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Dalseno D, Gajic N, Flanagan L, Tait SWG. Cell death and cancer: Metabolic interconnections. Cell Rep 2025; 44:115804. [PMID: 40489330 DOI: 10.1016/j.celrep.2025.115804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 02/14/2025] [Accepted: 05/19/2025] [Indexed: 06/11/2025] Open
Abstract
Recent findings in the cell death field have transformed our understanding of the interplay between metabolism and cell death in the context of cancer. In this review, we discuss the relationships between metabolism and the cell death pathways of apoptosis, necroptosis, pyroptosis, and ferroptosis, with a particular focus on recent advancements. We will also explore the regulation of metabolism by the BCL-2 family and the participation of oncometabolites in the regulation of cell death. Finally, we examine the emerging links between cell death signaling and cellular persistence. As we highlight in this review, the intersection of metabolic and cell death pathways has implications for cancer cell survival, treatment resistance, and the tumor microenvironment.
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Affiliation(s)
- Destiny Dalseno
- School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK.
| | - Nikolai Gajic
- School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK
| | - Lyndsey Flanagan
- School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK
| | - Stephen W G Tait
- School of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK; Cancer Research UK Scotland Institute, Switchback Road, Glasgow G61 1BD, UK.
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2
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Nadendla EK, Tweedell RE, Kasof G, Kanneganti TD. Caspases: structural and molecular mechanisms and functions in cell death, innate immunity, and disease. Cell Discov 2025; 11:42. [PMID: 40325022 PMCID: PMC12052993 DOI: 10.1038/s41421-025-00791-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 03/05/2025] [Indexed: 05/07/2025] Open
Abstract
Caspases are critical regulators of cell death, development, innate immunity, host defense, and disease. Upon detection of pathogens, damage-associated molecular patterns, cytokines, or other homeostatic disruptions, innate immune sensors, such as NLRs, activate caspases to initiate distinct regulated cell death pathways, including non-lytic (apoptosis) and innate immune lytic (pyroptosis and PANoptosis) pathways. These cell death pathways are driven by specific caspases and distinguished by their unique molecular mechanisms, supramolecular complexes, and enzymatic properties. Traditionally, caspases are classified as either apoptotic (caspase-2, -3, -6, -7, -8, -9, and -10) or inflammatory (caspase-1, -4, -5, and -11). However, extensive data from the past decades have shown that apoptotic caspases can also drive lytic inflammatory cell death downstream of innate immune sensing and inflammatory responses, such as in the case of caspase-3, -6, -7, and -8. Therefore, more inclusive classification systems based on function, substrate specificity, or the presence of pro-domains have been proposed to better reflect the multifaceted roles of caspases. In this review, we categorize caspases into CARD-, DED-, and short/no pro-domain-containing groups and examine their critical functions in innate immunity and cell death, along with their structural and molecular mechanisms, including active site/exosite properties and substrates. Additionally, we highlight the emerging roles of caspases in cellular homeostasis and therapeutic targeting. Given the clinical relevance of caspases across multiple diseases, improved understanding of these proteins and their structure-function relationships is critical for developing effective treatment strategies.
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Affiliation(s)
- Eswar Kumar Nadendla
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Rebecca E Tweedell
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Gary Kasof
- Cell Signaling Technology, Danvers, MA, USA
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Hu L, Lu J, Fan H, Niu C, Han Y, Caiyin Q, Wu H, Qiao J. FAS mediates apoptosis, inflammation, and treatment of pathogen infection. Front Cell Infect Microbiol 2025; 15:1561102. [PMID: 40330016 PMCID: PMC12052831 DOI: 10.3389/fcimb.2025.1561102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/25/2025] [Indexed: 05/08/2025] Open
Abstract
The FAS cell surface death receptor, a member of the tumor necrosis factor receptor family, activates both apoptotic and non-apoptotic signaling upon interaction with its ligand FASL. It is critical in cell migration, invasion, immune responses, and carcinogenesis. Pathogen infection can influence host cells' behavior by modulating the FAS/FASL pathway, thereby influencing disease progression. Understanding the role of FAS signaling in the context of pathogen interactions is therefore crucial. This review examines FAS-mediated apoptotic and non-apoptotic signaling pathways, with particular emphasis on the mechanisms of apoptosis and inflammation induced by bacterial and viral infections. Additionally, it highlights therapeutic strategies, including drug, cytokine, antibody, and FASL recombinant protein therapies, providing new directions for treating pathogenic infections and cancers, as well as insights into developing novel therapeutic approaches.
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Affiliation(s)
- Liying Hu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Juane Lu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Hongfei Fan
- Tianjin Key Laboratory of Food Science and Biotechnology, College of Biotechnology and Food Science, Tianjin University of Commerce, Tianjin, China
| | - Changcheng Niu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Yanping Han
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Qinggele Caiyin
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, China
- State Key Laboratory of Synthetic Biology, Tianjin University, Tianjin, China
| | - Hao Wu
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
| | - Jianjun Qiao
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
- Zhejiang Research Institute of Tianjin University (Shaoxing), Shaoxing, China
- Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, China
- State Key Laboratory of Synthetic Biology, Tianjin University, Tianjin, China
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Hong Y, He J, Deng D, Liu Q, Zu X, Shen Y. Targeting kinases that regulate programmed cell death: a new therapeutic strategy for breast cancer. J Transl Med 2025; 23:439. [PMID: 40229646 PMCID: PMC11995514 DOI: 10.1186/s12967-025-06367-9] [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: 12/09/2024] [Accepted: 03/08/2025] [Indexed: 04/16/2025] Open
Abstract
Breast cancer is one of the most prevalent malignant tumors among women and ranks as the second leading cause of cancer-related deaths in females, primarily due to delays in diagnosis and shortcomings in treatment strategies. Consequently, there is a pressing need to identify reliable therapeutic targets and strategies. In recent years, the identification of effective biomarkers-particularly novel molecular therapeutic targets-has become a focal point in breast cancer research, aimed at predicting disease aggressiveness and monitoring treatment responses. Simultaneously, advancements in understanding the molecular mechanisms underlying cellular programmed death have opened new avenues for targeting kinase-regulated programmed cell death as a viable therapeutic strategy. This review summarizes the latest research progress regarding kinase-regulated programmed death (including apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis) in breast cancer treatment. It covers the key kinases involved in this mechanism, their roles in the onset and progression of breast cancer, and strategies for modulating these kinases through pharmacological interventions.
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Affiliation(s)
- Yun Hong
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-Incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jun He
- Department of Spine Surgery, The Nanhua Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, China
| | - Dan Deng
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-Incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Qinyue Liu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-Incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xuyu Zu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
- Hunan Provincial Clinical Medical Research Center for Drug Evaluation of major chronic diseases, Hengyang, China.
| | - Yingying Shen
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China.
- Hunan Provincial Clinical Medical Research Center for Drug Evaluation of major chronic diseases, Hengyang, China.
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Hu T, Lai X, Li L, Li Y, Wang M, Zhang H, Yang Y, Zhang C, Yan Y, Wang B. UVB-Induced necroptosis of the skin cells via RIPK3-MLKL activation independent of RIPK1 kinase activity. Cell Death Discov 2025; 11:167. [PMID: 40221399 PMCID: PMC11993685 DOI: 10.1038/s41420-025-02471-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 03/29/2025] [Accepted: 04/02/2025] [Indexed: 04/14/2025] Open
Abstract
Ultraviolet B (UVB) is recognized for inducing inflammation and death of keratinocytes through the activation of death receptors and pattern recognition receptors (PRRs). Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 play pivotal roles in mediating necroptosis, which can be triggered by the activation of specific death receptors and PRRs. In this study, we observed a reduction of RIPK1 protein after UVB exposure which led to activation of Nuclear factor-kappa B (NF-κB) in HaCaT cells. This activation, in turn, promoted the production of IL-1β and TNF-α. However, RIPK1 kinase remained inactive and did not participate in cell death. Interestingly, UVB radiation triggered the activation of RIPK3 independently of RIPK1 kinase activity and subsequently induced phosphorylation of mixed-lineage kinase domain-like protein (MLKL), culminating in necroptosis and inflammation of the skin. At the same time, UVB-induced activation of RIPK3 also played a role in promoting the mitochondrial apoptotic pathway of Keratinocytes. In conclusion, UVB irradiation initiates an inflammatory response via RIPK1 pathway without necessitating its enzymatic activity. Simultaneously, RIPK3 can be activated by UVB exposure independently of RIPK1's activity, resulting in necroptosis and inflammation of the skin.
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Affiliation(s)
- Tairan Hu
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaodong Lai
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Li
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Li
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Meng Wang
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haini Zhang
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Yang
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chong Zhang
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Yan
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Baoxi Wang
- Department of Dermatology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Barbero-Úriz Ó, Valenti M, Molina M, Fernández-Acero T, Cid VJ. Modeling Necroptotic and Pyroptotic Signaling in Saccharomyces cerevisiae. Biomolecules 2025; 15:530. [PMID: 40305268 PMCID: PMC12025182 DOI: 10.3390/biom15040530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 03/28/2025] [Accepted: 04/01/2025] [Indexed: 05/02/2025] Open
Abstract
The yeast Saccharomyces cerevisiae is the paradigm of a eukaryotic model organism. In virtue of a substantial degree of functional conservation, it has been extensively exploited to understand multiple aspects of the genetic, molecular, and cellular biology of human disease. Many aspects of cell signaling in cancer, aging, or metabolic diseases have been tackled in yeast. Here, we review the strategies undertaken throughout the years for the development of humanized yeast models to study regulated cell death (RCD) pathways in general, and specifically, those related to innate immunity and inflammation, with an emphasis on pyroptosis and necroptosis. Such pathways involve the assembly of distinct modular signaling complexes such as the inflammasome and the necrosome. Like other supramolecular organizing centers (SMOCs), such intricate molecular arrangements trigger the activity of enzymes, like caspases or protein kinases, culminating in the activation of lytic pore-forming final effectors, respectively, Gasdermin D (GSDMD) in pyroptosis and MLKL in necroptosis. Even though pathways related to those governing innate immunity and inflammation in mammals are missing in fungi, the heterologous expression of their components in the S. cerevisiae model provides a "cellular test tube" to readily study their properties and interactions, thus constituting a valuable tool for finding novel therapies.
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Affiliation(s)
| | | | | | | | - Víctor J. Cid
- Department of Microbiology and Parasitology, School of Pharmacy, Universidad Complutense de Madrid, Pza. de Ramón y Cajal s/n, 28040 Madrid, Spain; (Ó.B.-Ú.); (M.V.); (M.M.); (T.F.-A.)
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Malone K, LaCasse E, Beug ST. Cell death in glioblastoma and the central nervous system. Cell Oncol (Dordr) 2025; 48:313-349. [PMID: 39503973 PMCID: PMC11997006 DOI: 10.1007/s13402-024-01007-8] [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] [Accepted: 10/20/2024] [Indexed: 04/15/2025] Open
Abstract
Glioblastoma is the commonest and deadliest primary brain tumor. Glioblastoma is characterized by significant intra- and inter-tumoral heterogeneity, resistance to treatment and dismal prognoses despite decades of research in understanding its biological underpinnings. Encompassed within this heterogeneity and therapy resistance are severely dysregulated programmed cell death pathways. Glioblastomas recapitulate many neurodevelopmental and neural injury responses; in addition, glioblastoma cells are composed of multiple different transformed versions of CNS cell types. To obtain a greater understanding of the features underlying cell death regulation in glioblastoma, it is important to understand the control of cell death within the healthy CNS during homeostatic and neurodegenerative conditions. Herein, we review apoptotic control within neural stem cells, astrocytes, oligodendrocytes and neurons and compare them to glioblastoma apoptotic control. Specific focus is paid to the Inhibitor of Apoptosis proteins, which play key roles in neuroinflammation, CNS cell survival and gliomagenesis. This review will help in understanding glioblastoma as a transformed version of a heterogeneous organ composed of multiple varied cell types performing different functions and possessing different means of apoptotic control. Further, this review will help in developing more glioblastoma-specific treatment approaches and will better inform treatments looking at more direct brain delivery of therapeutic agents.
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Affiliation(s)
- Kyle Malone
- Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Eric LaCasse
- Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Shawn T Beug
- Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
- Centre for Infection, Immunity and Inflammation, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
- Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
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Yang LK, Ma WJ, Wang X, Chen HR, Jiang YN, Sun H. Apoptosis in polycystic ovary syndrome: Mechanisms and therapeutic implications. Life Sci 2025; 363:123394. [PMID: 39809382 DOI: 10.1016/j.lfs.2025.123394] [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: 08/19/2024] [Revised: 12/30/2024] [Accepted: 01/10/2025] [Indexed: 01/16/2025]
Abstract
Polycystic ovary syndrome (PCOS) is a common disorder that affects the female reproductive system, with an incidence of 8 % to 15 %. It is characterized by irregular menstruation, hyperandrogenemia, and polycystic abnormalities in the ovaries. Nevertheless, there is still much to learn about the molecular pathways underlying PCOS. Apoptosis is the process by which cells actively destroy themselves, and it is vital to an organism's ability to develop normally and maintain homeostasis. In recent years, a growing body of research has indicated a connection between the pathophysiology of PCOS and apoptosis. Therefore, it is critical to comprehend the relationship between PCOS and apoptosis in greater detail, identify the pathophysiological underpinnings of PCOS, and provide fresh perspectives and targets for its treatment. This review aims to summarize the relationship between PCOS and apoptosis, discuss how apoptosis affects normal ovarian function and how it becomes dysfunctional in the ovaries of PCOS patients, and investigate the signaling pathways associated with apoptosis in PCOS, including PI3K-Akt, TNF, NF-κB, and p53. Additionally, potential therapeutic approaches for PCOS treatment are provided by summarizing the role of apoptosis in PCOS therapy.
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Affiliation(s)
- Ling-Kun Yang
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, PR China
| | - Wan-Jing Ma
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, PR China
| | - Xiao Wang
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, PR China
| | - Huan-Ran Chen
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, PR China
| | - Ya-Nan Jiang
- Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, PR China.
| | - Hui Sun
- Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150081, PR China.
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Baguma M, Kessels S, Bito V, Brône B, Triller A, Maynard S, Legendre P, Rigo JM, Le Corronc H, Chabwine JN. New insight into the molecular etiopathogenesis of konzo: Cyanate could be a plausible neurotoxin contributing to konzo, contrary to thiocyanate. Neurotoxicology 2024; 105:323-333. [PMID: 39608576 DOI: 10.1016/j.neuro.2024.11.004] [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: 07/18/2024] [Revised: 11/14/2024] [Accepted: 11/25/2024] [Indexed: 11/30/2024]
Abstract
INTRODUCTION Chronic cassava-derived cyanide poisoning is associated with the appearance of konzo, a tropical spastic paraparesis due to selective upper motor neuron damage. Whether the disease is caused by a direct action of cyanide or its metabolites is still an open question. This preliminary study assessed the neurotoxic effects of thiocyanate (SCN) and cyanate (OCN), two cyanide metabolites hypothesized to be plausible toxic agents in konzo. METHODS Cultured mouse neuroblastoma (Neuro-2A) and human neuroblastoma (SH-SY5Y) cell lines were incubated (24, 48, and 72 hours) in sodium OCN or sodium SCN in a disease-relevant concentration range. Cell viability, caspase (3, 8, and 9) activities, and reactive oxygen species (ROS) generation were evaluated using appropriate assay kits. Additionally, electrophysiological responses induced by OCN and SCN in primary spinal cord neurons (from Sprague Dawley rats) were assessed by whole-cell patch-clamp techniques. RESULTS Both OCN and SCN were toxic in a dose-dependent way, even if SCN toxicity appeared at very high concentrations (30 mM, corresponding to more than 100-fold higher than normal plasmatic levels), contrary to OCN (0.3-3 mM). OCN was markedly more toxic in a poor culture medium (MEM; IC50 = 3.2 mM) compared to a glucose- and amino acid-rich medium (DMEM; IC50=7.6 mM). OCN treatment increased the ROS generation by 8.9 folds, as well as the Caspase-3, Caspase-8, and Caspase-9 activities by 3.2, 2.5, and 2.6 folds, respectively. Finally, OCN (and SCN to a lesser extent) induced depolarizing currents in primary spinal cord neurons, through an activation of ionotropic glutamate receptors. CONCLUSION Our results suggest OCN as the most plausible neurotoxic agent involved in konzo, while SCN toxicity could be questioned at such high concentrations. Also, they support apoptosis, oxidative stress, and excitotoxicity as probable mechanisms of OCN neurotoxicity.
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Affiliation(s)
- Marius Baguma
- UHasselt, Neuroscience Research Group (NEURO), BIOMED, Agoralaan, 3590 Diepenbeek, Belgium; Université Catholique de Bukavu (UCB), Center for Tropical Diseases and Global Health (CTDGH), Bukavu, Democratic Republic Congo; Hôpital Provincial Général de Référence de Bukavu (HPGRB), Neurology Ward, Bukavu, Democratic Republic Congo.
| | - Sofie Kessels
- UHasselt, Neuroscience Research Group (NEURO), BIOMED, Agoralaan, 3590 Diepenbeek, Belgium
| | - Virginie Bito
- UHasselt, Cardio & Organ Systems (COST), BIOMED, Agoralaan, 3590 Diepenbeek, Belgium
| | - Bert Brône
- UHasselt, Neuroscience Research Group (NEURO), BIOMED, Agoralaan, 3590 Diepenbeek, Belgium
| | - Antoine Triller
- Institut de Biologie de l'École Normale Supérieure (IBENS), CNRS, Inserm, Université PSL, Paris, France
| | - Stéphanie Maynard
- Institut de Biologie de l'École Normale Supérieure (IBENS), CNRS, Inserm, Université PSL, Paris, France
| | - Pascal Legendre
- Sorbonne Université, INSERM, CNRS, Neurosciences Paris Seine - Institut de Biologie, Paris Seine (NPS - IBPS), Paris 75005, France
| | - Jean-Michel Rigo
- UHasselt, Neuroscience Research Group (NEURO), BIOMED, Agoralaan, 3590 Diepenbeek, Belgium
| | - Hervé Le Corronc
- Sorbonne Université, INSERM, CNRS, Neurosciences Paris Seine - Institut de Biologie, Paris Seine (NPS - IBPS), Paris 75005, France; Université d'Angers, Angers, France
| | - Joelle Nsimire Chabwine
- Université Catholique de Bukavu (UCB), Center for Tropical Diseases and Global Health (CTDGH), Bukavu, Democratic Republic Congo; University of Fribourg, Faculty of Science and Medicine, Department of Neuroscience and Movement Science, Fribourg, Switzerland
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Tu W, Guo M, Zhang Z, Li C. Pathogen-induced apoptosis in echinoderms: A review. FISH & SHELLFISH IMMUNOLOGY 2024; 155:109990. [PMID: 39481501 DOI: 10.1016/j.fsi.2024.109990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/16/2024] [Accepted: 10/26/2024] [Indexed: 11/02/2024]
Abstract
Echinoderms possess unique biological traits that make them valuable models in immunology, regeneration, and developmental biology studies. As a class rich in active substances with significant nutritional and medicinal value, echinoderms face threats from marine pathogens, including bacteria, viruses, fungi, protozoa, and parasites, which have caused substantial economic losses in echinoderm aquaculture. Echinoderms counteract pathogen invasion through innate immunity and programmed cell death, in particular, with apoptosis being essential for eliminating infected or damaged cells and maintaining homeostasis in many echinoderm cell types. Despite the importance of this process, there is a lack of comprehensive and updated reviews on this topic. This review underscores that echinoderm apoptotic pathways exhibit a complexity comparable to that of vertebrates, featuring proteins with unique domains that may indicate the presence of novel signaling mechanisms. We synthesize current knowledge on how echinoderms utilize diverse transcriptional and post-transcriptional mechanisms to regulate apoptosis in response to pathogen infections and explore how pathogens have evolved strategies to manipulate echinoderm apoptosis, either by inhibiting it to create survival niches or by inducing excessive apoptosis to weaken the host. By elucidating the primary apoptotic pathways in echinoderms and the host-pathogen interactions that modulate these pathways, this review aims to reveal new mechanisms of apoptosis in animal immune defense and provide insights into the evolutionary arms race between hosts and pathogens.
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Affiliation(s)
- Weitao Tu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Ming Guo
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
| | - Zhen Zhang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Chenghua Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, China.
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Sun Y, Liu K. Mechanistic Insights into Influenza A Virus-Induced Cell Death and Emerging Treatment Strategies. Vet Sci 2024; 11:555. [PMID: 39591329 PMCID: PMC11598850 DOI: 10.3390/vetsci11110555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 10/30/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
Influenza A virus (IAV) infection initiates a complex interplay of cell death modalities, including apoptosis, necroptosis, pyroptosis, and their integration, known as PANoptosis, which significantly impacts host immune responses and tissue integrity. These pathways are intricately regulated by viral proteins and host factors, contributing to both viral clearance and pathogenesis-related tissue damage. This review comprehensively explores the molecular mechanisms underlying these cell death processes in influenza infection. We highlight the roles of key regulatory proteins, such as ZBP1 (Z-DNA binding protein 1) and RIPK3 (receptor-interacting protein kinase 3), in orchestrating these responses, emphasizing the dual roles of cell death in both antiviral defense and tissue injury. Furthermore, we discuss emerging therapeutic strategies targeting these pathways, aiming to enhance antiviral efficacy while minimizing collateral tissue damage. Future research should focus on targeted approaches to modulate cell death mechanisms, aiming to reduce tissue damage and improve clinical outcomes for patients with severe influenza.
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Affiliation(s)
- Yuling Sun
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China
| | - Kaituo Liu
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China
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12
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Zhang J, Du C, Pan Y, Zhang Z, Feng R, Ma M, Wang T. Optimization of a novel expression system for recombinant protein production in CHO cells. Sci Rep 2024; 14:24913. [PMID: 39438721 PMCID: PMC11496728 DOI: 10.1038/s41598-024-76995-6] [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: 06/30/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024] Open
Abstract
Chinese hamster ovary (CHO) cells are common mammalian cell lines for expressing recombinant proteins, yet the expression level of recombinant proteins is still hindered. Vector optimization and cell line modification are the key factors to improve the expression of recombinant proteins. In this study, the vector was optimized by adding the regulatory elements Kozak and Leader to the upstream of target gene to detect the transient and stable expression of recombinant proteins. Results indicated that the expression level of target proteins with the addition of regulatory elements was significantly increased compared with the control group. In addition, the inhibition of apoptotic pathway has great potential to increase recombinant protein production, and Apaf1 protein dependent on the mitochondrial apoptosis pathway plays an important role in this respect. The knockout of apoptotic gene Apaf1 in CHO cells can also increase recombinant protein production. Therefore, the vector was optimized by adding regulatory elements, and the cell line was modified by using CRISPR/Cas9 technology to establish a novel CHO cell expression system, which remarkably improved the expression level of recombinant proteins and laid the foundation for the large-scale production of recombinant proteins.
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Affiliation(s)
- Junhe Zhang
- Institutes of Health Central Plains, Xinxiang Key Laboratory for Tumor Drug Screening and Targeted Therapy, Xinxiang Medical University, Xinxiang, 453003, China.
- International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Xinxiang Medical University, No. 601 Jinsui Road, Xinxiang, 453003, Henan, China.
- Xinxiang Medical University, Xinxiang, 453003, China.
| | - Chenyang Du
- Institutes of Health Central Plains, Xinxiang Key Laboratory for Tumor Drug Screening and Targeted Therapy, Xinxiang Medical University, Xinxiang, 453003, China
- International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Xinxiang Medical University, No. 601 Jinsui Road, Xinxiang, 453003, Henan, China
| | - Yue Pan
- Xinxiang Medical University, Xinxiang, 453003, China
| | - Zhan Zhang
- Xinxiang Medical University, Xinxiang, 453003, China
| | - Ruoyuan Feng
- Xinxiang Medical University, Xinxiang, 453003, China
| | - Mengyao Ma
- Xinxiang Medical University, Xinxiang, 453003, China
| | - Tianyun Wang
- International Joint Research Laboratory for Recombinant Pharmaceutical Protein Expression System of Henan, Xinxiang Medical University, No. 601 Jinsui Road, Xinxiang, 453003, Henan, China.
- Xinxiang Medical University, Xinxiang, 453003, China.
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13
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Yoon JH, Kim DO, Lee S, Lee BH, Kim ES, Son YK, Kopalli SR, Lee JH, Ju Y, Lee J, Cho JY. Anti-apoptotic, anti-inflammatory, and anti-melanogenic effects of the ethanol extract of Picrasma quassioides (D. Don) Benn. JOURNAL OF ETHNOPHARMACOLOGY 2024; 332:118374. [PMID: 38789093 DOI: 10.1016/j.jep.2024.118374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 05/26/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Picrasma quassioides (D. Don) Benn is a vascular plant belonging to the genus Picrasma of Simaroubaceae family and grows in Korea, China, India, Taiwan, and Japan. Picrasma quassioides extract has been reported to have anti-inflammatory, anti-bacterial, and anti-cancer properties. Moreover, this plant has been also traditionally used to alleviate symptoms of eczema, atopic dermatitis, psoriasis, scabies, and boils in skin. AIM OF THE STUDY The Pq-EE has been reported in Chinese pharmacopoeia for its pharmacological effects on skin. However, the detailed mechanism on alleviating skin conditions is not understood. Hence, we investigated the skin improvement potential of Pq-EE against skin damage. MATERIALS AND METHODS We used the human keratinocyte cell line (HaCaT) and mouse melanoma cell line (B16F10) to study the effects of Pq-EE on the epidermis. Additionally, in vitro antioxidant assays were performed using a solution that included either metal ions or free radicals. RESULTS In colorimetric antioxidant assays, Pq-EE inhibited free radicals in a dose-dependent manner. The Pq-EE did not affect cell viability and promoted cell survival under UVB exposure conditions in the MTT assay. The Pq-EE downregulated the mRNA levels of apoptotic factors. Moreover, MMP1 and inflammatory cytokine iNOS mRNA levels decreased with Pq-EE treatment. With regard to protein levels, caspases and cleaved caspases were more powerfully inhibited by Pq-EE than UVB-irritated conditions. p53 and Bax also decreased with Pq-EE treatment. The melanin contents and secretion were decreased at nontoxic concentrations of Pq-EE. The pigmentation pathway genes also were inhibited by treatment with Pq-EE. CONCLUSIONS In summary, we suggest the cell protective potential of Pq-EE against UVB and ROS, indicating its use in UV-protective cosmeceutical materials.
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Affiliation(s)
- Ji Hye Yoon
- Department of Interdisciplinary Program in Biocosmetics, Sungkyunkwan University, Suwon, 16419, South Korea.
| | - Dong-Ock Kim
- Department of Interdisciplinary Program in Biocosmetics, Sungkyunkwan University, Suwon, 16419, South Korea.
| | - Seungki Lee
- National Institute of Biological Resources, Environmental Research Complex, Incheon, 22689, South Korea.
| | - Byong-Hee Lee
- National Institute of Biological Resources, Environmental Research Complex, Incheon, 22689, South Korea.
| | - Eun Sil Kim
- National Institute of Biological Resources, Environmental Research Complex, Incheon, 22689, South Korea.
| | - Youn Kyoung Son
- National Institute of Biological Resources, Environmental Research Complex, Incheon, 22689, South Korea.
| | - Spandana Rajendra Kopalli
- Department of Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul, 05006, South Korea.
| | - Ji Heun Lee
- PharmacoBio Inc, Jungwon-gu, Seongnam, 13219, South Korea.
| | - Youngwoon Ju
- PharmacoBio Inc, Jungwon-gu, Seongnam, 13219, South Korea.
| | - Jongsung Lee
- Department of Interdisciplinary Program in Biocosmetics, Sungkyunkwan University, Suwon, 16419, South Korea; Department of Integrative Biotechnology, Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, South Korea.
| | - Jae Youl Cho
- Department of Interdisciplinary Program in Biocosmetics, Sungkyunkwan University, Suwon, 16419, South Korea; Department of Integrative Biotechnology, Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, South Korea.
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14
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Ge J, Wang Y, Li X, Lu Q, Yu H, Liu H, Ma K, Deng X, Luo ZQ, Liu X, Qiu J. Phosphorylation of caspases by a bacterial kinase inhibits host programmed cell death. Nat Commun 2024; 15:8464. [PMID: 39349471 PMCID: PMC11442631 DOI: 10.1038/s41467-024-52817-1] [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: 03/25/2024] [Accepted: 09/20/2024] [Indexed: 10/02/2024] Open
Abstract
The intracellular bacterial pathogen Legionella pneumophila utilizes the Dot/Icm system to translocate over 330 effectors into the host cytosol. These virulence factors modify a variety of cell processes, including pathways involved in cell death and survival, to promote bacterial proliferation. Here, we show that the effector LegK3 is a eukaryotic-like Ser/Thr kinase that functions to suppress host apoptosis. Mechanistically, LegK3 directly phosphorylates multiple caspases involved in apoptosis signaling, including Caspase-3, Caspase-7, and Caspase-9. LegK3-induced phosphorylation of these caspases occurs at serine (Ser29 in Caspase-3 and Ser199 in Caspase-7) or threonine (Thr102 in Caspase-9) residues located in the prodomain or interdomain linkers. These modifications interfere with the suitability of the caspases as the substrates of initiator caspases or upstream regulators without impacting their proteolytic activity. Collectively, our study reveals a novel strategy used by L. pneumophila to maintain the integrity of infected cells for its intracellular growth.
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Affiliation(s)
- Jinli Ge
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ying Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China
| | - Xueyu Li
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Qian Lu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Hangqian Yu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Hongtao Liu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Kelong Ma
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xuming Deng
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zhao-Qing Luo
- Purdue Institute for Inflammation, Immunology and Infectious Disease and Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
| | - Xiaoyun Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
- NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
| | - Jiazhang Qiu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
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15
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Yang J, Geng Y, Zhao B, Liu T, Luo JL, Gao XJ. Green tea polyphenols alleviate TBBPA-induced gastric inflammation and apoptosis by modulating the ROS-PERK/IRE-1/ATF6 pathway in mouse models. Food Funct 2024; 15:10179-10189. [PMID: 39301672 DOI: 10.1039/d4fo03012e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2024]
Abstract
Green tea polyphenols (GTP), an important phytochemical in the daily human diet, bind to various cellular receptors and exert anti-inflammatory and antioxidant benefits. The environmental contaminant tetrabromobisphenol A (TBBPA) enters the digestive system through multiple pathways, resulting in oxidative stress (OS), gastroenteritis, and mucosal injury. The aim of this study was to explore the molecular mechanisms of TBBPA-induced gastritis in mice treated with GTP in vivo and in an in vitro model. The results showed that exposure to TBBPA increased reactive oxygen species (ROS) levels, activated oxidative stress (OS) induced endoplasmic reticulum stress (ERS), and the expression of endoplasmic reticulum stress-related factors (e.g., GRP78, PERK, IRE-1, ATF-6, etc.) increased. The inflammatory pathway NF-κB was activated, and the pro-inflammatory factors TNF-α, IL-1β, and IL-6 increased, while triggering a cascade reaction mediated by caspase-3. However, the addition of GTP could inhibit OS, restore the balance of endoplasmic reticulum homeostasis, and improve the inflammatory infiltration and apoptosis of gastric mucosal epithelial cells. Therefore, GTP alleviated ERS, reduced inflammation and apoptosis, and restored the gastric mucosal barrier by alleviating TBBPA-induced OS in mouse gastric tissues and GES-1 cells. This provides basic information for exploring the antioxidant mechanism of GTP and further investigating the toxic effects of TBBPA on mouse gastric mucosa.
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Affiliation(s)
- Jie Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150000, China.
| | - Yuan Geng
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150000, China.
| | - Bing Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150000, China.
| | - Tianjing Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150000, China.
| | - Ji-Long Luo
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150000, China.
| | - Xue-Jiao Gao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150000, China.
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16
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Wang M, Chao M, Han H, Zhao T, Yan W, Yang G, Pang W, Cai R. Hinokiflavone resists HFD-induced obesity by promoting apoptosis in an IGF2BP2-mediated Bim m 6A modification dependent manner. J Biol Chem 2024; 300:107721. [PMID: 39214307 PMCID: PMC11465056 DOI: 10.1016/j.jbc.2024.107721] [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: 03/11/2024] [Revised: 07/29/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
Obesity has emerged as a major health risk on a global scale. Hinokiflavone (HF), a natural small molecule, extracted from plants like cypress, exhibits diverse chemical structures and low synthesis costs. Using high-fat diet-induced obese mice models, we found that HF suppresses obesity by inducing apoptosis in adipose tissue. Adipocyte apoptosis helps maintain tissue health by removing aging, damaged, or excess cells in adipose tissue, which is crucial in preventing obesity and metabolic diseases. We found that HF can specifically bind to insulin-like growth factor 2 mRNA binding protein 2 to promote the stability of N6-methyladenosine-modified Bim, inducing mitochondrial outer membrane permeabilization. Mitochondrial outer membrane permeabilization leads to Caspase9/3-mediated adipocyte mitochondrial apoptosis, alleviating obesity induced by a high-fat diet. The proapoptotic effect of HF offers a controlled means for weight loss. This study reveals the potential of small molecule HF in developing new therapeutic approaches in drug development and biomedical research.
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Affiliation(s)
- Mingyu Wang
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Mingkun Chao
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Haozhe Han
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Tiantian Zhao
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Wenyong Yan
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Gongshe Yang
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Weijun Pang
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
| | - Rui Cai
- Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
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17
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Rostro-Alonso GO, Castillo-Montoya AI, García-Acosta JC, Aguilar-Llanos EF, Quintas-Granados LI, Villegas-Vazquez EY, García-Aguilar R, Porras-Vázquez SA, Bustamante-Montes LP, Alvarado-Sansininea JJ, Jiménez-Estrada M, Cariño-Calvo L, Carmen MGD, Cortés H, Leyva-Gómez G, Figueroa-González G, Reyes-Hernández OD. Cacalol Acetate as Anticancer Agent: Antiproliferative, Pro-Apoptotic, Cytostatic, and Anti-Migratory Effects. Curr Issues Mol Biol 2024; 46:9298-9311. [PMID: 39329902 PMCID: PMC11430360 DOI: 10.3390/cimb46090550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/28/2024] Open
Abstract
Cacalol (C), a sesquiterpene isolated from Psacalium decompositum, has demonstrated anti-inflammatory and antioxidant activities. Its cytotoxic, antiproliferative, and pro-apoptotic effects have been previously shown in an in vitro breast cancer model. A derivative, cacalol acetate (CA), shows potential in regulating these processes, which has not been previously reported. This study focused on an in vitro cervical cancer model, assessing CA's antiproliferative, pro-apoptotic, cytostatic, and anti-migratory activities using the HeLa cell line. The natural anticancer agent indole-3-carbinol (I3C) was used as a control for comparison. CA demonstrated significant antitumor activities, including inhibiting cell growth, inducing apoptosis, arresting cells in the G2 phase of the cell cycle, and inhibiting cell migration. These effects were notably greater compared to I3C. I3C, while following a similar trend, did not induce Cas-3 expression, suggesting a different apoptotic pathway. Neither CA nor I3C increased p62 and LC3B levels, indicating they do not stimulate autophagy marker expression. Both compounds inhibited HeLa cell migration and induced cell cycle arrest. Despite both holding promise as anticancer agents for cervical cancer, CA's lower cytotoxicity and stronger regulation of tumor phenotypes make it a more promising agent compared to I3C.
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Affiliation(s)
- Gareth Omar Rostro-Alonso
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Alejandro Israel Castillo-Montoya
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Juan Carlos García-Acosta
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Erick Fernando Aguilar-Llanos
- Laboratorio de Biología Molecular del Cáncer, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autónoma de México, Iztapalapa, Mexico City 09230, Mexico
| | - Laura Itzel Quintas-Granados
- Colegio de Ciencias y Humanidades, Plantel Cuautepec, Universidad Autónoma de la Ciudad de México, Calle Dr. García Diego 168, Doctores, Cuauhtémoc, Mexico City 06720, Mexico
| | - Edgar Yebrán Villegas-Vazquez
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Rosario García-Aguilar
- Laboratorio de Citometría de Flujo y Hematología, Diagnóstico Molecular de Leucemias y Terapia Celular (DILETEC), Gustavo A. Madero, Mexico City 06350, Mexico
| | - Samantha Andrea Porras-Vázquez
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | | | - Jesús J Alvarado-Sansininea
- Laboratorio 2-10, Departamento de Productos Naturales, Instituto de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Manuel Jiménez-Estrada
- Laboratorio 2-10, Departamento de Productos Naturales, Instituto de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | | | | | - Hernán Cortés
- Laboratorio de Medicina Genómica, Departamento de Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Gerardo Leyva-Gómez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Gabriela Figueroa-González
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
| | - Octavio Daniel Reyes-Hernández
- Laboratorio de Farmacogenética, Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Esquina Fuerte de Loreto, Iztapalapa, Mexico City 09230, Mexico
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18
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Zhang J, Han H, Liu Y, Xu J, Zhang D, Wang W, Gao Y, Li Z, Qin Y. SKF96365 Inhibits Tumor Proliferation by Inducing Apoptosis and Autophagy in Human Esophageal Squamous Cell Carcinoma. Int J Genomics 2024; 2024:4501154. [PMID: 39165489 PMCID: PMC11335422 DOI: 10.1155/2024/4501154] [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: 03/14/2024] [Revised: 07/03/2024] [Accepted: 07/10/2024] [Indexed: 08/22/2024] Open
Abstract
Calcium channel blockers are emerging as a new generation of attractive anticancer drugs. SKF96365, originally thought to be a store-operated calcium entry (SOCE) inhibitor, is now often used as a TRPC channel blocker and is widely used in medical diagnostics. SKF96365 has shown antitumor effects on a variety of cancer cell lines. The objective of this study was to investigate the anticancer effect of SKF96365 on esophageal cancer in vivo and in vitro. Cell Counting Kit-8 (CCK-8) and colony formation were used to test the proliferation inhibition of SKF96365 on cell lines. Western blot and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to detect cell apoptosis rates. In addition, we demonstrated the antitumor effect of SKF96365 in vivo in xenografted mice. As a result, SKF96365 significantly inhibited the proliferation of K510, K30, and EC9706 in vitro. SKF96365 induces apoptosis in three cell lines through the poly(adenosine diphosphate-ribose) polymerase (PARP), caspase-9, and BCL-2 pathways in a dose-dependent and time-dependent manner. Moreover, SKF96365 treatment also induced apoptosis and inhibited tumor growth in nude mice. The calcium channel TRPC1 was significantly downregulated by SKF96365. Autophagy was also induced during the treatment of SKF96365. In summary, SKF96365 induces apoptosis (PARP, caspase-9, and BCL-2) and autophagy (LC3-A/B) by inhibiting TRPC1 in esophageal cancer cells, thereby inhibiting tumor growth.
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Affiliation(s)
- Jiaxin Zhang
- Department of OncologyThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Huiqiong Han
- Department of OncologyThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yihan Liu
- Department of OncologyThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jiayao Xu
- Department of OncologyThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Daidi Zhang
- Department of OncologyThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Wenjia Wang
- Department of OncologyThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yaping Gao
- Department of OncologyThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zhengrui Li
- Department of Oral and Maxillofacial-Head and Neck OncologyShanghai Ninth People's HospitalShanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Yanru Qin
- Department of OncologyThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
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19
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Guo X, Zhang RR, Sun JY, Liu Y, Yuan XS, Chen YY, Sun H, Liu C. The molecular mechanism of action for the potent antitumor component extracted using supercritical fluid extraction from Croton crassifolius root. JOURNAL OF ETHNOPHARMACOLOGY 2024; 327:117835. [PMID: 38490290 DOI: 10.1016/j.jep.2024.117835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/15/2024] [Accepted: 01/25/2024] [Indexed: 03/17/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The root of Croton crassifolius has been used as a traditional Chinese medicine (TCM), called Radix Croton Crassifolius, and commonly known as "Ji Gu Xiang" in Chinese. Its medicinal value has been recorded in several medical books or handbooks, such as "Sheng Cao Yao Xing Bei Yao", "Ben Cao Qiu Yuan" and "Zhong Hua Ben Cao". It has been traditional employed for treating sore throat, stomach-ache, rheumatism and cancer. AIM OF THE STUDY At present, there are limited studies on the evaluation of low-polarity extracts of roots in C. crassifolius. Consequently, the aim of this study was to evaluate the antitumor effect of the low-polarity extract of C. crassifolius root. MATERIALS AND METHODS Extracts were obtained by supercritical fluid extraction. The extracts were tested for antitumor effects in vitro on several cancer cell lines. A CCK-8 kit was used for further analysis of cell viability. A flow cytometer and propidium iodide staining were used to evaluate the cell cycle and apoptosis. Hoechst staining, JC-1 staining and the fluorescence probe DCFH-DA were used to evaluate apoptotic cells. Molecular mechanisms of action were analyzed by quantitative RT‒PCR and Western blotting. Immunohistochemistry was used for the evaluation of xenograft tumors in male BALB/c mice. Finally, molecular docking was employed to predict the bond between the desired bioactive compound and molecular targets. RESULTS Eleven diterpenoids were isolated from low-polarity C. crassifolius root extracts. Among the compounds, chettaphanin II showed the strongest activity (IC50 = 8.58 μM) against A549 cells. Evaluation of cell viability and the cell cycle showed that Chettaphanin II reduced A549 cell proliferation and induced G2/M-phase arrest. Chttaphanin II significantly induced apoptosis in A549 cells, which was related to the level of apoptosis-related proteins. The growth of tumor tissue was significantly inhibited by chettaphanin II in experiments performed on naked mice. The antitumor mechanism of chettaphanin II is that it can obstruct the mTOR/PI3K/Akt signaling pathway in A549 cells. Molecular docking established that chettaphanin II could bind to the active sites of Bcl-2 and Bax. CONCLUSIONS Taken together, the natural diterpenoid chettaphanin II was identified as the major antitumor active component, and its potential for developing anticancer therapies was demonstrated for the first time by antiproliferation evaluation in vitro and in vivo.
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Affiliation(s)
- Xu Guo
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202 Gongye North Road, Jinan, PR China.
| | - Rui-Rui Zhang
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202 Gongye North Road, Jinan, PR China.
| | - Jin-Yue Sun
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202 Gongye North Road, Jinan, PR China.
| | - Yan Liu
- Department of Nephrology, Tai'an City Central Hospital, Tai'an, Shandong, PR China.
| | - Xian-Shun Yuan
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324, Jingwu Road, Jinan, Shandong, PR China.
| | - Ying-Ying Chen
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202 Gongye North Road, Jinan, PR China.
| | - Hui Sun
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202 Gongye North Road, Jinan, PR China.
| | - Chao Liu
- Key Laboratory of Novel Food Resources Processing, Ministry of Agriculture and Rural Affairs/Key Laboratory of Agro-Products Processing Technology of Shandong Province/Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, 202 Gongye North Road, Jinan, PR China.
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20
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Xu F, He Y, Xu A, Ren L, Xu J, Shao Y, Wang M, Zhao W, Zhang Y, Lu P, Zhang L. Triphenyl phosphate induces cardiotoxicity through myocardial fibrosis mediated by apoptosis and mitophagy of cardiomyocyte in mice. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 346:123651. [PMID: 38408505 DOI: 10.1016/j.envpol.2024.123651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 02/05/2024] [Accepted: 02/23/2024] [Indexed: 02/28/2024]
Abstract
Triphenyl phosphate (TPHP) is an organophosphorus flame retardant, but its cardiac toxicity has not been adequately investigated. Therefore, in the current study, the effect of TPHP on the heart and the underlying mechanism involved was evaluated. C57BL/6 J mice were administered TPHP (0, 5, and 50 mg/kg/day) for 30 days. In addition, H9c2 cells were treated with three various concentrations (0, 50, and 150 μM) of TPHP, with and without the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine or the mitochondrial fusion promoter M1. TPHP caused cardiac fibrosis and increased the levels of CK-MB and LDH in the serum. TPHP increased the levels of ROS, malondialdehyde (MDA), and decreased the level of superoxide dismutase (SOD) and Glutathione peroxidase (GSH-Px). Furthermore, TPHP caused mitochondrial damage, and induced fusion and fission disorders that contributed to mitophagy in both the heart of C57BL/6 J mice and H9c2 cells. Transcriptome analysis showed that TPHP induced up- or down-regulated expression of various genes in myocardial tissue and revealed enriched apoptosis pathways. It was also found that TPHP could remarkably increase the expression levels of Bax, cleaved Caspase-9, cleaved Caspase-3, and decreased Bcl-2, thereby causing apoptosis in H9c2 cells. Taken together, the results suggested that TPHP promoted mitophagy through mitochondria fusion dysfunction resulting from oxidative stress, leading to fibrosis by inducing myocardial apoptosis.
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Affiliation(s)
- Feibo Xu
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Yu He
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Aili Xu
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Lihua Ren
- School of Nursing, Peking University, Beijing, 100191, China
| | - Jinyu Xu
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Yali Shao
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Minxin Wang
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Wei Zhao
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Ying Zhang
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China
| | - Peng Lu
- School of Public Health and Management, Binzhou Medical University, Yantai, 264003, China
| | - Lianshuang Zhang
- School of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China.
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21
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Zotta A, O'Neill LAJ, Yin M. Unlocking potential: the role of the electron transport chain in immunometabolism. Trends Immunol 2024; 45:259-273. [PMID: 38503657 DOI: 10.1016/j.it.2024.02.002] [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: 02/13/2024] [Revised: 02/20/2024] [Accepted: 02/23/2024] [Indexed: 03/21/2024]
Abstract
The electron transport chain (ETC) couples electron transfer with proton pumping to generate ATP and it also regulates particular innate and adaptive immune cell function. While NLRP3 inflammasome activation was initially linked to reactive oxygen species (ROS) produced from Complexes I and III, recent research suggests that an intact ETC fueling ATP is needed. Complex II may be responsible for Th1 cell proliferation and in some cases, effector cytokine production. Complex III is required for regulatory T (Treg) cell function, while oxidative phosphorylation (OXPHOS) and Complexes I, IV, and V sustain proliferation and antibody production in B lymphocytes, with OXPHOS also being required for B regulatory (Breg) cell function. Despite challenges, the ETC shows therapeutic targeting potential for immune-related diseases and in immuno-oncology.
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Affiliation(s)
- Alessia Zotta
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Luke A J O'Neill
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
| | - Maureen Yin
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
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22
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Li L, Jin M, Tan J, Xiao B. NcRNAs: A synergistically antiapoptosis therapeutic tool in Alzheimer's disease. CNS Neurosci Ther 2024; 30:e14476. [PMID: 37735992 PMCID: PMC11017435 DOI: 10.1111/cns.14476] [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: 07/12/2023] [Revised: 08/22/2023] [Accepted: 09/08/2023] [Indexed: 09/23/2023] Open
Abstract
AIMS The aim of this review is to systematically summarize and analyze the noncoding RNAs (ncRNAs), especially microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the cell apoptosis among Alzheimer's disease (AD) in recent years to demonstrate their value in the diagnosis and treatment of AD. METHODS We systematically summarized in vitro and in vivo studies focusing on the ncRNAs in the regulation of cell apoptosis among AD in PubMed, ScienceDirect, and Google Scholar. RESULTS We discover three patterns of ncRNAs (including 'miRNA-mRNA', 'lncRNA-miRNA-mRNA', and 'circRNA-miRNA-mRNA') form the ncRNA-based regulatory networks in regulating cell apoptosis in AD. CONCLUSIONS This review provides a future diagnosis and treatment strategy for AD patients based on ncRNAs.
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Affiliation(s)
- Liangxian Li
- Laboratory of Respiratory DiseaseAffiliated Hospital of Guilin Medical UniversityGuilinChina
- Guangxi Key Laboratory of Brain and Cognitive NeuroscienceGuilin Medical UniversityGuilinChina
| | - Mingyue Jin
- Guangxi Key Laboratory of Brain and Cognitive NeuroscienceGuilin Medical UniversityGuilinChina
| | - Jie Tan
- Guangxi Key Laboratory of Brain and Cognitive NeuroscienceGuilin Medical UniversityGuilinChina
| | - Bo Xiao
- Laboratory of Respiratory DiseaseAffiliated Hospital of Guilin Medical UniversityGuilinChina
- Guangxi Key Laboratory of Brain and Cognitive NeuroscienceGuilin Medical UniversityGuilinChina
- Key Laboratory of Respiratory DiseasesEducation Department of Guangxi Zhuang Autonomous RegionGuilinChina
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23
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Wang W, Su Y, Qi R, Li H, Jiang H, Li F, Li B, Sun H. Indoxacarb triggers autophagy and apoptosis through ROS accumulation mediated by oxidative phosphorylation in the midgut of Bombyx mori. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2024; 200:105812. [PMID: 38582584 DOI: 10.1016/j.pestbp.2024.105812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/01/2024] [Accepted: 02/03/2024] [Indexed: 04/08/2024]
Abstract
Indoxacarb has been widely utilized in agricultural pest management, posing a significant ecological threat to Bombyx mori, a non-target economic insect. In the present study, short-term exposure to low concentration of indoxacarb significantly suppressed the oxidative phosphorylation pathway, and resulted in an accumulation of reactive oxygen species (ROS) in the midgut of B. mori. While, the ATP content exhibited a declining trend but there was no significant change. Moreover, indoxacarb also significantly altered the transcription levels of six autophagy-related genes, and the transcription levels of ATG2, ATG8 and ATG9 were significantly up-regulated by 2.56-, 1.90-, and 3.36-fold, respectively. The protein levels of ATG8-I and ATG8-II and MDC-stained frozen sections further suggested an increase in autophagy. Furthermore, the protein level and enzyme activity of CASP4 showed a significant increase in accordance with the transcription levels of apoptosis-related genes, indicating the activation of the apoptotic signaling pathway. Meanwhile, the induction of apoptosis signals in the midgut cells triggered by indoxacarb was confirmed through TUNEL staining. These findings suggest that indoxacarb can promote the accumulation of ROS by inhibiting the oxidative phosphorylation pathway, thereby inducing autophagy and apoptosis in the midgut cells of B. mori.
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Affiliation(s)
- Wanwan Wang
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Yue Su
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Ruinan Qi
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Hao Li
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Hongrui Jiang
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Fanchi Li
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Guangxi Collaborative Innovation Center of Modern Sericulture and Silk, School of Chemistry and Bioengineering, Hechi University, Yizhou, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu 215123, PR China
| | - Bing Li
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Guangxi Collaborative Innovation Center of Modern Sericulture and Silk, School of Chemistry and Bioengineering, Hechi University, Yizhou, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu 215123, PR China.
| | - Haina Sun
- School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, PR China; Guangxi Collaborative Innovation Center of Modern Sericulture and Silk, School of Chemistry and Bioengineering, Hechi University, Yizhou, China; Sericulture Institute of Soochow University, Suzhou, Jiangsu 215123, PR China.
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24
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Sever AIM, Alderson TR, Rennella E, Aramini JM, Liu ZH, Harkness RW, Kay LE. Activation of caspase-9 on the apoptosome as studied by methyl-TROSY NMR. Proc Natl Acad Sci U S A 2023; 120:e2310944120. [PMID: 38085782 PMCID: PMC10743466 DOI: 10.1073/pnas.2310944120] [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: 06/28/2023] [Accepted: 10/23/2023] [Indexed: 12/18/2023] Open
Abstract
Mitochondrial apoptotic signaling cascades lead to the formation of the apoptosome, a 1.1-MDa heptameric protein scaffold that recruits and activates the caspase-9 protease. Once activated, caspase-9 cleaves and activates downstream effector caspases, triggering the onset of cell death through caspase-mediated proteolysis of cellular proteins. Failure to activate caspase-9 enables the evasion of programmed cell death, which occurs in various forms of cancer. Despite the critical apoptotic function of caspase-9, the structural mechanism by which it is activated on the apoptosome has remained elusive. Here, we used a combination of methyl-transverse relaxation-optimized NMR spectroscopy, protein engineering, and biochemical assays to study the activation of caspase-9 bound to the apoptosome. In the absence of peptide substrate, we observed that both caspase-9 and its isolated protease domain (PD) only very weakly dimerize with dissociation constants in the millimolar range. Methyl-NMR spectra of isotope-labeled caspase-9, within the 1.3-MDa native apoptosome complex or an engineered 480-kDa apoptosome mimic, reveal that the caspase-9 PD remains monomeric after recruitment to the scaffold. Binding to the apoptosome, therefore, organizes caspase-9 PDs so that they can rapidly and extensively dimerize only when substrate is present, providing an important layer in the regulation of caspase-9 activation. Our work highlights the unique role of NMR spectroscopy to structurally characterize protein domains that are flexibly tethered to large scaffolds, even in cases where the molecular targets are in excess of 1 MDa, as in the present example.
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Affiliation(s)
- Alexander I. M. Sever
- Department of Chemistry, University of Toronto, Toronto, ONM5S 3H6, Canada
- Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ONM5G 0A4, Canada
| | - T. Reid Alderson
- Department of Chemistry, University of Toronto, Toronto, ONM5S 3H6, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
| | - Enrico Rennella
- Department of Chemistry, University of Toronto, Toronto, ONM5S 3H6, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
| | - James M. Aramini
- Department of Chemistry, University of Toronto, Toronto, ONM5S 3H6, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
| | - Zi Hao Liu
- Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ONM5G 0A4, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
| | - Robert W. Harkness
- Department of Chemistry, University of Toronto, Toronto, ONM5S 3H6, Canada
- Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ONM5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
| | - Lewis E. Kay
- Department of Chemistry, University of Toronto, Toronto, ONM5S 3H6, Canada
- Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ONM5G 0A4, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
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25
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Mao L, Wang S, Qu Y, Wang H, Zhao Y, Zhu C, Zhang Z, Jin C, Herdewijn P, Liu FW, Wang Z. Design, synthesis, and anti-respiratory syncytial virus potential of novel 3-(1,2,3-triazol-1-yl)furoxazine-fused benzimidazole derivatives. Eur J Med Chem 2023; 261:115799. [PMID: 37722289 DOI: 10.1016/j.ejmech.2023.115799] [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: 07/16/2023] [Revised: 08/29/2023] [Accepted: 09/06/2023] [Indexed: 09/20/2023]
Abstract
Respiratory syncytial virus (RSV) is a major cause of serious lower respiratory tract infections in infants, children, and older persons. Currently, the only approved anti-viral chemotherapeutic drug for RSV treatment is ribavirin aerosol; however, its significant toxicity has led to restricted clinical use. In a previous study, we developed various benzimidazole derivatives against RSV. In this study, we synthesised 3-azide substituted furoxazine-fused benzimidazole derivatives by sulfonylation and azide substitution of the 3-hydroxyl group of the furoxazine-fused benzimidazole derivatives. Subsequently, a series of 3-(1,2,3-triazol-1-yl)-substituted furoxazine-fused benzimidazole derivatives were synthesised using the classical click reaction. Biological evaluations of the target compounds indicated that compound 4a-2 had higher activity against RSV (EC50 = 12.17 μM) and lower cytotoxicity (CC50 = 390.64 μM). Compound 4a-2 exerted anti-viral effects against the RSV Long strain by inhibiting apoptosis and the elevation of reactive oxygen species (ROS) and inflammatory factors caused by viral infection in vitro. Additionally, the clinical symptoms of the virus-infected mice were markedly relieved, and the viral load in the lung tissues was dramatically decreased. The biosafety profile of compound 4a-2 was also favourable, showing no detectable adverse effects on any of the major organs in vivo. These findings underscore the potential of compound 4a-2 as a valuable therapeutic option for combating RSV infections while also laying the foundation for further research and development in the field.
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Affiliation(s)
- Lu Mao
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of "Runliang" Anti-viral Medicines Research and Development, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Song Wang
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China
| | - Ying Qu
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of "Runliang" Anti-viral Medicines Research and Development, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Haixia Wang
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China
| | - Yifan Zhao
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China
| | - Chuantao Zhu
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China
| | - Zhongmou Zhang
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of "Runliang" Anti-viral Medicines Research and Development, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chengyun Jin
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Piet Herdewijn
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
| | - Feng-Wu Liu
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China.
| | - Zhenya Wang
- XNA Platform, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Key Laboratory of "Runliang" Anti-viral Medicines Research and Development, Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China; International Joint Research Centre of National Animal Immunology, College of Veterinary Medicine, Henan Agricultural University, Zhengdong New District Longzi Lake 15#, Zhengzhou 450046, China.
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Chakraborty S, Choudhuri A, Mishra A, Bhattacharyya C, Billiar TR, Stoyanovsky DA, Sengupta R. Nitric oxide and thioredoxin modulate the activity of caspase 9 in HepG2 cells. Biochim Biophys Acta Gen Subj 2023; 1867:130452. [PMID: 37652366 PMCID: PMC10592080 DOI: 10.1016/j.bbagen.2023.130452] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
The interdependent and finely tuned balance between the well-established redox-based modification, S-nitrosylation, and its counteractive mechanism of S-nitrosothiol degradation, i.e., S-denitrosylation of biological protein or non-protein thiols defines the cellular fate in the context of redox homeostasis. S-nitrosylation of cysteine residues by S-nitrosoglutathione, S-nitroso-L-cysteine-like physiological and S-nitroso-L-cysteine ethyl ester-like synthetic NO donors inactivate Caspase-3, 8, and 9, thereby hindering their apoptotic activity. However, spontaneous restoration of their activity upon S-denitrosylation of S-nitrosocaspases into their reduced, free thiol active states, aided by the members of the ubiquitous cellular redoxin (thioredoxin/ thioredoxin reductase/ NADPH) and low molecular weight dithiol (lipoic acid/ lipoamide dehydrogenase/ dihydrolipoic acid/ NADPH) systems imply a direct relevance to their proteolytic activities and further downstream signaling cascades. Additionally, our previous and current findings offer crucial insight into the concept of redundancy between thioredoxin and lipoic acid systems, and the redox-modulated control of the apoptotic and proteolytic activity of caspases, triggering their cyto- and neurotoxic effects in response to nitro-oxidative stress. Thus, this might lay the foundation for the exogenous introduction of precise and efficient NO or related donor drug delivery systems that can directly participate in catering to the S-(de)-nitrosylation-mediated functional outcomes of the cysteinyl proteases in pathophysiological settings.
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Affiliation(s)
- Surupa Chakraborty
- Amity Institute of Biotechnology, Amity University, Kolkata 700135, West Bengal, India
| | - Ankita Choudhuri
- Amity Institute of Biotechnology, Amity University, Kolkata 700135, West Bengal, India
| | - Akansha Mishra
- Amity Institute of Biotechnology, Amity University, Kolkata 700135, West Bengal, India
| | - Camelia Bhattacharyya
- Amity Institute of Biotechnology, Amity University, Kolkata 700135, West Bengal, India
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | | | - Rajib Sengupta
- Amity Institute of Biotechnology, Amity University, Kolkata 700135, West Bengal, India; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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Riegger J, Schoppa A, Ruths L, Haffner-Luntzer M, Ignatius A. Oxidative stress as a key modulator of cell fate decision in osteoarthritis and osteoporosis: a narrative review. Cell Mol Biol Lett 2023; 28:76. [PMID: 37777764 PMCID: PMC10541721 DOI: 10.1186/s11658-023-00489-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 09/11/2023] [Indexed: 10/02/2023] Open
Abstract
During aging and after traumatic injuries, cartilage and bone cells are exposed to various pathophysiologic mediators, including reactive oxygen species (ROS), damage-associated molecular patterns, and proinflammatory cytokines. This detrimental environment triggers cellular stress and subsequent dysfunction, which not only contributes to the development of associated diseases, that is, osteoporosis and osteoarthritis, but also impairs regenerative processes. To counter ROS-mediated stress and reduce the overall tissue damage, cells possess diverse defense mechanisms. However, cellular antioxidative capacities are limited and thus ROS accumulation can lead to aberrant cell fate decisions, which have adverse effects on cartilage and bone homeostasis. In this narrative review, we address oxidative stress as a major driver of pathophysiologic processes in cartilage and bone, including senescence, misdirected differentiation, cell death, mitochondrial dysfunction, and impaired mitophagy by illustrating the consequences on tissue homeostasis and regeneration. Moreover, we elaborate cellular defense mechanisms, with a particular focus on oxidative stress response and mitophagy, and briefly discuss respective therapeutic strategies to improve cell and tissue protection.
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Affiliation(s)
- Jana Riegger
- Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, Ulm University Medical Center, 89081, Ulm, Germany.
| | - Astrid Schoppa
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, 89081, Ulm, Germany
| | - Leonie Ruths
- Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, Ulm University Medical Center, 89081, Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, 89081, Ulm, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, 89081, Ulm, Germany
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Wu Y, Sun Y, Richet E, Han Z, Chai J. Structural basis for negative regulation of the Escherichia coli maltose system. Nat Commun 2023; 14:4925. [PMID: 37582800 PMCID: PMC10427625 DOI: 10.1038/s41467-023-40447-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 07/26/2023] [Indexed: 08/17/2023] Open
Abstract
Proteins from the signal transduction ATPases with numerous domains (STAND) family are known to play an important role in innate immunity. However, it remains less well understood how they function in transcriptional regulation. MalT is a bacterial STAND that controls the Escherichia coli maltose system. Inactive MalT is sequestered by different inhibitory proteins such as MalY. Here, we show that MalY interacts with one oligomerization interface of MalT to form a 2:2 complex. MalY represses MalT activity by blocking its oligomerization and strengthening ADP-mediated MalT autoinhibition. A loop region N-terminal to the nucleotide-binding domain (NBD) of MalT has a dual role in mediating MalT autoinhibition and activation. Structural comparison shows that ligand-binding induced oligomerization is required for stabilizing the C-terminal domains and conferring DNA-binding activity. Together, our study reveals the mechanism whereby a prokaryotic STAND is inhibited by a repressor protein and offers insights into signaling by STAND transcription activators.
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Affiliation(s)
- Yuang Wu
- Institute of Biochemistry, University of Cologne, Cologne, Germany
- Max Planck Institute for Plant Breeding Research, Cologne, Germany
| | - Yue Sun
- Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Evelyne Richet
- Institut Pasteur, Université Paris Cité, CNRS UMR6047, INSERM U1306, Unité Biologie et génétique de la paroi bactérienne, Paris, France
| | - Zhifu Han
- Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Jijie Chai
- Institute of Biochemistry, University of Cologne, Cologne, Germany.
- Max Planck Institute for Plant Breeding Research, Cologne, Germany.
- Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing, China.
- Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
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29
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Matsui Y, Djekidel MN, Lindsay K, Samir P, Connolly N, Wu G, Yang X, Fan Y, Xu B, Peng JC. SNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development. Nat Commun 2023; 14:4754. [PMID: 37553330 PMCID: PMC10409800 DOI: 10.1038/s41467-023-40487-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 07/28/2023] [Indexed: 08/10/2023] Open
Abstract
Stem cell survival versus death is a developmentally programmed process essential for morphogenesis, sizing, and quality control of genome integrity and cell fates. Cell death is pervasive during development, but its programming is little known. Here, we report that Smad nuclear interacting protein 1 (SNIP1) promotes neural progenitor cell survival and neurogenesis and is, therefore, integral to brain development. The SNIP1-depleted brain exhibits dysplasia with robust induction of caspase 9-dependent apoptosis. Mechanistically, SNIP1 regulates target genes that promote cell survival and neurogenesis, and its activities are influenced by TGFβ and NFκB signaling pathways. Further, SNIP1 facilitates the genomic occupancy of Polycomb complex PRC2 and instructs H3K27me3 turnover at target genes. Depletion of PRC2 is sufficient to reduce apoptosis and brain dysplasia and to partially restore genetic programs in the SNIP1-depleted brain in vivo. These findings suggest a loci-specific regulation of PRC2 and H3K27 marks to toggle cell survival and death in the developing brain.
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Affiliation(s)
- Yurika Matsui
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Mohamed Nadhir Djekidel
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Katherine Lindsay
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Parimal Samir
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
- Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd, Medical Research Building, Room 7, 138E, Galveston, TX, 77550, USA
| | - Nina Connolly
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Gang Wu
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Xiaoyang Yang
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Yiping Fan
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Beisi Xu
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jamy C Peng
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
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30
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Jin D, Huang NN, Wei JX. Hepatotoxic mechanism of cantharidin: insights and strategies for therapeutic intervention. Front Pharmacol 2023; 14:1201404. [PMID: 37383714 PMCID: PMC10293652 DOI: 10.3389/fphar.2023.1201404] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/01/2023] [Indexed: 06/30/2023] Open
Abstract
Cantharidin (CTD), a natural compound derived from Mylabris, is widely used in traditional Oriental medicine for its potent anticancer properties. However, its clinical application is restricted due to its high toxicity, particularly towards the liver. This review provides a concise understanding of the hepatotoxic mechanisms of CTD and highlights novel therapeutic strategies to mitigate its toxicity while enhancing its anticancer efficacy. We systematically explore the molecular mechanisms underlying CTD-induced hepatotoxicity, focusing on the involvement of apoptotic and autophagic processes in hepatocyte injury. We further discuss the endogenous and exogenous pathways implicated in CTD-induced liver damage and potential therapeutic targets. This review also summarizes the structural modifications of CTD derivatives and their impact on anticancer activity. Additionally, we delve into the advancements in nanoparticle-based drug delivery systems that hold promise in overcoming the limitations of CTD derivatives. By offering valuable insights into the hepatotoxic mechanisms of CTD and outlining potential avenues for future research, this review contributes to the ongoing efforts to develop safer and more effective CTD-based therapies.
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Affiliation(s)
- Dian Jin
- Department of Pharmacy, Sixth People’s Hospital of Chengdu, Chengdu, China
| | - Na-Na Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jing-Xia Wei
- Department of Pharmacy, Sixth People’s Hospital of Chengdu, Chengdu, China
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31
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Kowalski S, Karska J, Łapińska Z, Hetnał B, Saczko J, Kulbacka J. An overview of programmed cell death: Apoptosis and pyroptosis-Mechanisms, differences, and significance in organism physiology and pathophysiology. J Cell Biochem 2023. [PMID: 37269535 DOI: 10.1002/jcb.30413] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/12/2023] [Accepted: 04/17/2023] [Indexed: 06/05/2023]
Abstract
Regulated cell death is an essential and heterogeneous process occurring in the life cycle of organisms, from embryonic development and aging to the regulation of homeostasis and organ maintenance. Under this term, we can distinguish many distinct pathways, including apoptosis and pyroptosis. Recently, there has been an increasing comprehension of the mechanisms governing these phenomena and their characteristic features. The coexistence of different types of cell death and the differences and similarities between them has been the subject of many studies. This review aims to present the latest literature in the field of pyroptosis and apoptosis and compare their molecular pathway's elements and significance in the physiology and pathophysiology of the organism.
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Affiliation(s)
- Szymon Kowalski
- Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Julia Karska
- Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Zofia Łapińska
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Bartosz Hetnał
- Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Jolanta Saczko
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
- Department of Immunology, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
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32
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Devi S, Indramohan M, Jäger E, Carriere J, Chu LH, de Almeida L, Greaves DR, Stehlik C, Dorfleutner A. CARD-only proteins regulate in vivo inflammasome responses and ameliorate gout. Cell Rep 2023; 42:112265. [PMID: 36930645 PMCID: PMC10151391 DOI: 10.1016/j.celrep.2023.112265] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 01/10/2023] [Accepted: 02/28/2023] [Indexed: 03/18/2023] Open
Abstract
Inflammatory responses are crucial for controlling infections and initiating tissue repair. However, excessive and uncontrolled inflammation causes inflammatory disease. Processing and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 depend on caspase-1 activation within inflammasomes. Assembly of inflammasomes is initiated upon activation of cytosolic pattern recognition receptors (PRRs), followed by sequential polymerization of pyrin domain (PYD)-containing and caspase recruitment domain (CARD)-containing proteins mediated by homotypic PYD and CARD interactions. Small PYD- or CARD-only proteins (POPs and COPs, respectively) evolved in higher primates to target these crucial interactions to limit inflammation. Here, we show the ability of COPs to regulate inflammasome activation by modulating homotypic CARD-CARD interactions in vitro and in vivo. CARD16, CARD17, and CARD18 displace crucial CARD interactions between caspase-1 proteins through competitive binding and ameliorate uric acid crystal-mediated NLRP3 inflammasome activation and inflammatory disease. COPs therefore represent an important family of inflammasome regulators and ameliorate inflammatory disease.
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Affiliation(s)
- Savita Devi
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mohanalaxmi Indramohan
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Elisabeth Jäger
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jessica Carriere
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Lan H Chu
- Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Lucia de Almeida
- Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - David R Greaves
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
| | - Christian Stehlik
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; The Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
| | - Andrea Dorfleutner
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; The Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
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33
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Ji Y, Hawkins CJ. Reconstitution of human pyroptotic cell death in Saccharomyces cerevisiae. Sci Rep 2023; 13:3095. [PMID: 36813876 PMCID: PMC9946934 DOI: 10.1038/s41598-023-29464-5] [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: 08/16/2022] [Accepted: 02/06/2023] [Indexed: 02/24/2023] Open
Abstract
Pyroptosis is a lytic form of programmed cell death induced by the activation of gasdermins. The precise mechanism of gasdermin activation by upstream proteases remains incompletely understood. Here, we reconstituted human pyroptotic cell death in yeast by inducible expression of caspases and gasdermins. Functional interactions were reflected by the detection of cleaved gasdermin-D (GSDMD) and gasdermin-E (GSDME), plasma membrane permeabilization, and reduced growth and proliferative potential. Following overexpression of human caspases-1, -4, -5, and -8, GSDMD was cleaved. Similarly, active caspase-3 induced proteolytic cleavage of co-expressed GSDME. Caspase-mediated cleavage of GSDMD or GSDME liberated the ~ 30 kDa cytotoxic N-terminal fragments of these proteins, permeabilized the plasma membrane and compromised yeast growth and proliferation potential. Interestingly, the observation of yeast lethality mediated by co-expression of caspases-1 or -2 with GSDME signified functional cooperation between these proteins in yeast. The small molecule pan-caspase inhibitor Q-VD-OPh reduced caspase-mediated yeast toxicity, allowing us to expand the utility of this yeast model to investigate the activation of gasdermins by caspases that would otherwise be highly lethal to yeast. These yeast biological models provide handy platforms to study pyroptotic cell death and to screen for and characterize potential necroptotic inhibitors.
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Affiliation(s)
- Yanhao Ji
- grid.1018.80000 0001 2342 0938Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC Australia
| | - Christine J. Hawkins
- grid.1018.80000 0001 2342 0938Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC Australia
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Abstract
Significance: Thioredoxin (Trx) is a powerful antioxidant that reduces protein disulfides to maintain redox stability in cells and is involved in regulating multiple redox-dependent signaling pathways. Recent Advance: The current accumulation of findings suggests that Trx participates in signaling pathways that interact with various proteins to manipulate their dynamic regulation of structure and function. These network pathways are critical for cancer pathogenesis and therapy. Promising clinical advances have been presented by most anticancer agents targeting such signaling pathways. Critical Issues: We herein link the signaling pathways regulated by the Trx system to potential cancer therapeutic opportunities, focusing on the coordination and strengths of the Trx signaling pathways in apoptosis, ferroptosis, immunomodulation, and drug resistance. We also provide a mechanistic network for the exploitation of therapeutic small molecules targeting the Trx signaling pathways. Future Directions: As research data accumulate, future complex networks of Trx-related signaling pathways will gain in detail. In-depth exploration and establishment of these signaling pathways, including Trx upstream and downstream regulatory proteins, will be critical to advancing novel cancer therapeutics. Antioxid. Redox Signal. 38, 403-424.
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Affiliation(s)
- Junmin Zhang
- State Key Laboratory of Applied Organic Chemistry, School of Pharmacy, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China
| | - Xinming Li
- State Key Laboratory of Applied Organic Chemistry, School of Pharmacy, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China.,State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Zhengjia Zhao
- State Key Laboratory of Applied Organic Chemistry, School of Pharmacy, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China
| | | | - Jianguo Fang
- State Key Laboratory of Applied Organic Chemistry, School of Pharmacy, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China.,School of Chemistry and Chemical Engineering, Nanjing University of Science & Technology, Nanjing, China
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35
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Antitumor and antimicrobial effect of syringic acid urea cocrystal: Structural and spectroscopic characterization, DFT calculation and biological evaluation. J Mol Struct 2023. [DOI: 10.1016/j.molstruc.2023.135113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
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36
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Bock FJ, Riley JS. When cell death goes wrong: inflammatory outcomes of failed apoptosis and mitotic cell death. Cell Death Differ 2023; 30:293-303. [PMID: 36376381 PMCID: PMC9661468 DOI: 10.1038/s41418-022-01082-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
Apoptosis is a regulated cellular pathway that ensures that a cell dies in a structured fashion to prevent negative consequences for the tissue or the organism. Dysfunctional apoptosis is a hallmark of numerous pathologies, and treatments for various diseases are successful based on the induction of apoptosis. Under homeostatic conditions, apoptosis is a non-inflammatory event, as the activation of caspases ensures that inflammatory pathways are disabled. However, there is an increasing understanding that under specific conditions, such as caspase inhibition, apoptosis and the apoptotic machinery can be re-wired into a process which is inflammatory. In this review we discuss how the death receptor and mitochondrial pathways of apoptosis can activate inflammation. Furthermore, we will highlight how cell death due to mitotic stress might be a special case when it comes to cell death and the induction of inflammation.
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Affiliation(s)
- Florian J Bock
- Department of Radiation Oncology (Maastro), GROW School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, The Netherlands.
| | - Joel S Riley
- Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
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Jothimani G, Ganesan H, Pathak S, Banerjee A. Molecular Characterization of Primary and Metastatic Colon Cancer Cells to Identify Therapeutic Targets with Natural Compounds. Curr Top Med Chem 2022; 22:2598-2615. [PMID: 35366775 DOI: 10.2174/1568026622666220401161511] [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: 09/30/2021] [Revised: 02/01/2022] [Accepted: 02/10/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND Metastasis is the world's leading cause of colon cancer morbidity. Due to its heterogeneity, it has been challenging to understand primary to metastatic colon cancer progression and find a molecular target for colon cancer treatment. OBJECTIVES The current investigation aimed to characterize the immune and genotypic profiles of primary and metastatic colon cancer cell lines and identify a molecular target for colon cancer treatment. METHODS Colony-forming potential, migration and invasion potential, cytokine profiling, miRNA, and mRNA expression were examined. Molecular docking for the Wnt signaling proteins with various plant compounds was performed. RESULTS Colony formation, migration, and invasion potential were significantly higher in metastatic cells. The primary and metastatic cells' local immune and genetic status revealed TGF β-1, IL-8, MIP-1b, I-TAC, GM-CSF, and MCP-1 were highly expressed in all cancer cells. RANTES, IL-4, IL- 6, IFNγ, and G-CSF were less expressed in cancer cell lines. mRNA expression analysis displayed significant overexpression of proliferation, cell cycle, and oncogenes, whereas apoptosis cascade and tumor suppressor genes were significantly down-regulated in metastatic cells more evidently. Most importantly, the results of molecular docking with dysregulated Wnt signaling proteins shows that peptide AGAP and coronaridine had maximum hydrogen bonds to β-catenin and GSK3β with a better binding affinity. CONCLUSION This study emphasized genotypic differences between the primary and metastatic colon cancer cells, delineating the intricate mechanisms to understand the primary to metastatic advancement. The molecular docking aided in understanding the future molecular targets for bioactive- based colon cancer therapeutic interventions.
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Affiliation(s)
- Ganesan Jothimani
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai, India
| | - Harsha Ganesan
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai, India
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute (CHRI), Chettinad Academy of Research and Education (CARE), Chennai, India
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Yang J, Sun Q, Ma Q, Yu Q, Liu X, Liu Y, Han Y, Yang Y, Rong R. Mahuang Xixin Fuzi decoction ameliorates apoptosis via the mitochondrial-mediated signaling pathway in MCM cells. JOURNAL OF ETHNOPHARMACOLOGY 2022; 297:115538. [PMID: 35843410 DOI: 10.1016/j.jep.2022.115538] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/04/2022] [Accepted: 07/11/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Mahuang Xixin Fuzi Decoction (MXF), as a classical prescription of traditional Chinese medicine (TCM), has been used to treat the symptoms of fever, nasal congestion and headache in elderly people for almost a thousand years. AIM OF THE STUDY The purpose of this study was to evaluate the effects and possible mechanisms of MXF on thermal stimulation-induced mouse cardiac myocytes (MCM) cell apoptosis. MATERIALS AND METHODS The apoptosis of the MCM cell model was induced by a PCR-calculated temperature control system with a gradual heating pattern at 43 °C for 1 h. The cytotoxic effects were determined using real-time cell analyzer (RTCA) technology. Annexin V-FITC/7-AAD staining, and JC-1 fluorescence were used to assess apoptosis. Specific substrates, enzyme-linked immunosorbent assays (ELISAs), and Western blotting were used to identify proteins in the mitochondrial-mediated pathway. The identification of chemical components in the mouse heart was performed by ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry analysis. RESULTS MXF inhibited apoptosis through the mitochondrial-mediated signaling pathway, including ameliorating ∆Ψm reduction, blocking mitochondrial Cyt C release, reducing Bax levels and increasing Bcl-2 levels, suppressing caspase-9 and caspase-3 activation in cytoplasmic fractions. Moreover, the components of MXF that act on the heart are mainly ephedra alkaloids and aconitine alkaloids. CONCLUSIONS The findings demonstrated that MXF treatment markedly reduced MCM cell apoptosis induced by thermal stimulation, which may be ascribed to the mitochondrial-mediated signaling pathway.
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Affiliation(s)
- Jia Yang
- Shandong University of Traditional Chinese Medicine, PR China
| | - Qihui Sun
- Shandong University of Traditional Chinese Medicine, PR China
| | - Qingyun Ma
- Shandong University of Traditional Chinese Medicine, PR China
| | - Qinhui Yu
- Shandong University of Traditional Chinese Medicine, PR China
| | - Xiaoyun Liu
- Shandong University of Traditional Chinese Medicine, PR China; Shandong Provincial Collaborative Innovation Center for Antiviral Traditional Chinese Medicine, Jinan, Shandong, 250355, PR China
| | - Yanliang Liu
- Shandong University of Traditional Chinese Medicine, PR China
| | - Yuxiu Han
- Shandong University of Traditional Chinese Medicine, PR China
| | - Yong Yang
- Shandong University of Traditional Chinese Medicine, PR China; Shandong Provincial Collaborative Innovation Center for Antiviral Traditional Chinese Medicine, Jinan, Shandong, 250355, PR China.
| | - Rong Rong
- Shandong University of Traditional Chinese Medicine, PR China; Shandong Provincial Collaborative Innovation Center for Antiviral Traditional Chinese Medicine, Jinan, Shandong, 250355, PR China.
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39
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Zhan M, Wen L, Zhu M, Gong J, Xi C, Wen H, Xu G, Shen H. Integrative Analysis of Transcriptome and Metabolome Reveals Molecular Responses in Eriocheir sinensis with Hepatopancreatic Necrosis Disease. BIOLOGY 2022; 11:1267. [PMID: 36138745 PMCID: PMC9495758 DOI: 10.3390/biology11091267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/21/2022] [Accepted: 08/22/2022] [Indexed: 06/16/2023]
Abstract
Hepatopancreatic necrosis disease (HPND) is a highly lethal disease that first emerged in 2015 in Jiangsu Province, China. So far, most researchers believe that this disease is caused by abiotic factors. However, its true pathogenic mechanism remains unknown. In this study, the effects of HPND on the metabolism and other biological indicators of the Chinese mitten crab (Eriocheir sinensis) were evaluated by integrating transcriptomics and metabolomics. Our findings demonstrate that the innate immunity, antioxidant activity, detoxification ability, and nervous system of the diseased crabs were affected. Additionally, metabolic pathways such as lipid metabolism, nucleotide metabolism, and protein metabolism were dysregulated, and energy production was slightly increased. Moreover, the IL-17 signaling pathway was activated and high levels of autophagy and apoptosis occurred in diseased crabs, which may be related to hepatopancreas damage. The abnormal mitochondrial function and possible anaerobic metabolism observed in our study suggested that functional hypoxia may be involved in HPND progression. Furthermore, the activities of carboxylesterase and acetylcholinesterase were significantly inhibited, indicating that the diseased crabs were likely stressed by pesticides such as pyrethroids. Collectively, our findings provide new insights into the molecular mechanisms altered in diseased crabs, as well as the etiology and pathogenic mechanisms of HPND.
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Affiliation(s)
- Ming Zhan
- Wuxi Fisheries College, Nanjing Agricultural University, Nanjing 210095, China
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Lujie Wen
- Wuxi Fisheries College, Nanjing Agricultural University, Nanjing 210095, China
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Mengru Zhu
- Wuxi Fisheries College, Nanjing Agricultural University, Nanjing 210095, China
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Jie Gong
- Wuxi Fisheries College, Nanjing Agricultural University, Nanjing 210095, China
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Changjun Xi
- Wuxi Fisheries College, Nanjing Agricultural University, Nanjing 210095, China
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Haibo Wen
- Wuxi Fisheries College, Nanjing Agricultural University, Nanjing 210095, China
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Gangchun Xu
- Wuxi Fisheries College, Nanjing Agricultural University, Nanjing 210095, China
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Huaishun Shen
- Wuxi Fisheries College, Nanjing Agricultural University, Nanjing 210095, China
- Key Laboratory of Integrated Rice-Fish Farming Ecology, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
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In silico mutational analysis to identify the role and pathogenicity of BCL-w missense variants. J Genet Eng Biotechnol 2022; 20:120. [PMID: 35951173 PMCID: PMC9372248 DOI: 10.1186/s43141-022-00389-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 07/04/2022] [Indexed: 11/10/2022]
Abstract
Background Intrinsic pathway of apoptosis is generally mediated by BCL-2 (B cell lymphoma 2) family of proteins; they either induce or inhibit the apoptosis. Overexpression of BCL-2 in cancer cell may lead to delay in apoptosis. BCL-w is the pro-survival member of the BCL-2 family. BCL2L2 gene is present on chromosome number 14 in humans, and it encodes BCL-w protein; BCL-w protein is 193 amino acids residues in length. Interactions among the BCL-2 proteins are very specific. The fate of cell is determined by the ratio of pro-apoptotic proteins to pro-survival proteins. BCL-w promotes cell survival. Studies suggested that overexpression of BCL-w protein is associated with many cancers including DLBCL, BL, colorectal cancers, gastric cancers, and many more. The cause of overexpression is translocations or gene amplification which will subsequently result in cancerous activity. Process For in-silico analysis, BCL2L2 gene was retrieved from UniProt (UniProt ID: Q92843). 54 missense variants have been collected in BCL-w proteins from COSMIC database. Different tools were used to detect the deleteriousness of the variants. Result In silico mutational study reveals how the non-synonymous mutations directly affect the protein’s native structure and its function. Variant mutational analysis with PolyPhen-2 revealed that out of 55 variants, 28 of the missense mutations was probably damaging with a score ranging from 0.9 to 1, while 24 variants were benign with a score ranging from 0 to 0.4. Conclusions This in silico work aims to determine how missense mutations in BCL-w protein affect the activity of the protein, the stability of the protein, and to determine the pathogenicity of the variants. Prediction of pathogenicity of variants will reveal if the missense mutation has a damaging effect on the native structure of protein or not. Prediction of protein stability will reveal whether the mutation has a stabilizing or destabilizing effect on the protein.
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Lee WJ, Kim MJ, Choi HW, Lee JJ, Jung SK. Effect of Methyl Gallate on 1-Nitropyrene-Induced Keratinocyte Toxicity in a Human and Canine Skin Model. J Microbiol Biotechnol 2022; 32:869-876. [PMID: 35880479 PMCID: PMC9628917 DOI: 10.4014/jmb.2206.06004] [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: 06/07/2022] [Revised: 06/22/2022] [Accepted: 06/27/2022] [Indexed: 12/15/2022]
Abstract
The skin, which is the largest organ of the human body, is in direct contact with pollutants in the surrounding atmosphere. Meanwhile, 1-nitropyrene (1-NP), the most abundant nitro-polycyclic aromatic hydrocarbon found in particulate matter, is known to have carcinogenic effects; however, studies on its toxicity in human and canine skin are still needed. In this study, we investigated 1-NP-induced apoptosis and inflammatory pathways in HaCaT cells. In addition, we also measured the cytoprotective effect of methyl gallate (MG), which is widely distributed in medicinal and edible plants and is well known for its anti-inflammatory and antioxidant properties. MG inhibited 1-NP-induced cell death and apoptosis pathways, including the cleavage of PARP and activation of caspase-3, -7, and -9. MG also suppressed 1-NP-induced COX-2 expression and phosphorylation of mitogen-activated protein kinases (MAPKs) and MAPK kinases (MAPKKs). Our findings suggest that 1-NP induces skin toxicity in human and canine through apoptosis and inflammatory responses, and moreover, that this can be prevented by treatment with MG.
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Affiliation(s)
- Woo Jin Lee
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Min Jeong Kim
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Hyun-Wook Choi
- Department of Functional Food and Biotechnology, Jeonju University, Jeonju 55069, Republic of Korea
| | - Jeong Jae Lee
- Institute of Agricultural Science and Technology, Kyungpook National University, Daegu 41566, Republic of Korea,Corresponding authors J.J. Lee Phone: +82-53-950-6654 E-mail:
| | - Sung Keun Jung
- School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea,Tailored Food Technology, Kyungpook National University, Daegu 41566, Republic of Korea,
S.K. Jung Phone: +82-53-950-7764 Fax: +82-53-950-7762 E-mail:
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An Z, Chen X, Li J. Response to Different Oxygen Partial Pressures and Evolution Analysis of Apoptosis-Related Genes in Plateau Zokor ( Myospalax baileyi). Front Genet 2022; 13:865301. [PMID: 35754836 PMCID: PMC9214310 DOI: 10.3389/fgene.2022.865301] [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: 01/29/2022] [Accepted: 04/28/2022] [Indexed: 11/30/2022] Open
Abstract
The plateau zokor (Myospalax baileyi) is a native species of the Qinghai–Tibet Plateau that spends its entire life underground in sealed burrows with hypoxic conditions. The present study aimed to assess the sequence characteristics of apoptosis-related genes and the response to different oxygen partial pressures (pO2) in plateau zokor and Sprague-Dawley rats. The sequences of the p53-induced protein with a death domain (Pidd), p53-upregulated modulator of apoptosis (Puma), insulin-like growth factor binding protein 3 (Igfbp3), and apoptosis protease-activating factor 1 (Apaf1) were evaluated concerning homology and convergent evolution sites, and their mRNA levels were evaluated in different tissues under 14.13 (3,300 m) and 16.12 kPa (2,260 m) pO2 conditions. Our results showed that, (1) the sequences of the apoptosis-related genes in plateau zokor were highly similar to those of Nannospalax galili, followed by Rattus norvegicus; (2). Pidd, Puma, Igfbp3, and Apaf1 of plateau zokor were found to have five, one, two, and five convergent sites in functional domains with N. galili, respectively. Lastly (3), under low pO2, the expression of Pidd and Puma was downregulated in the lung of plateau zokors. In turn, Igfbp3 and Apaf1 were upregulated in the liver and lung, and Puma was upregulated in the skeletal muscle of plateau zokor under low pO2. In Sprague-Dawley rats, low pO2 downregulated Puma and Apaf1 expression in the liver and downregulated Igfbp3 and Puma in the lung and skeletal muscle separately. In contrast, low pO2 upregulated Pidd expression in the liver and skeletal muscle of Sprague-Dawley rats. Overall, the expression patterns of Apaf1, Igfbp3, and Puma showed the opposite pattern in the liver, lung, and skeletal muscle, respectively, of plateau zokor as compared with Sprague-Dawley rats. In conclusion, for the long-time adaptation to hypoxic environments, Pidd, Puma, Igfbp3, and Apaf1 of plateau zokor underwent convergent evolution, which we believe may have led to upregulation of their levels under low oxygen partial pressures to induce apoptosis, so as to suppress tumorigenesis under hypoxic environments in plateau zokor.
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Affiliation(s)
- Zhifang An
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, China
| | - Xiaoqi Chen
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, China.,Department of Obstetrics and Gynaecology, Affiliated Hospital of Qinghai University, Xining, China.,Research Center for High Altitude Medicine, Qinghai University, Xining, China
| | - Jimei Li
- State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, China.,Research Center for High Altitude Medicine, Qinghai University, Xining, China.,Department of General Medicine, Qinghai Provincial People's Hospital, Xining, China
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Somade OT, Adeyi OE, Ajayi BO, Asunde OO, Iloh PD, Adesanya AA, Babalola OI, Folorunsho OT, Olakunle DA, Lawal OF. Syringic and ascorbic acids prevent NDMA-induced pulmonary fibrogenesis, inflammation, apoptosis, and oxidative stress through the regulation of PI3K-Akt/PKB-mTOR-PTEN signaling pathway. Metabol Open 2022; 14:100179. [PMID: 35340717 PMCID: PMC8943260 DOI: 10.1016/j.metop.2022.100179] [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: 02/08/2022] [Revised: 03/12/2022] [Accepted: 03/13/2022] [Indexed: 12/18/2022] Open
Abstract
Idiopathic lung fibrosis (ILF) is a severe and life threatening lung disorder that is characterized by scarring of lung tissue, leading to thickening and stiffening of affected areas. This study looked at the role played by PI3K-Akt/PKB-mToR signaling pathway in the pathogenesis of N-Nitrosodimethylamine (NDMA)-induced lung fibrotic injury, and the effects of syringic acid (SYR) and ascorbic acid (ASC) treatments in male Wistar rats. Pulmonary fibrosis was induced by intraperitoneal injection of 10 mg/kg NDMA once daily, thrice (consecutively) a week for four weeks, and this condition was treated daily with SYR (50 mg/kg) and ASC (100 mg/kg) acids orally for four weeks. Fibrogenesis, following NDMA administration was marked by a significant increase in collagen-1 and α-SMA levels, while oxidative stress was marked by a significant decrease in GSH level, GST, GPx, CAT, and SOD activities. Also, NDMA significantly increased lung Bax, p53, caspase-3, TNF-α, IL-1β, NFkB, and decreased Bcl-2, mdm2, cyclin D1 and Nrf-2 levels. Looking at the PI3K-Akt-mTOR signaling pathway, NDMA administration significantly activated lung PI3K, Akt, and mTOR, and deactivated PTEN, FoxO1 and TSC2. Treatments with SYR and ASC significantly reduced oxidative stress by restoring the antioxidant systems via Nrf2 activation, decreased the levels of inflammatory markers through inhibition of NFkB, downregulated p53, Bax, and caspase-3 via up-regulation of mdm2 and cyclin D1. SYR and ASC also regulated the PI3K-Akt-mTOR signaling pathway via the deactivation of PI3K, Akt, and mTOR, and up-regulation of PTEN, FoxO1 and TSC2. Overall, SYR and ASC modulate the PI3K-Akt-mTOR signaling pathway via inhibition of oxidative stress, inflammation and apoptosis in NDMA-induced lung fibrosis.
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Affiliation(s)
- Oluwatobi T. Somade
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - Olubisi E. Adeyi
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - Babajide O. Ajayi
- Department of Chemical Sciences, Faculty of Natural Sciences, Ajayi Crowther University, Oyo, Nigeria
| | - Osiro O. Asunde
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - Precious D. Iloh
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - Adedayo A. Adesanya
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - Olanrewaju I. Babalola
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - Oluwaseyi T. Folorunsho
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - Deborah A. Olakunle
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
| | - Opeyemi F. Lawal
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta, Nigeria
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Zhang DM, Deng JJ, Wu YG, Tang T, Xiong L, Zheng YF, Xu XM. MicroRNA-223-3p Protect Against Radiation-Induced Cardiac Toxicity by Alleviating Myocardial Oxidative Stress and Programmed Cell Death via Targeting the AMPK Pathway. Front Cell Dev Biol 2022; 9:801661. [PMID: 35111759 PMCID: PMC8801819 DOI: 10.3389/fcell.2021.801661] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Objectives: Radiotherapy improves the survival rate of cancer patients, yet it also involves some inevitable complications. Radiation-induced heart disease (RIHD) is one of the most serious complications, especially the radiotherapy of thoracic tumors, which is characterized by cardiac oxidative stress disorder and programmed cell death. At present, there is no effective treatment strategy for RIHD; in addition, it cannot be reversed when it progresses. This study aims to explore the role and potential mechanism of microRNA-223-3p (miR-223-3p) in RIHD.Methods: Mice were injected with miR-223-3p mimic, inhibitor, or their respective controls in the tail vein and received a single dose of 20 Gy whole-heart irradiation (WHI) for 16 weeks after 3 days to construct a RIHD mouse model. To inhibit adenosine monophosphate activated protein kinase (AMPK) or phosphodiesterase 4D (PDE4D), compound C (CompC) and AAV9-shPDE4D were used.Results: WHI treatment significantly inhibited the expression of miR-223-3p in the hearts; furthermore, the levels of miR-223-3p decreased in a radiation time-dependent manner. miR-223-3p mimic significantly relieved, while miR-223-3p inhibitor aggravated apoptosis, oxidative damage, and cardiac dysfunction in RIHD mice. In addition, we found that miR-223-3p mimic improves WHI-induced myocardial injury by activating AMPK and that the inhibition of AMPK by CompC completely blocks these protective effects of miR-223-3p mimic. Further studies found that miR-223-3p lowers the protein levels of PDE4D and inhibiting PDE4D by AAV9-shPDE4D blocks the WHI-induced myocardial injury mediated by miR-223-3p inhibitor.Conclusion: miR-223-3p ameliorates WHI-induced RIHD through anti-oxidant and anti-programmed cell death mechanisms via activating AMPK by PDE4D regulation. miR-223-3p mimic exhibits potential value in the treatment of RIHD.
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Affiliation(s)
- Dao-ming Zhang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jun-jian Deng
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yao-gui Wu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tian Tang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lin Xiong
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yong-fa Zheng
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Yong-fa Zheng, ; Xi-ming Xu,
| | - Xi-ming Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Yong-fa Zheng, ; Xi-ming Xu,
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Huan W, Yandong L, Chao W, Sili Z, Jun B, Mingfang L, Yu C, Lefeng Q. YKL-40 Aggravates Early-Stage Atherosclerosis by Inhibiting Macrophage Apoptosis in an Aven-dependent Way. Front Cell Dev Biol 2021; 9:752773. [PMID: 34950656 PMCID: PMC8688858 DOI: 10.3389/fcell.2021.752773] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
Objective: programmed cell removal in atherosclerotic plaques plays a crucial role in retarding lesion progression. Macrophage apoptosis has a critical role in PrCR, especially in early-stage lesions. YKL-40 has been shown to be elevated as lesions develop and is closely related to macrophages. This study aimed to determine the effect of YKL-40 on regulating macrophage apoptosis and early-stage atherosclerosis progression. Research design and Methods: The correlations among the expression level of YKL-40, the area of early-stage plaque, and the macrophage apoptosis rate in plaques have been shown in human carotid atherosclerotic plaques through pathological and molecular biological detection. These results were successively confirmed in vivo (Ldlr−/- mice treated by YKL-40 recombinant protein/neutralizing antibody) and in vitro (macrophages that Ykl40 up-/down-expressed) experiments. The downstream targets were predicted by iTRAQ analysis. Results: In early-stage human carotid plaques and murine plaques, the YKL-40 expression level had a significant positive correlation with the area of the lesion and a significant negative correlation with the macrophage apoptosis rate. In vivo, the plaque area of aortic roots was significantly larger in the recomb-YKL-40 group than that in IgG group (p = 0.0247) and was significantly smaller in the anti-YKL-40 group than in the IgG group (p = 0.0067); the macrophage apoptosis rate of the plaque in aortic roots was significantly lower in the recomb-YKL-40 group than that in IgG group (p = 0.0018) and was higher in anti-YKL-40 group than that in VC group. In vitro, the activation level of caspase-9 was significantly lower in RAW264.7 with Ykl40 overexpressed than that in controls (p = 0.0054), while the expression level of Aven was significantly higher than that in controls (p = 0.0031). The apoptosis rate of RAW264.7 treated by recomb-YKL40 was significantly higher in the Aven down-regulated group than that in the control group (p < 0.001). The apoptosis inhibitor Aven was confirmed as the target molecule of YKL-40. Mechanistically, YKL-40 could inhibit macrophage apoptosis by upregulating Aven to suppress the activation of caspase-9. Conclusion: YKL-40 inhibits macrophage apoptosis by upregulating the apoptosis inhibitor Aven to suppress the activation of caspase-9, which may impede normal PrCR and promote substantial accumulation in early-stage plaques, thereby leading to the progression of atherosclerosis.
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Affiliation(s)
- Wei Huan
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Liu Yandong
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Wang Chao
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Zou Sili
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Bai Jun
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Liao Mingfang
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chen Yu
- Yueyang Hospital of Integrated Traditional Chinese Medicine & Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qu Lefeng
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
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Arancibia SMF, Grecco HE, Morelli LG. Effective description of bistability and irreversibility in apoptosis. Phys Rev E 2021; 104:064410. [PMID: 35030833 DOI: 10.1103/physreve.104.064410] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 11/29/2021] [Indexed: 06/14/2023]
Abstract
Apoptosis is a mechanism of programmed cell death in which cells engage in a controlled demolition and prepare to be digested without damaging their environment. In normal conditions, apoptosis is repressed until it is irreversibly induced by an appropriate signal. In adult organisms, apoptosis is a natural way to dispose of damaged cells and its disruption or excess is associated with cancer and autoimmune diseases. Apoptosis is regulated by a complex signaling network controlled by caspases, specialized enzymes that digest essential cellular components and promote the degradation of genomic DNA. In this work, we propose an effective description of the signaling network focused on caspase-3 as a readout of cell fate. We integrate intermediate network interactions into a nonlinear feedback function acting on caspase-3 and introduce the effect of pro-apoptotic stimuli and regulatory elements as a saturating activation function. We show that activation dynamics in the theory is similar to previously reported experimental results. We compute bifurcation diagrams and obtain cell fate maps describing how stimulus intensity and feedback strength affect cell survival and death fates. These fates overlap within a bistable region that depends on total caspase concentration, regulatory elements, and feedback nonlinearity. We study a strongly nonlinear regime to obtain analytical expressions for bifurcation curves and fate map boundaries. For a broad range of parameters, strong stimuli can induce an irreversible switch to the death fate. We use the theory to explore dynamical stimulation conditions and determine how cell fate depends on stimulation temporal patterns. This analysis predicts a critical relation between transient stimuli intensity and duration to trigger irreversible apoptosis. We derive an analytical expression for this critical relation, valid for short stimuli. Our description provides distinct predictions and offers a framework to study how this signaling network processes different stimuli to make a cell fate decision.
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Affiliation(s)
- Sol M Fernández Arancibia
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET/Partner Institute of the Max Planck Society, Polo Científico Tecnológico, Godoy Cruz 2390, Buenos Aires C1425FQD, Argentina
| | - Hernán E Grecco
- Department of Physics, FCEN, University of Buenos Aires, Ciudad Universitaria, 1428 Buenos Aires, Argentina
- IFIBA, CONICET, 1428 Buenos Aires, Argentina
- Max Planck Institute for Molecular Physiology, Department of Systemic Cell Biology, Otto-Hahn-Strasse 11, Dortmund D-44227, Germany
| | - Luis G Morelli
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET/Partner Institute of the Max Planck Society, Polo Científico Tecnológico, Godoy Cruz 2390, Buenos Aires C1425FQD, Argentina
- Department of Physics, FCEN, University of Buenos Aires, Ciudad Universitaria, 1428 Buenos Aires, Argentina
- Max Planck Institute for Molecular Physiology, Department of Systemic Cell Biology, Otto-Hahn-Strasse 11, Dortmund D-44227, Germany
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Apoptosis, Pyroptosis, and Necroptosis-Oh My! The Many Ways a Cell Can Die. J Mol Biol 2021; 434:167378. [PMID: 34838807 DOI: 10.1016/j.jmb.2021.167378] [Citation(s) in RCA: 227] [Impact Index Per Article: 56.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/12/2021] [Accepted: 11/21/2021] [Indexed: 12/12/2022]
Abstract
Cell death is an essential process in all living organisms and occurs through different mechanisms. The three main types of programmed cell death are apoptosis, pyroptosis, and necroptosis, and each of these pathways employs complex molecular and cellular mechanisms. Although there are mechanisms and outcomes specific to each pathway, they share common components and features. In this review, we discuss recent discoveries in these three best understood modes of cell death, highlighting their singularities, and examining the intriguing notion that common players shape different individual pathways in this highly interconnected and coordinated cell death system. Understanding the similarities and differences of these cell death processes is crucial to enable targeted strategies to manipulate these pathways for therapeutic benefit.
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Araya LE, Soni IV, Hardy JA, Julien O. Deorphanizing Caspase-3 and Caspase-9 Substrates In and Out of Apoptosis with Deep Substrate Profiling. ACS Chem Biol 2021; 16:2280-2296. [PMID: 34553588 DOI: 10.1021/acschembio.1c00456] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Caspases are a family of enzymes that regulate biological processes such as inflammation and programmed cell death, through proteolysis. For example, in the intrinsic pathway of apoptosis, cell death signaling involves cytochrome c release from the mitochondria, which leads to the activation of caspase-9 and eventually the executioners caspase-3 and -7. One key step in our understanding of these proteases is to identify their respective protein substrates. Although hundreds of substrates have been linked to caspase-3, only a small handful of substrates have been reported for caspase-9. Employing deep profiling by subtiligase N-terminomics, we present here an unbiased analysis of caspase-3 and caspase-9 substrates in native cell lysates. We identified 906 putative protein substrates associated with caspase-3 and 124 protein substrates for caspase-9. This is the most comprehensive list of caspase substrates reported for each of these proteases, revealing a pool of new substrates that could not have been discovered using other approaches. Over half of the caspase-9 substrates were also cleaved by caspase-3, but often at unique sites, suggesting an evolved functional redundancy for these two proteases. Correspondingly, nearly half of the caspase-9 cleavage sites were not recognized by caspase-3. Our results suggest that in addition to its important role in activating the executioners, the role of caspase-9 is likely broader and more complex than previously appreciated, which includes proteolysis of key apoptotic substrates other than just caspase-3 and -7 and involvement in non-apoptotic pathways. Our results are well poised to aid the discovery of new biological functions for these two caspases.
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Affiliation(s)
- Luam E. Araya
- Department of Biochemistry, University of Alberta, Edmonton T6G 2H7, Alberta, Canada
| | - Ishankumar V. Soni
- Department of Chemistry, University of Massachusetts, Amherst 01003, Massachusetts, United States
| | - Jeanne A. Hardy
- Department of Chemistry, University of Massachusetts, Amherst 01003, Massachusetts, United States
| | - Olivier Julien
- Department of Biochemistry, University of Alberta, Edmonton T6G 2H7, Alberta, Canada
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Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy. Int J Mol Sci 2021; 22:ijms222212466. [PMID: 34830349 PMCID: PMC8618802 DOI: 10.3390/ijms222212466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 01/18/2023] Open
Abstract
Research in biomedical sciences has changed dramatically over the past fifty years. There is no doubt that the discovery of apoptosis and autophagy as two highly synchronized and regulated mechanisms in cellular homeostasis are among the most important discoveries in these decades. Along with the advancement in molecular biology, identifying the genetic players in apoptosis and autophagy has shed light on our understanding of their function in physiological and pathological conditions. In this review, we first describe the history of key discoveries in apoptosis with a molecular insight and continue with apoptosis pathways and their regulation. We touch upon the role of apoptosis in human health and its malfunction in several diseases. We discuss the path to the morphological and molecular discovery of autophagy. Moreover, we dive deep into the precise regulation of autophagy and recent findings from basic research to clinical applications of autophagy modulation in human health and illnesses and the available therapies for many diseases caused by impaired autophagy. We conclude with the exciting crosstalk between apoptosis and autophagy, from the early discoveries to recent findings.
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Barati M, Darvishi B, Javidi MA, Mohammadian A, Shariatpanahi SP, Eisavand MR, Madjid Ansari A. Cellular stress response to extremely low-frequency electromagnetic fields (ELF-EMF): An explanation for controversial effects of ELF-EMF on apoptosis. Cell Prolif 2021; 54:e13154. [PMID: 34741480 PMCID: PMC8666288 DOI: 10.1111/cpr.13154] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/21/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Impaired apoptosis is one of the hallmarks of cancer, and almost all of the non‐surgical approaches of eradicating tumour cells somehow promote induction of apoptosis. Indeed, numerous studies have stated that non‐ionizing non‐thermal extremely low‐frequency magnetic fields (ELF‐MF) can modulate the induction of apoptosis in exposed cells; however, much controversy exists in observations. When cells are exposed to ELF‐EMF alone, very low or no statistically significant changes in apoptosis are observed. Contrarily, exposure to ELF‐EMF in the presence of a co‐stressor, including a chemotherapeutic agent or ionizing radiation, can either potentiate or inhibit apoptotic effects of the co‐stressor. In our idea, the main point neglected in interpreting these discrepancies is “the cellular stress responses” of cells following ELF‐EMF exposure and its interplay with apoptosis. The main purpose of the current review was to outline the triangle of ELF‐EMF, the cellular stress response of cells and apoptosis and to interpret and unify discrepancies in results based on it. Therefore, initially, we will describe studies performed on identifying the effect of ELF‐EMF on induction/inhibition of apoptosis and enumerate proposed pathways through which ELF‐EMF exposure may affect apoptosis; then, we will explain cellular stress response and cues for its induction in response to ELF‐EMF exposure; and finally, we will explain why such controversies have been observed by different investigators.
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Affiliation(s)
- Mojdeh Barati
- Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Behrad Darvishi
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Mohammad Amin Javidi
- Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Ali Mohammadian
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Mohammad Reza Eisavand
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Alireza Madjid Ansari
- Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
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