Glioma pathophysiology: insights emerging from proteomics.
Ontology highlight
ABSTRACT:
SUBMITTER: Deighton RF
PROVIDER: S-EPMC8094634 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of brain tumor-related death in children, with median survival of less than one year. Despite decades of clinical trials, there has been no improvement in prognosis since the introduction of radiotherapy over thirty years ago. OBJECTIVE:To review the clinical features and current treatment challenges of DIPG, and discuss emerging insights into the unique genomic and epigenomic mechanisms driving DIPG pathogenesis that present new opportunities for the identification of therapeutic targets. CONCLUSION:In recent years, an increased availability of biopsy and rapid autopsy tissue samples for preclinical investigation has combined with the advent of new genomic and epigenomic profiling tools to yield remarkable advancements in our understanding of DIPG disease mechanisms. As well, a deeper understanding of the developmental context of DIPG is shedding light on therapeutic targets in the microenvironment of the childhood brain.
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Project description:Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, characterized by abdominal pain, bloating, and changes in bowel habits. These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS. Therefore, IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination. Although a great deal of research has been carried out in this area, the pathophysiology of IBS is complex and not completely understood. Multiple factors are thought to contribute to the symptoms in IBS patients; altered gastrointestinal motility, visceral hypersensitivity, and the brain-gut interaction are important classical concepts in IBS pathophysiology. New areas of research in this arena include inflammation, postinfectious low-grade inflammation, genetic and immunologic factors, an altered microbiota, dietary factors, and enteroendocrine cells. These emerging studies have not shown consistent results, provoking controversy in the IBS field. However, certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients, confirming that IBS symptoms cannot be explained by a single etiological mechanism. Therefore, it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.
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Project description:Eukaryotic proteomes are enormously sophisticated through versatile post-translational modifications (PTMs) of proteins. A large variety of code generated via PTMs of proteins by ubiquitin (ubiquitination) and ubiquitin-like proteins (Ubls), such as interferon (IFN)-stimulated gene 15 (ISG15), small ubiquitin-related modifier (SUMO) and neural precursor cell expressed, developmentally downregulated 8 (NEDD8), not only provides distinct signals but also orchestrates a plethora of biological processes, thereby underscoring the necessity for sophisticated and fine-tuned mechanisms of code regulation. Deubiquitinases (DUBs) play a pivotal role in the disassembly of the complex code and removal of the signal. Ubiquitin-specific protease 18 (USP18), originally referred to as UBP43, is a major DUB that reverses the PTM of target proteins by ISG15 (ISGylation). Intriguingly, USP18 is a multifaceted protein that not only removes ISG15 or ubiquitin from conjugated proteins in a deconjugating activity-dependent manner but also acts as a negative modulator of type I IFN signaling, irrespective of its catalytic activity. The function of USP18 has become gradually clear, but not yet been completely addressed. In this review, we summarize recent advances in our understanding of the multifaceted roles of USP18. We also highlight new insights into how USP18 is implicated not only in physiology but also in pathogenesis of various human diseases, involving infectious diseases, neurological disorders, and cancers. Eventually, we integrate a discussion of the potential of therapeutic interventions for targeting USP18 for disease treatment.
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Project description:The kynurenine pathway (KP) is the principal route of L-tryptophan (TRP) catabolism leading to the production of kynurenine (KYN), the neuroprotectants, kynurenic acid (KYNA) and picolinic acid (PIC), the excitotoxin, quinolinic acid (QUIN) and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+)). The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1), indoleamine 2,3-dioxygenase-2 (IDO-2) and tryptophan 2,3-dioxygenase (TDO-2) initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1) cultured human glioma cells and 2) plasma from patients with glioblastoma (GBM). Our data revealed that interferon-gamma (IFN-?) stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU), kynurenine hydroxylase (KMO) and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD) and kynurenine aminotransferase-I (KAT-I) expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP) was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18) compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD(+), which is necessary for energy production and DNA repair.
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Project description:Background:Medication-induced tremor (MIT) is common in clinical practice and there are many medications/drugs that can cause or exacerbate tremors. MIT typically occurs by enhancement of physiological tremor (EPT), but not all drugs cause tremor in this way. In this manuscript, we review how some common examples of MIT have informed us about the pathophysiology of tremor. Methods:We performed a PubMed literature search for published articles dealing with MIT and attempted to identify articles that especially dealt with the medication's mechanism of inducing tremor. Results:There is a paucity of literature that deals with the mechanisms of MIT, with most manuscripts only describing the frequency and clinical settings where MIT is observed. That being said, MIT emanates from multiple mechanisms depending on the drug and it often takes an individualized approach to manage MIT in a given patient. Discussion:MIT has provided some insight into the mechanisms of tremors we see in clinical practice. The exact mechanism of MIT is unknown for most medications that cause tremor, but it is assumed that in most cases physiological tremor is influenced by these medications. Some medications (epinephrine) that cause EPT likely lead to tremor by peripheral mechanisms in the muscle (?-adrenergic agonists), but others may influence the central component (amitriptyline). Other drugs can cause tremor, presumably by blockade of dopamine receptors in the basal ganglia (dopamine-blocking agents), by secondary effects such as causing hyperthyroidism (amiodarone), or by other mechanisms. We will attempt to discuss what is known and unknown about the pathophysiology of the most common MITs.
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Project description:The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by an elevated risk for arterial and venous thrombosis and pregnancy-related morbidity. Since the discovery of the disease in 1980s, numerous studies in cell culture systems, in animal models, and in patient populations have been reported, leading to a deeper understanding of the pathogenesis of APS. These studies have determined that circulating autoantibodies, collectively called antiphospholipid antibodies (aPL), the majority of which recognize cell surface proteins attached to the plasma membrane phospholipids, play a causal role in the development of the disease. The binding of aPL to the cell surface antigens triggers interaction of the complex with transmembrane receptors to initiate intracellular signaling in critical cell types, including platelets, monocytes, endothelial cells, and trophoblasts. Subsequent alteration of various cell functions results in inflammation, thrombus formation, and pregnancy complications. Apolipoprotein E receptor 2 (apoER2), a lipoprotein receptor family member, has been implicated as a mediator for aPL actions in platelets and endothelial cells. Nitric oxide (NO) is a signaling molecule known to exert potent antithrombotic, anti-inflammatory, and anti-atherogenic effects. NO insufficiency and oxidative stress have been linked to APS pathogenesis. This review will focus on the recent findings on how apoER2 and dysregulation of NO production contribute to aPL-mediated pathologies in APS.
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