Endosome positioning coordinates spatially selective GPCR signaling

Nature Chemical Biology, Год журнала: 2023, Номер 20(2), С. 151 - 161

Опубликована: Июль 27, 2023

Язык: Английский

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Targeting Glucosylceramide Synthase: Innovative Drug Repurposing Strategies for Lysosomal Diseases

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(5), С. 2195 - 2195

Опубликована: Фев. 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

Язык: Английский

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Impaired Autophagy in Krabbe Disease: The Role of BCL2 and Beclin-1 Phosphorylation

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5984 - 5984

Опубликована: Март 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.

Язык: Английский

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Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases

Biology, Год журнала: 2024, Номер 13(1), С. 34 - 34

Опубликована: Янв. 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.

Язык: Английский

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Application and Suggestions of Morpholine Ring as a Lysosome Targeting Group

Chemistry, Год журнала: 2025, Номер 7(3), С. 82 - 82

Опубликована: Май 21, 2025

Lysosomes are widely present in eukaryotic cells and play an extremely important role cell growth development, their dysfunction is closely related to a variety of diseases. The development precise lysosomal targeting strategies great significance for the detection physiological functions diagnosis treatment Morpholino ring modification has become commonly used strategy, but its effects have not been systematically evaluated. This review summarizes morpholine rings fluorescent probes recent years. results show that as groups excellent structural adaptability, localization effect influenced by log p value charge overall molecule, this differences. In addition, since morpholino essentially acidic microenvironmental moiety, it carries risk off-targeting other sites.

Язык: Английский

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Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB

iScience, Год журнала: 2024, Номер 27(3), С. 108959 - 108959

Опубликована: Янв. 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.

Язык: Английский

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Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(6), С. 3246 - 3246

Опубликована: Март 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

Язык: Английский

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RAS-p110α signalling in macrophages is required for effective inflammatory response and resolution of inflammation

Опубликована: Фев. 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.

Язык: Английский

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Lysosomes’ fallback strategies: more than just survival or death

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Март 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

Язык: Английский

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RAS–p110α signalling in macrophages is required for effective inflammatory response and resolution of inflammation

eLife, Год журнала: 2025, Номер 13

Опубликована: Апрель 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.

Язык: Английский

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