Long-Term Exposure to Nanosized TiO2 Triggers Stress Responses and Cell Death Pathways in Pulmonary Epithelial Cells

There is little in vitro data available on long-term effects of TiO2 exposure. Such data are important for improving the understanding of underlying mechanisms of adverse health effects of TiO2. Here, we exposed pulmonary epithelial cells to two doses (0.96 and 1.92 µg/cm2) of TiO2 for 13 weeks and effects on cell cycle and cell death mechanisms, i.e., apoptosis and autophagy were determined after 4, 8 and 13 weeks of exposure. Changes in telomere length, cellular protein levels and lipid classes were also analyzed at 13 weeks of exposure. We observed that the TiO2 exposure increased the fraction of cells in G1-phase and reduced the fraction of cells in G2-phase, which was accompanied by an increase in the fraction of late apoptotic/necrotic cells. This corresponded with an induced expression of key apoptotic proteins i.e., BAD and BAX, and an accumulation of several lipid classes involved in cellular stress and apoptosis. These findings were further supported by quantitative proteome profiling data showing an increase in proteins involved in cell stress and genomic maintenance pathways following TiO2 exposure. Altogether, we suggest that cell stress response and cell death pathways may be important molecular events in long-term health effects of TiO2.

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OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

10.1101/2021.12.26.474226 ◽

2021 ◽

Author(s):

Daisuke Oikawa ◽

Min Gi ◽

Hidetaka Kosako ◽

Kouhei Shimizu ◽

Hirotaka Takahashi ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cell Death ◽

Stress Responses ◽

Inflammatory Responses ◽

Reactive Oxygen ◽

Antioxidant Response ◽

Oxygen Species ◽

Ubiquitin Chain ◽

Intrinsically Disordered ◽

Cell Death Pathways

Deubiquitylating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolysing K63-linked ubiquitin chains from NF-κB signalling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. The N-terminal intrinsically disordered region of OTUD1, which contains an EGTE motif, is indispensable for KEAP1-binding and NF-κB suppression. OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1-/--mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.

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Approach to stress endocrine response: somatization in the context of gastroenterological symptoms: a systematic review

African Health Sciences ◽

10.4314/ahs.v19i3.29 ◽

2019 ◽

Vol 19 (3) ◽

pp. 2537-2545

Author(s):

Gülseren Keskin

Keyword(s):

Stress Responses ◽

Stressful Life Events ◽

Physiological Stress ◽

Gastrointestinal Symptoms ◽

Endocrine System ◽

Traumatic Experiences ◽

Long Term Effects ◽

Endocrine Response ◽

Response To Stress

Background: Stress can be defined as an acute threat to the homeostasis of an organism, and in order to manage stress, and maintain stability, the allostatic systems activate an adaptive response. Stress has been shown to have both short - and long-term effects on the function of the gastrointestinal tract, but long-term exposure to stress is more likely to cause endocrine disorders.Objective: The aim of this study was to investigate the endocrine response to stress, and evaluate the relationship between somatization and gastrointestinal symptoms.Methods: A systematic literature search was conducted on several academic databases, which included, Pubmed, EBSCO and Science Direct. The search was performed using the keywords, “endocrine response to stress”, “somatization” and “gastrointestinal symptoms”. Results: The hypothalamic-pituitary-adrenal (HPA) axis is essential in controlling physiological stress responses. Dysfunction is related to several mental disorders, including anxiety and depression, or somatization. Symptoms associated with genetic, or other traumatic experiences of individuals under stress, can lead to a maladaptive response to stress. These stressful life events were found to be associated with digestive system-related chronic diseases. Gastrointestinal disorders significantly affect millions of people worldwide. Conclusion: This study examined how the endocrine system responds to stress, and the effect this has in causing stress-related gastrointestinal distresses. Our findings indicate that stress-related psychological disorders are strongly associated with the severity of gastrointestinal symptoms.Keywords: Stress, endocrine response, somatization, gastrointestinal symptoms.

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Cell Stress Signaling Cascades Regulating Cell Fate

Current Pharmaceutical Design ◽

10.2174/1381612824666180711122753 ◽

2018 ◽

Vol 24 (27) ◽

pp. 3176-3183 ◽

Cited By ~ 2

Author(s):

Rohit Gundamaraju ◽

Ravichandra Vemuri ◽

Wai Chin Chong ◽

Dominic P. Geraghty ◽

Rajaraman Eri

Keyword(s):

Cell Death ◽

Cell Fate ◽

Stress Responses ◽

Cellular Stress ◽

Cell Stress ◽

Signaling Cascades ◽

Stress Signaling ◽

Cell Type ◽

Induce Cell Death ◽

Stressed Cell

Initiating anti-apoptotic signaling or triggering cell death depends to a great extent on the nature or source of cellular stress and cell type. Interplay between each stress response eventually determines the fate of stressed cell. Numerous factors induce cell death by a number of pathways including apoptosis, autophagy and necrosis. Not surprisingly, some of the pathways are interrelated to each other through a mediator that could articulate the entire mechanism. The present review attempts to consolidate all the pathways included in intrinsic cellular stress such as oxidative stress and autophagy, endoplasmic reticular stress (ERS) and mitophagy and apoptosis as fate in cell stress. These stress responses are a hallmark of numerous diseases including neurodegenerative diseases, diabetes and cancer. Understanding the cross-talk between different intrinsic cell stress responses will help to develop new therapeutic targets and hence lead to the development of new therapeutics.

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Prevalence of Concussion in Quidditch

Neurology ◽

10.1212/01.wnl.0000581032.51679.e1 ◽

2019 ◽

Vol 93 (14 Supplement 1) ◽

pp. S21.1-S21

Author(s):

Michael Pepper ◽

Jeff Wayland ◽

Adam Elwood ◽

Spencer Walser ◽

Vi Tran ◽

...

Keyword(s):

Head Injury ◽

Health Effects ◽

Head Injuries ◽

Return To Play ◽

Long Term Effects ◽

Basic Care ◽

Significant Burden ◽

Traditional Sports ◽

Repetitive Injury

ObjectiveThe aim of our study is to assess the rate of concussion occurring while engaging in nontraditional sports such as Quidditch, and the effects that injury during a novelty sport may have on concussion detection when compared to more traditional sports.BackgroundConcussions, once dismissed as nonconsequential, are rapidly attracting notice for acute and long-term health effects. Rates of recovery with repeated trauma is known to decrease with each occurrence. In novelty sports, regulation of concussions and proper return-to-play(RTP) protocol are not routinely enforced, resulting in repetitive injury to the detriment of players.Design/MethodsIRB approval was obtained prior to survey distribution to all players associated with Major League Quidditch (MLQ). Responses were recorded and analyzed.Results157 responses were received. 63% were male and 37% female with mean age 22.9. 146 (93%) respondents confirmed or denied quidditch-related head injury. 22 (15%) denied head injury and 124 (85%) indicated hitting their heads while participating in the sport. 19% of respondents indicated >10 head injuries. 67 (54%) reported suspected concussion with an additional 41 (33%) reporting formal diagnosis with at least one concussion. EMS reported 18 injuries at MLQ matches. 5 (27.8%) were preliminarily diagnosed with concussion. 3 had no further treatment, 1 RTP and 1 received basic care. 0 recieved formal neurologic evaluation. Players were also asked about head injuries sustained in non-quidditch activities for comparison. 43 (27%) reported having medically diagnosed concussions outside of quidditch. 53 (34%) reported at least one suspected concussion without formal diagnosis. 24 (15%) answered maybe.ConclusionsOur data supports that concussion is a significant burden in novelty sports such as quidditch. It is vital to recognize that with the rise of nontraditional sports, the prevalence of concussions in younger nontraditional athletes may be underreported and that concussion specialists must be cognizant of both traditional and novelty sports when evaluating long term effects of head trauma.

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Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells

Journal of Virology ◽

10.1128/jvi.01718-17 ◽

2017 ◽

Vol 92 (2) ◽

Cited By ~ 3

Author(s):

Emily H. Payne ◽

Dhivya Ramalingam ◽

Donald T. Fox ◽

Mary E. Klotman

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Epithelial Cells ◽

Cell Survival ◽

Renal Cell ◽

Cell Biology ◽

Renal Tubule ◽

Mitotic Cell ◽

Hiv Positive

ABSTRACTPrior studies have found that HIV, through the Vpr protein, promotes genome reduplication (polyploidy) in infection-surviving epithelial cells within renal tissue. However, the temporal progression and molecular regulation through which Vpr promotes polyploidy have remained unclear. Here we define a sequential progression to Vpr-mediated polyploidy in human renal tubule epithelial cells (RTECs). We found that as in many cell types, Vpr first initiates G2cell cycle arrest in RTECs. We then identified a previously unreported cascade of Vpr-dependent events that lead to renal cell survival and polyploidy. Specifically, we found that a fraction of G2-arrested RTECs reenter the cell cycle. Following this cell cycle reentry, two distinct outcomes occur. Cells that enter complete mitosis undergo mitotic cell death due to extra centrosomes and aberrant division. Conversely, cells that abort mitosis undergo endoreplication to become polyploid. We further show that multiple small-molecule inhibitors of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, including those that target ATR, ATM, and mTOR, indirectly prevent Vpr-mediated polyploidy by preventing G2arrest. In contrast, an inhibitor that targets DNA-dependent protein kinase (DNA-PK) specifically blocks the Vpr-mediated transition from G2arrest to polyploidy. These findings outline a temporal, molecularly regulated path to polyploidy in HIV-positive renal cells.IMPORTANCECurrent cure-focused efforts in HIV research aim to elucidate the mechanisms of long-term persistence of HIV in compartments. The kidney is recognized as one such compartment, since viral DNA and mRNA persist in the renal tissues of HIV-positive patients. Further, renal disease is a long-term comorbidity in the setting of HIV. Thus, understanding the regulation and impact of HIV infection on renal cell biology will provide important insights into this unique HIV compartment. Our work identifies mechanisms that distinguish between HIV-positive cell survival and death in a known HIV compartment, as well as pharmacological agents that alter these outcomes.

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Hydrogen Peroxide Is Crucial for NLRP3 Inflammasome-Mediated IL-1β Production and Cell Death in Pneumococcal Infections of Bronchial Epithelial Cells

Journal of Innate Immunity ◽

10.1159/000517855 ◽

2021 ◽

pp. 1-15

Author(s):

Surabhi Surabhi ◽

Lana H. Jachmann ◽

Patience Shumba ◽

Gerhard Burchhardt ◽

Sven Hammerschmidt ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Cell Death ◽

Epithelial Cells ◽

Respiratory Tract ◽

Nlrp3 Inflammasome ◽

Lower Respiratory Tract ◽

Pneumococcal Infections ◽

Cell Death Pathways ◽

Epithelial Cell Death

Epithelial cells play a crucial role in detection of the pathogens as well as in initiation of the host immune response. Streptococcus pneumoniae (pneumococcus) is a typical colonizer of the human nasopharynx, which can disseminate to the lower respiratory tract and subsequently cause severe invasive diseases such as pneumonia, sepsis, and meningitis. Hydrogen peroxide (H2O2) is produced by pneumococci as a product of the pyruvate oxidase SpxB. However, its role as a virulence determinant in pneumococcal infections of the lower respiratory tract is not well understood. In this study, we investigated the role of pneumococcal-derived H2O2 in initiating epithelial cell death by analyzing the interplay between 2 key cell death pathways, namely, apoptosis and pyroptosis. We demonstrate that H2O2 primes as well as activates the NLRP3 inflammasome and thereby mediates IL-1β production and release. Furthermore, we show that pneumococcal H2O2 causes cell death via the activation of both apoptotic as well as pyroptotic pathways which are mediated by the activation of caspase-3/7 and caspase-1, respectively. However, H2O2-mediated IL-1β release itself occurs mainly via apoptosis.

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Stress-Responses of Performance and Microbial Community in Anaerobic Digestion System Under Long-Term Enrichment of Phenanthrene

10.3233/atde210322 ◽

2021 ◽

Author(s):

Yongsen Shi ◽

Chunli Xu ◽

Jingyi Li ◽

Yilin Yao ◽

Qigui Niu

Keyword(s):

Microbial Community ◽

Stress Responses ◽

System Performance ◽

Oxygen Demand ◽

Granular Sludge ◽

Long Term Effects ◽

Term Enrichment ◽

Fermentative Bacteria ◽

Soluble Chemical Oxygen Demand

The expanded granular sludge blanket reactor (EGSB) was operated for 198 days to study the long-term effects of phenanthrene (PHE) enrichment on system performance and microbial community. The results showed that the PHE was significantly enriched in the reactor. The final PHE concentration in effluent and sludge reached to 1.764±0.05 mg/L and 12.52±0.42 mg/gTS, respectively. While the average daily methane production was decreased by 5.0%-9.8% under long-term PHE exposure. The 3D-EEM of effluent indicated that PHE stimulated the microbial metabolism with the higher intensity of soluble microbial byproduct-like materials (SMP) and proteins. Moreover, the removal efficiency of soluble chemical oxygen demand (SCOD) and NH4+-N gradually diminished with the enrichment of PHE. PHE shaped the microbial community, and the predominant fermentative bacteria (Mesotoga) was severely inhibited. Contrarily, the bacteria (Syntrophorhabdus, Acinetobacter, Desulfovibrio, Desulfomicrobium) involved in PHE-degradation was enriched at end of Phase V. In addition, the relative abundance (RA) of hydrotrophic methanogens (Methanofastidiosum, Methanolinea, Methanobacterium, Methanomassiliicoccus) increased by 0.96-fold with the long-term enrichment of PHE, while the RA of acetoclastic Methanosaeta obviously decreased.

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Partial Prion Cross-Seeding between Fungal and Mammalian Amyloid Signaling Motifs

mBio ◽

10.1128/mbio.02782-20 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Thierry Bardin ◽

Asen Daskalov ◽

Sophie Barrouilhet ◽

Alexandra Granger-Farbos ◽

Bénédicte Salin ◽

...

Keyword(s):

Cell Death ◽

Filamentous Fungi ◽

Sequence Similarity ◽

Podospora Anserina ◽

Content Type ◽

Cell Death Pathways ◽

Prion Propagation ◽

Signaling Modules ◽

Β Sheet

ABSTRACT In filamentous fungi, NLR-based signalosomes activate downstream membrane-targeting cell death-inducing proteins by a mechanism of amyloid templating. In the species Podospora anserina, two such signalosomes, NWD2/HET-S and FNT1/HELLF, have been described. An analogous system involving a distinct amyloid signaling motif, termed PP, was also identified in the genome of the species Chaetomium globosum and studied using heterologous expression in Podospora anserina. The PP motif bears resemblance to the RIP homotypic interaction motif (RHIM) and to RHIM-like motifs controlling necroptosis in mammals and innate immunity in flies. We identify here a third NLR signalosome in Podospora anserina comprising a PP motif and organized as a two-gene cluster encoding an NLR and an HELL domain cell death execution protein termed HELLP. We show that the PP motif region of HELLP forms a prion we term [π] and that [π] prions trigger the cell death-inducing activity of full-length HELLP. We detect no prion cross-seeding between HET-S, HELLF, and HELLP amyloid motifs. In addition, we find that, like PP motifs, RHIMs from human RIP1 and RIP3 kinases are able to form prions in Podospora and that [π] and [Rhim] prions partially cross-seed. Our study shows that Podospora anserina displays three independent cell death-inducing amyloid signalosomes. Based on the described functional similarity between RHIM and PP, it appears likely that these amyloid motifs constitute evolutionarily related cell death signaling modules. IMPORTANCE Amyloids are β-sheet-rich protein polymers that can be pathological or display a variety of biological roles. In filamentous fungi, specific immune receptors activate programmed cell death execution proteins through a process of amyloid templating akin to prion propagation. Among these fungal amyloid signaling sequences, the PP motif stands out because it shows similarity to the RHIM, an amyloid sequence controlling necroptotic cell death in mammals. We characterized an amyloid signaling system comprising a PP motif in the model species Podospora anserina, thus bringing to three the number of independent amyloid signaling cell death pathways described in that species. We then showed that human RHIMs not only propagate as prions in P. anserina but also partially cross-seed with fungal PP prions. These results indicate that, in addition to showing sequence similarity, the PP and RHIM motifs are at least partially functionally related, supporting a model of long-term evolutionary conservation of amyloid signaling mechanisms from fungi to mammals.

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Radiation exposure and health effects of the residents around the former Soviet Union nuclear test site in Kazakhstan -A new perspective: radioactive microparticles

Impact ◽

10.21820/23987073.2020.3.70 ◽

2020 ◽

Vol 2020 (3) ◽

pp. 70-72 ◽

Cited By ~ 1

Author(s):

Masaharu Hoshi

Keyword(s):

Soviet Union ◽

Radiation Exposure ◽

Health Effects ◽

Former Soviet Union ◽

Test Site ◽

Professor Emeritus ◽

Long Term Effects ◽

The World ◽

New Perspective

Harnessing atomic particles and radiation led to powerful and world changing technologies. The field of medical imaging has saved countless lives and continues to push the boundaries of medical interventions and research, which would have been impossible without the first x-ray machines. Unfortunately, not all inventions have been so altruistic. The advent of nuclear weapons showed the world the destructive potential possible via scientific inquiry. While the dangerous effects of radiation exposure were documented from the inception of this technology, catastrophic events like the bombing of Hiroshima and Nagasaki and nuclear disasters at Chernobyl Semipalatinsk or Fukushima provide a real-time glimpse into the long-term effects of exposure. Investigating the causes of this exposure in order to prevent future accidents is essential, but so too is cataloguing the rates and types of exposure among the victims. With this information correlations between exposure and health effects, both short- and long-term can be interrogated. This data is crucial for the understanding of the mechanisms behind radiations effects on living creatures and in assessing risks, safety protocols and treatment. Dr Masaharu Hoshi, Professor Emeritus at the Hiroshima University, has spent most of his career travelling around the world, visiting the sites of nuclear disasters in an effort to fully comprehend the risks. He is now using case studies to investigate the radiation exposure and health effects of the residents of radioactive microparticles.

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