile in the liver and serum of rats after EEE exposure, in which metabolites in serum such as flavin mononucleotide, phenylacetylglycine, glutathione, l-tryptophan, and sphingomyelin were able to accurately identify liver injury caused by EEE and could be used as serum markers to reflect EEE-induced liver injury. The KEGG pathway enrichment analysis revealed that EEE caused extensive effects on rats' metabolic pathways. Some of the most affected pathways included glutathione metabolism, glutamate metabolism pathway, primary bile acid biosynthesis pathway, and sphingolipid metabolism pathway, which were all directed to the biological process of ferroptosis. Then, the main markers related to ferroptosis in the liver were examined, and the results demonstrated that the content of malondialdehyde was significantly increased, the activity of superoxide dismutase was significantly reduced, the ferroptosis inhibitory proteins GPX4 and System xc - were significantly downregulated, and the ferroptosis-promoting protein ACSL4 was significantly up-regulated. Judging from these results, we concluded that the mechanism of hepatotoxicity of Epimedium koreanum Nakai was probably related to the induction of ferroptosis in hepatocytes.
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Affiliation(s)
| | - Lin Zhang
- Beijing Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | | | | | | | | | | | | | | | - Ting Wang
- Beijing Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Non-Canonical Programmed Cell Death in Colon Cancer. Cancers (Basel) 2022; 14:cancers14143309. [PMID: 35884370 PMCID: PMC9320762 DOI: 10.3390/cancers14143309] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/24/2022] [Accepted: 07/05/2022] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Non-canonical PCD is an important player in colon cancer cell suicide. It influences colon cancer in many ways, such as through tumorigenesis, treatment, and prognosis. In this review, we present the mechanism, application, and prospect of different types of non-canonical PCD in colon cancer. Abstract Programmed cell death (PCD) is an evolutionarily conserved process of cell suicide that is regulated by various genes and the interaction of multiple signal pathways. Non-canonical programmed cell death (PCD) represents different signaling excluding apoptosis. Colon cancer is the third most incident and the fourth most mortal worldwide. Multiple factors such as alcohol, obesity, and genetic and epigenetic alternations contribute to the carcinogenesis of colon cancer. In recent years, emerging evidence has suggested that diverse types of non-canonical programmed cell death are involved in the initiation and development of colon cancer, including mitotic catastrophe, ferroptosis, pyroptosis, necroptosis, parthanatos, oxeiptosis, NETosis, PANoptosis, and entosis. In this review, we summarized the association of different types of non-canonical PCD with tumorigenesis, progression, prevention, treatments, and prognosis of colon cancer. In addition, the prospect of drug-resistant colon cancer therapy related to non-canonical PCD, and the interaction between different types of non-canonical PCD, was systemically reviewed.
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Hu X, Li C, Wang Q, Wei Z, Chen T, Wang Y, Li Y. Dimethyl Fumarate Ameliorates Doxorubicin-Induced Cardiotoxicity By Activating the Nrf2 Pathway. Front Pharmacol 2022; 13:872057. [PMID: 35559248 PMCID: PMC9089305 DOI: 10.3389/fphar.2022.872057] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/21/2022] [Indexed: 01/01/2023] Open
Abstract
Doxorubicin (DOX) is limited in clinical application because of its cardiotoxicity. Oxidative stress and apoptosis are crucial in DOX-induced cardiac injury. Dimethyl fumarate (DMF) is an FDA-approved oral drug with powerful effects to reduce oxidative stress and apoptosis through the Nrf2 pathway. This study was aimed to determine whether DMF can protect against DOX-induced cardiac injury. We used both neonatal rat cardiomyocytes (NRCMs) in vitro and DOX-induced cardiac toxicity in vivo to explore the effects of DMF. The results showed that DMF significantly improved cell viability and morphology in NRCMs. In addition, DMF alleviated DOX-induced cardiac injury in rats, as evidenced by decreased CK-MB, LDH levels, improved survival rates, cardiac function, and pathological changes. Moreover, DMF significantly inhibited cardiac oxidative stress by reducing MDA levels and increasing GSH, SOD, and GSH-px levels. And DMF also inhibited DOX-induced cardiac apoptosis by modulating Bax, Bcl-2 and cleaved caspase-3 expression. Moreover, DMF exerted its protective effects against DOX by promoting Nrf2 nuclear translocation, which activated its downstream antioxidant gene Hmox1. Silencing of Nrf2 attenuated the protective effects of DMF in NRCMs as manifested by increased intracellular oxidative stress, elevated apoptosis levels, and decreased cell viability. In addition, DMF showed no protective effects on the viability of DOX-treated tumor cells, which suggested that DMF does not interfere with the antitumor effect of DOX in vitro. In conclusion, our data confirmed that DMF alleviated DOX-induced cardiotoxicity by regulating oxidative stress and apoptosis through the Nrf2 pathway. DMF may serve as a new candidate to alleviate DOX-related cardiotoxicity in the future.
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Affiliation(s)
- Xiaoliang Hu
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cheng Li
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Wang
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhixing Wei
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Taizhong Chen
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuepeng Wang
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yigang Li
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Wang X, Hua P, He C, Chen M. Non-apoptotic cell death-based cancer therapy: Molecular mechanism, pharmacological modulators, and nanomedicine. Acta Pharm Sin B 2022; 12:3567-3593. [PMID: 36176912 PMCID: PMC9513500 DOI: 10.1016/j.apsb.2022.03.020] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/25/2022] [Accepted: 02/16/2022] [Indexed: 02/08/2023] Open
Abstract
As an emerging cancer therapeutic target, non-apoptotic cell death such as ferroptosis, necroptosis and pyroptosis, etc., has revealed significant potential in cancer treatment for bypassing apoptosis to enhance the undermined therapeutic efficacy triggered by apoptosis resistance. A variety of anticancer drugs, synthesized compounds and natural products have been proven recently to induce non-apoptotic cell death and exhibit excellent anti-tumor effects. Moreover, the convergence of nanotechnology with functional materials and biomedicine science has provided tremendous opportunities to construct non-apoptotic cell death-based nanomedicine for innovative cancer therapy. Nanocarriers are not only employed in targeted delivery of non-apoptotic inducers, but also used as therapeutic components to induce non-apoptotic cell death to achieve efficient tumor treatment. This review first introduces the main characteristics, the mechanism and various pharmacological modulators of different non-apoptotic cell death forms, including ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, lysosomal-dependent cell death, and oncosis. Second, we comprehensively review the latest progresses of nanomedicine that induces various forms of non-apoptotic cell death and focus on the nanomedicine targeting different pathways and components. Furthermore, the combination therapies of non-apoptotic cell death with photothermal therapy, photodynamic therapy, immunotherapy and other modalities are summarized. Finally, the challenges and future perspectives in this regard are also discussed.
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Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction. Cell Death Dis 2022; 13:281. [PMID: 35351877 PMCID: PMC8964685 DOI: 10.1038/s41419-022-04737-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 02/25/2022] [Accepted: 03/15/2022] [Indexed: 12/23/2022]
Abstract
Podocyte damage mediated by in situ complement activation in the glomeruli is a key factor in the pathogenesis of membranous nephropathy (MN), but the molecular mechanism has not been fully elucidated. Pyroptosis is a special type of programmed cell death, mediate inflammatory response and induce tissue injury. However, it is not clear whether pyroptosis is involved in the development and progression of MN. Here, we report that pyroptosis plays an important role in promoting podocyte injury in MN. We first observed the occurrence of pyroptosis in the kidneys of MN patients and validated that complement stimulation triggered pyroptosis in podocytes and that inhibiting pyroptosis reversed complement-induced podocyte damage in vitro. In addition, stimulation of complement caused mitochondrial depolarization and reactive oxygen species (ROS) production in podocytes, and inhibition of ROS reversed complement-induced pyroptosis in podocytes. Interestingly, inhibition of pyroptosis in turn partially alleviated these effects. Furthermore, we also found the involvement of pyroptosis in the kidneys of passive Heymann nephritis (PHN) rats, and inhibitors of pyroptosis-related molecules relieved PHN-induced kidney damage in vivo. Our findings demonstrate that pyroptosis plays a critical role in complement-induced podocyte damage in MN and mitochondrial dysfunction is an important mechanism underlying this process. It provides new insight that pyroptosis may serve as a novel therapeutic target for MN treatment in future studies.
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Zhao W, Song Y, Wang QQ, Han S, Li XX, Cui Y, Gao H, Yuan R, Yang S. Cryptotanshinone Induces Necroptosis through Ca2+ Release and ROS Production in vitro and in vivo. Curr Mol Pharmacol 2022; 15:1009-1023. [PMID: 35086466 DOI: 10.2174/1874467215666220127112201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 10/15/2021] [Accepted: 11/01/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Necroptosis is a type of programmed necrosis mediated by receptor-interacting protein kinases 1 and 3 (RIP1 and RIP3), which is morphologically characterized by enlarged organelles, ruptured plasma membrane, and subsequent loss of intracellular contents. Cryptotanshinone (CPT), a diterpene quinone compound extracted from the root of Salvia miltiorrhiza Bunge, has been reported to have significant anticancer activities. However, the detailed mechanism of CPT has not been clearly illustrated. OBJECTIVE The present study aimed to explore the cell death type and mechanisms of CPT-induced in non-small cell lung cancer (NSCLC) cells. METHODS The cytotoxicity of CPT on A549 cells was assessed by MTS assay. Ca2+ release and reactive oxygen species (ROS) generation were detected by flow cytometry. The changes in mitochondrial membrane potential (MMP) were observed through JC-1 staining. The expressions of p-RIP1, p-RIP3, p-MLKL, and MAPKs pathway proteins were analyzed by western blotting analysis. The efficacy of CPT in vivo was evaluated by the Lewis lung carcinoma (LLC) xenograft mice model. Blood samples were collected for hematology analysis. ELISA investigated the effects of CPT on tumor necrosis factor α (TNF-α). Hematoxylin and eosin staining (HE) was used to determine the tumor tissues. Proteins' expression of tumor tissues was quantified by western blotting. RESULTS CPT inhibited the cell viability of A549 cells in a time- and concentration-dependent manner, which was reversed by Necrostatin-1 (Nec-1). In addition, CPT treatment increased the expression of p-RIP1, p-RIP3, p-MLKL, the release of Ca2+, ROS generation, and the MAPKs pathway activated in A549 cells. Moreover, animal experiment results showed that intraperitoneal injection of CPT (15 mg/kg and 30 mg/kg) significantly inhibited tumor growth in C57BL/6 mice without affecting the bodyweight and injuring the organs. CONCLUSION Our findings suggested that CPT-induced necroptosis via RIP1/RIP3/MLKL signaling pathway both in vitro and in vivo, indicating that CPT may be a promising agent in the treatment of NSCLC.
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Affiliation(s)
- Wentong Zhao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Yuanbo Song
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine
| | - Qin-Qin Wang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning 530200, China
| | - Shan Han
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Xin-Xing Li
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Yushun Cui
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Guangxi Engineering Technology Research Center of Advantage Chinese Patent Drug and Ethnic Drug Development, Nanning 530200, China
| | - Hongwei Gao
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Renyikun Yuan
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Shilin Yang
- College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530000, China
- Jiangxi University of Chinese Medicine, Nanchang, 330004, China
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Li H, Wang Y, Su R, Jia Y, Lai X, Su H, Fan Y, Wang Y, Xing W, Qin J. Dimethyl Fumarate Combined With Vemurafenib Enhances Anti-Melanoma Efficacy via Inhibiting the Hippo/YAP, NRF2-ARE, and AKT/mTOR/ERK Pathways in A375 Melanoma Cells. Front Oncol 2022; 12:794216. [PMID: 35141161 PMCID: PMC8820202 DOI: 10.3389/fonc.2022.794216] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 01/05/2022] [Indexed: 12/18/2022] Open
Abstract
Melanoma is a deadly form of skin cancer with high rates of resistance to traditional chemotherapy and radiotherapy. BRAF inhibitors (BRAFi) can achieve initial efficacy when used to treat melanoma patients, but drug resistance and relapse are common, emphasizing the need for new therapeutic strategies. Herein, we reported that combination of dimethyl fumarate (DMF) and vemurafenib (Vem) inhibited melanoma cell proliferation more significantly and induced more cell death than single agent did both in vitro and in vivo. DMF/Vem treatment induced cell death through inhibiting the expression and transcriptional activity of NRF2 thereby resulting in more reactive oxygen species (ROS) and via inhibiting the expression of YAP, a key downstream effector of Hippo pathway. DMF/Vem treatment also reduced phosphorylation of AKT, 4EBP1, P70S6K and ERK in AKT/mTOR/ERK signaling pathways. RNA-seq analysis revealed that DMF/Vem treatment specifically suppressed 4561 genes which belong to dozens of cell signaling pathways. These results indicated that DMF/Vem treatment manifested an enhanced antitumor efficacy through inhibiting multiple cell signaling pathways, and thus would be a novel promising therapeutic approach targeted for melanoma.
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Affiliation(s)
- Hongxia Li
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Yaping Wang
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Rina Su
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Yuchen Jia
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Xiong Lai
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Huimin Su
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Yaochun Fan
- Inner Mongolia Autonomous Region Center for Disease Control and Prevention, Hohhot, China
| | - Yuewu Wang
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, College of Life Sciences, Inner Mongolia University, Hohhot, China
| | - Wanjin Xing
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, College of Life Sciences, Inner Mongolia University, Hohhot, China
- *Correspondence: Wanjin Xing, ; Jianzhong Qin,
| | - Jianzhong Qin
- College of Biological Sciences and Biotechnology, Dalian University, Dalian, China
- *Correspondence: Wanjin Xing, ; Jianzhong Qin,
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Liu YP, Lei J, Yin MM, Chen Y. Organoantimony (III) Derivative induces necroptosis in human breast cancer MDA-MB-231 cells. Anticancer Agents Med Chem 2022; 22:2448-2457. [PMID: 35040419 DOI: 10.2174/1871520622666220118093643] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/01/2021] [Accepted: 12/09/2021] [Indexed: 11/22/2022]
Abstract
PURPOSE This study aimed to investigate the anticancer effect and the underlying mechanisms of organoantimony (III) fluoride on MDA-MB-231 human breast cancer cells. METHODS Five cancer and one normal cell line were treated with an organoantimony (III) compound 6-cyclohexyl-12-fluoro-5,6,7,12-tetrahydrodibenzo[c,f][1,5]azastibocine (denoted as C4). The cell viability was detected by MTT assay. Induction of cell death was determined by Hoechst 33342/PI staining and Annexin-V/PI staining. The effect of C4 on the necroptotic relative protein was determined by Western blot analysis. RESULTS Among the five cancer cell lines, C4 decreased the viability of MDA-MB-231, MCF-7 and A2780/cisR, and showed less toxicity to normal human embryonic kidney cells. In breast cancer cell line MDA-MB-231, the C4 treatment induced the percentage of necrotic cell death as well as LDH releasing in a time- and dose-dependent manner. Moreover, C4 could increase the expression of phosphorylated RIPK3 and MLKL proteins. Overall, the C4 treatment resulted in reduction of mitochondrial transmembrane potential and accumulation ROS in MDA-MB-231 cells. CONCLUSION C4-induced necroptosis could be ascribed to glutathione depletion and ROS elevation in MDA-MB-231 cells. Our findings illustrate that C4 is a potential necroptosis inducer for breast cancer treatment.
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Affiliation(s)
- Yong-Ping Liu
- Department of Physiology, School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan,410208, PR China
| | - Jian Lei
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan, 410082, PR China
| | - Ming-Ming Yin
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan,410208, PR China
| | - Yi Chen
- Department of Physiology, School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan,410208, PR China
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Fu Y, Hu N, Cao M, Li WF, Yang XR, Gao JL, Zhao J, Jiang M, Ma MH, Sun ZJ, Dong DL. Anthelmintic niclosamide attenuates pressure-overload induced heart failure in mice. Eur J Pharmacol 2021; 912:174614. [PMID: 34736968 DOI: 10.1016/j.ejphar.2021.174614] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/03/2021] [Accepted: 10/29/2021] [Indexed: 02/05/2023]
Abstract
The heart is a high energy demand organ and enhancing mitochondrial function is proposed as the next-generation therapeutics for heart failure. Our previous study found that anthelmintic drug niclosamide enhanced mitochondrial respiration and increased adenosine triphosphate (ATP) production in cardiomyocytes, therefore, this study aimed to determine the effect of niclosamide on heart failure in mice and the potential molecular mechanisms. The heart failure model was induced by transverse aortic constriction (TAC) in mice. Oral administration of niclosamide improved TAC-induced cardiac hypertrophy, cardiac fibrosis, and cardiac dysfunction in mice. Oral administration of niclosamide reduced TAC-induced increase of serum IL-6 in heart failure mice. In vitro, niclosamide within 0.1 μM increased mitochondrial respiration and ATP production in mice heart tissues. At the concentrations more than 0.1 μM, niclosamide reduced the increased interleukin- 6 (IL-6) mRNA expression in lipopolysaccharide (LPS)-stimulated RAW264.7 and THP-1 derived macrophages. In cultured primary cardiomyocytes and cardiac fibroblasts, niclosamide (more than 0.1 μM) suppressed IL-6- and phenylephrine-induced cardiomyocyte hypertrophy, and inhibited collagen secretion from cardiac fibroblasts. In conclusion, niclosamide attenuates heart failure in mice and the underlying mechanisms include enhancing mitochondrial respiration of cardiomyocytes, inhibiting collagen secretion from cardiac fibroblasts, and reducing the elevated serum inflammatory mediator IL-6. The present study suggests that niclosamide might be therapeutic for heart failure.
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Affiliation(s)
- Yao Fu
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China
| | - Nan Hu
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China
| | - Ming Cao
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China
| | - Wen-Feng Li
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China
| | - Xin-Rui Yang
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China
| | - Jin-Lai Gao
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China
| | - Jing Zhao
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China
| | - Man Jiang
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China
| | - Ming-Hui Ma
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China
| | - Zhi-Jie Sun
- Department of Pharmacology, China Pharmaceutical University, Nanjing, PR China
| | - De-Li Dong
- Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, 150086, PR China.
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Zhang K, Song W, Wei M, Sun Y, Wang N, Ma L, Yu X, Gao R, Wang R, Zhang Y, Zheng N, Li N, Mu L, Tang Z, Li X, Yang C, Yang G. A Novel Anticancer Stem Cell Compound Derived from Pleuromutilin Induced Necroptosis of Melanoma Cells. J Med Chem 2021; 64:15825-15845. [PMID: 34704758 DOI: 10.1021/acs.jmedchem.1c01123] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Necroptosis has been recently confirmed as a non-apoptotic form of programmed cell death. Discovery of novel chemical entities, capable of inducing necroptosis of cancer cells, is likely to act as an alternative strategy for dealing with drug resistance clinically. In this study, the identification of a novel Pleuromutilin derivative (compound 38) is presented, capable of significantly increasing the cellular level of ROS and inducing melanoma cancer cell death via necroptosis. Furthermore, compound 38 noticeably ablated various cancer stem cells and inhibited the growth of melanoma cancer cells both in vitro and in vivo. Moreover, 38 exhibited low toxicity in animal models and excellent PK properties, which is currently being verified as a potential anticancer drug candidate.
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Affiliation(s)
- Kun Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Wei Song
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Mingming Wei
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Yue Sun
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Ning Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Lan Ma
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Xuan Yu
- Tianjin Institute for Drug Control, Tianjin 300021, P. R. China
| | - Ruolin Gao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Ruonan Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Yan Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Nan Zheng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Ning Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Linrong Mu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Zhiwen Tang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Xuechun Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
| | - Guang Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China
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D’Errico S, Russa RL, Maiese A, Santurro A, Scopetti M, Romano S, Zanon M, Frati P, Fineschi V. Atypical antipsychotics and oxidative cardiotoxicity: review of literature and future perspectives to prevent sudden cardiac death. J Geriatr Cardiol 2021; 18:663-685. [PMID: 34527032 PMCID: PMC8390928 DOI: 10.11909/j.issn.1671-5411.2021.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Oxidative stress is considered the principal mediator of myocardial injury under pathological conditions. It is well known that reactive oxygen (ROS) or nitrogen species (RNS) are involved in myocardial injury and repair at the same time and that cellular damage is generally due to an unbalance between generation and elimination of the free radicals due to an inadequate mechanism of antioxidant defense or to an increase in ROS and RNS. Major adverse cardiovascular events are often associated with drugs with associated findings such as fibrosis or inflammation of the myocardium. Despite efforts in the preclinical phase of the development of drugs, cardiotoxicity still remains a great concern. Cardiac toxicity due to second-generation antipsychotics (clozapine, olanzapine, quetiapine) has been observed in preclinical studies and described in patients affected with mental disorders. A role of oxidative stress has been hypothesized but more evidence is needed to confirm a causal relationship. A better knowledge of cardiotoxicity mechanisms should address in the future to establish the right dose and length of treatment without impacting the physical health of the patients.
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Affiliation(s)
- Stefano D’Errico
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Raffaele La Russa
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
- IRCSS Neuromed Mediterranean Neurological Institute, Pozzilli, Italy
| | - Aniello Maiese
- IRCSS Neuromed Mediterranean Neurological Institute, Pozzilli, Italy
- Department of Surgical Pathology, Medical, Molecular and Critical Area, University of Pisa, Pisa, Italy
| | - Alessandro Santurro
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Matteo Scopetti
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Silvia Romano
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Martina Zanon
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Paola Frati
- IRCSS Neuromed Mediterranean Neurological Institute, Pozzilli, Italy
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Vittorio Fineschi
- IRCSS Neuromed Mediterranean Neurological Institute, Pozzilli, Italy
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy
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Khan MN, Parmar DK, Das D. Recent Applications of Azo Dyes: A Paradigm Shift from Medicinal Chemistry to Biomedical Sciences. Mini Rev Med Chem 2021; 21:1071-1084. [PMID: 33231147 DOI: 10.2174/1389557520999201123210025] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/18/2020] [Accepted: 08/20/2020] [Indexed: 11/22/2022]
Abstract
Azo molecules possess the characteristic azo bond (-N=N-) and are considered fascinating motifs in organic chemistry. Since the last century, these brightly colored compounds have been widely employed as dyes across several industries in applications for printing, food, paper, cosmetics, lasers, electronics, optics, material sciences, etc. The discovery of Prontosil, an antibacterial drug, propelled azo compounds into the limelight in the field of medicinal chemistry. Subsequent discoveries including Phenazopyridine, Basalazide, and Sulfasalazine enabled azo compounds to occupy a significant role in the drug market. Furthermore, azo compounds have been employed as antibacterial, antimalarial, antifungal, antioxidant, as well as antiviral agents. The metabolic degradation of many azo dyes can induce liver problems if ingested, posing a safety concern and limiting their application as azo dyes in medicinal chemistry. However, azo dyes remain particularly significant for applications in cancer chemotherapy. Recently, a paradigm shift has been observed in the use of azo dyes: from medicinal chemistry to biomedical sciences. The latter benefits from azo dye application are related to imaging, drug delivery, photo-pharmacology and photo switching. Herein, we have compiled and discussed recent works on azo dye compounds obtained so far, focusing on their medicinal importance and future prospects.
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Affiliation(s)
- Md Nasim Khan
- Department of Chemistry, RK University, Rajkot, Gujrat-360020, India
| | - Digvijaysinh K Parmar
- Department of Chemistry, Education Hub, Kevdi, Diu college, DHES, Diu (U.T.) - 362520, India
| | - Debasis Das
- Discovery Chemistry Research, ArromaxPharmatech Co. Ltd. Sangtian Island Innovation Park, No. 1 Huayun Road, Suzhou 215123, China
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Singhal R, Mitta SR, Das NK, Kerk SA, Sajjakulnukit P, Solanki S, Andren A, Kumar R, Olive KP, Banerjee R, Lyssiotis CA, Shah YM. HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron. J Clin Invest 2021; 131:143691. [PMID: 33914705 DOI: 10.1172/jci143691] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 04/28/2021] [Indexed: 12/13/2022] Open
Abstract
Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, and metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factors hypoxia-inducible factor 1α (HIF-1α) and HIF-2α. Our work demonstrates that HIF-2α is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult, and tumors rapidly acquire resistance to inhibitors of HIF-2α. To overcome this limitation, we performed a small molecule screen to identify HIF-2α-dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell-permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2α-expressing tumor enteroids. Our work demonstrated that HIF-2α integrated 2 independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2α upregulated lipid and iron regulatory genes in CRC cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Second, via an iron-dependent, lipid peroxidation-independent pathway, HIF-2α activation potentiated ROS via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2α decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrated a mechanistic vulnerability in cancer cells that were dependent on HIF-2α that can be leveraged for CRC treatment.
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Affiliation(s)
| | | | - Nupur K Das
- Department of Molecular and Integrative Physiology
| | - Samuel A Kerk
- Department of Internal Medicine, Division of Gastroenterology.,Rogel Cancer Center, and
| | | | | | | | - Roshan Kumar
- Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Kenneth P Olive
- Department of Pathology.,Division of Digestive and Liver Diseases, Department of Medicine, and.,Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA
| | - Ruma Banerjee
- Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology.,Department of Internal Medicine, Division of Gastroenterology.,Rogel Cancer Center, and
| | - Yatrik M Shah
- Department of Molecular and Integrative Physiology.,Department of Internal Medicine, Division of Gastroenterology.,Rogel Cancer Center, and
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Eniafe J, Jiang S. The functional roles of TCA cycle metabolites in cancer. Oncogene 2021; 40:3351-3363. [PMID: 33864000 DOI: 10.1038/s41388-020-01639-8] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022]
Abstract
The tricarboxylic acid cycle (TCA cycle) has been known for decades as a hub for generating cellular energy and precursors for biosynthetic pathways. Several cancers harbor mutations that affect the integrity of this cycle, mostly at the levels of isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH). This results in dysregulation in the production of TCA cycle metabolites and is probably implicated in cancer initiation. By modulating cellular activities, including metabolism and signaling, TCA cycle intermediates are able to impact the processes of cancer development and progression. In this review, we discuss the functional roles of the TCA cycle intermediates in suppressing or promoting the progression of cancers. A further understanding of TCA metabolites' roles and molecular mechanisms in oncogenesis would prompt developing novel metabolite-based cancer therapy in the future.
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Affiliation(s)
- Joseph Eniafe
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Shuai Jiang
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA.
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Chen K, Wu S, Ye S, Huang H, Zhou Y, Zhou H, Wu S, Mao Y, Shangguan F, Lan L, Chen B. Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma. Front Pharmacol 2021; 12:617714. [PMID: 33692690 PMCID: PMC7937954 DOI: 10.3389/fphar.2021.617714] [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: 10/15/2020] [Accepted: 01/15/2021] [Indexed: 01/22/2023] Open
Abstract
Dimethyl fumarate (DMF) is an approved drug used in the treatment of multiple sclerosis (MS) and psoriasis therapy. Multiple studies have demonstrated other pharmacological activities of DMF such as an anti-cancer agent. In particular, studies have shown that DMF can modulate the NRF2/HO1/NQO1 antioxidant signal pathway and inactivate NF-κB to suppress the growth of colon and breast cancer cells, and induce cell death. In this study, we aimed to evaluate the anti-tumor activities of DMF in pancreatic cancer (PC) focusing on cell death as the predominant mechanism of response. We showed that both mitochondrial respiration and aerobic glycolysis were severely depressed following treatment with DMF and the effects could be abrogated by treatment with L-cysteine and N-acetyl-L-cysteine (NAC). Importantly, we verified that DMF induced metabolic crisis and that cell death was not related to alterations in ROS. Our data implied that MTHFD1 could be a potential downstream target of DMF identified by molecular docking analysis. Finally, we confirmed that MTHFD1 is up-regulated in PC and overexpression of MTHFD1 was negatively related to outcomes of PC patients. Our data indicate that DMF induces metabolic crisie to suppress cell growth and could be a potential novel therapy in the treatment of PC.
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Affiliation(s)
- Kaiyuan Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shanshan Wu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Laboratory of Precision Medical Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Sisi Ye
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Laboratory of Precision Medical Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huimin Huang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi Zhou
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongfei Zhou
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shijia Wu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yefan Mao
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fugen Shangguan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Linhua Lan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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