Necroptosis: a crucial pathogenic mediator of human disease

Choi, Mary E.; Price, David R.; Ryter, Stefan W.; Choi, Augustine M.K.

doi:10.1172/jci.insight.128834

Cited by 319 publications

(301 citation statements)

References 137 publications

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“…Different types of cell death are seen in uterine and placental tissue during healthy and pathological pregnancy (51-54). To extend our observations on the effect of DHT and INS on ferroptosis and mitochondrial impairment, we analyzed the expression of necroptosis ( Mlkl, Ripk1 , and Ripk3 ), anti-apoptosis ( Bcl2 and Bcl-xl ) and pro-apoptosis ( Bax, Bak, Casp3 , and cleaved caspase-3) mRNAs and proteins (6, 8, 10) in the gravid uterus and placenta. As shown in Figure 6A , DHT+INS-exposure significantly decreased uterine Ripk1 mRNA expression, while uterine Mlkl and Ripk3 mRNAs were increased by DHT and/or INS exposure when compared to control pregnant rats ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Ferroptosis is a recently described, iron-dependent form of regulated necrosis induced by oxidative stress, and it is distinct from other established forms of cell death such as apoptosis and necroptosis due to its unique morphological and biochemical features (6, 7). Growing evidence indicates that excessive or impaired ferroptosis plays a causative role in a variety of pathological conditions and diseases (8-11). It appears that the outcome of ferroptosis is programmed cell death, but which specific physiological processes or pathological conditions and disorders lead to ferroptosis activation remain poorly explored.…”

Section: Introductionmentioning

confidence: 99%

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Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

Zhang

Jia

et al. 2020

Preprint

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Ferroptosis, a form of regulated necrotic cell death, plays roles in diverse physiological processes and diseases. Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance (HAIR) and an increased risk of miscarriage and placental dysfunction during pregnancy. However, whether maternal HAIR alters mechanisms leading to ferroptosis in the gravid uterus and placenta remains unknown. Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces HAIR and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., region-dependent Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction. In contrast, in placentas co-exposed to DHT and INS we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA (a mitochondria-encoded iron-export factor). Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

Zhang

Jia

et al. 2020

Preprint

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“…Degradation of RIPK1 induces oligomerization and phosphorylation of RIPK3, which in turn phosphorylate, and MLKL . Activated MLKL undergoes oligomerization and translocation to nuclear and plasma membranes where it forms pores, which can induce necroptosis . Crystal‐induced loss of the MOMP also leads to cyclophilin D (CYPD)‐dependent mitochondrial permeability transition‐related regulated necrosis .…”

Section: How Do Crystals Activate Cells From the Inside To Induce Necmentioning

confidence: 99%

A guide to crystal‐related and nano‐ or microparticle‐related tissue responses

et al. 2020

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Crystals and nano‐ and microparticles form inside the human body from intrinsic proteins, minerals, or metabolites or enter the body as particulate matter from occupational and environmental sources. Associated tissue injuries and diseases mostly develop from cellular responses to such crystal deposits and include inflammation, cell necrosis, granuloma formation, tissue fibrosis, and stone‐related obstruction of excretory organs. But how do crystals and nano‐ and microparticles trigger these biological processes? Which pathomechanisms are identical across different particle types, sizes, and shapes? In addition, which mechanisms are specific to the atomic or molecular structure of crystals or to specific sizes or shapes? Do specific cellular or molecular mechanisms qualify as target for therapeutic interventions? Here, we provide a guide to approach this diverse and multidisciplinary research domain. We give an overview about the clinical spectrum of crystallopathies, about shared and specific pathomechanisms as a conceptual overview before digging deeper into the specialty field of interest.

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“…[43] KEGG: Necroptosis Necroptosis is implicated in pulmonary diseases and sepsis-associated organ injury. [53,54] KEGG: NOD-like receptor signalling pathway Activation of Toll-like and NOD-like receptor signalling protects mice from polymicrobial sepsisassociated lethality.…”

Section: D) Correlations Between Absolute Changes In Mean Gene Expresmentioning

confidence: 99%

Discovery of pharmaceutically-targetable pathways and prediction of survivorship for pneumonia and sepsis patients from the view point of ensemble gene noise

Guryev

Moshkin

2020

Preprint

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Finding novel biomarkers for human pathologies and predicting clinical outcomes for patients is rather challenging. This stems from the heterogenous response of individuals to disease which is also reflected in the inter-individual variability of gene expression responses. This in turn obscures differential gene expression analysis (DGE). In the midst of the COVID-19 pandemic, we wondered whether an alternative to DGE approaches could be applied to dissect the molecular nature of a host-response to infection exemplified here by an analysis of H1N1 influenza, community/hospital acquired pneumonia (CAP) and sepsis. To this end, we turned to the analysis of ensemble gene noise. Ensemble gene noise, as we defined it here, represents a variance within an individual for a collection of genes encoding for either members of known biological pathways or subunits of annotated protein complexes. From the law of total variance, ensemble gene noise depends on the stoichiometry of the ensemble genes' expression and on their average noise (variance). Thus, rather than focusing on specific genes, ensemble gene noise allows for the holistic identification and interpretation of gene expression disbalance on the level of gene networks and systems. Comparing H1N1, CAP and sepsis patients we spotted common disturbances in a number of pathways/protein complexes relevant to the sepsis pathology which lead to an increase in the ensemble gene noise. Among others, these include mitochondrial respiratory chain complex I and peroxisomes which could be readily targeted for adjuvant treatment by methylene blue and 4-phenylbutyrate respectively. Finally, we showed that ensemble gene noise could be successfully applied for the prediction of clinical outcome, namely mortality, of CAP and sepsis patients. Thus, we conclude that ensemble gene noise represents a promising approach for the investigation of molecular mechanisms of a pathology through a prism of alterations in coherent expression of gene circuits.

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Necroptosis: a crucial pathogenic mediator of human disease

Cited by 319 publications

References 137 publications

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

A guide to crystal‐related and nano‐ or microparticle‐related tissue responses

Discovery of pharmaceutically-targetable pathways and prediction of survivorship for pneumonia and sepsis patients from the view point of ensemble gene noise

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