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Chembiochem : a European Journal of... Oct 2023During translation, messenger RNAs (mRNAs) are decoded by ribosomes which can stall for various reasons. These include chemical damage, codon composition, starvation, or... (Review)
Review
During translation, messenger RNAs (mRNAs) are decoded by ribosomes which can stall for various reasons. These include chemical damage, codon composition, starvation, or translation inhibition. Trailing ribosomes can collide with stalled ribosomes, potentially leading to dysfunctional or toxic proteins. Such aberrant proteins can form aggregates and favor diseases, especially neurodegeneration. To prevent this, both eukaryotes and bacteria have evolved different pathways to remove faulty nascent peptides, mRNAs and defective ribosomes from the collided complex. In eukaryotes, ubiquitin ligases play central roles in triggering downstream responses and several complexes have been characterized that split affected ribosomes and facilitate degradation of the various components. As collided ribosomes signal translation stress to affected cells, in eukaryotes additional stress response pathways are triggered when collisions are sensed. These pathways inhibit translation and modulate cell survival and immune responses. Here, we summarize the current state of knowledge about rescue and stress response pathways triggered by ribosome collisions.
Topics: Protein Biosynthesis; Ubiquitination; Ribosomes; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 37382189
DOI: 10.1002/cbic.202300264 -
Hypertension (Dallas, Tex. : 1979) Mar 2024Salt sensitivity concerns blood pressure alterations after a change in salt intake (sodium chloride). The heart is a pump, and vessels are tubes; sodium can affect both.... (Review)
Review
Salt sensitivity concerns blood pressure alterations after a change in salt intake (sodium chloride). The heart is a pump, and vessels are tubes; sodium can affect both. A high salt intake increases cardiac output, promotes vascular dysfunction and capillary rarefaction, and chronically leads to increased systemic vascular resistance. More recent findings suggest that sodium also acts as an important second messenger regulating energy metabolism and cellular functions. Besides endothelial cells and fibroblasts, sodium also affects innate and adaptive immunometabolism, immune cell function, and influences certain microbes and microbiota-derived metabolites. We propose the idea that the definition of salt sensitivity should be expanded beyond high blood pressure to cellular and molecular salt sensitivity.
Topics: Humans; Sodium; Sodium Chloride, Dietary; Endothelial Cells; Hypertension; Sodium Chloride; Blood Pressure
PubMed: 37675565
DOI: 10.1161/HYPERTENSIONAHA.123.19489 -
Investigative Ophthalmology & Visual... Feb 2024Müller glia, the main glial cell of the retina, are critical for neuronal and vascular homeostasis in the retina. During age-related macular degeneration (AMD)... (Review)
Review
Müller glia, the main glial cell of the retina, are critical for neuronal and vascular homeostasis in the retina. During age-related macular degeneration (AMD) pathogenesis, Müller glial activation, remodeling, and migrations are reported in the areas of retinal pigment epithelial (RPE) degeneration, photoreceptor loss, and choroidal neovascularization (CNV) lesions. Despite this evidence indicating glial activation localized to the regions of AMD pathogenesis, it is unclear whether these glial responses contribute to AMD pathology or occur merely as a bystander effect. In this review, we summarize how Müller glia are affected in AMD retinas and share a prospect on how Müller glial stress might directly contribute to the pathogenesis of AMD. The goal of this review is to highlight the need for future studies investigating the Müller cell's role in AMD. This may lead to a better understanding of AMD pathology, including the conversion from dry to wet AMD, which has no effective therapy currently and may shed light on drug intolerance and resistance to current treatments.
Topics: Humans; Ependymoglial Cells; Macula Lutea; Retina; Cell Communication; Wet Macular Degeneration; Geographic Atrophy
PubMed: 38416457
DOI: 10.1167/iovs.65.2.42 -
Cellular and Molecular Life Sciences :... Jan 2024Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if... (Review)
Review
Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration.
Topics: Animals; Humans; Diabetes Mellitus, Type 2; Neuroinflammatory Diseases; Neuroglia; Diabetic Retinopathy; Inflammation; Peripheral Nervous System Diseases
PubMed: 38236305
DOI: 10.1007/s00018-023-05024-y -
Nature Communications Jul 2023The accumulation of atypical, cytotoxic 1-deoxysphingolipids (1-dSLs) has been linked to retinal diseases such as diabetic retinopathy and Macular Telangiectasia Type 2....
The accumulation of atypical, cytotoxic 1-deoxysphingolipids (1-dSLs) has been linked to retinal diseases such as diabetic retinopathy and Macular Telangiectasia Type 2. However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remain poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define biological pathways that modulate 1-dSL toxicity in human retinal organoids. Our results demonstrate that 1-dSLs differentially activate signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Müller glia. Using a combination of pharmacologic activators and inhibitors, we show that sustained PERK signaling through the integrated stress response (ISR) and deficiencies in signaling through the protective ATF6 arm of the UPR are implicated in 1-dSL-induced photoreceptor toxicity. Further, we demonstrate that pharmacologic activation of ATF6 mitigates 1-dSL toxicity without impacting PERK/ISR signaling. Collectively, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different arms of the UPR.
Topics: Humans; Diabetic Retinopathy; Sphingolipids; Retinal Telangiectasis; Unfolded Protein Response
PubMed: 37433773
DOI: 10.1038/s41467-023-39775-w -
Molecular and Cellular Endocrinology Oct 2023Reactive gliosis of Müller cells plays an important role in the pathogenesis of diabetic retinopathy (DR). Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R)...
Reactive gliosis of Müller cells plays an important role in the pathogenesis of diabetic retinopathy (DR). Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been shown to improve DR by inhibiting reactive gliosis. However, the mechanism of inhibition has yet to be elucidated. This study investigated the effects of liraglutide on Müller glia reactivity in the early stages of DR and the underlying mechanisms. Proteomics combined with bioinformatics analysis, HE staining, and immunofluorescence staining revealed ganglion cell loss, reactive gliosis of Müller cells, and extracellular matrix (ECM) imbalance in rats with early stages of DR. High glucose (HG) exposure up-regulated GFAP and TNF-α expression and down-regulated ITGB1 expression and FN1 content in extracellular fluid in rMC1 cells, thereby promoting reactive gliosis. GLP-1R knockdown and HG+DAPT inhibition experiments show that liraglutide balances ECM levels by inhibiting activation of the Notch1/Hes1 pathway and ameliorates high-glucose-induced Müller glia reactivity. Thus, the study provides new targets and ideas for improvement of DR in early stages.
Topics: Rats; Animals; Liraglutide; Ependymoglial Cells; Gliosis; Diabetic Retinopathy; Inflammation; Extracellular Matrix; Glucose; Glucagon-Like Peptide-1 Receptor
PubMed: 37442365
DOI: 10.1016/j.mce.2023.112013 -
International Journal of Molecular... Aug 2023Inflammation and fibrosis are key features of proliferative vitreoretinal disorders. We aimed to define the macrophage phenotype and investigate the role of...
Inflammation and fibrosis are key features of proliferative vitreoretinal disorders. We aimed to define the macrophage phenotype and investigate the role of macrophage-myofibroblast transition (MMT) in the contribution to myofibroblast populations present in epiretinal membranes. Vitreous samples from proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR) and nondiabetic control patients, epiretinal fibrovascular membranes from PDR patients and fibrocellular membranes from PVR patients, human retinal Müller glial cells and human retinal microvascular endothelial cells (HRMECs) were studied by ELISA, immunohistochemistry and flow cytometry analysis. Myofibroblasts expressing α-SMA, fibroblast activation protein-α (FAP-α) and fibroblast-specific protein-1 (FSP-1) were present in all membranes. The majority of CD68 monocytes/macrophages co-expressed the M2 macrophage marker CD206. In epiretinal membranes, cells undergoing MMT were identified by co-expression of the macrophage marker CD68 and myofibroblast markers α-SMA and FSP-1. Further analysis revealed that CD206 M2 macrophages co-expressed α-SMA, FSP-1, FAP-α and ß-catenin. Soluble (s) CD206 and sFAP-α levels were significantly higher in vitreous samples from PDR and PVR patients than in nondiabetic control patients. The proinflammatory cytokine TNF-α and the hypoxia mimetic agent cobalt chloride induced upregulation of sFAP-α in culture media of Müller cells but not of HRMECs. The NF-ĸß inhibitor BAY11-7085 significantly attenuated TNF-α-induced upregulation of sFAP-α in Müller cells. Our findings suggest that the process of MMT might contribute to myofibroblast formation in epiretinal membranes, and this transition involved macrophages with a predominant M2 phenotype. In addition, sFAP-α as a vitreous biomarker may be derived from M2 macrophages transitioned to myofibroblasts and from Müller cells.
Topics: Humans; Endothelial Cells; Myofibroblasts; Epiretinal Membrane; Tumor Necrosis Factor-alpha; Eye Diseases; Diabetic Retinopathy; Vitreoretinopathy, Proliferative
PubMed: 37686317
DOI: 10.3390/ijms241713510 -
Disease Models & Mechanisms Sep 2023Diabetic retinopathy (DR) is characterised by dysfunction of the retinal neurovascular unit, leading to visual impairment and blindness. Müller cells are key components...
Diabetic retinopathy (DR) is characterised by dysfunction of the retinal neurovascular unit, leading to visual impairment and blindness. Müller cells are key components of the retinal neurovascular unit and diabetes has a detrimental impact on these glial cells, triggering progressive neurovascular pathology of DR. Amongst many factors expressed by Müller cells, interleukin-33 (IL-33) has an established immunomodulatory role, and we investigated the role of endogenous IL-33 in DR. The expression of IL-33 in Müller cells increased during diabetes. Wild-type and Il33-/- mice developed equivalent levels of hyperglycaemia and weight loss following streptozotocin-induced diabetes. Electroretinogram a- and b-wave amplitudes, neuroretina thickness, and the numbers of cone photoreceptors and ganglion cells were significantly reduced in Il33-/- diabetic mice compared with those in wild-type counterparts. The Il33-/- diabetic retina also exhibited microglial activation, sustained gliosis, and upregulation of pro-inflammatory cytokines and neurotrophins. Primary Müller cells from Il33-/- mice expressed significantly lower levels of neurotransmitter-related genes (Glul and Slc1a3) and neurotrophin genes (Cntf, Lif, Igf1 and Ngf) under high-glucose conditions. Our results suggest that deletion of IL-33 promotes inflammation and neurodegeneration in DR, and that this cytokine is critical for regulation of glutamate metabolism, neurotransmitter recycling and neurotrophin secretion by Müller cells.
Topics: Animals; Mice; Cytokines; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Ependymoglial Cells; Inflammation; Interleukin-33; Retina
PubMed: 37671525
DOI: 10.1242/dmm.050174 -
ELife Oct 2023Mononuclear cells are involved in the pathogenesis of retinal diseases, including age-related macular degeneration (AMD). Here, we examined the mechanisms that underlie...
Mononuclear cells are involved in the pathogenesis of retinal diseases, including age-related macular degeneration (AMD). Here, we examined the mechanisms that underlie macrophage-driven retinal cell death. Monocytes were extracted from patients with AMD and differentiated into macrophages (hMdɸs), which were characterized based on proteomics, gene expression, and ex vivo and in vivo properties. Using bioinformatics, we identified the signaling pathway involved in macrophage-driven retinal cell death, and we assessed the therapeutic potential of targeting this pathway. We found that M2a hMdɸs were associated with retinal cell death in retinal explants and following adoptive transfer in a photic injury model. Moreover, M2a hMdɸs express several CCRI (C-C chemokine receptor type 1) ligands. Importantly, CCR1 was upregulated in Müller cells in models of retinal injury and aging, and CCR1 expression was correlated with retinal damage. Lastly, inhibiting CCR1 reduced photic-induced retinal damage, photoreceptor cell apoptosis, and retinal inflammation. These data suggest that hMdɸs, CCR1, and Müller cells work together to drive retinal and macular degeneration, suggesting that CCR1 may serve as a target for treating these sight-threatening conditions.
Topics: Humans; Animals; Retinal Degeneration; Ependymoglial Cells; Photoreceptor Cells; Retina; Macular Degeneration; Cell Death; Disease Models, Animal; Receptors, CCR1
PubMed: 37903056
DOI: 10.7554/eLife.81208