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Cell Death in Biology and Diseases 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (16 July 2021) | Viewed by 28322

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Dr. Peter Richter

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Gravitational Biology Group, Department of Biology, Cell Biology Division, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany
Interests: cell biology; plant physiology; photodynamic therapy
Special Issues, Collections and Topics in MDPI journals

Dr. Marcus Krüger

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Guest Editor

Environmental Cell Biology Group, Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University, 39106 Magdeburg, Germany
Interests: cell biology; cancer biology; environmental influences; microgravity; cellular communication; photodynamic therapy; cancer treatment; antimicrobial resistance; tumor microbiome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cell death is a major biological phenomenon. Like other cellular processes (e.g., cell proliferation or cell differentiation), cell death is a choice that a cell has to make—sometimes voluntarily, other times accidentally. Cell death serves a purpose in the biology of multicellular organisms. However, the machinery for cell death is evolutionarily conserved, and the elements can also be found in single-celled organisms. The molecular mechanisms of cell death (or conversely cell survival) are complex and often closely connected to other cellular processes, such as cell proliferation or differentiation, and are thus part of a broad signaling network. The disruption of these mechanisms often causes developmental abnormalities, and factors that trigger cell death can directly contribute to the pathogenesis of many diseases, including cancer, neurodegenerative diseases, and tissue injury. Additionally, in plants, programmed cell death plays an important role in the formation of sclerenchyma and xylem (water and mineral transport).

This Special Issue will focus on the exploration of the role of cell death in disease development and the modulation of cell death for the treatment of diseases, as it is important that our knowledge in this field is constantly updated. This Special Issue highly welcomes original research articles, short communications, and review manuscripts. Interdisciplinary contributions will help to get a detailed overview of this exciting research field in medicine, pest control, and other areas, providing great opportunities for new discoveries and applications in life science.

Dr. Peter Richter
Dr. Marcus Krüger
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

programmed cell death
apoptosis
necrosis
autoimmune diseases
cancer research
pharmacognosy
photodynamic therapy
immune system

Published Papers (10 papers)

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Editorial

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3 pages, 1067 KiB

Open AccessEditorial

To Die or Not to Die: Cell Death in Biology and Disease

by Marcus Krüger and Peter Richter

Int. J. Mol. Sci. 2022, 23(12), 6734; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126734 - 16 Jun 2022

Cited by 5 | Viewed by 5044

Abstract

Cell death is a fundamental and highly organized biological phenomenon that was long considered nothing more than the inevitable endpoint of life; this is reflected in the meaning of the Greek word, ἀπόπτωσις (“falling leaves from a tree”) [...] Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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Research

Jump to: Editorial, Review

13 pages, 3640 KiB

Open AccessArticle

Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells

by Theodoros Eleftheriadis, Georgios Pissas, Georgios Filippidis, Maria Efthymiadi, Vassilios Liakopoulos and Ioannis Stefanidis

Int. J. Mol. Sci. 2022, 23(24), 16107; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232416107 - 17 Dec 2022

Cited by 4 | Viewed by 1861

Abstract

Gliflozins are a new class of antidiabetic drugs with renoprotective properties. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to high-glucose conditions in the presence or absence of dapagliflozin, we evaluated cellular senescence pathways. High glucose increased sodium–glucose cotransporter-2 (SGLT-2) expression and glucose consumption, enhancing reactive oxygen species production. The latter induced DNA damage, ataxia telangiectasia mutated kinase (ATM), and p53 phosphorylation. Stabilized p53 increased the cell cycle inhibitor p21, resulting in cell cycle arrest and increasing the cellular senescence marker beta-galactosidase (GLB-1). RPTECs under high glucose acquired a senescence-associated secretory phenotype, which was detected by the production of IL-1β, IL-8, and TGF-β1. By decreasing SGLT-2 expression and glucose consumption, dapagliflozin inhibited the above pathway and prevented RPTEC senescence. In addition, dapagliflozin reduced the cell cycle inhibitor p16 independently of the glucose conditions. Neither glucose concentration nor dapagliflozin affected the epithelial-to-mesenchymal transition when assessed with α-smooth muscle actin (α-SMA). Thus, high glucose induces p21-dependent RPTEC senescence, whereas dapagliflozin prevents it. Since cellular senescence contributes to the pathogenesis of diabetic nephropathy, delineating the related molecular mechanisms and the effects of the widely used gliflozins on them is of particular interest and may lead to novel therapeutic approaches. Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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21 pages, 3624 KiB

Open AccessArticle

Molecular Physicochemical Properties of Selected Pesticides as Predictive Factors for Oxidative Stress and Apoptosis-Dependent Cell Death in Caco-2 and HepG2 Cells

by Amélia M. Silva, Carlos Martins-Gomes, Sandrine S. Ferreira, Eliana B. Souto and Tatiana Andreani

Int. J. Mol. Sci. 2022, 23(15), 8107; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158107 - 23 Jul 2022

Cited by 9 | Viewed by 1949

Abstract

In this work, three pesticides of different physicochemical properties: glyphosate (GLY, herbicide), imidacloprid (IMD, insecticide), and imazalil (IMZ, fungicide), were selected to assess their cytotoxicity against Caco-2 and HepG2 cells. Cell viability was assessed by the Alamar Blue assay, after 24 and 48 h exposure to different concentrations, and IC₅₀ values were calculated. The mechanisms underlying toxicity, namely cellular reactive oxygen species (ROS), glutathione (GSH) content, lipid peroxidation, loss of mitochondrial membrane potential (MMP), and apoptosis/necrosis induction were assessed by flow cytometry. Cytotoxic profiles were further correlated with the molecular physicochemical parameters of pesticides, namely: water solubility, partition coefficient in an n-octanol/water (Log P_ow) system, topological polar surface area (TPSA), the number of hydrogen-bonds (donor/acceptor), and rotatable bonds. In vitro outputs resulted in the following toxicity level: IMZ (Caco-2: IC₅₀ = 253.5 ± 3.37 μM, and HepG2: IC₅₀ = 94 ± 12 μM) > IMD (Caco-2: IC₅₀ > 1 mM and HepG2: IC₅₀ = 624 ± 24 μM) > GLY (IC₅₀ >>1 mM, both cell lines), after 24 h treatment, being toxicity time-dependent (lower IC₅₀ values at 48 h). Toxicity is explained by oxidative stress, as IMZ induced a higher intracellular ROS increase and lipid peroxidation, followed by IMD, while GLY did not change these markers. However, the three pesticides induced loss of MMP in HepG2 cells while in Caco-2 cells only IMZ produced significant MMP loss. Increased ROS and loss of MMP promoted apoptosis in Caco-2 cells subjected to IMZ, and in HepG2 cells exposed to IMD and IMZ, as assessed by Annexin-V/PI. The toxicity profile of pesticides is directly correlated with their Log P_ow, as affinity for the lipophilic environment favours interaction with cell membranes governs, and is inversely correlated with their TPSA; however, membrane permeation is favoured by lower TPSA. IMZ presents the best molecular properties for membrane interaction and cell permeation, i.e., higher Log P_ow, lower TPSA and lower hydrogen-bond (H-bond) donor/acceptor correlating with its higher toxicity. In conclusion, molecular physicochemical factors such as Log P_ow, TPSA, and H-bond are likely to be directly correlated with pesticide-induced toxicity, thus they are key factors to potentially predict the toxicity of other compounds. Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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20 pages, 5032 KiB

Open AccessArticle

Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist

by Yi He, Salvador Alejo, Prabhakar Pitta Venkata, Jessica D. Johnson, Ilanna Loeffel, Uday P. Pratap, Yi Zou, Zhao Lai, Rajeshwar R. Tekmal, Edward R. Kost and Gangadhara R. Sareddy

Int. J. Mol. Sci. 2022, 23(13), 7159; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137159 - 28 Jun 2022

Cited by 9 | Viewed by 2472

Abstract

Ovarian cancer (OCa) is the deadliest gynecologic cancer. Emerging studies suggest ovarian cancer stem cells (OCSCs) contribute to chemotherapy resistance and tumor relapse. Recent studies demonstrated estrogen receptor beta (ERβ) exerts tumor suppressor functions in OCa. However, the status of ERβ expression in OCSCs and the therapeutic utility of the ERβ agonist LY500307 for targeting OCSCs remain unknown. OCSCs were enriched from ES2, OV90, SKOV3, OVSAHO, and A2780 cells using ALDEFLUOR kit. RT-qPCR results showed ERβ, particularly ERβ isoform 1, is highly expressed in OCSCs and that ERβ agonist LY500307 significantly reduced the viability of OCSCs. Treatment of OCSCs with LY500307 significantly reduced sphere formation, self-renewal, and invasion, while also promoting apoptosis and G2/M cell cycle arrest. Mechanistic studies using RNA-seq analysis demonstrated that LY500307 treatment resulted in modulation of pathways related to cell cycle and apoptosis. Western blot and RT-qPCR assays demonstrated the upregulation of apoptosis and cell cycle arrest genes such as FDXR, p21/CDKN1A, cleaved PARP, and caspase 3, and the downregulation of stemness markers SOX2, Oct4, and Nanog. Importantly, treatment of LY500307 significantly attenuated the tumor-initiating capacity of OCSCs in orthotopic OCa murine xenograft models. Our results demonstrate that ERβ agonist LY500307 is highly efficacious in reducing the stemness and promoting apoptosis of OCSCs and shows significant promise as a novel therapeutic agent in treating OCa. Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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16 pages, 2920 KiB

Open AccessArticle

Hypofractionated Radiotherapy Upregulates Several Immune Checkpoint Molecules in Head and Neck Squamous Cell Carcinoma Cells Independently of the HPV Status While ICOS-L Is Upregulated Only on HPV-Positive Cells

by Sebastian Wimmer, Lisa Deloch, Michael Hader, Anja Derer, Fridolin Grottker, Thomas Weissmann, Markus Hecht, Antoniu-Oreste Gostian, Rainer Fietkau, Benjamin Frey and Udo S. Gaipl

Int. J. Mol. Sci. 2021, 22(17), 9114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179114 - 24 Aug 2021

Cited by 10 | Viewed by 2423

Abstract

While the treatment of squamous cell carcinoma of the head and neck (HNSCC) with radiotherapy (RT) is complemented more and more by immunotherapy in clinical trials, little is known about the impact of the human papillomavirus (HPV) status or the applied RT scheme on the immune phenotype of the tumor cells. Therefore, we aimed to examine the impact of the HPV status of four human HNSCC cell lines on cell death and the expression of immune checkpoint molecules (ICMs) after RT with either hypofractionation irradiation (5x3.0Gy) or a high single dose (1x19.3Gy) via multicolor flow cytometry and quantitative PCR at an early time point after therapy. In our study, 5x3.0Gy RT induced high numbers of early and late apoptotic cells independent of the HPV status, but necrosis was only increased in the HPV-positive UM-Scc-47 cells. Generally, the immune stimulatory ICMs (CD70, CD137-L, ICOS-L) were less affected by RT compared to the immune suppressive ones (PD-L1, PD-L2, and the herpesvirus entry mediator (HVEM)). A significant higher surface expression of the analyzed ICMs was found after hypofractionated RT compared to a single high dose; however, regardless of the HPV status, with the exception of ICOS-L. Here, HPV-positive HNSCC tumor cells showed a stronger response to 5x3.0Gy than HPV-negative ones. On the RNA level, only minor alterations of ICMs were observed following RT, with the exception of the HPV negative cell line CAL33 treated with 5x3.0Gy, where PD-L2, HVEM and CD70 were significantly increased. We conclude that the HPV status may not distinctly predict immunological responses following RT, and thus cannot be used as a single predictive marker for therapy responses in HNSCC. In contrast, the patient-specific individual expression of ICMs following RT is preferable for the targeted patient selection for immune therapy directed against distinct ICM. Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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18 pages, 2660 KiB

Open AccessArticle

Individual and Combined Treatments with Methylated Resveratrol Analogue DMU-214 and Gefitinib Inhibit Tongue Cancer Cells Growth via Apoptosis Induction and EGFR Inhibition

by Malgorzata Jozkowiak, Marta Dyszkiewicz-Konwinska, Piotr Ramlau, Wieslawa Kranc, Julia Spaczynska, Marcin Wierzchowski, Mariusz Kaczmarek, Jadwiga Jodynis-Liebert and Hanna Piotrowska-Kempisty

Int. J. Mol. Sci. 2021, 22(12), 6180; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126180 - 08 Jun 2021

Cited by 6 | Viewed by 2089

Abstract

The methylated resveratrol analogue 3′-hydroxy-3,4,5,4′-tetramethoxystilbene (DMU-214) has been revealed to exert the anti-cancer activity by a block of the cell cycle at the G2/M phase, apoptosis induction, and metastasis inhibition. These biological events may be involved in crosstalk with the epidermal growth factor receptor (EGFR), which belongs to the ErbB family of receptor tyrosine kinases. Several cancer therapeutic approaches employ small molecules capable of inhibiting tyrosine kinases (e.g., gefitinib). According to more recent reports, combining gefitinib with chemotherapeutics, such as cisplatin, seems to be more effective than monotherapy. The present study aimed to assess the molecular mechanism of the potential anti-proliferative activity of individual and combined treatments with DMU-214 and gefitinib in SCC-25 and CAL-27 human tongue cancer cell lines. We showed for the first time the anti-cancer effects of DMU-214, gefitinib, and their combination in tongue cancer cells triggered via cell cycle arrest, apoptosis induction, and inhibition of the EGFR signaling pathway. The anti-proliferative effects of DMU-214 and gefitinib are also suggested to be related to the EGFR and EGFRP (phosphorylated epidermal growth factor receptor) expression status since we found significantly weaker cytotoxic activity of the compounds tested in SCC-25 cells, which overexpressed EGFR and EGFRP proteins. Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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14 pages, 2823 KiB

Open AccessArticle

Methyl-Donors Can Induce Apoptosis and Attenuate Both the Akt and the Erk1/2 Mediated Proliferation Pathways in Breast and Lung Cancer Cell Lines

by Eva Kiss, Gertrud Forika, Reka Mohacsi, Zsuzsanna Nemeth, Tibor Krenacs and Magdolna Dank

Int. J. Mol. Sci. 2021, 22(7), 3598; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073598 - 30 Mar 2021

Cited by 8 | Viewed by 2216

Abstract

Dietary methyl-donors play important roles in physiological processes catalyzed by B vitamins as coenzymes, and are used for complementary support in oncotherapy. Our hypothesis was that methyl-donors can not only assist in tolerating cancer treatment but may also directly interfere with tumor growth and proliferation. Therefore, we investigated the proposed cancer inhibitory effects of methyl-donors (in a mixture of L-methionine, choline chloride, folic acid, and vitamin B12) on MCF7 and T47D breast cancer as well as A549 and H1650 lung cancer cell lines. Indeed, methyl-donor treatment significantly reduced the proliferation in all cell lines, possibly through the downregulation of MAPK/ERK and AKT signaling. These were accompanied by the upregulation of the pro-apoptotic Bak and Bax, both in MCF7 and H1650 cells, at reduced anti-apoptotic Mcl-1 and Bcl-2 levels in MCF7 and H1650 cells, respectively. The treatment-induced downregulation of p-p53(Thr55) was likely to contribute to protecting the nuclear localization and apoptosis inducing functions of p53. The presented features are known to improve the sensitivity of cancer therapy. Therefore, these data support the hypothesis, i.e., that methyl-donors may promote apoptotic signaling by protecting p53 functions through downregulating both the MAPK/ERK and the AKT pathways both in breast and lung adenocarcinoma cell lines. Our results can emphasize the importance and benefits of the appropriate dietary supports in cancer treatments. However, further studies are required to confirm these effects without any adverse outcome in clinical settings. Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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17 pages, 3229 KiB

Open AccessArticle

Apoptotic Cells induce Proliferation of Peritoneal Macrophages

by Anne-Kathrin Knuth, Arnaud Huard, Zumer Naeem, Peter Rappl, Rebekka Bauer, Ana Carolina Mota, Tobias Schmid, Ingrid Fleming, Bernhard Brüne, Simone Fulda and Andreas Weigert

Int. J. Mol. Sci. 2021, 22(5), 2230; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052230 - 24 Feb 2021

Cited by 2 | Viewed by 2811

Abstract

The interaction of macrophages with apoptotic cells is required for efficient resolution of inflammation. While apoptotic cell removal prevents inflammation due to secondary necrosis, it also alters the macrophage phenotype to hinder further inflammatory reactions. The interaction between apoptotic cells and macrophages is often studied by chemical or biological induction of apoptosis, which may introduce artifacts by affecting the macrophages as well and/or triggering unrelated signaling pathways. Here, we set up a pure cell death system in which NIH 3T3 cells expressing dimerizable Caspase-8 were co-cultured with peritoneal macrophages in a transwell system. Phenotype changes in macrophages induced by apoptotic cells were evaluated by RNA sequencing, which revealed an unexpectedly dominant impact on macrophage proliferation. This was confirmed in functional assays with primary peritoneal macrophages and IC-21 macrophages. Moreover, inhibition of apoptosis during Zymosan-induced peritonitis in mice decreased mRNA levels of cell cycle mediators in peritoneal macrophages. Proliferation of macrophages in response to apoptotic cells may be important to increase macrophage numbers in order to allow efficient clearance and resolution of inflammation. Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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Review

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12 pages, 402 KiB

Open AccessReview

Cell Death by Entosis: Triggers, Molecular Mechanisms and Clinical Significance

by Mostafa Kianfar, Anna Balcerak, Mateusz Chmielarczyk, Leszek Tarnowski and Ewa A. Grzybowska

Int. J. Mol. Sci. 2022, 23(9), 4985; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094985 - 30 Apr 2022

Cited by 15 | Viewed by 2728

Abstract

Entosis—a homotypic insertion of one cell into another, resulting in a death of the invading cell—has been described in many reports, but crucial aspects of its molecular mechanisms and clinical significance still remain controversial. While actomyosin contractility of the invading cell is very well established as a driving force in the initial phase, and autophagy induced in the outer cell is determined as the main mechanism of degradation of the inner cell, many details remain unresolved. The multitude of triggering factors and crisscrossing molecular pathways described in entosis regulation make interpretations difficult. The question of the physiological role of entosis also remains unanswered. In this review, we summarize the knowledge of molecular mechanisms and clinical data concerning entosis accumulated so far, highlighting both coherent explanations and controversies. Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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17 pages, 3713 KiB

Open AccessReview

Context-Dependent Roles of RNA Modifications in Stress Responses and Diseases

by Emma Wilkinson, Yan-Hong Cui and Yu-Ying He

Int. J. Mol. Sci. 2021, 22(4), 1949; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041949 - 16 Feb 2021

Cited by 35 | Viewed by 3380

Abstract

RNA modifications are diverse post-transcriptional modifications that regulate RNA metabolism and gene expression. RNA modifications, and the writers, erasers, and readers that catalyze these modifications, serve as important signaling machineries in cellular stress responses and disease pathogenesis. In response to stress, RNA modifications are mobilized to activate or inhibit the signaling pathways that combat stresses, including oxidative stress, hypoxia, therapeutic stress, metabolic stress, heat shock, DNA damage, and ER stress. The role of RNA modifications in response to these cellular stressors is context- and cell-type-dependent. Due to their pervasive roles in cell biology, RNA modifications have been implicated in the pathogenesis of different diseases, including cancer, neurologic and developmental disorders and diseases, and metabolic diseases. In this review, we aim to summarize the roles of RNA modifications in molecular and cellular stress responses and diseases. Full article

(This article belongs to the Special Issue Cell Death in Biology and Diseases 2.0)

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