10,334 results
Search Results
2. Unraveling the Mechanism of Cork Spot-like Physiological Disorders in 'Kurenainoyume' Apples Based on Occurrence Location.
- Author
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Imura, Eichi, Nakagomi, Mitsuho, Hayashida, Taishi, Fujita, Tomomichi, Sato, Saki, and Matsumoto, Kazuhiro
- Subjects
CORK ,COMPUTED tomography ,APPLES ,FRUIT development ,PAPER bags ,CELL death - Abstract
Cork spot-like physiological disorder (CSPD) is a newly identified issue in 'Kurenainoyume' apples, yet its mechanism remains unclear. To investigate CSPD, we conducted morphological observations on 'Kurenainoyume' apples with and without pre-harvest fruit-bagging treatment using light-impermeable paper bags. Non-bagged fruit developed CSPD in mid-August, while no CSPD symptoms were observed in bagged fruit. The bagging treatment significantly reduced the proportion of opened lenticels, with only 17.9% in bagged fruit compared to 52.0% in non-bagged fruits. In non-bagged fruit, CSPD spots tended to increase from the lenticels, growing in size during fruit development. The cuticular thickness and cross-sectional area of fresh cells in CSPD spots were approximately 16 µm and 1600 µm², respectively. Healthy non-bagged fruit reached these values around 100 to 115 days after full bloom from mid- to late August. Microscopic and computerized tomography scanning observations revealed that many CSPD spots developed at the tips of vascular bundles. Therefore, CSPD initiation between opened lenticels and vascular bundle tips may be influenced by water stress, which is potentially caused by water loss, leading to cell death and the formation of CSPD spots. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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3. The boundary-spanning mechanisms of Nobel Prize winning papers
- Author
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Chaomei Chen and Yakub Sebastian
- Subjects
FOS: Computer and information sciences ,Computer and Information Sciences ,Cell Physiology ,Entropy ,Autophagic Cell Death ,Science ,Boundary spanning ,Space (commercial competition) ,Bibliometrics ,Research and Analysis Methods ,Betweenness centrality ,Citation analysis ,Medicine and Health Sciences ,Centrality ,Digital Libraries (cs.DL) ,Sociology ,Multidisciplinary ,Cell Death ,Physics ,Publications ,Biology and Life Sciences ,Computer Science - Digital Libraries ,Cell Biology ,Research Assessment ,Nobel Prize ,Databases as Topic ,Cell Processes ,Citation Analysis ,Physical Sciences ,Thermodynamics ,Medicine ,Bibliographies as Topic ,Mathematical economics ,Network Analysis ,Research Article - Abstract
The breakthrough potentials of research papers can be explained by their boundary-spanning qualities. Here, for the first time, we apply the structural variation analysis (SVA) model and its affiliated metrics to investigate the extent to which such qualities characterize a group of Nobel Prize winning papers. We find that these papers share remarkable boundary-spanning traits, marked by exceptional abilities to connect disparate and topically-diverse clusters of research papers. Further, their publications exert structural variations on the scale that significantly alters the betweenness centrality distributions of existing intellectual space. Overall, SVA not only provides a set of leading indicators for describing future Nobel Prize winning papers, but also broadens our understanding of the similar prize-winning properties that may have been overlooked among other regular publications., 27 pages, 8 figures, 9 tables. Submitted to Frontiers in Research Metrics and Analytics
- Published
- 2021
4. HSP27 role in cardioprotection by modulating chemotherapeutic doxorubicin-induced cell death.
- Author
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Ramani S and Park S
- Subjects
- Animals, Antibiotics, Antineoplastic therapeutic use, Apoptosis drug effects, Apoptosis genetics, Cardiomyopathies etiology, Cardiomyopathies metabolism, Cardiotoxicity etiology, Cardiotoxicity metabolism, Cell Survival drug effects, Cell Survival genetics, Disease Susceptibility, Doxorubicin therapeutic use, HSP27 Heat-Shock Proteins metabolism, Heart Failure etiology, Heart Failure metabolism, Humans, Oxidative Stress drug effects, Antibiotics, Antineoplastic adverse effects, Cell Death drug effects, Cell Death genetics, Doxorubicin adverse effects, HSP27 Heat-Shock Proteins genetics
- Abstract
The common phenomenon expected from any anti-cancer drug in use is to kill the cancer cells without any side effects to non-malignant cells. Doxorubicin is an anthracycline derivative anti-cancer drug active over different types of cancers with anti-cancer activity but attributed to unintended cytotoxicity and genotoxicity triggering mitogenic signals inducing apoptosis. Administration of doxorubicin tends to both acute and chronic toxicity resulting in cardiomyopathy (left ventricular dysfunction) and congestive heart failure (CHF). Cardiotoxicity is prevented through administration of different cardioprotectants along with the drug. This review elaborates on mechanism of drug-mediated cardiotoxicity and attenuation principle by different cardioprotectants, with a focus on Hsp27 as cardioprotectant by prevention of drug-induced oxidative stress, cell survival pathways with suppression of intrinsic cell death. In conclusion, Hsp27 may offer an exciting/alternating cardioprotectant, with a wider study being need of the hour, specifically on primary cell line and animal models in conforming its cardioprotectant behaviour.
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- 2021
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5. Research Trends and Most Influential Clinical Studies on Anti-PD1/PDL1 Immunotherapy for Cancers: A Bibliometric Analysis.
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Liu, Yanhao, Xu, Yan, Cheng, Xi, Lin, Yaru, Jiang, Shu, Yu, Haiming, Zhang, Zhen, Lu, Linlin, and Zhang, Xiaotao
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NON-small-cell lung carcinoma ,BIBLIOMETRICS ,IMMUNOTHERAPY ,CELL death - Abstract
In this study, a bibliometric analysis was carried out to identify the most influential clinical studies and research trends on anti-programmed cell death 1/programmed cell death 1 ligand 1 (anti-PD1/PDL1) immunotherapy. On January 1, 2022, we used Web of Science to identify the 100 most frequently cited papers on clinical studies investigating anti-PD1/PDL1 immunotherapy, and extracted the following data: publication year, source title, country/region, institution, and the total number of citations. The research design and area were classified independently by the authors. Subsequently, we carried out a bibliometric analysis to determine the trends and identify the major journals on anti-PD1/PDL1 immunotherapy. The authors analyzed the current research hotspots based on papers published in major journals from 2020 to 2021. These 100 papers were cited a total of 138,840 times, and the median number of citations was 899.5 (range: 341–7,983). "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer" by Topalian et al. had the highest number of citations (7,983 times). New England Journal of Medicine had the highest number of top-cited papers (40 papers), average citations per paper (1,558.3 citations), and rate of top-cited papers (65.6%). Authors from the USA contributed most of the papers (76 papers). Lung cancer (30 papers, 46,422 citations) and melanoma (20 papers, 30,881 citations) were the most cited research areas. In summary, anti-PD1/PDL1 has become standard treatment for various cancer, while adjuvant anti-PD1/PDL1 therapy is currently a research hotspot. New England Journal of Medicine was identified as the most influential journal in this area. Non-small cell lung cancer and melanoma are the most well-studied cancers, while nivolumab and pembrolizumab are the most commonly investigated anti-PD1/PDL1 antibodies. Further studies are warranted to identify effective predictive biomarkers or models, clarify the molecular mechanism of combined therapy, and establish optimal therapeutic strategies. This study may assist researchers in obtaining a comprehensive impression of the landscape and current trends in anti-PD1/PDL1 immunotherapy and gain inspiration to conduct further studies. [ABSTRACT FROM AUTHOR]
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- 2022
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6. RESEARCH PAPER: miR-19 is a key oncogenic component of mir-17-92.
- Author
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Olive, Virginie, Bennett, Margaux J., Walker, James C., Cong Ma, Jiang, Iris, Cordon-Cardo, Carlos, Qi-Jing Li, Lowe, Scott W., Hannon, Gregory J., and Lin He
- Subjects
- *
LYMPHOMAS , *CANCER genetics , *TUMOR suppressor genes , *LABORATORY mice , *CELL death - Abstract
Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the Eμ1/4-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient for promoting c-myc-induced lymphomagenesis by repressing apoptosis. The oncogenic activity of miR-19 is at least in part due to its repression of the tumor suppressor Pten. Consistently, miR-19 activates the Akt?"mTOR (mammalian target of rapamycin) pathway, thereby functionally antagonizing Pten to promote cell survival. Our findings reveal the essential role of miR-19 in mediating the oncogenic activity of mir-17-92, and implicate the functional diversity of mir-17-92 components as the molecular basis for its pleiotropic effects during tumorigenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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7. Exploring the Role of Different Cell-Death-Related Genes in Sepsis Diagnosis Using a Machine Learning Algorithm.
- Author
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Wang, Xuesong, Wang, Ziyi, Guo, Zhe, Wang, Ziwen, Chen, Feng, and Wang, Zhong
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MACHINE learning ,SEPSIS ,APOPTOSIS ,GENES ,CELL death - Abstract
Sepsis, a disease caused by severe infection, has a high mortality rate. At present, there is a lack of reliable algorithmic models for biomarker mining and diagnostic model construction for sepsis. Programmed cell death (PCD) has been shown to play a vital role in disease occurrence and progression, and different PCD-related genes have the potential to be targeted for the treatment of sepsis. In this paper, we analyzed PCD-related genes in sepsis. Implicated PCD processes include apoptosis, necroptosis, ferroptosis, pyroptosis, netotic cell death, entotic cell death, lysosome-dependent cell death, parthanatos, autophagy-dependent cell death, oxeiptosis, and alkaliptosis. We screened for diagnostic-related genes and constructed models for diagnosing sepsis using multiple machine-learning models. In addition, the immune landscape of sepsis was analyzed based on the diagnosis-related genes that were obtained. In this paper, 10 diagnosis-related genes were screened for using machine learning algorithms, and diagnostic models were constructed. The diagnostic model was validated in the internal and external test sets, and the Area Under Curve (AUC) reached 0.7951 in the internal test set and 0.9627 in the external test set. Furthermore, we verified the diagnostic gene via a qPCR experiment. The diagnostic-related genes and diagnostic genes obtained in this paper can be utilized as a reference for clinical sepsis diagnosis. The results of this study can act as a reference for the clinical diagnosis of sepsis and for target discovery for potential therapeutic drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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8. Ferroptosis as a New Type of Cell Death and its Role in Cancer Treatment.
- Author
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Skoupilová H, Michalová E, and Hrstka R
- Subjects
- Humans, Neoplasms drug therapy, Cell Death, Iron metabolism, Neoplasms metabolism, Reactive Oxygen Species metabolism
- Abstract
Background: Ferroptosis is a recently discovered type of cell death. It is genetically, morphologically, and biochemically distinct from other types of programmed cell death, such as necrosis, apoptosis, and autophagy. The level of intracellular free iron and reactive oxygen species formation are important for ferroptosis activation, which can occur through either of two key inhibitory processes. The first one involves inhibition of cystine transfer into cells by the cystine/glutamate antiporter system (Xc-). Cystine serves as a precursor for the synthesis of glutathione, a major cellular antioxidant. The second one involves the inhibition of glutathione peroxidase 4, which protects cells from lipid peroxidation. Ferroptosis is associated with many metabolic disorders, including neurological diseases and cancer. Molecules involved in the activation of ferroptotic pathways are involved in protecting cells against stress conditions, and in the maintenance of nicotinamide adenine dinucleotide phosphate and glutathione levels, as well as iron homeostasis. Also important is the connection with autophagy, so called ferritinophagy, in which iron is released from lysosomes into the cytosol. Cascade reactions of free unstable iron atoms with other molecules result in the production of reactive oxygen species that initiate the cellular stress that triggers ferroptosis. In diseases such as cancer where cell death inducing mechanisms, including apoptosis, are usually suppressed by genetic changes, the induction of alternative pathways leading to cell death could provide an attractive treatment strategy., Conclusion: In recent years, research into new antimetastatic drugs has focused on the activation of alternative cell death pathways that might overcome disturbed metabolic processes inside cancer cells or the chemotherapy resistance acquired in the course of routine treatment. A number of molecules have been found to induce ferroptosis in tumor cells, suggesting that they may offer new alternatives for anticancer treatment. Key words: cell death - cancer - autophagy - ferroptosis - ferritinophagy - cellular stress - ROS This work was supported by the projects GAČR 17-05838S, MEYS - NPS I - LO1413 and MH CZ- -DRO (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Accepted: 31. 8. 2018.
- Published
- 2018
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9. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions.
- Author
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Yan, Lei, Shi, Jia, and Zhu, Jiazuo
- Subjects
COLORECTAL cancer ,EPIGENOMICS ,CELL death ,DRUG resistance ,CARCINOGENS ,CELL analysis ,GENETIC mutation - Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies. Highlights: Colorectal cancer (CRC) is one of the leading causes of death among patients. CRC has been characterized with changes at the genetic and epigenetic factors. The molecular factors can be used as diagnostic and prognostic factors in CRC. The cell death mechanisms demonstrate dysregulation in CRC. Autophagy has aberrant activation in CRC and exerts dual function. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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10. A bibliometric analysis of the research hotspots and frontiers related to cell death in spinal cord injury.
- Author
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Kelin He, Han Yu, Jieqi Zhang, Lei Wu, Dexiong Han, and Ruijie Ma
- Subjects
BIBLIOMETRICS ,CELL death ,SPINAL cord injuries ,CHINA-United States relations ,DATABASES - Abstract
Background: Spinal cord injury (SCI) is a severe central nervous trauma that can cause serious consequences. Cell death is emerging as a common pathogenesis after SCI. In the last two decades, numerous studies have been published in the field of cell death after SCI. However, it is still rare to find relevant bibliometric analyses. This bibliometric study aims to visually represent global research trends in the field of cell death after SCI. Methods: Bibliometric data were sourced from the Web of Science Core Collection (WoSCC) database. VOSviewer, CiteSpace, and R software ("bibliometrix" package) were used to analyze and visualize bibliometric data. Annual scientific production, countries/regions, institutions, authors, journals, highly cited papers, keywords, and literature co-citation were evaluated to determine research performance. Results: An analysis of 5,078 publications extracted from the WoSCC database revealed a fluctuating yet persistent growth in the field of cell death after SCI over the past 23 years. China and the United States, contributing 69% of the total publications, were the main driving force in this field. The Wenzhou Medical University from China contributed to the most papers. In terms of authors, Salvatore Cuzzocrea from the University of Messina had the highest number of publications. The "Journal of Neurotrauma" was the top journal in terms of the number of publications, however, the "Journal of Neuroscience" was the top journal in terms of the number of citations. The theme of the highly cited articles mainly focused on the mechanism of cell death after SCI. The keyword and literature co-citation analysis mainly focused on the mode of cell death, mechanism research of cell death, and functional recovery after SCI. Conclusion: This study analyzes the research hotspots, frontiers, and development trends in the field of cell death after SCI, which is important for future studies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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11. A detailed overview of quercetin: implications for cell death and liver fibrosis mechanisms.
- Author
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Fei Xiong, Yichen Zhang, Ting Li, Yiping Tang, Si-Yuan Song, Qiao Zhou, and Yi Wang
- Subjects
HEPATIC fibrosis ,CELL death ,CARBON tetrachloride ,QUERCETIN ,LIVER cells ,PHYSICAL organic chemistry ,FLAVONOIDS - Abstract
Background: Quercetin, a widespread polyphenolic flavonoid, is known for its extensive health benefits and is commonly found in the plant kingdom. The natural occurrence and extraction methods of quercetin are crucial due to its bioactive potential. Purpose: This review aims to comprehensively cover the natural sources of quercetin, its extraction methods, bioavailability, pharmacokinetics, and its role in various cell death pathways and liver fibrosis. Methods: A comprehensive literature search was performed across several electronic databases, including PubMed, Embase, CNKI, Wanfang database, and ClinicalTrials.gov, up to 10 February 2024. The search terms employedwere "quercetin", "natural sources of quercetin", "quercetin extraction methods", "bioavailability of quercetin", "pharmacokinetics of quercetin", "cell death pathways", "apoptosis", "autophagy", "pyroptosis", "necroptosis", "ferroptosis", "cuproptosis", "liver fibrosis", and "hepatic stellate cells". These keywords were interconnected using AND/OR as necessary. The search focused on studies that detailed the bioavailability and pharmacokinetics of quercetin, its role in different cell death pathways, and its effects on liver fibrosis. Results: This review details quercetin's involvement in various cell death pathways, including apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis, with particular attention to its regulatory influence on apoptosis and autophagy. It dissects the mechanisms through which quercetin affects these pathways across different cell types and dosages. Moreover, the paper delves into quercetin's effectson liver fibrosis, its interactions with hepatic stellate cells, and its modulation of pertinent signaling cascades. Additionally, it articulates from a physical organic chemistry standpoint the uniqueness of quercetin's structure and its potential for specific actions in the liver. Conclusion: The paper provides a detailed analysis of quercetin, suggesting its significant role in modulating cell death mechanisms and mitigating liver fibrosis, underscoring its therapeutic potential. [ABSTRACT FROM AUTHOR]
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- 2024
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12. The crosstalk between cell death and pregnancy related diseases: A narrative review.
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Xie X, Liu J, Gao J, Shang C, Jiang Y, Chen L, Qian Z, Liu L, Wu D, Zhang Y, Ru Z, and Zhang Y
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- Humans, Pregnancy, Female, Animals, Signal Transduction, Apoptosis physiology, Autophagy physiology, Cell Death physiology, Pregnancy Complications metabolism, Pregnancy Complications pathology
- Abstract
Programmed cell death is intricately linked to various physiological phenomena such as growth, development, and metabolism, as well as the proper function of the pancreatic β cell and the migration and invasion of trophoblast cells in the placenta during pregnancy. Traditional and recently identified programmed cell death include apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis. In addition to cancer and degenerative diseases, abnormal activation of cell death has also been implicated in pregnancy related diseases like preeclampsia, gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, fetal growth restriction, and recurrent miscarriage. Excessive or insufficient cell death and pregnancy related diseases may be mutually determined, ultimately resulting in adverse pregnancy outcomes. In this review, we systematically describe the characteristics and mechanisms underlying several types of cell death and their roles in pregnancy related diseases. Moreover, we discuss potential therapeutic strategies that target cell death signaling pathways for pregnancy related diseases, hoping that more meaningful treatments will be applied in clinical practice in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
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- 2024
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13. Good Versus Bad Cells
- Published
- 2009
14. Photodynamic Therapy and Adaptive Immunity Induced by Reactive Oxygen Species: Recent Reports.
- Author
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Aebisher, David, Woźnicki, Paweł, and Bartusik-Aebisher, Dorota
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TUMOR treatment ,MYELOID-derived suppressor cells ,REACTIVE oxygen species ,SYSTEMATIC reviews ,MEDLINE ,METABOLITES ,CELL death ,PHOTODYNAMIC therapy ,INFLAMMATION ,ONLINE information services ,CYTOKINES ,EXTRACELLULAR matrix ,IMMUNITY - Abstract
Simple Summary: Photodynamic therapy (PDT) is a cancer treatment that uses photogenerated reactive oxygen species (ROS) to damage target cells. The unique mechanism of action of PDT involves the systemic or local administration of a photosensitizing compound (photosensitizer), which is then activated by light of a specific energy. PDT induces a very strong local inflammatory response. A number of adaptive mechanisms are induced within the tumor, related to increased amino acid metabolism and damage to lymphatic vessels. In this review, we are describing the adaptive immune response induced by ROS and generated by PDT. Cancer is one of the most significant causes of death worldwide. Despite the rapid development of modern forms of therapy, results are still unsatisfactory. The prognosis is further worsened by the ability of cancer cells to metastasize. Thus, more effective forms of therapy, such as photodynamic therapy, are constantly being developed. The photodynamic therapeutic regimen involves administering a photosensitizer that selectively accumulates in tumor cells or is present in tumor vasculature prior to irradiation with light at a wavelength corresponding to the photosensitizer absorbance, leading to the generation of reactive oxygen species. Reactive oxygen species are responsible for the direct and indirect destruction of cancer cells. Photodynamically induced local inflammation has been shown to have the ability to activate an adaptive immune system response resulting in the destruction of tumor lesions and the creation of an immune memory. This paper focuses on presenting the latest scientific reports on the specific immune response activated by photodynamic therapy. We present newly discovered mechanisms for the induction of the adaptive response by analyzing its various stages, and the possible difficulties in generating it. We also present the results of research over the past 10 years that have focused on improving the immunological efficacy of photodynamic therapy for improved cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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15. Rotigotine protects against oxidized low-density lipoprotein(ox-LDL)-induced damages in human umbilical vein endothelial cells(HUVECs)
- Author
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Ge Cao, Hui Kang, Hui Yu, and Jingxiu Fan
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huvecs ,Tetrahydronaphthalenes ,Bioengineering ,Thiophenes ,Pharmacology ,Protective Agents ,Applied Microbiology and Biotechnology ,Umbilical vein ,Monocytes ,chemistry.chemical_compound ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,Cell adhesion ,nf-κb ,chemistry.chemical_classification ,Reactive oxygen species ,NADPH oxidase ,biology ,Cell Death ,Chemistry ,Cholesterol ,NF-kappa B ,rotigotine ,Rotigotine ,NF-κB ,General Medicine ,ox-ldl ,cardiovascular diseases ,Lipoproteins, LDL ,Oxidative Stress ,Receptors, LDL ,biology.protein ,Cytokines ,Inflammation Mediators ,Proprotein Convertase 9 ,Cell Adhesion Molecules ,TP248.13-248.65 ,medicine.drug ,Lipoprotein ,Research Article ,Research Paper ,Sterol Regulatory Element Binding Protein 2 ,Biotechnology - Abstract
Rotigotine is a non-ergoline dopamine agonist that has been licensed for the treatment of Parkinson’s disease. Cardiovascular diseases are the world’s leading cause of death. Ox-LDL- induced endothelial damages are involved in the initiation and progression of cardiovascular diseases. In this study, we assessed the beneficial properties of Rotigotine on ox-LDL-induced insults to HUVECs to highlight its potential use in the treatment of cardiovascular diseases. Our findings show that Rotigotine suppresses the expressions of low-density lipoprotein receptor (LDL-R), proprotein convertase subtilisin/kexin type 9 (PCSK-9), and sterol regulatory element-binding protein (SREBP-2). It also inhibits ox-LDL-induced cholesterol accumulation in endothelial cells (ECs), improves U937 monocytes adhesion, and decreases the representation of NADPH oxidase (NOX-4) and generation of reactive oxygen species (ROS) in endothelial cells (ECs). Furthermore, Rotigotine inhibited the expressions of both vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HUVECs and had anti-inflammatory efficacy in ox-LDL-induced cells by inhibiting the expressions of pro-inflammatory cytokines. Notably, Rotigotine inhibits the activation of nuclear factor-kappaB (NF-κB) by preventing nuclear translocation of NF-κB p65 and reducing the luciferase activity of NF-κB reporter. We, therefore, conclude that these effects of Rotigotine on HUVECs suggest that it may play a therapeutic role in cardiovascular diseases.
- Published
- 2021
16. Exploration of the mechanism of luteolin against ischemic stroke based on network pharmacology, molecular docking and experimental verification
- Author
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Rui Dong, Renxuan Huang, Xiaohua Shi, Zhongxin Xu, and Jing Mang
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Cell Survival ,Bioengineering ,target prediction ,Network Pharmacology ,Applied Microbiology and Biotechnology ,PC12 Cells ,enrichment analysis ,ischemic stroke ,Animals ,Humans ,Protein Interaction Maps ,Luteolin ,Cell Death ,Reproducibility of Results ,General Medicine ,Rats ,Molecular Docking Simulation ,Oxygen ,Gene Ontology ,Glucose ,Gene Expression Regulation ,Caco-2 Cells ,TP248.13-248.65 ,Biotechnology ,Research Article ,Research Paper - Abstract
Stroke is a leading cause of morbidity and mortality worldwide. As the most common type of stroke cases, treatment effectiveness is still limited despite intensive research. Recently, traditional Chinese medicine has attracted attention because of potential benefits for stroke treatment. Among these, luteolin, a natural plant flavonoid compound, offers neuroprotection following against ischemic stroke, although the specific mechanisms are unknown. Here we used network pharmacology, molecular docking, and experimental verification to explore the mechanisms whereby luteolin can benefit stroke recovery. The pharmacological and molecular properties of luteolin were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The potential targets of luteolin and ischemic stroke were collected from interrogating public databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed by Funrich and Database for Annotation, Visualization and Integrated Discovery respectively, a luteolin-target-pathway network constructed using Cytoscape, Autodock vina was used for molecular docking simulation with Discovery Studio was used to visualize and analyze the docked conformations. Lastly, we employed an in vitro model of stroke injury to evaluate the effects of luteolin on cell survival and expression of the putative targets. From 95 candidate luteolin target genes, our analysis identified six core targets . KEGG analysis of the candidate targets identified that luteolin provides therapeutic effects on stroke through TNF signaling and other pathways. Our experimental analyses confirmed the conclusions analyzed above. In summary, the molecular and pharmacological mechanisms of luteolin against stroke are indicated in our study from a systematic perspective.
- Published
- 2021
17. Zafirlukast ameliorates Docetaxel-induced activation of NOD-like receptor protein 3 (NLRP3) inflammasome, mediated by sirtuin1 (SIRT1) in hepatocytes
- Author
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Ziyi Guo, Xunjin Zeng, and Yu Zheng
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Indoles ,Inflammasomes ,zafirlukast ,sirt1 ,Phenylcarbamates ,Bioengineering ,Pharmacology ,Applied Microbiology and Biotechnology ,Cell Line ,chemistry.chemical_compound ,Sirtuin 1 ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Humans ,docetaxel ,Viability assay ,Gene Silencing ,Zafirlukast ,Receptor ,neoplasms ,Liver injury ,Membrane Potential, Mitochondrial ,Sulfonamides ,ldh ,Cell Death ,Leukotriene receptor ,Chemistry ,General Medicine ,Glutathione ,medicine.disease ,Mitochondria ,Oxidative Stress ,Apoptosis ,Toxicity ,hepatocytes ,TP248.13-248.65 ,medicine.drug ,Research Article ,Research Paper ,Biotechnology - Abstract
Docetaxel-associated liver injury has become a serious public health problem, resulting in therapy discontinuation, liver failure, and death. Zafirlukast is a typical leukotriene receptor antagonist used for prophylaxis and chronic treatment of asthma. In this study, we investigate whether treatment with Zafirlukast could alleviate Docetaxel-induced cytotoxicity in hepatocytes. Our results indicate that Zafirlukast mitigated Docetaxel-induced toxicity in LO-2 hepatocytes. Firstly, Zafirlukast reduced the production of 8-hydroxy-2p-deoxyguanosine (8-OHdG) and increased the levels of reduced glutathione (GSH) against Docetaxel. Secondly, Zafirlukast elevated the levels of mitochondrial membrane potential (ΔΨm) and adenosine triphosphate (ATP). Thirdly, Zafirlukast prevented Docetaxel-induced release of lactate dehydrogenase (LDH) and increased cell viability of LO-2 hepatocytes against Docetaxel. We also found that Zafirlukast ameliorated Docetaxel-induced apoptosis by reducing Caspase-3 and Caspase-9 activity. Mechanistically, our results demonstrate that Zafirlukast inhibited the activation of NOD-like receptor protein 3 (NLRP3), mediated by SIRT1. Based on these findings, we conclude that the administration of Zafirlukast might have a protective effect against Docetaxel-induced cytotoxicity in hepatocytes.
- Published
- 2021
18. Mechanism of metal ion-induced cell death in gastrointestinal cancer.
- Author
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Luan M, Feng Z, Zhu W, Xing Y, Ma X, Zhu J, Wang Y, and Jia Y
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- Humans, Animals, Ferroptosis drug effects, Ions metabolism, Antineoplastic Agents pharmacology, Gastrointestinal Neoplasms pathology, Gastrointestinal Neoplasms drug therapy, Metals, Cell Death drug effects
- Abstract
Gastrointestinal (GI) cancer is one of the most severe types of cancer, with a significant impact on human health worldwide. Due to the urgent demand for more effective therapeutic strategies against GI cancers, novel research on metal ions for treating GI cancers has attracted increasing attention. Currently, with accumulating research on the relationship between metal ions and cancer therapy, several metal ions have been discovered to induce cell death. In particular, the three novel modes of cell death, including ferroptosis, cuproptosis, and calcicoptosis, have become focal points of research in the field of cancer. Meanwhile, other metal ions have also been found to trigger cell death through various mechanisms. Accordingly, this review focuses on the mechanisms of metal ion-induced cell death in GI cancers, hoping to provide theoretical support for further GI cancer therapies., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest. All the authors agree to the content of the paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
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19. The interplay of transition metals in ferroptosis and pyroptosis.
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Vana, Frantisek, Szabo, Zoltan, Masarik, Michal, and Kratochvilova, Monika
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LEAD ,COPPER ,CELL death ,PYROPTOSIS ,URANIUM ,TRANSITION metals ,TRACE elements - Abstract
Cell death is one of the most important mechanisms of maintaining homeostasis in our body. Ferroptosis and pyroptosis are forms of necrosis-like cell death. These cell death modalities play key roles in the pathophysiology of cancer, cardiovascular, neurological diseases, and other pathologies. Transition metals are abundant group of elements in all living organisms. This paper presents a summary of ferroptosis and pyroptosis pathways and their connection to significant transition metals, namely zinc (Zn), copper (Cu), molybdenum (Mo), lead (Pb), cobalt (Co), iron (Fe), cadmium (Cd), nickel (Ni), mercury (Hg), uranium (U), platinum (Pt), and one crucial element, selenium (Se). Authors aim to summarize the up-to-date knowledge of this topic. In this review, there are categorized and highlighted the most common patterns in the alterations of ferroptosis and pyroptosis by transition metals. Special attention is given to zinc since collected data support its dual nature of action in both ferroptosis and pyroptosis. All findings are presented together with a brief description of major biochemical pathways involving mentioned metals and are visualized in attached comprehensive figures. This work concludes that the majority of disruptions in the studied metals' homeostasis impacts cell fate, influencing both death and survival of cells in the complex system of altered pathways. Therefore, this summary opens up the space for further research. [ABSTRACT FROM AUTHOR]
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- 2024
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20. SLC7A11: the Achilles heel of tumor?
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Yulang Jiang and Mingyu Sun
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GLUTAMATE transporters ,AMINO acid metabolism ,APOPTOSIS ,MORPHOLOGY - Abstract
The non-natriuretic-dependent glutamate/cystine inverse transporter-system Xc- is composed of two protein subunits, SLC7A11 and SLC3A2, with SLC7A11 serving as the primary functional component responsible for cystine uptake and glutathione biosynthesis. SLC7A11 is implicated in tumor development through its regulation of redox homeostasis, amino acid metabolism, modulation of immune function, and induction of programmed cell death, among other processes relevant to tumorigenesis. In this paper, we summarize the structure and biological functions of SLC7A11, and discuss its potential role in tumor therapy, which provides a new direction for precision and personalized treatment of tumors. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Research Progress on Micro(nano)plastic-Induced Programmed Cell Death Associated with Disease Risks.
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Liu, Huanpeng, Li, Huiqi, Chen, Ting, Yu, Fan, Lin, Qizhuan, Zhao, Haiyang, Jin, Libo, and Peng, Renyi
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APOPTOSIS ,CELL death ,POLLUTANTS ,FOOD chains ,CELL aggregation - Abstract
Due to their robust migration capabilities, slow degradation, and propensity for adsorbing environmental pollutants, micro(nano)plastics (MNPs) are pervasive across diverse ecosystems. They infiltrate various organisms within different food chains through multiple pathways including inhalation and dermal contact, and pose a significant environmental challenge in the 21st century. Research indicates that MNPs pose health threats to a broad range of organisms, including humans. Currently, extensive detection data and studies using experimental animals and in vitro cell culture indicate that MNPs can trigger various forms of programmed cell death (PCD) and can induce various diseases. This review provides a comprehensive and systematic analysis of different MNP-induced PCD processes, including pyroptosis, ferroptosis, autophagy, necroptosis, and apoptosis, based on recent research findings and focuses on elucidating the links between PCD and diseases. Additionally, targeted therapeutic interventions for these diseases are described. This review provides original insights into the opportunities and challenges posed by current research findings. This review evaluates ways to mitigate various diseases resulting from cell death patterns. Moreover, this paper enhances the understanding of the biohazards associated with MNPs by providing a systematic reference for subsequent toxicological research and health risk mitigation efforts. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for hepatocellular carcinoma: recent research progress.
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Ziwei Li, Dongyu Duan, Li Li, Dan Peng, Yue Ming, Rui Ni, and Yao Liu
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HEPATOCELLULAR carcinoma ,IMMUNOTHERAPY ,MACROPHAGES ,CELL death ,PROGRAMMED death-ligand 1 - Abstract
Hepatocellular carcinoma (HCC) is one of the cancers that seriously threaten human health. Immunotherapy serves as the mainstay of treatment for HCC patients by targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. However, the effectiveness of anti-PD-1/PDL1 treatment is limited when HCC becomes drug-resistant. Tumor-associated macrophages (TAMs) are an important factor in the negative regulation of PD-1 antibody targeted therapy in the tumor microenvironment (TME). Therefore, as an emerging direction in cancer immunotherapy research for the treatment of HCC, it is crucial to elucidate the correlations and mechanisms between TAMs and PD-1/PD-L1-mediated immune tolerance. This paper summarizes the effects of TAMs on the pathogenesis and progression of HCC and their impact on HCC anti-PD-1/PD-L1 immunotherapy, and further explores current potential therapeutic strategies that target TAMs in HCC, including eliminating TAMs in the TME, inhibiting TAMs recruitment to tumors and functionally repolarizing M2-TAMs (tumor-supportive) to M1-TAMs (antitumor type). [ABSTRACT FROM AUTHOR]
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- 2024
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23. Global publication trends and research trends of necroptosis application in tumor: A bibliometric analysis.
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Yun-Yun Wu, Chang-chun Li, Xiao Lin, Feng Xu, Su-Kang Shan, Bei Guo, Fu-Xing-Zi Li, Ming-Hui Zheng, Qiu-Shuang Xu, Li-Min Lei, Jia-Yue Duan, Ke-Xin Tang, Ye-Chi Cao, and Ling-Qing Yuan
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BIBLIOMETRICS ,INTERNATIONAL cooperation ,APOPTOSIS ,SCHOLARLY periodicals ,CELL death - Abstract
Introduction: Necroptosis is an alternative, caspase-independent programmed cell death that appears when apoptosis is inhibited. A gowing number of studies have reflected the link between necroptosis and tumors. However, only some systematical bibliometric analyses were focused on this field. In this study, we aimed to identify and visualize the cooperation between countries, institutions, authors, and journals through a bibliometric analysis to help understand the hotspot trends and emerging topics regarding necroptosis and cancer research. Methods: The articles and reviews on necroptosis and cancer were obtained from the Web of Science Core Collection on 16 September 2022. Countries, institutions, authors, references, and keywords in this field were visually analyzed by CtieSpace 5.8.R3, VOSviewer 1.6.18, and R package "bibliometrix." Results: From 2006 to 2022, 2,216 qualified original articles and reviews on necroptosis in tumors were published in 685 academic journals by 13,009 authors in 789 institutions from 75 countries/regions. Publications focusing on necroptosis and cancer have increased violently in the past 16 years, while the citation number peaked around 2008-2011. Most publications were from China, while the United States maintained the dominant position as a "knowledge bridge" in necroptosis and cancer research; meanwhile, Ghent University and the Chinese Academy of Sciences were the most productive institutions. Moreover, only a tiny portion of the articles were multiplecountry publications. Peter Vandenabeele had the most significant publications, while Alexei Degterev was most often co-cited. Peter Vandenabeele also gets the highest h-index and g-index in this research field. Cell Death and Disease was the journal with the most publications on necroptosis and cancer, which was confirmed to be the top core source by Bradford's Law. At the same time, Cell was the leading co-cited journal, and the focus area of these papers was molecular, biology, and immunology. High-frequency keywords mainly contained those that are molecularly related (MLKL, NF-kB, TNF, RIPK3, RIPK1), pathological process related (necroptosis, apoptosis, cell-death, necrosis, autophagy), and mechanism related (activation, expression, mechanisms, and inhibition). Conclusion: This study comprehensively overviews necroptosis and cancer research using bibliometric and visual methods. Research related to necroptosis and cancer is flourishing. Cooperation and communication between countries and institutions must be further strengthened. The information in our paper would provide valuable references for scholars focusing on necroptosis and cancer. [ABSTRACT FROM AUTHOR]
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- 2023
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24. Single-cell transcriptome dissection of the toxic impact of Di (2-ethylhexyl) phthalate on primordial follicle assembly
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Yu Tian, Li Kong, Ming-Hao Li, Fa-Li Zhang, Jun-Jie Wang, Yan-Qin Feng, and Wei Shen
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0301 basic medicine ,endocrine system ,Somatic cell ,Granulosa cell ,LIM-Homeodomain Proteins ,Medicine (miscellaneous) ,Growth Differentiation Factor 9 ,Biology ,Andrology ,primordial follicle assembly ,03 medical and health sciences ,Follicle ,chemistry.chemical_compound ,Mice ,FIGLA ,Ovarian Follicle ,Plasticizers ,Diethylhexyl Phthalate ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,RNA-Seq ,Smad3 Protein ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Bone Morphogenetic Protein Receptors, Type I ,Cell Proliferation ,Ovum ,Granulosa Cells ,030102 biochemistry & molecular biology ,DEHP ,Cell Death ,Gene Expression Profiling ,Phthalate ,Gene Expression Regulation, Developmental ,single-cell transcriptome ,granulosa cell ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Animals, Newborn ,female germ cell ,Female ,Folliculogenesis ,Single-Cell Analysis ,Reproductive toxicity ,Germ cell ,Research Paper ,Transcription Factors - Abstract
Rationale: Accumulated evidence indicates that environmental plasticizers are a threat to human and animal fertility. Di (2-ethylhexyl) phthalate (DEHP), a plasticizer to which humans are exposed daily, can trigger reproductive toxicity by acting as an endocrine-disrupting chemical. In mammals, the female primordial follicle pool forms the lifetime available ovarian reserve, which does not undergo regeneration once it is established during the fetal and neonatal period. It is therefore critical to examine the toxicity of DEHP regarding the establishment of the ovarian reserve as it has not been well investigated. Methods: The ovarian cells of postnatal pups, following maternal DEHP exposure, were prepared for single cell-RNA sequencing, and the effects of DEHP on primordial follicle formation were revealed using gene differential expression analysis and single-cell developmental trajectory. In addition, further biochemical experiments, including immunohistochemical staining, apoptosis detection, and Western blotting, were performed to verify the dataset results. Results: Using single-cell RNA sequencing, we revealed the gene expression dynamics of female germ cells and granulosa cells following exposure to DEHP in mice. Regarding germ cells: DEHP impeded the progression of follicle assembly and interfered with their developmental status, while key genes such as Lhx8, Figla, and others, strongly evidenced the reduction. As for granulosa cells: DEHP likely inhibited their proliferative activity, and activated the regulation of cell death. Furthermore, the interaction between ovarian cells mediated by transforming growth factor-beta signaling, was disrupted by DEHP exposure, since the expression of GDF9, BMPR1A, and SMAD3 was affected. In addition, DNA damage and apoptosis were elevated in germ cells and/or somatic cells. Conclusion: These findings offer substantial novel insights into the reproductive toxicity of DEHP exposure during murine germ cell cyst breakdown and primordial follicle formation. These results may enhance the understanding of DEHP exposure on reproductive health.
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- 2021
25. The BAX-binding protein MOAP1 associates with LC3 and promotes closure of the phagophore
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Yajun Wu, Boon-Huat Bay, Chong Teik Tan, Hao-Chun Chang, Ran N. Tao, and Victor C. Yu
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0301 basic medicine ,Programmed cell death ,autophagy ,Closure (topology) ,Fluorescent Antibody Technique ,Biology ,03 medical and health sciences ,Mice ,LIR motif ,Microscopy, Electron, Transmission ,Animals ,Humans ,Immunoprecipitation ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Mice, Knockout ,030102 biochemistry & molecular biology ,Binding protein ,Autophagy ,Autophagosomes ,Cell Biology ,LC3-binding protein ,Autophagosome formation ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,cell death ,HEK293 Cells ,nutrient deprivation ,Apoptosis ,Apoptosis Regulatory Proteins ,Microtubule-Associated Proteins ,Research Article ,Research Paper ,HeLa Cells - Abstract
MOAP1 (modulator of apoptosis 1) is a BAX-binding protein tightly regulated by the ubiquitin-proteasome system. Apoptotic stimuli stabilize MOAP1 protein and facilitate its interaction with BAX to promote apoptosis. Here we show that in contrast to being resistant to apoptotic stimuli, MOAP1-deficient cells are hypersensitive to cell death mediated by starvation rendered by EBSS treatment. MOAP1-deficient cells exhibited impairment in macroautophagy/autophagy signaling induced by EBSS. Mechanistic analysis revealed that MOAP1-deficient cells had no notable defect in the recruitment of the pre-autophagosomal phosphatidylinositol-3-phosphate (PtdIns3P)-binding proteins, ZFYVE1/DFCP1 and WIPI2, nor in the LC3 lipidation mechanism regulated by the ATG12–ATG5-ATG16L1 complex upon EBSS treatment. Interestingly, MOAP1 is required for facilitating efficient closure of phagophore in the EBSS-treated cells. Analysis of LC3-positive membrane structures using Halo-tagged LC3 autophagosome completion assay showed that predominantly unclosed phagophore rather than closed autophagosome was present in the EBSS-treated MOAP1-deficient cells. The autophagy substrate SQSTM1/p62, which is normally contained within the enclosed autophagosome under EBSS condition, was also highly sensitive to degradation by proteinase K in the absence of MOAP1. MOAP1 binds LC3 and the binding is critically dependent on a LC3-interacting region (LIR) motif detected at its N-terminal region. Re-expression of MOAP1, but not its LC3-binding defective mutant, MOAP1-LIR, in the MOAP1-deficient cells, restored EBSS-induced autophagy. Together, these observations suggest that MOAP1 serves a distinct role in facilitating autophagy through interacting with LC3 to promote efficient phagophore closure during starvation. Abbreviations: CQ: Chloroquine; EBSS: Earle’s Balanced Salt Solution; GABARAP: Gamma-Amino Butyric Acid Receptor Associated Protein; IF: Immunofluorescence; IP: Immunoprecipitation; LAMP1: Lysosomal-Associated Membrane Protein 1; LIR: LC3-Interacting Region; MAP1LC3/LC3: Microtubule Associated Protein 1 Light Chain 3; MEF: Mouse Embryonic Fibroblast; MOAP1: Modulator of Apoptosis 1; PE: Phosphatidylethanolamine; PtdIns3K: class III PtdIns3K complex I; PtdIns3P: Phosphatidylinositol-3-phosphate; STX17: Syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.
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- 2021
26. The Development of a Fluorescence‐Based Competitive Assay Enabled the Discovery of Dimeric Cyclic Peptide Modulators of Ubiquitin Chains
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Ashraf Brik, Roman Meledin, Ganga B. Vamisetti, Mickal Nawatha, and Hiroaki Suga
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High-throughput screening ,Peptides | Hot Paper ,Peptide ,010402 general chemistry ,Ligands ,01 natural sciences ,high-throughput screening ,Peptides, Cyclic ,Catalysis ,Fluorescence ,Ubiquitin ,Drug Development ,In vivo ,Protein biosynthesis ,Humans ,chemistry.chemical_classification ,fluorescence-based assay ,biology ,Cell Death ,Dose-Response Relationship, Drug ,010405 organic chemistry ,Communication ,dimeric peptides ,cyclic peptides ,General Medicine ,General Chemistry ,Combinatorial chemistry ,Cyclic peptide ,Communications ,0104 chemical sciences ,High-Throughput Screening Assays ,chemistry ,biology.protein ,peptide engineering ,Conjugate ,HeLa Cells - Abstract
Development of modulators targeting specific interactions of ubiquitin‐based conjugates with their partners is a formidable task since it requires a suitable screening assay and homogeneous ubiquitin conjugates. We developed a novel high‐throughput strategy for screening ligands for Lys48‐linked tetraubiquitin chain in a relatively simple, fast, and affordable manner. This approach combined with a state‐of‐the‐art toolbox of chemical protein synthesis and a specially optimized Cys deprotection protocol enabled us to design highly potent, Lys48‐linked tetraubiquitin chain selective “next generation” dimeric peptide modulators. The dimeric peptide exhibited cancer cell permeability and induced cell death with higher efficiency compared to its monocyclic analogue. These features make our dimeric peptide a promising candidate for further studies using in vivo models. Our assay can be adopted for other various ubiquitin chains in their free or anchored forms as well as conjugates for Ub‐like modifiers., A fluorescence‐based competitive assay was developed, which enabled the high‐throughput screening of various cyclic peptides targeting the Lys48‐linked tetraubiquitin chain. This assay combined with chemical tools enabled the design of a potent dimeric cyclic peptide, which induced cell death with higher efficiency compared to its monocyclic analogue.
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- 2021
27. Identification of biomarkers related to Tumor-Infiltrating Lymphocytes (TILs) infiltration with gene co-expression network in colorectal cancer
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Qi-Zhi Ma, Rong Liao, Qing Zhu, Ning-Na Weng, Congya Zhou, Yang Yang, and Jun-Jun Li
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0301 basic medicine ,Colorectal cancer ,Bioengineering ,Applied Microbiology and Biotechnology ,tils ,Immune tolerance ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,adam8 ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Humans ,Gene Regulatory Networks ,colorectal cancer (crc) ,timer ,cibersort ,Cell Death ,Tumor-infiltrating lymphocytes ,business.industry ,weighted gene co-expression network analysis (wgcna) ,Cancer ,Membrane Proteins ,Reproducibility of Results ,General Medicine ,medicine.disease ,Prognosis ,Gene Expression Regulation, Neoplastic ,ADAM Proteins ,030104 developmental biology ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Cancer research ,Gene co-expression network ,ADAM8 Gene ,business ,Colorectal Neoplasms ,ADAM8 ,TP248.13-248.65 ,Genes, Neoplasm ,Signal Transduction ,Research Article ,Research Paper ,Biotechnology - Abstract
Colorectal cancer (CRC) is one of the most common tumors, ranking second in the global cause of death from cancer. The prognosis of advanced patients is still very poor. In this study, hub modules with the highest association with tumor-infiltrating immune cells were identified by weighted gene co-expression network analysis based on CRC expression data from the Gene Expression Omnibus database. Next, three hub genes (ADAM8, IL-1A, VAV3) related to infiltrating immune cells were identified by co-expression network and prognostic analysis. After analysis and verification of the TIMER database, ADAM8 was selected as a prognostic biomarker. Finally, the result of functional test showed that ADAM8 gene expression down-regulation partially reversed the immune tolerance of CRC cells to TILs. By bioinformatics analysis methods and the experimental techniques, we identified ADAM8 as a prognostic biomarker and clinical therapeutic target related to tumor-infiltrating immune cells in CRC., Graphical abstract
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- 2021
28. The regulation of long non-coding RNA 00958 (LINC00958) for oral squamous cell carcinoma (OSCC) cells death through absent in melanoma 2 (AIM2) depending on microRNA-4306 and Sirtuin1 (SIRT1) in vitro
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Xiaofeng Wang, Lei Jiang, Yifei Cui, and Wenyu Ge
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p53 ,Programmed cell death ,sirt1 ,linc00958 ,Bioengineering ,Biology ,oscc ,Applied Microbiology and Biotechnology ,Flow cytometry ,Downregulation and upregulation ,Sirtuin 1 ,Cell Line, Tumor ,microRNA ,medicine ,Gene silencing ,Humans ,medicine.diagnostic_test ,Cell Death ,Cell growth ,Squamous Cell Carcinoma of Head and Neck ,Pyroptosis ,aim2 ,General Medicine ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Cancer cell ,Cancer research ,Mouth Neoplasms ,RNA, Long Noncoding ,Tumor Suppressor Protein p53 ,TP248.13-248.65 ,Research Article ,Research Paper ,mir-4306 ,Biotechnology - Abstract
Long non-coding RNAs (lncRNAs) have been proposed as potential targets in OSCC gene therapy. Thus, the study aims to analyze how they exert functions in OSCC. LINC00958, AIM2, Gasdermin D (GSDMD) and tumor protein p53 (TP53) expression levels are analyzed by Quantitative Real-time PCR (qPCR) or Western blotting (WB) in OSCC cells lines. The roles of LINC00958 in cell proliferation, cell death, and GSDMD expression respectively were analyzed by Cell Counting Kit-8 (CCK8) assay, flow cytometry and Immunofluorescence (IF) assay. In addition, expressions of pyroptosis- and autophagy-related proteins are evaluated by WB detection. The targeted binding of LINC00958 and miR-4306 or AIM2 mRNA is predicted by bioinformatics analysis and detected by biodual luciferase system. RIP and qPCR assays analyze whether LINC00958 interacts with SIRT1. We found that LINC00958 showed upregulation in OSCC cells compared to normal oral epithelial cells. LINC00958 silencing significantly suppressed OSCC cell proliferation, induced cell death and reduced autophagy. LINC00958 regulated the levels of miR-4306 which binds to the 3ʹUTR of AIM2, and interacts with and modulates SIRT1 protein expression. LINC00958 regulated GSDMD and AIM2 levels, as well as p53 and SIRT1 levels. SIRT1 overexpression markedly reversed aforementioned effects of LINC00958. LINC00958 not only downregulated miR-4306 levels to activate the pyroptosis pathway mediated by AIM2 and promoted cancer cell survival but also induced a decrease in SIRT protein expression to further reduce p53 levels., Graphical abstract
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- 2021
29. Tumor necrosis factor receptor-associated factor 6 interaction with alpha-synuclein enhances cell death through the Nuclear Factor-kB pathway
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Alexandre Denadai-Souza, Adriana Oliveira Manfiolli, L. M. Yshii, Marcelo D. Gomes, Paula Fernanda Kinoshita, and Cristoforo Scavone
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0301 basic medicine ,CHIP, carboxyl terminus of Hsp70-interaction protein ,Programmed cell death ,TRAF6 and NF-kappa B ,PROMOTES ,alpha-synuclein ,NF-KAPPA-B ,PROTEIN ,FARMACOLOGIA ,PD, Parkinson's disease ,lcsh:RC321-571 ,ACTIVATION ,TRAF6, tumor necrosis factor receptor-associated factor 6 ,SIAH, seven in absentia homolog ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ubiquitin ,LB, Lewy bodies ,EMSA, Electrophoretic Mobility Shift Assay ,Transcription factor ,MUTATION ,asyn, alpha-synuclein ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Alpha-synuclein ,Science & Technology ,biology ,SYNPHILIN-1 ,General Neuroscience ,Neurosciences ,LEWY BODIES ,cytokines ,Ubiquitin ligase ,Cell biology ,030104 developmental biology ,cell death ,Proteasome ,chemistry ,biology.protein ,Tumor necrosis factor alpha ,ATYPICAL UBIQUITINATION ,Neurosciences & Neurology ,Signal transduction ,NF-κB, nuclear factor κB ,PARKINSON ,Life Sciences & Biomedicine ,TRAF6 and NF-κB ,030217 neurology & neurosurgery ,Research Paper - Abstract
Highlights • TRAF6 binds to both WT and the mutant form A30 P asyn in SH-SY5Y cell model. • The activation of NF-κB leads to changes in cytokines levels induced by TRAF6 - WT asyn interaction decreasing cell viability. • The interaction between TRAF6 and A30P asyn does not induce NF-κB activation and cytokine regulation in SH-SY5Y cells. • The present work demonstrates a novel role of TRAF6 in the pathophysiology of Parkinson's disease., Background Parkinson's disease (PD) is a neurodegenerative disease characterized by intracellular inclusions named Lewy bodies (LB), and alpha-synuclein (asyn) is the major component of these protein aggregates. The precise physiological and pathological roles of asyn are not fully understood. Nevertheless, asyn present in LB is ubiquitinated but fails to reach the 26S proteasome. The mutation A30 P is related to an aggressive and early-onset form of PD. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase, and it interacts and ubiquitinates the asyn in atypical chains (lysine K6, K27, K29, and K33). Methods: Here, we investigated the role of TRAF6 interaction with asyn and the involvement of nuclear factor κB (NF-κB), a key transcription factor in pro-inflammatory signaling pathway activation. Results and Conclusion We demonstrated that TRAF6 binds to both WT and the mutant form A30 P asyn in an SH-SY5Y cell model. Additionally, the interaction between TRAF6 and WT asyn induced an increase in the activation of NF-κB, leading to changes in TNF, IL-1β and IL-10 levels and culminating in reduced cell viability. Interestingly, the activation of NF-κB and gene regulation were not found in A30 P asyn. These data point to a novel role of TRAF6 in the pathophysiology of PD.
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- 2020
30. Apelin protects against ischemia-reperfusion injury in diabetic myocardium via inhibiting apoptosis and oxidative stress through PI3K and p38-MAPK signaling pathways
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Junbo Ge, Xi Wang, Shi Huairui, Songtao An, Hua Meng, Xueqiang Zhang, Dongchang Chen, and Wenbo Li
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Cardiac function curve ,Aging ,Nitric Oxide Synthase Type III ,MAP Kinase Signaling System ,Ischemia ,Nitric Oxide Synthase Type II ,Apoptosis ,Myocardial Reperfusion Injury ,Pharmacology ,medicine.disease_cause ,urologic and male genital diseases ,ischemia and type 2 diabetic mellitus ,Diabetes Mellitus, Experimental ,Phosphatidylinositol 3-Kinases ,Enos ,Diabetes mellitus ,Natriuretic Peptide, Brain ,Medicine ,oxidative stress ,Animals ,Myocytes, Cardiac ,cardiovascular diseases ,bcl-2-Associated X Protein ,biology ,Cell Death ,business.industry ,urogenital system ,Caspase 3 ,diabetic myocardial ischemia reperfusion injury ,Myocardium ,fungi ,Cell Biology ,Genetic Therapy ,biology.organism_classification ,medicine.disease ,female genital diseases and pregnancy complications ,Peptide Fragments ,Apelin ,Rats ,apelin ,Diabetes Mellitus, Type 2 ,Proto-Oncogene Proteins c-bcl-2 ,business ,Reperfusion injury ,Oxidative stress ,Research Paper - Abstract
Among all diabetes mellitus-associated cardiovascular diseases, morbidity of diabetic myocardium with ischemia reperfusion injury (D-IRI) is increasing year by year. We aimed to discover a therapeutic biomarker and investigate its mechanism in D-IRI. High-fat diet and streptozotocin-induced diabetes rats were operated with IRI or sham. Recombined lentiviral vector encoding Apelin was injected into D-IRI rat via tail vein. Cardiac function, infarct size, cellular death and oxidative stress were major outcome measures. Cardiomyocyte ischemia reperfusion injury was more serious in D-IRI rats than in non-diabetes ischemia reperfusion injury (ND-IRI) rats. The secretion of NTproBNP was increased in D-IRI compared with ND-IRI. Bcl-2 expression was decreased, and Bax and cleaved caspase-3 expression was increased in D-IRI rats compared with ND-IRI rats, which were reversed after treatment with Apelin. Apelin-upregulation improved cardiomyocyte ischemia reperfusion injury and decreased NT-proBNP levels in D-IRI rats. Apelin overexpression enhanced PI3K and eNOS levels while reduced those of p38-MAPK and iNOS in D-IRI rats. Apelin overexpression protected against D-IRI through inhibiting apoptosis and oxidative stress via PI3K and p38MAPK signaling pathways in D-IRI rats. These findings provide critical new insight into understanding of Apelin's cardio-protective effects, which may become a novel therapeutic target for the diabetic IRI patients.
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- 2020
31. Severe congenital neutropenia‐associated JAGN1 mutations unleash a calpain‐dependent cell death programme in myeloid cells
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Miriam Entesarian, Magnus Nordenskjöld, Avinash Khandagale, Daniel Nilsson, Krzysztof Kałwak, Teresa Holmlund, Bengt Fadeel, Maja Klaudel-Dreszler, Jan-Inge Henter, and Göran Carlsson
- Subjects
Programmed cell death ,Neutropenia ,Necroptosis ,necroptosis ,HL-60 Cells ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Point Mutation ,Congenital Bone Marrow Failure Syndromes ,Myeloid Cells ,Congenital Neutropenia ,Caspase ,calcium ,biology ,Cell Death ,business.industry ,Calpain ,apoptosis ,Membrane Proteins ,Hematology ,medicine.disease ,Haematopoiesis ,Cell culture ,Apoptosis ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Cancer research ,business ,030215 immunology ,Research Paper - Abstract
Summary Severe congenital neutropenia (SCN) of autosomal recessive inheritance, also known as Kostmann disease, is characterised by a lack of neutrophils and a propensity for life‐threatening infections. Using whole‐exome sequencing, we identified homozygous JAGN1 mutations (p.Gly14Ser and p.Glu21Asp) in three patients with Kostmann‐like SCN, thus confirming the recent attribution of JAGN1 mutations to SCN. Using the human promyelocytic cell line HL‐60 as a model, we found that overexpression of patient‐derived JAGN1 mutants, but not silencing of JAGN1, augmented cell death in response to the pro‐apoptotic stimuli, etoposide, staurosporine, and thapsigargin. Furthermore, cells expressing mutant JAGN1 were remarkably susceptible to agonists that normally trigger degranulation and succumbed to a calcium‐dependent cell death programme. This mode of cell death was completely prevented by pharmacological inhibition of calpain but unaffected by caspase inhibition. In conclusion, our results confirmed the association between JAGN1 mutations and SCN and showed that SCN‐associated JAGN1 mutations unleash a calcium‐ and calpain‐dependent cell death in myeloid cells.
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- 2020
32. ESX secretion system: The gatekeepers of mycobacterial survivability and pathogenesis
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Sadhana Roy, Debika Ghatak, Somdeb BoseDasgupta, and Payel Das
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0301 basic medicine ,Metal ion homeostasis ,Review Paper ,ESX secretion system ,Tuberculosis ,biology ,phagosomal rupture ,030106 microbiology ,Virulence ,biology.organism_classification ,medicine.disease ,Microbiology ,mycobacterium ,Mycobacterium tuberculosis ,03 medical and health sciences ,030104 developmental biology ,Immune system ,cell death ,medicine ,Macrophage ,Secretion ,Mycobacterium - Abstract
Mycobacterium tuberculosis, the causative agent of Tuberculosis has plagued humankind for ages and has surfaced stronger than ever with the advent of drug resistance. Mycobacteria are adept at evading the host immune system and establishing infection by engaging host factors and secreting several virulence factors. Hence these secretion systems play a key role in mycobacterial pathogenesis. The type VII secretion system or ESX (early secretory antigenic target (ESAT6) secretion) system is one such crucial system that comprises five different pathways having distinct roles in mycobacterial proliferation, pathogenesis, cytosolic escape within macrophages, regulation of macrophage apoptosis, metal ion homeostasis, etc. ESX 1–5 systems are implicated in the secretion of a plethora of proteins, of which only a few are functionally characterized. Here we summarize the current knowledge of ESX secretion systems of mycobacteria with a special focus on ESX-1 and ESX-5 systems that subvert macrophage defenses and help mycobacteria to establish their niche within the macrophage.
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- 2020
33. Transferrin improved the generation of cardiomyocyte from human pluripotent stem cells for myocardial infarction repair
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Chunlan Wang, Hui Qiu, Xiao-Hui Dong, Changyong Wang, Jie Na, Jin Zhou, and Fengzhi Zhang
- Subjects
0301 basic medicine ,Pluripotent Stem Cells ,Programmed cell death ,Histology ,hPSC ,Physiology ,Cell ,Myocardial Infarction ,Cardiomyocyte ,Biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Chemically defined ,medicine ,Animals ,Humans ,Regeneration ,Myocytes, Cardiac ,Induced pluripotent stem cell ,Protein Kinase Inhibitors ,chemistry.chemical_classification ,Original Paper ,Glycogen Synthase Kinase 3 beta ,Cell Death ,Gene Expression Profiling ,Transferrin ,Cell Differentiation ,Cell Biology ,General Medicine ,Ascorbic acid ,Cell biology ,Rats ,Transplantation ,Chemically defined medium ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Gene Expression Regulation ,030217 neurology & neurosurgery - Abstract
Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) hold great promise for the repair of the injured heart, but optimal cell production in a fully chemically defined and cost-effective system is essential for the efficacy and safety of cell transplantation therapies. In this study, we provided a simple and efficient strategy for cardiac differentiation from hPSCs and performed functional evaluation in a rat model of myocardial infarction. Using a chemically defined medium including four components, recombinant human albumin, ascorbic acid, human transferrin, and RPMI 1640, we developed a manageable and cost-effective protocol for robust generation of CMs from hPSCs. Interestingly, the addition of transferrin helped hPSCs to transit from TeSR-E8 medium to the simple cardiac differentiation medium and successfully initiated mesoderm differentiation without significant cell death. The CM generation efficiency was up to 85% based on cTnT expression. We performed transcriptome profiling from differentiation day 0 to 35, and characterized interesting dynamic change of cardiac genes. CMs derived from transferrin-supplemented simple medium have similar transcriptome and the maturation level compared to those generated in B27 minus insulin medium as well as their in vivo counterparts. Importantly, after transplantation, hPSC-derived CMs survived in the infarcted rat heart, significantly improved the physiological function and reduced fibrosis. Our study offers an easy-to-use and cost-effective method for cardiac differentiation and facilitates the translational application of hPSC-derived CMs for heart repair. Electronic supplementary material The online version of this article (10.1007/s10735-020-09926-0) contains supplementary material, which is available to authorized users.
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- 2020
34. The growth of the cell death field: an analysis from the ISI-Science citation index.
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Garfield, Eugene and Melino, Gerry
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APOPTOSIS ,BIBLIOMETRICS ,CELL death - Abstract
Presents the results of a bibliometric of apoptosis. Use of the ISI-indicators file for 1981-1995, the 'Science Citation Index' on CD-ROM and the SCI-Search Dialog file; Definition and importance of apoptosis; Growth of the cell death field.
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- 1997
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35. The mirid bug Apolygus lucorum deploys a glutathione peroxidase as a candidate effector to enhance plant susceptibility
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Maofeng Jing, Qingyue Xia, Chenyang Wang, Meiqian Zhang, Daolong Dou, Ai Xia, Karani T. Nyawira, Shuwen Wu, Yidong Wu, Danyu Shen, Dong Liang, Yumei Dong, and Kairan Zuo
- Subjects
0106 biological sciences ,0301 basic medicine ,Nymph ,Programmed cell death ,Physiology ,Plant Science ,01 natural sciences ,plant–insect interaction ,Transcriptome ,Heteroptera ,03 medical and health sciences ,Animals ,Secretion ,Apolygus lucorum ,Gene ,chemistry.chemical_classification ,Glutathione Peroxidase ,biology ,Effector ,AcademicSubjects/SCI01210 ,Glutathione peroxidase ,fungi ,ROS ,Feeding Behavior ,biology.organism_classification ,Research Papers ,Cell biology ,030104 developmental biology ,Secretory protein ,cell death ,effector ,chemistry ,Plant—Environment Interactions ,Aphids ,010606 plant biology & botany - Abstract
A candidate effector with glutathione peroxidase activity from the Apolygus lucorum salivary gland suppressed PAMP-triggered cell death and ROS accumulation to enhance plant susceptibility to insects and pathogens., The mirid bug Apolygus lucorum has become a major agricultural pest since the large-scale cultivation of Bt-cotton. It was assumed that A. lucorum, similarly to other phloem sap insects, could secrete saliva that contains effector proteins into plant interfaces to perturb host cellular processes during feeding. However, the secreted effectors of A. lucorum are still uncharacterized and unstudied. In this study, 1878 putative secreted proteins were identified from the transcriptome of A. lucorum, which either had homology with published aphid effectors or shared common features with plant pathogens and insect effectors. One hundred and seventy-two candidate effectors were used for cell death-inducing/suppressing assays, and a putative salivary gland effector, Apolygus lucorum cell death inhibitor 6 (Al6), was characterized. The mRNAs of Al6 were enriched at feeding stages (nymph and adult) and, in particular, in salivary glands. Moreover, we revealed that the secreted Al6 encoded an active glutathione peroxidase that reduced reactive oxygen species (ROS) accumulation induced by INF1 or Flg22. Expression of the Al6 gene in planta altered insect feeding behavior and promoted plant pathogen infections. Inhibition of cell death and enhanced plant susceptibility to insect and pathogens are dependent on glutathione peroxidase activity of Al6. Thus, this study shows that a candidate salivary gland effector, Al6, functions as a glutathione peroxidase and suppresses ROS induced by pathogen-associated molecular pattern to inhibit pattern-triggered immunity (PTI)-induced cell death. The identification and molecular mechanism analysis of the Al6 candidate effector in A. lucorum will provide new insight into the molecular mechanisms of insect–plant interactions.
- Published
- 2020
36. Theranostic nanobubble encapsulating a plasmon-enhanced upconversion hybrid nanosystem for cancer therapy
- Author
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Ming-Hsien Chan, Michael Hsiao, Xueyuan Chen, Wen-Tse Huang, and Ru-Shi Liu
- Subjects
Diagnostic Imaging ,upconversion hybrid nanosystem ,Materials science ,Lung Neoplasms ,Cancer therapy ,Medicine (miscellaneous) ,Nanoparticle ,Nanotechnology ,02 engineering and technology ,Enhanced permeability and retention effect ,Pyrimidinones ,near-infrared ,Theranostic Nanomedicine ,03 medical and health sciences ,Mice ,plasmonic enhancement ,Cell Line, Tumor ,dual-model phototherapy ,Animals ,Humans ,Photosensitizer ,Nir laser ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Plasmon ,030304 developmental biology ,0303 health sciences ,Photosensitizing Agents ,Cell Death ,Hyperthermia, Induced ,Photothermal therapy ,Phototherapy ,021001 nanoscience & nanotechnology ,Photon upconversion ,Models, Animal ,Nanoparticles ,cancer theranostics ,Gold ,0210 nano-technology ,Research Paper - Abstract
Nanobubble (NB), which simultaneously enhances ultrasound (US) images and access therapeutic platforms, is required for future cancer treatment. Methods: We designed a theranostic agent for novel cancer treatment by using an NB-encapsulated hybrid nanosystem that can be monitored by US and fluorescent imaging and activated by near-infrared (NIR) light. The nanosystem was transported to the tumor through the enhanced permeability and retention effect. The hybrid nanosystem comprised upconversion nanoparticle (UCNP) and mesoporous silica-coated gold nanorod (AuNR@mS) with the photosensitizer merocyanine 540 to realize dual phototherapy. Results: With the NIR light-triggered, the luminous intensity of the UCNP was enhanced by doping holmium ion and emitted visible green and red lights at 540 and 660 nm. The high optical density state between the UCNP and AuNR@mS can induce plasmonic enhancement to improve the photothermal and photodynamic effects, resulting in cell death by apoptosis. The nanosystem showed excellent stability to avoid the aggregation of nanoparticles during the treatment. JC-1 dye was used as an indicator of mitochondrial membrane potential to identify the mechanism of cell death. The results of in vitro and in vivo analyses confirmed the curative effect of improved dual phototherapy. Conclusion: We developed and showed the therapeutic functions of a novel nanosystem with the combination of multiple theranostic nanoplatforms that can be triggered and activated by 808 nm NIR laser and US.
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- 2020
37. Hepatomas are exquisitely sensitive to pharmacologic ascorbate (P-AscH-)
- Author
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Qianlin Xia, Yanling Feng, Xiaoyan Zhang, Li Xu, Tiefu Liu, Jin Wang, Xiaohui Zhou, Zehuan Li, Feng Liu, Shanshan Liu, Jingpu Zhang, Longqiang Shen, Xuan Zhang, Xiuhua Peng, Jianqing Xu, Christopher Corpe, Xiaomeng He, Weiping Chen, and Shun Li
- Subjects
0301 basic medicine ,Carcinoma, Hepatocellular ,medicine.medical_treatment ,Intraperitoneal injection ,Cell ,Medicine (miscellaneous) ,vitamin C ,mitochondrial respiration ,Antineoplastic Agents ,Apoptosis ,Ascorbic Acid ,Pharmacology ,medicine.disease_cause ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,cancer ,Animals ,Ascorbate ,Vitamin C ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cancer ,Cell Proliferation ,Hepatoma ,Cell Death ,Chemistry ,Liver Neoplasms ,ROS ,hepatoma ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Hepatic stellate cell ,Reactive Oxygen Species ,Oxidative stress ,Intracellular ,Mitochondrial respiration ,Research Paper ,Signal Transduction - Abstract
Rationale: Ascorbate is an essential micronutrient known for redox functions at normal physiologic concentrations. In recent decades, pharmacological ascorbate has been found to selectively kill tumour cells. However, the dosing frequency of pharmacologic ascorbate in humans has not yet been defined. Methods: We determined that among five hepatic cell lines, Huh-7 cells were the most sensitive to ascorbate. The effects of high-dose ascorbate on hepatoma were therefore assessed using Huh-7 cells and xenograft tumour mouse model. Results: In Huh-7 cells, ascorbate induced a significant increase in the percentage of cells in the G0/G1 phase, apoptosis and intracellular levels of ROS. High doses of ascorbate (4.0 pmol cell -1), but not low doses of ascorbate (1.0 pmol cell -1), also served as a pro-drug that killed hepatoma cells by altering mitochondrial respiration. Furthermore, in a Huh-7 cell xenograft tumour mouse model, intraperitoneal injection of ascorbate (4.0 g/kg/3 days) but not a lower dose of ascorbate (2.0 g/kg/3 days) significantly inhibited tumour growth. Gene array analysis of HCC tumour tissue from xenograft mice given IP ascorbate (4.0 g/kg/3 days) identified changes in the transcript levels of 192 genes/ncRNAs involved in insulin receptor signalling, metabolism and mitochondrial respiration. Consistent with the array data, gene expression levels of AGER, DGKK, ASB2, TCP10L2, Lnc-ALCAM-3, and Lnc-TGFBR2-1 were increased 2.05-11.35 fold in HCC tumour tissue samples from mice treated with high-dose ascorbate, and IHC staining analysis also verified that AGER/RAGE and DGKK proteins were up-regulated, which implied that AGER/RAGE and DGKK activation might be related to oxidative stress, leading to hepatoma cell death. Conclusions: Our studies identified multiple mechanisms are responsible for the anti-tumour activity of ascorbate and suggest high doses of ascorbate with less frequency will act as a novel therapeutic agent for liver cancer in vivo.
- Published
- 2019
38. Isolation of pancreatic microbiota from cystic precursors of pancreatic cancer with intracellular growth and DNA damaging properties
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Halimi, Asif, Gabarrini, Giorgio, Sobkowiak, Michał Jacek, Ateeb, Zeeshan, Davanian, Haleh, Gaiser, Rogier Aäron, Arnelo, Urban, Valente, Roberto, Wong, Alicia Y.W., Moro, Carlos Fernández, Del Chiaro, Marco, Özenci, Volkan, and Chen, Margaret Sällberg
- Subjects
Aged, 80 and over ,Male ,Microbial Viability ,Bacteria ,Cell Death ,IPMN ,Microbiota ,Pancreatic Intraductal Neoplasms ,Pilot Projects ,Gastroenterology and Hepatology ,RC799-869 ,Pancreatic cancer ,Diseases of the digestive system. Gastroenterology ,Anti-Bacterial Agents ,Cell Line ,pancreatic cystic neoplasm ,microbiota ,Gastroenterologi ,Humans ,Female ,Research Article ,Research Paper ,Aged ,DNA Damage - Abstract
Emerging research suggests gut microbiome may play a role in pancreatic cancer initiation and progression, but cultivation of the cancer microbiome remains challenging. This pilot study aims to investigate the possibility to cultivate pancreatic microbiome from pancreatic cystic lesions associated with invasive cancer. Intra-operatively acquired pancreatic cyst fluid samples showed culture-positivity mainly in the intraductal papillary mucinous neoplasm (IPMN) group of lesions. MALDI-TOF MS profiling analysis shows Gammaproteobacteria and Bacilli dominate among individual bacteria isolates. Among cultivated bacteria, Gammaproteobacteria, particularly Klebsiella pneumoniae, but also Granulicatella adiacens and Enterococcus faecalis, demonstrate consistent pathogenic properties in pancreatic cell lines tested in ex vivo co-culture models. Pathogenic properties include intracellular survival capability, cell death induction, or causing DNA double-strand breaks in the surviving cells resembling genotoxic effects. This study provides new insights into the role of the pancreatic microbiota in the intriguing link between pancreatic cystic lesions and cancer.
- Published
- 2021
39. Alpha1-antitrypsin counteracts heme-induced endothelial cell inflammatory activation, autophagy dysfunction and death
- Author
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Abid Aljabri, Harshit R. Shah, Srinu Tumpara, Stephan Immenschuh, Christoph Nikolin, Sabina Janciauskiene, Elena Korenbaum, Kukuh Madyaningrana, Vijith Vijayan, Heiko R. Fuchs, and Metodi V. Stankov
- Subjects
Cell death ,Programmed cell death ,Medicine (General) ,QH301-705.5 ,Clinical Biochemistry ,Heme ,Biochemistry ,chemistry.chemical_compound ,R5-920 ,Endothelial cell ,alpha1-antitrypsin ,Lysosome ,Autophagy ,Extracellular ,medicine ,Humans ,Biology (General) ,Inflammation ,Organic Chemistry ,Endothelial Cells ,Hemopexin ,Cell biology ,Endothelial stem cell ,medicine.anatomical_structure ,chemistry ,alpha 1-Antitrypsin ,Heme-binding proteins ,Endothelium, Vascular ,Heme Oxygenase-1 ,Intracellular ,Research Paper - Abstract
Free heme toxicity in the vascular endothelium is critical for the pathogenesis of hemolytic disorders including sickle cell disease. In the current study, it is demonstrated that human alpha1-antitrypsin (A1AT), a serine protease inhibitor with high binding-affinity for heme, rescues endothelial cell (EC) injury caused by free heme. A1AT provided endothelial protection against free heme toxicity via a pathway that differs from human serum albumin and hemopexin, two prototypical heme-binding proteins. A1AT inhibited heme-mediated pro-inflammatory activation and death of ECs, but did not affect the increase in intracellular heme levels and up-regulation of the heme-inducible enzyme heme oxygenase-1. Moreover, A1AT reduced heme-mediated generation of mitochondrial reactive oxygen species. Extracellular free heme led to an increased up-take of A1AT by ECs, which was detected in lysosomes and was found to reduce heme-dependent alkalization of these organelles. Finally, A1AT was able to restore heme-dependent dysfunctional autophagy in ECs. Taken together, our findings show that A1AT rescues ECs from free heme-mediated pro-inflammatory activation, cell death and dysfunctional autophagy. Hence, A1AT therapy may be useful in the treatment of hemolytic disorders such as sickle cell disease., Graphical abstract Image 1
- Published
- 2021
40. Cuproptosis: potential new direction in diabetes research and treatment.
- Author
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Jiashu Qu, Yifan Wang, and Qiuyue Wang
- Subjects
TYPE 2 diabetes ,DIABETES ,CELL death ,PANCREATIC beta cells ,COPPER ,HOMEOSTASIS - Abstract
Cuproptosis, a recently discovered form of cell death, stems from an overabundance of copper ions infiltrating mitochondria. These ions directly engage lipoylated proteins, prompting their oligomerization and subsequent loss of iron-sulfur clusters. This sequence induces proteotoxic stress, ultimately culminating in cell death. Type 2 diabetes, a chronic metabolic disorder resulting from a complex interplay of genetic and environmental factors, has not yet been fully understood in terms of its etiology and pathogenesis. Intricately, it is linked to various modalities of cell death, including mitochondrial autophagy, apoptosis, pyroptosis, and ferroptosis. Studies have discovered impaired copper metabolism in individuals with Type 2 diabetes, hinting at a unique role for copper homeostasis in the progression of the disease. To this end, the present research aims to delineate the potential correlation between cuproptosis and Type 2 diabetes by exhaustively reviewing the existing literature. By synthesizing relevant research on cuproptosis, the paper intends to lay the groundwork for a thorough exploration of the pathogenesis of Type 2 diabetes and the development of targeted therapeutic interventions. The ultimate objective is to facilitate a deeper understanding of Type 2 diabetes and to identify novel therapeutic strategies associated with cuproptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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41. Pyroptosis mediates osteoporosis via the inflammation immune microenvironment.
- Author
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Te Chen, Linyu Jin, Jingyi Li, and Yikai Liu
- Subjects
PYROPTOSIS ,APOPTOSIS ,OSTEOPOROSIS ,BONE fractures ,DISEASE progression ,OLDER people ,CELL death - Abstract
Osteoporosis represents a systemic imbalance in bone metabolism, augmenting the susceptibility to fractures among patients and emerging as a notable mortality determinant in the elderly population. It has evolved into a worldwide concern impacting the physical well-being of the elderly, imposing a substantial burden on both human society and the economy. Presently, the precise pathogenesis of osteoporosis remains inadequately characterized and necessitates further exploration. The advancement of osteoporosis is typically linked to the initiation of an inflammatory response. Cells in an inflammatory environment can cause inflammatory death including pyroptosis. Pyroptosis is a recently identified form of programmed cell death with inflammatory properties, mediated by the caspase and gasdermin families. It is regarded as the most inflammatory form of cell death in contemporary medical research. Under the influence of diverse cytokines, macrophages, and other immune cells may undergo pyroptosis, releasing inflammatory factors, such as IL-1β and IL-18. Numerous lines of evidence highlight the pivotal role of pyroptosis in the pathogenesis of inflammatory diseases, including cancer, intestinal disorders, hepatic conditions, and cutaneous ailments. Osteoporosis progression is frequently associated with inflammation; hence, pyroptosis may also play a role in the pathogenesis of osteoporosis to a certain extent, making it a potential target for treatment. This paper has provided a comprehensive summary of pertinent research concerning pyroptosis and its impact on osteoporosis. The notion proposing that pyroptosis mediates osteoporosis via the inflammatory immune microenvironment is advanced, and we subsequently investigate potential targets for treating osteoporosis through the modulation of pyroptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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42. Ferroptosis inhibitors: past, present and future.
- Author
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Lei Zhang, Yi Lin Luo, Yang Xiang, Xin Yue Bai, Rong Rong Qiang, Xin Zhang, Yan Ling Yang, and Xiao Long Liu
- Subjects
APOPTOSIS ,SMALL molecules ,DRUG design ,GENE therapy ,CELL death - Abstract
Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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43. Effect of Statin Lipophilicity on the Proliferation of Hepatocellular Carcinoma Cells.
- Author
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Glebavičiūtė, Goda, Vijaya, Akshay Kumar, and Preta, Giulio
- Subjects
HEPATOCELLULAR carcinoma ,STATINS (Cardiovascular agents) ,CANCER cell growth ,LIPOPHILICITY ,BLOOD cholesterol ,LIVER cells ,CELL death - Abstract
Simple Summary: This study examines how statins, which are drugs commonly used to lower cholesterol, affect the growth of liver cancer cells. Statins can be either lipophilic (lipid-soluble) or hydrophilic (water-soluble), and this characteristic influences how they enter cells. In our research, we compared the effects of lipophilic simvastatin and hydrophilic pravastatin. We found that simvastatin significantly reduces cancer cell growth and increases cell death depending on the dosage and duration of treatment. In contrast, pravastatin, due to its limited uptake, has a minimal impact on cancer cells. These findings suggest that the type of statin used could be crucial in cancer treatment, potentially offering better outcomes for patients with liver cancer. The HMG-CoA reductase inhibitors, statins, are drugs used globally for lowering the level of cholesterol in the blood. Different clinical studies of statins in cancer patients have indicated a decrease in cancer mortality, particularly in patients using lipophilic statins compared to those on hydrophilic statins. In this paper, we selected two structurally different statins (simvastatin and pravastatin) with different lipophilicities and investigated their effects on the proliferation and apoptosis of hepatocellular carcinoma cells. Lipophilic simvastatin highly influences cancer cell growth and survival in a time- and concentration-dependent manner, while pravastatin, due to its hydrophilic structure and limited cellular uptake, showed minimal cytotoxic effects. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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44. The Proteasome Inhibitor CEP-18770 Induces Cell Death in Medulloblastoma.
- Author
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Nath Varma, Swastina, Ye, Shany, Ferlin, Sara, Comer, Charley, Cotton, Kian, and Niklison-Chirou, Maria Victoria
- Subjects
PROTEASOME inhibitors ,MEDULLOBLASTOMA ,ANTINEOPLASTIC agents ,CELL death ,CISPLATIN ,MULTIPLE myeloma - Abstract
Medulloblastomas (MBs) represent the most prevalent malignant solid tumors in kids. The conventional treatment regimen for MBs includes surgical removal of the tumor, followed by radiation and chemotherapy. However, this approach is associated with significant morbidity and detrimental side effects. Consequently, there is a critical demand for more precise and less harmful treatments to enhance the quality of life for survivors. CEP-18770, a novel proteasome inhibitor that targets the 20S subunit, has emerged as a promising candidate, due to its anticancer activity in metastatic solid tumors and multiple myeloma, coupled with an acceptable safety profile. In this study, we aimed to assess the anticancer efficacy of CEP-18770 by employing a variety of MB patient-derived cells and cell lines. Our preclinical investigations revealed that CEP-18770 effectively inhibits proteasome activity and induces apoptosis in MBs cells. Furthermore, we discovered that CEP-18770 and cisplatin, a current component of MB therapy, exhibit a synergistic apoptotic effect. This paper shows that CEP-18770 holds potential as an adjunctive treatment for MB tumors, thereby paving the way for more targeted and less toxic therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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45. Non‐apoptotic regulated cell death mediates reprogramming of the tumour immune microenvironment by macrophages.
- Author
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Sun, Chengpeng, Zhan, Jianhao, Li, Yao, Zhou, Chulin, Huang, Shuo, Zhu, Xingen, and Huang, Kai
- Subjects
CELL death ,TUMOR microenvironment ,IMMUNE checkpoint inhibitors ,MACROPHAGES ,PYROPTOSIS - Abstract
Tumour immune microenvironment (TIME) plays an indispensable role in tumour progression, and tumour‐associated macrophages (TAMs) are the most abundant immune cells in TIME. Non‐apoptotic regulated cell death (RCD) can avoid the influence of tumour apoptosis resistance on anti‐tumour immune response. Specifically, autophagy, ferroptosis, pyroptosis and necroptosis mediate the crosstalk between TAMs and tumour cells in TIME, thus reprogram TIME and affect the progress of tumour. In addition, although some achievements have been made in immune checkpoint inhibitors (ICIs), there is still defect that ICIs are only effective for some people because non‐apoptotic RCD can bypass the apoptosis resistance of tumour. As a result, ICIs combined with targeting non‐apoptotic RCD may be a promising solution. In this paper, the basic molecular mechanism of non‐apoptotic RCD, the way in which non‐apoptotic RCD mediates crosstalk between TAMs and tumour cells to reprogram TIME, and the latest research progress in targeting non‐apoptotic RCD and ICIs are reviewed. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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46. Non-enzymatic lipid peroxidation initiated by photodynamic therapy drives a distinct ferroptosis-like cell death pathway
- Author
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Marcus Conrad, Sufang Shui, Hao Wang, Guoquan Liu, and Zenglu Zhao
- Subjects
0301 basic medicine ,Cell death ,Programmed cell death ,Medicine (General) ,QH301-705.5 ,medicine.medical_treatment ,Clinical Biochemistry ,Lipid peroxidation ,Photodynamic therapy ,Mitochondrion ,GPX4 ,Biochemistry ,Mice ,03 medical and health sciences ,Lipoxygenase ,chemistry.chemical_compound ,Cell Death ,Ferroptosis ,Liperoptosis ,Lipid Peroxidation ,Pdt ,0302 clinical medicine ,R5-920 ,PDT ,medicine ,Animals ,Biology (General) ,biology ,Chemistry ,Organic Chemistry ,Glutathione ,Phospholipid Hydroperoxide Glutathione Peroxidase ,3. Good health ,Cytosol ,030104 developmental biology ,Photochemotherapy ,Cancer research ,biology.protein ,030217 neurology & neurosurgery ,Research Paper - Abstract
Ferroptosis is primarily triggered by a failure of the glutathione (GSH)-glutathione peroxidase 4 (GPX4) reductive system and associated overwhelming lipid peroxidation, in which enzymes regulating polyunsaturated fatty acid (PUFA) metabolism, and in particular acyl-CoA synthetase long chain family member 4 (ACSL4), are central. Here, we found that exogenous oxygen radicals generated by photodynamic therapy (PDT) can directly peroxidize PUFAs and initiate lipid autoxidation, coinciding with cellular GSH depletion. Different from canonical ferroptosis induced by RSL3 or erastin, PDT-initiated lipid peroxidation and ferroptotis-like cell death is independent of lipoxygenase (ALOXs) and ACSL4. Especially, this form of cell death modality can be triggered in malignant cells insensitive to or acquired resistance to canonical ferroptosis inducers. We also observed a distinct iron metabolism pathway in this PDT-triggered cell death modality, in which cytosolic labile iron is decreased probably due to its relocation to mitochondria. Inhibition of the mitochondrial Ca2+ and Fe2+ uniporter (MCU) effectively prevented PDT-triggered lipid peroxidation and subsequent cell death. Therefore, we tentatively term this distinct ferroptosis-like cell death as liperoptosis. Moreover, using the clinically approved photosensitizer Verteporfin, PDT inhibited tumor growth through inducing prevailing ferroptosis-like cell death in a mouse xenograft model. With its site-specific advantages, these findings highlight the value of using PDT to trigger lipid peroxidation and ferroptosis-like cell death in vivo, and will benefit exploring the exact molecular mechanism of immunological effects of PDT in cancer treatment.
- Published
- 2021
47. Precise Control of Glioma Cell Apoptosis Induced by Micro-Plasma-Activated Water (μ-PAW).
- Author
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Zhang, Yuhan, Du, Xiaoxia, Shi, Qihao, Xiao, Wenxiang, and Li, Hua
- Subjects
GLIOMAS ,ULTRAVIOLET spectrophotometry ,REACTIVE nitrogen species ,BEER-Lambert law ,APOPTOSIS ,CELL death ,FOOT - Abstract
To verify the existence of plasma with the potential to kill tumor cells, this paper designed a novel helium (He) micro-plasma jet array device and detected the concentration of typical long-lived reactive oxygen and nitrogen species (RONS) with oxidative activity generated by it. The paper described a new He micro-plasma jet array device consisting of nine flexible quartz capillaries with an inner diameter of 75 μm arranged in a 3 × 3 array. Sterilized ultrapure water (up water) was first treated with the He micro-plasma jet array device to activate it to form enriched RONS micro-plasma-activated water (μ-PAW), and then μ-PAW was added to the cell culture medium (with cells) to observe the proliferation of human glioma cells. The concentration of long-lived RONS, such as nitrate (NO
3 − ), was detected according to Beer–Lambert's law in combination with UV spectrophotometry as well as a color development method. The MTT Cell Proliferation and Cytotoxicity Assay Kit combined with the Hoechst Staining Kit were used to assess the proliferation status of the cells. The results showed that the range of RONS concentration variation could be controlled in the order of micromoles (µmol), while plasma-induced tumor cell death is apoptosis that does not affect the surrounding environment. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
48. Agent‑based modelling and parameter sensitivity analysis with a finite‑element method for skin contraction
- Author
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Fred J. Vermolen and Qiyao Peng
- Subjects
Contraction (grammar) ,0206 medical engineering ,Finite Element Analysis ,Wound healing ,Apoptosis ,02 engineering and technology ,Positive correlation ,Wound contractions ,Models, Biological ,Monte Carlo simulations ,Diffusion ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Signalling molecules ,Skin Physiological Phenomena ,Humans ,Density ratio ,Myofibroblasts ,Mathematics ,Cell Proliferation ,Skin ,Inflammation ,Original Paper ,Cell Death ,integumentary system ,Mechanical Engineering ,Fibroblasts ,Models, Theoretical ,Finite-element method ,020601 biomedical engineering ,Finite element method ,Agent-based modelling ,Wound area ,Phenotype ,Modeling and Simulation ,Collagen ,Negative correlation ,Cell Division ,Biotechnology ,Biomedical engineering ,Signal Transduction - Abstract
In this paper, we extend the model of wound healing by Boon et al. (J Biomech 49(8):1388–1401, 2016). In addition to explaining the model explicitly regarding every component, namely cells, signalling molecules and tissue bundles, we categorized fibroblasts as regular fibroblasts and myofibroblasts. We do so since it is widely documented that myofibroblasts play a significant role during wound healing and skin contraction and that they are the main phenotype of cells that is responsible for the permanent deformations. Furthermore, we carried out some sensitivity tests of the model by modifying certain parameter values, and we observe that the model shows some consistency with several biological phenomena. Using Monte Carlo simulations, we found that there is a significant strong positive correlation between the final wound area and the minimal wound area. The high correlation between the wound area after 4 days and the final/minimal wound area makes it possible for physicians to predict the most probable time evolution of the wound of the patient. However, the collagen density ratio at the time when the wound area reaches its equilibrium and minimum, cannot indicate the degree of wound contractions, whereas at the 4th day post-wounding, when the collagen is accumulating from null, there is a strong negative correlation between the area and the collagen density ratio. Further, under the circumstances that we modelled, the probability that patients will end up with 5% contraction is about 0.627.
- Published
- 2020
49. ABT-199 (Venetoclax), a BH3-mimetic Bcl-2 inhibitor, does not cause Ca2+-signalling dysregulation or toxicity in pancreatic acinar cells
- Author
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Oleg Vsevolodovich Gerasimenko, Julia Vladimirovna Gerasimenko, Monika A. Jakubowska, Martijn Kerkhofs, Claudio Martines, Pawel E. Ferdek, Ole H. Petersen, Tim Vervliet, Dimitar G. Efremov, and Geert Bultynck
- Subjects
Male ,0301 basic medicine ,Programmed cell death ,BH3 mimetic ,pancreatic acinar cells ,Antineoplastic Agents ,Acinar Cells ,ABT-199/Venetoclax ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Proto-Oncogene Proteins ,Ca2+ signalling ,Animals ,Medicine ,Bcl-2 ,Calcium Signaling ,Pancreas ,Pharmacology ,Sulfonamides ,business.industry ,Venetoclax ,Bridged Bicyclo Compounds, Heterocyclic ,Peptide Fragments ,3. Good health ,Mice, Inbred C57BL ,Cytosol ,030104 developmental biology ,medicine.anatomical_structure ,cell death ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,Cancer cell ,Toxicity ,Cancer research ,Themed Section: Research Papers ,business ,030217 neurology & neurosurgery ,Homeostasis ,Intracellular ,Research Paper - Abstract
BACKGROUND AND PURPOSE: Many cancer cells depend on anti-apoptotic B-cell lymphoma 2 (Bcl-2) proteins for their survival. Bcl-2 antagonism through Bcl-2 homology 3 (BH3) mimetics has emerged as a novel anti-cancer therapy. ABT-199 (Venetoclax), a recently developed BH3 mimetic that selectively inhibits Bcl-2, was introduced into the clinic for treatment of relapsed chronic lymphocytic leukaemia. Early generations of Bcl-2 inhibitors evoked sustained Ca2+ responses in pancreatic acinar cells (PACs) inducing cell death. Therefore, BH3 mimetics could potentially be toxic for the pancreas when used to treat cancer. Although ABT-199 was shown to kill Bcl-2-dependent cancer cells without affecting intracellular Ca2+ signalling, its effects on PACs have not yet been determined. Hence, it is essential and timely to assess whether this recently approved anti-leukaemic drug might potentially have pancreatotoxic effects. EXPERIMENTAL APPROACH: Single-cell Ca2+ measurements and cell death analysis were performed on isolated mouse PACs. KEY RESULTS: Inhibition of Bcl-2 via ABT-199 did not elicit intracellular Ca2+ signalling on its own or potentiate Ca2+ signalling induced by physiological/pathophysiological stimuli in PACs. Although ABT-199 did not affect cell death in PACs, under conditions that killed ABT-199-sensitive cancer cells, cytosolic Ca2+ extrusion was slightly enhanced in the presence of ABT-199. In contrast, inhibition of Bcl-xL potentiated pathophysiological Ca2+ responses in PACs, without exacerbating cell death. CONCLUSION AND IMPLICATIONS: Our results demonstrate that apart from having a modest effect on cytosolic Ca2+ extrusion, ABT-199 does not substantially alter intracellular Ca2+ homeostasis in normal PACs and should be safe for the pancreas during cancer treatment. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc. ispartof: BRITISH JOURNAL OF PHARMACOLOGY vol:176 issue:22 pages:4402-4415 ispartof: location:England status: published
- Published
- 2019
50. Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration
- Author
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Lydian Knoop, Alwin Kamermans, Susanne M. A. van der Pol, Svenja Kiljan, Marc Franssen, Geert J. Schenk, Carmen Picón, Jack van Horssen, Evelien Drost, Nicholas D. Mazarakis, Sandra Amor, Lynn van Olst, Richard Reynolds, Helga E. de Vries, Rachel E. James, Maarten E. Witte, Iliana Michailidou, Jeroen J. G. Geurts, Carla Rodriguez-Mogeda, Molecular cell biology and Immunology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Anatomy and neurosciences, Amsterdam Neuroscience - Neurodegeneration, Pathology, AII - Inflammatory diseases, ACS - Microcirculation, and Amsterdam Neuroscience - Neurovascular Disorders
- Subjects
Adult ,Programmed cell death ,Multiple Sclerosis ,Population ,Inflammation ,Biology ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,Meninges ,Neuroinflammation ,Cortex (anatomy) ,medicine ,Animals ,Humans ,Neurodegeneration ,education ,Aged ,Cerebral Cortex ,Neurons ,Original Paper ,education.field_of_study ,Cell Death ,Microglia ,Multiple sclerosis ,Neurodegenerative Diseases ,Middle Aged ,medicine.disease ,Rats ,Cortical pathology ,Disease Models, Animal ,Phenotype ,medicine.anatomical_structure ,nervous system ,Neuroinflammatory Diseases ,Female ,Neurology (clinical) ,medicine.symptom ,Neuroscience ,Demyelinating Diseases - Abstract
Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2 months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02293-4.
- Published
- 2021
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