RAS-p110a signalling in macrophages is required for effective inflammatory response and resolution of inflammation DOI Open Access
Alejandro Rosell,

Agata Krygowska,

Marta Alcón Pérez

et al.

Published: Nov. 14, 2024

Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that RAS-p110α signalling pathway, known its involvement various biological processes and tumorigenesis, regulates two vital aspects of response macrophages: initial monocyte movement later-stage lysosomal function. Disrupting this either a mouse model or through drug intervention, hampers leading to delayed resolution development more severe acute reactions live models. This discovery uncovers previously unknown role p110α isoform regulation within macrophages, offering insight into complex mechanisms governing their function during inflammation. With emerging potential activate using small molecules, targeting pathway could be promising approach treating chronic therapeutic prospect holds significant promise easing disorders improving quality life affected patients.

Language: Английский

Targeting Glucosylceramide Synthase: Innovative Drug Repurposing Strategies for Lysosomal Diseases DOI Open Access

Giorgia Canini,

Elena Mazzinelli, Giuseppina Nocca

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2195 - 2195

Published: Feb. 28, 2025

Sphingolipidoses, a subgroup of lysosomal storage diseases (LSDs), are rare and debilitating disorders caused by defects in sphingolipid metabolism. Despite advancements treatment, therapeutic options remain limited. Miglustat, glucosylceramide synthase EC 2.4.1.80 (GCS) inhibitor, is one the few available pharmacological treatments; however, it associated with significant adverse effects that impact patients’ quality life. Drug repurposing offers promising strategy to identify new agents from approved drugs, expanding treatment for limited alternatives. This study aims potential alternative inhibitors GCS through drug-repurposing approach, using computational experimental methods assess their sphingolipidoses. A library drugs was screened advanced techniques, including molecular docking, dynamics simulations, metadynamics, inhibitors. Promising candidates were selected further vitro validation evaluate inhibitory activity as alternatives Miglustat. Computational screening identified several inhibitors, Dapagliflozin emerging most candidate. Experimental confirmed its efficacy, revealing complementary mechanism action Miglustat while potentially offering more favorable side effect profile. underscores utility methodologies drug diseases. The identification inhibitor provides foundation preclinical clinical evaluation, supporting application

Language: Английский

Citations

1
Endosome positioning coordinates spatially selective GPCR signaling DOI
Blair K. A. Willette, Jinfan Zhang, Jin Zhang

et al.

Nature Chemical Biology, Journal Year: 2023, Volume and Issue: 20(2), P. 151 - 161

Published: July 27, 2023

Language: Английский

Citations

20
Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases DOI Creative Commons
Elisabet Uribe-Carretero, Verónica Rey, José M. Fuentes

et al.

Biology, Journal Year: 2024, Volume and Issue: 13(1), P. 34 - 34

Published: Jan. 7, 2024

Lysosomes are the main organelles responsible for degradation of macromolecules in eukaryotic cells. Beyond their fundamental role degradation, lysosomes involved different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with etiologies known storage disorders (LSDs). These can result from deficiencies primary enzymes, dysfunction enzyme activators, alterations modifiers that impact function, or changes membrane-associated proteins, among other factors. The clinical phenotype observed affected patients hinges on type location accumulating substrate, influenced by genetic mutations residual activity. this context, scientific community is dedicated to exploring potential therapeutic approaches, striving not only extend lifespan but also enhance overall quality life individuals afflicted LSDs. This review provides insights into a molecular perspective, particularly context diseases, highlights recent advancements breakthroughs field.

Language: Английский

Citations

4
Impaired Autophagy in Krabbe Disease: The Role of BCL2 and Beclin-1 Phosphorylation DOI Open Access
Nadia Papini,

Roberta Todisco,

Paola Giussani

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5984 - 5984

Published: March 22, 2023

Autophagic impairment was identified in many lysosomal storage diseases and adult neurodegenerative diseases. It seems that this defect could be directly related to the appearance of a phenotype contribute worsen metabolite accumulation distress. Thus, autophagy is becoming promising target for supportive therapies. Autophagy alterations were recently also Krabbe disease. disease characterized by extensive demyelination dysmyelination it due genetic loss function enzyme galactocerebrosidase (GALC). This leads galactosylceramide, psychosine, secondary substrates such as lactosylceramide. In paper, we induced through starvation examined cellular response occurring fibroblasts isolated from patients. We demonstrated inhibitory AKT-mediated phosphorylation beclin-1 BCL2-beclin-1 complex concur reduce autophagosomes formation starvation. These events not dependent on which previously possible player autophagic believe these data better elucidate capability stimuli disease, order identify molecules able stimulate process.

Language: Английский

Citations

10
RAS-p110α signalling in macrophages is required for effective inflammatory response and resolution of inflammation DOI Open Access
Alejandro Rosell,

Agata Krygowska,

Marta Alcón Pérez

et al.

Published: Feb. 3, 2025

Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that RAS-p110α signalling pathway, known its involvement various biological processes and tumorigenesis, regulates two vital aspects of response macrophages: initial monocyte movement later-stage lysosomal function. Disrupting this either a mouse model or through drug intervention, hampers leading to delayed resolution development more severe acute reactions live models. This discovery uncovers previously unknown role p110α isoform regulation within macrophages, offering insight into complex mechanisms governing their function during inflammation opening new avenues modulating responses.

Language: Английский

Citations

0
Lysosomes’ fallback strategies: more than just survival or death DOI Creative Commons
Quan Wang, Ruolin Wang, Hanqing Hu

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: March 11, 2025

Lysosomes are heterogeneous, acidic organelles whose proper functionality is critically dependent on maintaining the integrity of their membranes and acidity within lumen. When subjected to stress, lysosomal membrane can become permeabilized, posing a significant risk organelle’s survival necessitating prompt repair. Although numerous mechanisms for repair have been identified in recent years, progression lysosome-related diseases more closely linked alternative strategies when fail, particularly contexts aging pathogen infection. This review explores responses damage, including secretion contents interactions with lysosome-associated endolysosomal system. Furthermore, it examines role outside this system, such as endoplasmic reticulum (ER) Golgi apparatus, auxiliary These crucial understanding disease progression. For instance, spread misfolded proteins play key roles neurodegenerative advancement, while escape via lysosomotropic drug expulsion underlie cancer treatment resistance. Reexamining these fallback could provide new perspectives biology contribution

Language: Английский

Citations

0
RAS–p110α signalling in macrophages is required for effective inflammatory response and resolution of inflammation DOI Creative Commons
Alejandro Rosell,

Agata Krygowska,

Marta Alcón Pérez

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: April 24, 2025

Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that RAS–p110α signalling pathway, known its involvement various biological processes and tumourigenesis, regulates two vital aspects of response macrophages: initial monocyte movement later-stage lysosomal function. Disrupting this either a mouse model or through drug intervention, hampers leading to delayed resolution development more severe acute reactions live models. This discovery uncovers previously unknown role p110α isoform regulation within macrophages, offering insight into complex mechanisms governing their function during inflammation opening new avenues modulating responses.

Language: Английский

Citations

0
The Role of Tau in Neuronal Function and Neurodegeneration DOI Creative Commons
Gonzálo Emiliano Aranda-Abreu, Fausto Rojas-Durán, Marı́a Elena Hernández

et al.

Neurology International, Journal Year: 2025, Volume and Issue: 17(5), P. 75 - 75

Published: May 13, 2025

Tau protein plays a pivotal role in maintaining neuronal structure and function through its regulation of microtubule stability polarity. Encoded by the MAPT gene, exists multiple isoforms due to alternative mRNA splicing, with differential expression central peripheral nervous systems. In healthy neurons, tau is selectively localized translated axons, process tightly regulated untranslated regions (UTRs) RNA-binding proteins such as HuD FMRP. Pathologically, undergoes hyperphosphorylation, misfolding, aggregation, which contribute neurodegeneration range disorders collectively known tauopathies. Alzheimer’s disease (AD) most prevalent tauopathy, where abnormal accumulation temporal frontal lobes correlates cognitive decline behavioral symptoms. Other tauopathies, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Frontotemporal Dementia Parkinsonism (FTDP-17), Pick’s disease, are distinguished predominance specific (3R or 4R), cellular distribution, affected brain regions. Notably, astroglial tauopathies highlight pathological glial cells, expanding understanding beyond neurons. Despite advances imaging biomarkers (e.g., Tau-PET) molecular diagnostics, effective disease-modifying therapies for remain elusive. Ongoing research targets immunotherapies, splicing modulators, kinase inhibitors, antisense oligonucleotides, aiming mitigate pathology deleterious effects. Understanding multifaceted roles contexts critical developing future therapeutic strategies against

Language: Английский

Citations

0
Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB DOI Creative Commons
Melania Scarcella, Gianluca Scerra, Mariangela Ciampa

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 108959 - 108959

Published: Jan. 29, 2024

Mucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and defects in MPS I, IIIA IIIB patient fibroblasts. We investigated PI3K/Akt pathway, is crucial importance neuronal function survival, demonstrate PI3K inhibition abolishes therapeutic effects. identified autophagy inhibition, by Beclin1 silencing, reduces phenotype downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution autophagosome biogenesis MPS. Indeed, metabolomic analyses revealed mitochondrial activity accompanied anaerobic metabolism AMP-activated protein kinase (AMPK), acts on autophagy, defects. These results provide insights into the molecular mechanisms physiopathology, supporting development new promising approaches based metabolic rewiring to correct pathology MPSs.

Language: Английский

Citations

3
Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages DOI Open Access
Lester J. Rosario-Rodríguez, Yadira M. Cantres-Rosario, Kelvin Carrasquillo

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3246 - 3246

Published: March 13, 2024

HIV-associated neurocognitive disorders (HAND) affect 15–55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain these individuals, promoting neurotoxicity. We demonstrated an increased expression cathepsin B (CATB), a lysosomal protease, in monocytes post-mortem tissues women with HAND. Increased CATB release from MDM leads to neurotoxicity, their secretion is associated NF-κB activation, oxidative stress, exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, secretion, neurotoxicity MDM, but mechanisms not entirely understood. hypothesized that infection upregulates proteins stress CB2R agonist could reverse effects. were isolated healthy donors (n = 3), infected HIV-1ADA, treated JWH-133. After 13 days post-infection, cell lysates labeled by Tandem Mass Tag (TMT) analyzed LC/MS/MS quantitative proteomics bioinformatics. While upregulated CATB, signaling, Nrf2-mediated response, exocytosis, JWH-133 treatment downregulated involved pathways. Our results suggest potential alternative therapy against HIV-induced warrant vivo studies test its

Language: Английский

Citations

3