When cell death goes wrong:inflammatory outcomes of failed apoptosis and mitotic cell death

Apoptosis is a regulated cellular pathway that ensures that a cell dies in a structured fashion to prevent negative consequences for the tissue or the organism. Dysfunctional apoptosis is a hallmark of numerous pathologies, and treatments for various diseases are successful based on the induction of apoptosis. Under homeostatic conditions, apoptosis is a non-inflammatory event, as the activation of caspases ensures that inflammatory pathways are disabled. However, there is an increasing understanding that under specific conditions, such as caspase inhibition, apoptosis and the apoptotic machinery can be re-wired into a process which is inflammatory. In this review we discuss how the death receptor and mitochondrial pathways of apoptosis can activate inflammation. Furthermore, we will highlight how cell death due to mitotic stress might be a special case when it comes to cell death and the induction of inflammation

Mitochondrial DNA in inflammation and immunity

Mitochondria are cellular organelles that orchestrate a vast range of biological processes, from energy production and metabolism to cell death and inflammation. Despite this seemingly symbiotic relationship, mitochondria harbour within them a potent agonist of innate immunity: their own genome. Release of mitochondrial DNA into the cytoplasm and out into the extracellular milieu activates a plethora of different pattern recognition receptors and innate immune responses, including cGAS‐STING, TLR9 and inflammasome formation leading to, among others, robust type I interferon responses. In this Review, we discuss how mtDNA can be released from the mitochondria, the various inflammatory pathways triggered by mtDNA release and its myriad biological consequences for health and disease

Evaluating Nanoshells and a Potent Biladiene Photosensitizer for Dual Photothermal and Photodynamic Therapy of Triple Negative Breast Cancer Cells.

Light-activated therapies are ideal for treating cancer because they are non-invasive and highly specific to the area of light application. Photothermal therapy (PTT) and photodynamic therapy (PDT) are two types of light-activated therapies that show great promise for treating solid tumors. In PTT, nanoparticles embedded within tumors emit heat in response to laser light that induces cancer cell death. In PDT, photosensitizers introduced to the diseased tissue transfer the absorbed light energy to nearby ground state molecular oxygen to produce singlet oxygen, which is a potent reactive oxygen species (ROS) that is toxic to cancer cells. Although PTT and PDT have been extensively evaluated as independent therapeutic strategies, they each face limitations that hinder their overall success. To overcome these limitations, we evaluated a dual PTT/PDT strategy for treatment of triple negative breast cancer (TNBC) cells mediated by a powerful combination of silica core/gold shell nanoshells (NSs) and palladium 10,10-dimethyl-5,15-bis(pentafluorophenyl)biladiene-based (Pd[DMBil1]-PE

Parkin-independent mitophagy controls chemotherapeutic response in cancer cells

Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance

Comparing bladder neck contracture rate between robotic intracorporeal and extracorporeal neobladder construction

Robot-assisted radical cystectomy (RARC) has become more accessible to surgeons worldwide, and descriptions of intracorporeal urinary diversion techniques, such as orthotopic neobladder construction, have increased. In this study, we aim to compare the rate of bladder neck contracture (BNC) formation between RARC and two different urinary diversion techniques. We retrospectively reviewed our institutional database for patients with bladder cancer who underwent RARC with intracorporeal neobladder (ICNB) construction (n = 11) or extracorporeal neobladder (ECNB) construction (n = 11) between 2012 and 2020. BNC was defined by the need for an additional surgical procedure (e.g., dilatation, urethrotomy). Patients who underwent RARC with ICNB (n = 11) were compared to patients who underwent RARC with ECNB (n = 11) across patient characteristics and postoperative BNC formation rates. Kaplan-Meier curves were generated for freedom from BNC based on the neobladder approach and compared with the log-rank test. For patients who received an ECNB, 73% (8/11) developed a BNC; in comparison, none of the patients in the ICNB group experienced a BNC. Kaplan-Meier survival analysis demonstrates the ECNB group\u27s median probability of freedom from BNC as 1.3 years, while the ICNB group was free of BNC over the study period (p \u3c 0.001). RARC with ICNB creation demonstrated a significantly reduced BNC rate in contrast to RARC with ECNB construction. Longer-term follow-up is needed to assess the durability of this difference in BNC rates

Limited mitochondrial permeabilisation causes DNA-damage and genomic instability in the absence of cell death

During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event. Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term "minority MOMP." Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death. Instead, this caspase activity leads to DNA damage that, in turn, promotes genomic instability, cellular transformation, and tumorigenesis. Our data demonstrate that, in contrast to its well-established tumor suppressor function, apoptosis also has oncogenic potential that is regulated by the extent of MOMP. These findings have important implications for oncogenesis following either physiological or therapeutic engagement of apoptosis

<i>Pseudomonas aeruginosa</i> AlgF is a protein-protein interaction mediator required for acetylation of the alginate exopolysaccharide

Enzymatic modifications of bacterial exopolysaccharides enhance immune evasion and persistence during infection. In the Gram-negative opportunistic pathogen Pseudomonas aeruginosa, acetylation of alginate reduces opsonic killing by phagocytes and improves reactive oxygen species scavenging. Although it is well-known that alginate acetylation in P. aeruginosa requires AlgI, AlgJ, AlgF, and AlgX, how these proteins coordinate polymer modification at a molecular level remains unclear. Here, we describe the structural characterization of AlgF and its protein interaction network. We characterize direct interactions between AlgF and both AlgJ and AlgX in vitro, and demonstrate an association between AlgF and AlgX, as well as AlgJ and AlgI, in P. aeruginosa. We determine that AlgF does not exhibit acetylesterase activity and is unable to bind to polymannuronate in vitro. Therefore, we propose that AlgF functions to mediate protein-protein interactions between alginate acetylation enzymes, forming the periplasmic AlgJFXK (AlgJ-AlgF-AlgX-AlgK) acetylation and export complex required for robust biofilm formation.</p

Altered language network activity in young people at familial high-risk for schizophrenia

Background—Abnormalities in language and language neural circuitry are observed in schizophrenia (SZ). Similar, but less pronounced language deficits are also seen in young first degree relatives of people with SZ, who are at higher familial risk (FHR) for the disorder than the general population. The neural underpinnings of these deficits in people with FHR are unclear. Methods—Participants were 43 people with FHR and 32 comparable controls. fMRI scans were collected while participants viewed associated and unrelated word pairs, and performed a lexical decision task. fMRI analyses conducted in SPM8 examined group differences in the modulation of hemodynamic activity by semantic association. Results—There were no group differences in demographics, IQ or behavioral semantic priming, but FHR participants had more schizotypal traits than controls. Controls exhibited the expected suppression of hemodynamic activity to associated versus unrelated word pairs. Compared to controls, FHR participants showed an opposite pattern of hemodynamic modulation to associated versus unrelated word pairs, in the left inferior frontal gyrus (IFG), right superior and middle temporal gyrus (STG) and the left cerebellum. Group differences in activation were significant, FWE-corrected for multiple comparisons (p<0.05). Activity within the IFG during the unrelated condition predicted schizotypal symptoms in FHR participants. Conclusions—FHR for SZ is associated with abnormally increased neural activity to semantic associates within an inferior frontal/temporal network. This might increase the risk of developing unusual ideas, perceptions and disorganized language that characterize schizotypal traits, potentially predicting which individuals are at greater risk to develop a psychotic disorder

Text-mining of PubMed abstracts by natural language processing to create a public knowledge base on molecular mechanisms of bacterial enteropathogens

<p>Abstract</p> <p>Background</p> <p>The Enteropathogen Resource Integration Center (ERIC; <url>http://www.ericbrc.org</url>) has a goal of providing bioinformatics support for the scientific community researching enteropathogenic bacteria such as <it>Escherichia coli </it>and <it>Salmonella </it>spp. Rapid and accurate identification of experimental conclusions from the scientific literature is critical to support research in this field. Natural Language Processing (NLP), and in particular Information Extraction (IE) technology, can be a significant aid to this process.</p> <p>Description</p> <p>We have trained a powerful, state-of-the-art IE technology on a corpus of abstracts from the microbial literature in PubMed to automatically identify and categorize biologically relevant entities and predicative relations. These relations include: Genes/Gene Products and their Roles; Gene Mutations and the resulting Phenotypes; and Organisms and their associated Pathogenicity. Evaluations on blind datasets show an F-measure average of greater than 90% for entities (genes, operons, etc.) and over 70% for relations (gene/gene product to role, etc). This IE capability, combined with text indexing and relational database technologies, constitute the core of our recently deployed text mining application.</p> <p>Conclusion</p> <p>Our Text Mining application is available online on the ERIC website <url>http://www.ericbrc.org/portal/eric/articles</url>. The information retrieval interface displays a list of recently published enteropathogen literature abstracts, and also provides a search interface to execute custom queries by keyword, date range, etc. Upon selection, processed abstracts and the entities and relations extracted from them are retrieved from a relational database and marked up to highlight the entities and relations. The abstract also provides links from extracted genes and gene products to the ERIC Annotations database, thus providing access to comprehensive genomic annotations and adding value to both the text-mining and annotations systems.</p

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD