11,082 results
Search Results
2. Unraveling the Mechanism of Cork Spot-like Physiological Disorders in 'Kurenainoyume' Apples Based on Occurrence Location.
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Imura, Eichi, Nakagomi, Mitsuho, Hayashida, Taishi, Fujita, Tomomichi, Sato, Saki, and Matsumoto, Kazuhiro
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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]
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- 2024
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3. The boundary-spanning mechanisms of Nobel Prize winning papers
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Chaomei Chen and Yakub Sebastian
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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
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- 2021
4. HSP27 role in cardioprotection by modulating chemotherapeutic doxorubicin-induced cell death.
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Ramani S and Park S
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- 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. I think autophagy controls the death of my cells: What do I do to get my paper published?
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Andrew Thorburn
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Publishing ,Programmed cell death ,Cell Death ,Mechanism (biology) ,Research ,Publications ,Autophagy ,Cell Biology ,Biology ,Cell biology ,Apoptosis ,Humans ,Molecular Biology ,Neuroscience - Abstract
Many people are studying how autophagy intersects with cell death. While most of those studies relate to autophagy acting as a protective mechanism (e.g., to block apoptosis), many papers conclude that autophagy is a death mechanism, and there is a widespread belief that autophagy (in most, but not all cases, we are talking about macroautophagy) can both kill and protect cells depending on the circumstances. Not surprisingly therefore, many of the papers submitted to Autophagy study the relationship between autophagy and cell death.
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- 2011
7. RESEARCH PAPER: miR-19 is a key oncogenic component of mir-17-92.
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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
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- *
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]
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- 2009
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8. Exploring the Role of Different Cell-Death-Related Genes in Sepsis Diagnosis Using a Machine Learning Algorithm.
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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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9. 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
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- 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.
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- 2018
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10. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions.
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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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11. A detailed overview of quercetin: implications for cell death and liver fibrosis mechanisms.
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Fei Xiong, Yichen Zhang, Ting Li, Yiping Tang, Si-Yuan Song, Qiao Zhou, and Yi Wang
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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. A bibliometric analysis of the research hotspots and frontiers related to cell death in spinal cord injury.
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Kelin He, Han Yu, Jieqi Zhang, Lei Wu, Dexiong Han, and Ruijie Ma
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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]
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- 2024
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13. Photodynamic Therapy and Adaptive Immunity Induced by Reactive Oxygen Species: Recent Reports.
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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]
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- 2024
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14. 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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15. Enhanced Intracellular Reactive Oxygen Species by Photodynamic Therapy Effectively Promotes Chemoresistant Cell Death
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Xiaolin Xu, Chenglong Wang, Peipei Zhang, Xuzhu Gao, Wencai Guan, Fanchen Wang, Xin Li, Jia Yuan, Hongjing Dou, and Guoxiong Xu
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Mice, Inbred BALB C ,Cell Death ,malignant tumor ,oxidative phosphorylation ,ROS ,Cell Biology ,glycolysis ,Xenograft Model Antitumor Assays ,Applied Microbiology and Biotechnology ,Mice ,Photochemotherapy ,photodynamic therapy ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Animals ,Humans ,Female ,Reactive Oxygen Species ,Molecular Biology ,Chemoresistance ,Ecology, Evolution, Behavior and Systematics ,Research Paper ,Developmental Biology - Abstract
Anti-cancer chemo-drugs can cause a rapid elevation of intracellular reactive oxygen species (ROS) levels. An imbalance in ROS production and elimination systems leads to cancer cell resistance to chemotherapy. This study aimed to evaluate the mechanism and effect of ROS on multidrug resistance in various human chemoresistant cancer cells by detecting the changes in the amount of ROS, the expression of ROS-related and glycolysis-related genes, and cell death. We found that ROS was decreased while oxidative phosphorylation was increased in chemoresistant cells. We verified that the chemoresistance of cancer cells was achieved in two ways. First, chemoresistant cells preferred oxidative phosphorylation instead of anaerobic glycolysis for energy generation, which increased ATPase activity and produced much more ATP to provide energy. Second, ROS-scavenging systems were enhanced in chemoresistant cancer cells, which in turn decreased ROS amount and thus inhibited chemo-induced cell death. Our in vitro and in vivo photodynamic therapy further demonstrated that elevated ROS production efficiently inhibited chemo-drug resistance and promoted chemoresistant cell death. Taken together, targeting ROS systems has a great potential to treat cancer patients with chemoresistance.
- Published
- 2022
16. Phyto‐fabricated silver nanoparticles inducing microbial cell death via reactive oxygen species‐mediated membrane damage
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Ch. V. Ramana Devi and L. Srinivas Naik
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Silver ,Biocompatibility ,Metal Nanoparticles ,Microbial Sensitivity Tests ,Bacillus subtilis ,Silver nanoparticle ,Enterobacteriaceae ,Momordica dioica ,Electrical and Electronic Engineering ,Cell Death ,biology ,Plant Extracts ,Chemistry ,Biofilm ,Antimicrobial ,biology.organism_classification ,Anti-Bacterial Agents ,Electronic, Optical and Magnetic Materials ,Original Research Paper ,Membrane ,Nucleic acid ,Reactive Oxygen Species ,Original Research Papers ,TP248.13-248.65 ,Biotechnology ,Nuclear chemistry - Abstract
Eco‐friendly synthesis of the silver nanoparticles (AgNPs) has a number of advantages like simplicity, biocompatibility, low toxicity in nature over their physical and chemical methods. In the present study, the authors report biosynthesized AgNPs using the root extract of the perennial plant ‘Spiny gourd’ (Momordica dioica) and investigated their anti‐bacterial application with mechanistic approaches. Different biophysical techniques such as UV‐Vis spectroscopy, FTIR, XRD, TEM, SAED, and DLS were employed for AgNPs characterization. The synthesized AgNPs were polydispersed, crystalline in nature, with anionic surface (−22.3 mV), spherical in shape with an average size of 13.2 nm. In addition, the AgNPs were stable in room temperature and in different biological buffers. The anti‐bacterial activities of AgNPs were studied with respect to the pathogens such as Bacillus subtilis, Staphylococcus aureus (Gram‐positive), Pseudomonas aeruginosa, Escherichia coli, Klebsiella planticola (Gram‐negative), and Candida albicans. Also, mechanistic studies of AgNPs such as protein leakage assay, nucleic acid leakage assay, ATP leakage assay, ROS accumulation, determination of biofilm degrading activity, measurement of potassium, showing that the synthesized AgNPs are capable of containing a potential application in the antimicrobial therapeutic agents and the pharmaceutical industry.
- Published
- 2021
17. Celecoxib prevents tumor necrosis factor-α (TNF-α)-induced cellular senescence in human chondrocytes
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Qunli Wang, Qi Chen, Jie Sui, Yuanyuan Tu, Xiang Guo, and Feng Li
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Cyclin-Dependent Kinase Inhibitor p21 ,chondrocytes ,Bioengineering ,Ataxia Telangiectasia Mutated Proteins ,Resting Phase, Cell Cycle ,Applied Microbiology and Biotechnology ,Cell Line ,Humans ,Phosphorylation ,Telomerase ,Cellular Senescence ,Cell Death ,Tumor Necrosis Factor-alpha ,G1 Phase ,Cell Cycle Checkpoints ,General Medicine ,Checkpoint Kinase 2 ,osteoarthritis ,Celecoxib ,cell senescence ,Tumor Suppressor Protein p53 ,Reactive Oxygen Species ,TP248.13-248.65 ,Research Article ,Research Paper ,Biotechnology - Abstract
Osteoarthritis (OA) is a cartilage degenerative disease commonly observed in the elderly population and significantly impacts the normal life of OA patients. It has been reported that the development of pathological cell senescence in chondrocytes is involved in the pathogenesis of OA. Celecoxib is a common non-steroidal anti-inflammatory drug, and it has been recently reported to exert therapeutic effects on OA. However, its underlying mechanism is still unclear. The present study intends to explore its mechanism and provide fundamental evidence for the application of Celecoxib in the treatment of clinical OA. Tumor necrosis factor-α (TNF-α) was utilized to establish an in vitro model of chondrocytes senescence. The elevated reactive oxygen species (ROS) generation, increased cell cycle arrest in G0/G1 phase, reduced telomerase activity, and upregulated senescence-associatedβ-galactosidase (SA-β-Gal) staining were all observed in TNF-α-treated chondrocytes, which were then dramatically reversed by 10 and 20 μM Celecoxib. In addition, the upregulated DNA damage biomarkers, p-ATM, and p-CHK2, observed in TNF-α-treated chondrocytes were significantly downregulated by 10 and 20 μM Celecoxib. Lastly, the expression level of p21 and p53 was greatly elevated in chondrocytes by stimulation with TNF-α which was then pronouncedly repressed by treatment with Celecoxib. Taken together, our data reveal that Celecoxib ameliorated TNF-α-induced cellular senescence in human chondrocytes.
- Published
- 2021
18. 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
19. Exploration of the mechanism of luteolin against ischemic stroke based on network pharmacology, molecular docking and experimental verification
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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
20. Zafirlukast ameliorates Docetaxel-induced activation of NOD-like receptor protein 3 (NLRP3) inflammasome, mediated by sirtuin1 (SIRT1) in hepatocytes
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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
21. Good Versus Bad Cells
- Published
- 2009
22. Investigating the in vitro photothermal effect of green synthesized apigenin‐coated gold nanoparticle on colorectal carcinoma
- Author
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Seyed Mohammad Amini, Ali Neshasteh-Riz, Elham Mohammadi, Ali Shakeri-Zadeh, Shaghayegh Askarian-Amiri, and Yaser Azizi
- Subjects
Programmed cell death ,Metal Nanoparticles ,Nanoparticle ,Mice ,chemistry.chemical_compound ,Animals ,Apigenin ,Electrical and Electronic Engineering ,Cell Death ,Chemistry ,Photothermal effect ,Photothermal therapy ,bacterial infections and mycoses ,equipment and supplies ,Combinatorial chemistry ,Electronic, Optical and Magnetic Materials ,Original Research Paper ,Colloidal gold ,Apoptosis ,bacteria ,Chemical binding ,Gold ,Colorectal Neoplasms ,Original Research Papers ,TP248.13-248.65 ,Biotechnology - Abstract
Applying toxic chemical to the synthesis of stable gold nanoparticles is one of the limitations of gold nanoparticles for therapeutic applications such as photothermal therapy. Plant compounds such as apigenin (API) with therapeutic potential can be applied in the synthesis of gold nanoparticles. API‐coated gold nanoparticles (Api@AuNPs) with an average size of 19.1 nm and a surface charge of −4.3 mV have been synthesized by a simple and efficient technique. The stability of Api@AuNPs in the biological environment was verified through UV‐Vis spectroscopy. Based on Raman and FTIR spectroscopy analysis, chemical binding of API on the surface of Api@AuNPs through hydroxyl and carbonyl functional groups was found to be the main reason for the stability of the Api@AuNPs in comparison with citrate‐coated gold nanoparticles (Cit@AuNPs). The synthesized Api@AuNPs do not cause major toxic effects up to 128 ppm. Api@AuNP‐mediated photothermal therapy leads to the indiscriminate eradication of almost half of both mouse fibroblastic (L929) and colorectal cancer (CT26) cells. Flow‐cytometry analysis revealed that the cell death mechanism is mainly apoptosis. In the apoptosis triggered cell death in photothermal treatment, Api@AuNPs are preferred over commonly used gold nanoparticles in photothermal treatments which mostly trigger the necrosis cell death pathway.
- Published
- 2021
23. 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.)
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- 2024
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24. 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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25. SLC7A11: the Achilles heel of tumor?
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Yulang Jiang and Mingyu Sun
- Subjects
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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26. Research Progress on Micro(nano)plastic-Induced Programmed Cell Death Associated with Disease Risks.
- Author
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Liu, Huanpeng, Li, Huiqi, Chen, Ting, Yu, Fan, Lin, Qizhuan, Zhao, Haiyang, Jin, Libo, and Peng, Renyi
- Subjects
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]
- Published
- 2024
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27. Tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for hepatocellular carcinoma: recent research progress.
- Author
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Ziwei Li, Dongyu Duan, Li Li, Dan Peng, Yue Ming, Rui Ni, and Yao Liu
- Subjects
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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28. Cuproptosis: potential new direction in diabetes research and treatment.
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Jiashu Qu, Yifan Wang, and Qiuyue Wang
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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]
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- 2024
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29. Pyroptosis mediates osteoporosis via the inflammation immune microenvironment.
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Te Chen, Linyu Jin, Jingyi Li, and Yikai Liu
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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]
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- 2024
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30. Ferroptosis inhibitors: past, present and future.
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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]
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- 2024
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31. 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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32. Synthesis and Characterization of Telmisartan‐Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia
- Author
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Anna M. Schoepf, Ronald Gust, Verena Hohn, Petra Obexer, Florina Veider, and Stefan Salcher
- Subjects
Programmed cell death ,Indoles ,Cell ,Carbazoles ,01 natural sciences ,Biochemistry ,peroxisome proliferator-activated receptor gamma ,chronic myeloid leukemia ,Cancer stem cell ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Chlorocebus aethiops ,Drug Discovery ,medicine ,Animals ,Humans ,Telmisartan ,General Pharmacology, Toxicology and Pharmaceutics ,Receptor ,Pharmacology ,Full Paper ,Cell Death ,Molecular Structure ,010405 organic chemistry ,Chemistry ,structure-activity relationship ,Organic Chemistry ,Myeloid leukemia ,Imatinib ,Full Papers ,0104 chemical sciences ,PPAR gamma ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Drug Resistance, Neoplasm ,sensitizers ,COS Cells ,imatinib resistance ,Imatinib Mesylate ,Cancer research ,Molecular Medicine ,K562 Cells ,K562 cells ,medicine.drug - Abstract
New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator‐activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death‐modulating effects of the telmisartan‐derived lead 4′‐((2‐propyl‐1H‐benzo[d]imidazol‐1‐yl)methyl)‐[1,1′‐biphenyl]‐2‐carboxylic acid (3 b) was investigated. Inspired by the pharmacodynamics of HYL‐6d and the selective PPARγ ligand VSP‐51, the benzimidazole was replaced by a carbazole or an indole core. The results indicate no correlation between PPARγ activation and sensitization of resistant CML cells to imatinib. The 2‐COOH derivatives of the carbazoles or indoles achieved low activity at PPARγ, while the benzimidazoles showed 60‐100 % activation. Among the 2‐CO2CH3 derivatives, only the ester of the lead (2 b) slightly activated PPARγ. Sensitizing effects were further observed for this non‐cytotoxic 2 b (80 % cell death), and to a lesser extent for the lead 3 b or the 5‐Br‐substituted ester of the benzimidazoles (5 b)., Heterocyclic compounds with carbazole, benzimidazole, or indole core were synthesized as sensitizers to imatinib treatment in resistant chronic myelogenous leukemia cells. The benzimidazole derivatives were clearly more potent as cell death modulators than the respective carbazoles or indoles. These results are important for the further development of effective sensitizers to circumvent tyrosine kinase inhibitor resistance.
- Published
- 2020
33. Identification of novel hepatitis B virus therapeutic vaccine candidates derived from polymerase protein
- Author
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Jinming Wu, Yilun Xu, Juzeng Zheng, Yang Liu, Xianfan Lin, Ziqiang Xia, Sisi Jin, and Zhanfan Ou
- Subjects
Gene Expression Regulation, Viral ,Hepatitis B virus ,Aging ,Peptide binding ,DNA-Directed DNA Polymerase ,Biology ,medicine.disease_cause ,Peripheral blood mononuclear cell ,Fluorescence ,Epitope ,Epitopes ,Interferon-gamma ,Viral Proteins ,Immune system ,Cell Line, Tumor ,vaccine ,Gene expression ,medicine ,Humans ,Amino Acid Sequence ,Polymerase ,epitope ,Cell Death ,Viral Vaccines ,bioinformatics ,Cell Biology ,Virology ,digestive system diseases ,Molecular Docking Simulation ,polymerase ,Viral replication ,biology.protein ,Peptides ,Protein Binding ,Research Paper - Abstract
Hepatitis B virus (HBV) infection is a worldwide health problem with high morbidity and mortality rates. The therapeutic vaccine is a promising method of treatment, and HBV polymerase plays a vital role in viral replication. Therefore, a therapeutic vaccine that binds to HBV DNA polymerase may control HBV infection. We predicted and selected epitopes of polymerase using online databases and analysis software. We then performed molecular docking and peptide binding assays to evaluate the binding energies and affinities between polymerase epitopes and the HLA-A0201 molecule. Finally, we induced T cells from the peripheral blood mononuclear cells (PBMCs) of healthy donors using each epitope and quantified the functions of epitope-specific T cells by IFN-γELISPOT assay, T2 cell cytotoxicity assay, HepG2.2.15 cell cytotoxicity assay and HBV gene expression assays. Four epitopes (RVTGGVFLV, GLLGFAAPF, LLDDEAGPL and YMDDVVLGA) had low binding energy and two epitopes (RVTGGVFLV and GLLGFAAPF) had a high binding affinity. The T cells stimulated by two epitopes (GLLGFAAPF and HLYSHPIIL) had a greater ability to induce immune response and suppress HBV. The HBV DNA polymerase epitopes identified in this study are promising targets for designing an epitope-based therapeutic vaccine against HBV.
- Published
- 2021
34. Lipotoxicity reduces DDX58/Rig-1 expression and activity leading to impaired autophagy and cell death
- Author
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Raymond G. Franks, Dividutta Das, Alyssa M. Brown, Michael Hayward, Joseph T. Nickels, Jessie Lee Cunningham, and Karla K. Frietze
- Subjects
0301 basic medicine ,Programmed cell death ,Palmitic Acid ,Biology ,Mice ,03 medical and health sciences ,Sequestosome 1 ,Non-alcoholic Fatty Liver Disease ,Enhancer binding ,Sequestosome-1 Protein ,Nonalcoholic fatty liver disease ,Autophagy ,CEBPB ,medicine ,Animals ,education ,Molecular Biology ,Inflammation ,education.field_of_study ,Cell Death ,030102 biochemistry & molecular biology ,Cell Biology ,medicine.disease ,030104 developmental biology ,Lipotoxicity ,Saturated fatty acid ,Cancer research ,Research Paper - Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally. NAFLD is a consequence of fat accumulation in the liver leading to lipotoxicity. Increasing evidence has demonstrated the critical role of autophagy in NAFLD. This study uncovers the unexpected role of immune surveillance protein DDX58/Rig-1 (DExD/H box helicase 58) in activating macroautophagy/autophagy and protecting from lipotoxicity associated with NAFLD. Here we show for the first time that DDX58 protein is significantly reduced in nonalcoholic steatohepatitis (NASH) mouse model, an aggressive form of NAFLD characterized by inflammation and fibrosis of the liver. In addition to decreased expression of DDX58, we found that DDX58 activity can be attenuated by treatments with palmitic acid (PA), a saturated fatty acid. To investigate whether PA inhibition of DDX58 is harmful to the cell, we characterized DDX58 function in hepatocytes when exposed to high doses of PA in the presence and/or absence of DDX58. We show that siRNA knockdown of DDX58 promotes apoptosis. Importantly, we show that stable overexpression of DDX58 is protective against toxic levels of PA and stimulates autophagy. This study begins to demonstrate the regulation of the autophagy receptor protein SQSTM1/p62 through DDX58. DDX58 expression directly influences SQSTM1 mRNA and protein levels. This work proposes a model in which activating DDX58 increases an autophagic response and this aids in clearing toxic lipid inclusion bodies, which leads to inflammation and apoptosis. Activating a DDX58-induced autophagy response may be a strategy for treating NAFLD. Abbreviations:5ʹpppdsRNA: 5ʹ triphosphate double-stranded RNA; CDAHFD: choline-deficient, L-amino acid defined high-fat diet; CEBPB: CCAAT/enhancer binding protein (C/EBP), beta; CQ: chloroquine; DDX58/retinoic acid inducible gene 1/Rig-1: DExD/H box helicase 58; h: hours; IFIH1/MDA5: interferon induced with helicase C domain 1; IFNB/IFN-β: interferon beta 1, fibroblast; KO: knockout; MAVS: mitochondrial antiviral signaling protein; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; PA: palmitic acid; poly:IC: polyinosinic:polycytidylic acid; PRR: pattern recognition receptors; PSR: picrosirus red; RAP: rapamycin; RLR: RIG-I-like receptor; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK-binding kinase 1.
- Published
- 2021
35. Acetyl oxygen benzoate engeletin ester promotes KLF4 degradation leading to the attenuation of pulmonary fibrosis via inhibiting TGFβ1–smad/p38MAPK–lnc865/lnc556–miR-29b-2-5p–STAT3 signal pathway
- Author
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Youlei Wang, Ruiqiong Li, Xiaodong Song, Ke Shen, Changjun Lv, Bo Liu, Xiaoli Zhang, Guiwu Qu, Rongrong Li, and Minge Li
- Subjects
STAT3 Transcription Factor ,Aging ,Flavonols ,Kruppel-Like Transcription Factors ,Engeletin ,Smad Proteins ,SMAD ,Bleomycin ,Models, Biological ,p38 Mitogen-Activated Protein Kinases ,Cell Line ,STAT3 ,Transforming Growth Factor beta1 ,Kruppel-Like Factor 4 ,chemistry.chemical_compound ,lncRNA ,Pulmonary fibrosis ,medicine ,Animals ,Glycosides ,Fibroblast ,miRNA ,pulmonary fibrosis ,Cell Death ,biology ,Activator (genetics) ,Cell Biology ,medicine.disease ,KLF4 ,Mice, Inbred C57BL ,MicroRNAs ,medicine.anatomical_structure ,chemistry ,Proteolysis ,Cancer research ,biology.protein ,RNA, Long Noncoding ,Research Paper ,Signal Transduction - Abstract
Pulmonary fibrosis is a common pulmonary interstitial disease of pathogenesis without effective drugs for treatment. Therefore, discovering new and effective drugs is urgently needed. In the present study, we prepared a novel compound named acetyl oxygen benzoate engeletin ester (AOBEE), investigated its effect on experimental pulmonary fibrosis, and proposed a long non-coding RNA (lncRNA)-mediated mechanism of its action. Bleomycin-induced pulmonary fibrosis in mice exhibited that AOBEE improved forced vital capacity (FVC) and alveolar structure and inhibited α-SMA, vimentin, and collagen expression. TGFβ1-stimulated fibroblast L929 cells showed that AOBEE reduced these fibrotic proteins expression and inhibited the activated-fibroblast proliferation and migration. Whole transcriptome sequencing was performed to screen out lncRNA-lnc865 and lnc556 with high expression under bleomycin treatment, but AOBEE caused a considerable decrease in lnc865 and lnc556. Mechanistic study elucidated that AOBEE alleviated pulmonary fibrosis through lnc865- and lnc556-mediated mechanism, in which both lnc865 and lnc556 sponged miR-29b-2-5p to target signal transducer and activator of transcription 3 (STAT3). Further signal pathway inhibitors and the Cignal Finder 45-pathway reporter array illustrated that the up- and downstream pathways were TGFβ1-smad2/3 and p38MAPK, and Krüppel-like factor 4 (KLF4), respectively. In conclusion, AOBEE promoted KLF4 degradation leading to the attenuation of pulmonary fibrosis by inhibiting TGFβ1-smad/p38MAPK-lnc865/lnc556-miR-29b-2-5p-STAT3 signal pathway. We hope this work will provide valuable information to design new drugs and therapeutic targets of lncRNAs for pulmonary fibrosis treatment.
- Published
- 2021
36. Exploration of p53 plus interferon-beta gene transfer for the sensitization of human colorectal cancer cell lines to cell death
- Author
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Rodrigo Esaki Tamura, Samir Andrade Mendonça, Fernanda Antunes, Bryan E. Strauss, Daniela B Zanatta, Aline Hunger, and Paulo Roberto Del Valle
- Subjects
0301 basic medicine ,Cancer Research ,Programmed cell death ,Colorectal cancer ,medicine.medical_treatment ,Genetic enhancement ,Apoptosis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Sensitization ,Pharmacology ,Chemotherapy ,Cell Death ,business.industry ,Gene Transfer Techniques ,Interferon-beta ,HCT116 Cells ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Immunogenic cell death ,Tumor Suppressor Protein p53 ,Colorectal Neoplasms ,business ,Research Paper - Abstract
While treatments for colorectal cancer continue to improve, some 50% of patients succumb within 5 years, pointing to the need for additional therapeutic options. We have developed a modified non-replicating adenoviral vector for gene transfer, called AdRGD-PG, which offers improved levels of transduction and transgene expression. Here, we employ the p53-responsive PG promoter to drive expression of p53 or human interferon-β (hIFNβ) in human colorectal cancer cell lines HCT116(wt) (wtp53), HCT116(−/-) (p53 deficient) and HT29 (mutant p53). The HCT116 cell lines were both easily killed with p53 gene transfer, while combined p53 and hIFNβ cooperated for the induction of HT29 cell death and emission of immunogenic cell death (ICD) markers. Elevated annexinV staining and caspase 3/7 activity point to cell death by a mechanism consistent with apoptosis. P53 gene transfer alone or in combination with hIFNβ sensitized all cell lines to chemotherapy, permitting the application of low drug doses while still achieving significant loss of viability. While endogenous p53 status was not sufficient to predict response to treatment, combined p53 and hIFNβ provided an additive effect in HT29 cells. We propose that this approach may prove effective for the treatment of colorectal cancer, permitting the use of limited drug doses.
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- 2021
37. 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
38. 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
39. 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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40. CPI-1189 protects neuronal cells from oxygen glucose deprivation/re-oxygenation-induced oxidative injury and cell death
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Chengliang Yang, Yueli Zhan, Chengrui Li, Jianhong Sun, and Yong-Jun Li
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Aging ,Programmed cell death ,oxidative injury ,p38 mitogen-activated protein kinases ,Apoptosis ,Neuroprotection ,Cell Line ,Lipid peroxidation ,chemistry.chemical_compound ,Animals ,Neurons ,chemistry.chemical_classification ,Reactive oxygen species ,Cell Death ,oxygen glucose deprivation/re-oxygenation ,Depolarization ,Cell Biology ,Glutathione ,CPI-1189 ,Cell biology ,Oxygen ,Oxidative Stress ,Glucose ,nervous system ,chemistry ,Butanes ,Tumor necrosis factor alpha ,Lipid Peroxidation ,signaling ,Reactive Oxygen Species ,Research Paper - Abstract
Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) induces profound oxidative injury and neuronal cell death. It mimics ischemia-reperfusion neuronal injury. CPI-1189 is a novel tumor necrosis factor alpha-inhibiting compound with potential neuroprotective function. Here in SH-SY5Y neuronal cells and primary murine cortical neurons, CPI-1189 pretreatment potently inhibited OGDR-induced viability reduction and cell death. In OGDR-stimulated neuronal cells, p38 phosphorylation was blocked by CPI-1189. In addition, CPI-1189 alleviated OGDR-induced reactive oxygen species production, lipid peroxidation, and glutathione consumption. OGDR-induced neuronal cell apoptosis was also inhibited by CPI-1189 pretreatment. Furthermore, in SH-SY5Y cells and cortical neurons, CPI-1189 alleviated OGDR-induced programmed necrosis by inhibiting mitochondrial p53-cyclophilin D-adenine nucleotide translocase 1 association, mitochondrial depolarization, and lactate dehydrogenase release to the medium. In summary, CPI-1189 potently inhibited OGDR-induced oxidative injury and neuronal cell death.
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- 2021
41. 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
42. Triptolide improves neurobehavioral functions, inflammation, and oxidative stress in rats under deep hypothermic circulatory arrest
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Jian-Feng Liu, Zeng-Chun Wang, Hua Cao, Qiang Chen, and Yu-Qing Lei
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Male ,Aging ,deep hypothermia circulatory arrest (DHCA) ,Spatial Learning ,Morris water navigation task ,Pharmacology ,neurotrophins ,medicine.disease_cause ,Neuroprotection ,neuroinflammation ,chemistry.chemical_compound ,medicine ,Animals ,Nerve Growth Factors ,Neuroinflammation ,Inflammation ,TUNEL assay ,Behavior, Animal ,Cell Death ,business.industry ,Brain ,Cell Biology ,Phenanthrenes ,Triptolide ,Hypothermia ,Rats ,Circulatory Arrest, Deep Hypothermia Induced ,Oxidative Stress ,Memory, Short-Term ,Neuroprotective Agents ,chemistry ,triptolide ,Deep hypothermic circulatory arrest ,Epoxy Compounds ,Microglia ,Diterpenes ,medicine.symptom ,business ,Oxidative stress ,Research Paper - Abstract
This study investigated the neuroprotective effects of triptolide (TPL) in a rat model of cardiopulmonary bypass with deep hypothermia circulatory arrest (DHCA). Rats were randomly divided into six groups: control, sham, DHCA, and DHCA + TPL (100, 200, 300 μg/kg). Neurobehavioral functions were measured using the elevated plus-maze, Y-maze, and Morris water maze tests. Levels of inflammatory cytokines, oxidative stress indices, and brain neurotrophins were measured by ELISA. Microglial activation and cell death was measured by immunofluorescence staining and TUNEL assay, respectively. Finally, activation of the Nrf2 pathway and NF-κB were detected by western blot. The elevated plus-maze, Y-maze, and Morris water maze tests all showed that TPL mitigated anxiety-like behavior, working memory, spatial learning, and memory in DHCA rats. TPL inhibited inflammatory responses and oxidative stress, as well as increased brain neurotrophin levels in DHCA rats. Moreover, TPL attenuated microglia activation and cell death in DHCA rats. Finally, TPL activated the Nrf2 pathway and inhibited NF-κB activity in DHCA rats. These results demonstrated that TPL improved neurobehavioral functions, neuroinflammation, and oxidative stress in DHCA rats, which may be associated with the Nrf2 and NF-κB pathways.
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- 2021
43. Orthogonal targeting of osteoclasts and myeloma cells for radionuclide stimulated dynamic therapy induces multidimensional cell death pathways
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Lynne Marsala, Gregory M. Lanza, Julie L. Prior, Alexander Zheleznyak, Xiaoxia Yang, Baogang Xu, Samuel Achilefu, Steven Fletcher, Grace Cui, Francesca Fontana, and Matthew Mixdorf
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Programmed cell death ,bone marrow ,Osteolysis ,photosensitizer ,Osteoclasts ,Medicine (miscellaneous) ,Apoptosis ,Bone Neoplasms ,Bone and Bones ,Theranostic Nanomedicine ,Mice ,Cerenkov radiation ,Fluorodeoxyglucose F18 ,In vivo ,Cell Line, Tumor ,Bone cell ,Organometallic Compounds ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,orthogonal drug delivery ,Radioisotopes ,Tumor microenvironment ,nanomicelles ,Cell Death ,Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,multiple myeloma ,medicine.anatomical_structure ,Tumor progression ,Cancer research ,Bone marrow ,Radiopharmaceuticals ,Reactive Oxygen Species ,Integrin alpha Chains ,Research Paper ,Signal Transduction - Abstract
Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death. The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC). In the “vicious cycle” of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC. Disrupting these cancer-stroma interactions would enhance treatment response. Methods: To disrupt this cycle, we orthogonally targeted nanomicelles (NM) loaded with non-therapeutic doses of a photosensitizer, titanocene (TC), to VLA-4 (α4ß1, CD49d/CD29) expressing MMC (MM1.S) and αvß3 (CD51/CD61) expressing OC. Concurrently, a non-lethal dose of a radiopharmaceutical, 18F-fluorodeoxyglucose ([18F]FDG) administered systemically interacted with TC (radionuclide stimulated therapy, RaST) to generate cytotoxic reactive oxygen species (ROS). The in vitro and in vivo effects of RaST were characterized in MM1.S cell line, as well as in xenograft and isograft MM animal models. Results: Our data revealed that RaST induced non-enzymatic hydroperoxidation of cellular lipids culminating in mitochondrial dysfunction, DNA fragmentation, and caspase-dependent apoptosis of MMC using VLA-4 avid TC-NMs. RaST upregulated the expression of BAX, Bcl-2, and p53, highlighting the induction of apoptosis via the BAK-independent pathway. The enhancement of multicopper oxidase enzyme F5 expression, which inhibits lipid hydroperoxidation and Fenton reaction, was not sufficient to overcome RaST-induced increase in the accumulation of irreversible function-perturbing α,ß-aldehydes that exerted significant and long-lasting damage to both DNA and proteins. In vivo, either VLA-4-TC-NM or αvß3-TC-NMs RaST induced a significant therapeutic effect on immunocompromised but not immunocompetent MM-bearing mouse models. Combined treatment with both VLA-4-TC-NM and αvß3-TC-NMs synergistically inhibited osteolysis, reduced tumor burden, and prevented rapid relapse in both in vivo models of MM. Conclusions: By targeting MM and bone cells simultaneously, combination RaST suppressed MM disease progression through a multi-prong action on the vicious cycle of bone cancer. Instead of using the standard multidrug approach, our work reveals a unique photophysical treatment paradigm that uses nontoxic doses of a single light-sensitive drug directed orthogonally to cancer and bone cells, followed by radionuclide-stimulated generation of ROS to inhibit tumor progression and minimize osteolysis in both immunocompetent murine and immunocompromised human MM models.
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- 2021
44. Conditioned medium from adipose-derived stem cells attenuates ischemia/reperfusion-induced cardiac injury through the microRNA-221/222/PUMA/ETS-1 pathway
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Shu-Rung Lin, Chiang-Wen Lee, Yu-Chen Chen, Chi-Ming Pu, I-Ta Lee, Jaw-Shiun Tsai, Tzu-Lin Lee, Shu-Wha Lin, Yuh-Lien Chen, and Tsai-Chun Lai
- Subjects
Male ,0301 basic medicine ,p38 mitogen-activated protein kinases ,Myocardial Infarction ,Medicine (miscellaneous) ,Apoptosis ,Myocardial Reperfusion Injury ,Ischemia/reperfusion injury ,Proto-Oncogene Protein c-ets-1 ,Andrology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Reperfusion therapy ,Annexin ,Fibrosis ,Puma ,Animals ,Medicine ,Myocytes, Cardiac ,p53 upregulated modulator of apoptosis ,ADSC-CM ,miR-221/222 ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Mice, Knockout ,TUNEL assay ,Cell Death ,biology ,business.industry ,Myocardium ,Stem Cells ,Tumor Suppressor Proteins ,fibrosis ,Mesenchymal Stem Cells ,medicine.disease ,biology.organism_classification ,Mice, Inbred C57BL ,MicroRNAs ,030104 developmental biology ,Adipose Tissue ,Culture Media, Conditioned ,Reperfusion Injury ,030220 oncology & carcinogenesis ,Reperfusion ,biology.protein ,Apoptosis Regulatory Proteins ,business ,Research Paper - Abstract
Rationale: Cardiovascular diseases, such as myocardial infarction (MI), are the leading causes of death worldwide. Reperfusion therapy is the common standard treatment for MI. However, myocardial ischemia/reperfusion (I/R) causes cardiomyocyte injury, including apoptosis and fibrosis. We aimed to investigate the effects of conditioned medium from adipose-derived stem cells (ADSC-CM) on apoptosis and fibrosis in I/R-treated hearts and hypoxia/reoxygenation (H/R)-treated cardiomyocytes and the underlying mechanisms. Methods: ADSC-CM was collected from ADSCs. The effects of intramuscular injection of ADSC-CM on cardiac function, cardiac apoptosis, and fibrosis examined by echocardiography, Evans blue/TTC staining, TUNEL assay, and Masson's trichrome staining in I/R-treated mice. We also examined the effects of ADSC-CM on apoptosis and fibrosis in H/R-treated H9c2 cells by annexin V/PI flow cytometry, TUNEL assay, and immunocytochemistry. Results: ADSC-CM treatment significantly reduced heart damage and fibrosis of I/R-treated mice and H/R-treated cardiomyocytes. In addition, the expression of apoptosis-related proteins, such as p53 upregulated modulator of apoptosis (PUMA), p-p53 and B-cell lymphoma 2 (BCL2), as well as the fibrosis-related proteins ETS-1, fibronectin and collagen 3, were significantly reduced by ADSC-CM treatment. Moreover, we demonstrated that ADSC-CM contains a large amount of miR-221/222, which can target and regulate PUMA or ETS-1 protein levels. Furthermore, the knockdown of PUMA and ETS-1 decreased the induction of apoptosis and fibrosis, respectively. MiR-221/222 overexpression achieved similar results. We also observed that cardiac I/R markedly increased apoptosis and fibrosis in miR-221/222 knockout (KO) mice, while ADSC-CM decreased these effects. The increased phosphorylation of p38 and NF‐κB not only mediated myocardial apoptosis through the PUMA/p53/BCL2 pathway but also regulated fibrosis through the ETS-1/fibronectin/collagen 3 pathway. Conclusions: Overall, our results show that ADSC-CM attenuates cardiac apoptosis and fibrosis by reducing PUMA and ETS-1 expression, respectively. The protective effect is mediated via the miR-221/222/p38/NF-κB pathway.
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- 2021
45. 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
46. 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
47. Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer
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Li-Qiang Qin, Cai-Long Chen, Meng-Lan Lu, Haitao Lv, Kai Yang, Jia-Ying Xu, Zheng Zhang, Xing Tong, and Yun-Hong Li
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0301 basic medicine ,China ,Programmed cell death ,DNA damage ,Iron ,Mice, Nude ,Medicine (miscellaneous) ,Breast Neoplasms ,Triple Negative Breast Neoplasms ,SLC7A11 ,Biomarkers, Pharmacological ,Lipid peroxidation ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Holo-Lf ,Cell Line, Tumor ,Tumor Microenvironment ,Animals ,Ferroptosis ,Humans ,skin and connective tissue diseases ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,radiotherapy ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Reactive oxygen species ,Cell Death ,biology ,hypoxia ,Glutathione ,Malondialdehyde ,Lactoferrin ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,triple-negative breast cancer ,MCF-7 Cells ,Cancer research ,biology.protein ,Female ,Lipid Peroxidation ,Reactive Oxygen Species ,Research Paper - Abstract
Rationale: Iron-saturated Lf (Holo-Lactoferrin, Holo-Lf) exhibits a superior anticancer property than low iron-saturated Lf (Apo-Lf). Ferroptosis is an iron-dependent cell death characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). Radiotherapy also exerts its therapeutic effect through ROS. Methods: The effect of different iron-saturated Lf on ferroptosis and radiotherapy were tested on triple-negative breast cancer (TNBC) cell line MDA-MB-231 and non-TNBC cell line MCF-7. Results: Holo-Lf significantly increased the total iron content, promoted ROS generation, increased lipid peroxidation end product, malondialdehyde (MDA), and enhanced ferroptosis of MDA-MB-231 cells. By contrast, Apo-Lf upregulated SLC7a11 expression, increased GSH generation and inhibited ferroptosis of MDA-MB-231 cells. However, non-TNBC MCF-7 cells were resistant to Holo-Lf-induced ferroptosis because MCF-7 cells have a higher redox balance capacity than MDA-MB-231 cells. More importantly, Holo-Lf downregulated HIF-1α expression, ameliorated the hypoxia microenvironment in subcutaneous MDA-MB-231 tumors, and promoted radiation-induced DNA damage to hypoxic MDA-MB-231 cells. Finally, the efficacy of radiotherapy to MDA-MB-231 tumors was enhanced by Holo-Lf. Conclusion: Holo-Lf could induce ferroptosis in MDA-MB-231 cells and sensitize MDA-MB-231 tumors to radiotherapy.
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- 2021
48. Compensatory combination of mTOR and TrxR inhibitors to cause oxidative stress and regression of tumors
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Tingting Zhang, Ri Cui, Jundixia Chen, Lin Hong, Fengjiao Wu, Fang Wu, Yiqun Xia, Yun Yu, Chenyu Qiu, Wei Chen, Xin Shen, Chenxin Xu, Congying Xie, Peng Zou, Rongrong Shao, and Peisen Zheng
- Subjects
0301 basic medicine ,autophagy ,Programmed cell death ,Thioredoxin-Disulfide Reductase ,Auranofin ,MAP Kinase Signaling System ,Mice, Nude ,Medicine (miscellaneous) ,Mice ,03 medical and health sciences ,0302 clinical medicine ,c-Jun N-terminal Kinase ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,PI3K/AKT/mTOR pathway ,Mice, Inbred BALB C ,Everolimus ,Cell Death ,business.industry ,TOR Serine-Threonine Kinases ,Autophagy ,Cancer ,thioredoxin reductase ,Endoplasmic Reticulum Stress ,HCT116 Cells ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,mTOR ,Cancer research ,Signal transduction ,business ,Research Paper ,Signal Transduction ,medicine.drug - Abstract
Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.
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- 2021
49. Identification of a novel and potent small molecule inhibitor of SRPK1: mechanism of dual inhibition of SRPK1 for the inhibition of cancer progression
- Author
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Imteyaz Qamar, Nagendra Singh, Anshuman Chandra, and Hanumappa Ananda
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Aging ,flow cytometery ,Cell Survival ,Apoptosis ,Protein Serine-Threonine Kinases ,SRPK1 ,environment and public health ,Serine ,Inhibitory Concentration 50 ,Jurkat Cells ,Humans ,RNA, Messenger ,Phosphorylation ,Binding site ,Protein kinase A ,Protein Kinase Inhibitors ,Cell Proliferation ,chemistry.chemical_classification ,MTT assay ,Cell Death ,Serine-Arginine Splicing Factors ,Kinase ,splicing inhibitor ,Cell Biology ,virtual screening ,Small molecule ,Cell biology ,Molecular Docking Simulation ,Enzyme ,chemistry ,A549 Cells ,structure based drug design ,Drug Design ,Drug Screening Assays, Antitumor ,K562 Cells ,Research Paper ,HeLa Cells - Abstract
Protein kinases are the family of attractive enzyme targets for drug design with relevance to cancer biology. Serine arginine protein kinase 1 (SRPK1) is responsible for the phosphorylation of serine/arginine (SR)-rich proteins. Alternative Splicing Factor/Splicing Factor 2 (ASF/SF2) involved in mRNA editing. ASF/SF2 is over expressed in many cancers and plays crucial roles in the cell survival. Phosphorylation of ASF/SF2 is decisive for its functions in cancer. In search of potential anticancer therapeutic agents for attenuating phosphorylation of ASF/SF2, we have explored specific and potential inhibitors of SRPK1 from natural and drug like compounds databases using in-silico methods. Compound ZINC02154892 (C02) was found to be the most potent inhibitor for SRPK1. In-vitro molecular and cell biology studies have shown C02 as a potent and specific inhibitor of phosphorylation of ASF/SF2 and cell survival in leukemic cell line. Structural analysis of SRPK1 with compound C02 revealed a unique pattern of binding targeting ATP binding site along with inhibiting recruitment of ASF/SF2 by SRPK1. The possibilities of compound C02 to be used as a lead compound paving way for the development of potent and specific inhibitors of SRPK1 for designing of novel potential anticancer inhibitor is inferred from the current studies.
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- 2020
50. Tumor necrosis factor receptor-associated factor 6 interaction with alpha-synuclein enhances cell death through the Nuclear Factor-kB pathway
- Author
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Alexandre Denadai-Souza, Adriana Oliveira Manfiolli, L. M. Yshii, Marcelo D. Gomes, Paula Fernanda Kinoshita, and Cristoforo Scavone
- Subjects
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.
- Published
- 2020
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