Dynamic interplay of autophagy and membrane repair during Mycobacterium tuberculosis Infection

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(1), P. e1012830 - e1012830

Published: Jan. 2, 2025

Autophagy plays a crucial role in the host response to Mycobacterium tuberculosis (Mtb) infection, yet dynamics and regulation of autophagy induction on Mtb-containing vacuoles (MCVs) remain only partially understood. We employed time-lapse confocal microscopy investigate recruitment LC3B (LC3), key marker, MCVs at single cell level with our newly developed workflow for MCV tracking fluorescence quantification. show that approximately 70% exhibited LC3 but was lost about 40% those MCVs. The displayed high variability timing independent size or bacterial burden. Most notably, LC3-positive did not acidify, indicating does necessarily lead formation mature autophagolysosomes. Interferon-gamma pre-treatment affect frequency autophagosome acidification increased susceptibility macrophage Mtb-induced death. lysotracker staining were mutually exclusive events, alternating some multiple times thus demonstrating reversible aspect response. associated galectin-3 oxysterol-binding protein 1 staining, correlation membrane damage repair mechanisms. ATG7 knock-down impact repair, suggesting is directly involved this process coregulated by In summary, findings provide novel insights into dynamic variable nature over time during Mtb infection. Our data support either cell-autonomous defense against human macrophages. addition, combined Lysoview emerged as promising markers investigating processes phagosomal membranes.

Language: Английский

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Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson’s Disease with Potential Therapeutic Implications

Biomolecules, Journal Year: 2025, Volume and Issue: 15(1), P. 149 - 149

Published: Jan. 19, 2025

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder marked by the progressive degeneration of midbrain dopaminergic neurons and resultant locomotor dysfunction. Despite over two centuries recognition as chronic disease, exact pathogenesis PD remains elusive. The onset progression involve multiple complex pathological processes, with dysfunctional autophagy elevated oxidative stress serving critical contributors. Notably, emerging research has underscored interplay between in pathogenesis. Given limited efficacy therapies targeting either dysfunction or stress, it crucial to elucidate intricate mechanisms governing their develop more effective therapeutics. This review overviews role nuclear factor erythroid 2-related 2 (Nrf2), pivotal transcriptional regulator orchestrating cellular defense against these processes. By elucidating key processes PD, this will deepen our comprehensive understanding multifaceted underlying may uncover potential strategies for its prevention treatment.

Language: Английский

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Histone demethylases in autophagy and inflammation

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 13, 2025

Autophagy dysfunction is associated with changes in autophagy-related genes. Various factors are connected to autophagy, and the mechanism regulating autophagy highly complicated. Epigenetic changes, such as aberrant expression of histone demethylase, actively not only oncogenesis but also inflammatory responses. Among post-translational modifications, lysine methylation holds significant importance. There over 30 members demethylases (KDMs), which act epigenetic regulators physiological processes diseases. Importantly, KDMs abnormally expressed regulation cellular inflammation, representing a crucial affecting inflammation-related This article reviewed function proteins inflammation. Specifically, It focused on specific regulatory mechanisms underlying activation or inhibition well their abnormal By analyzing each KDM modification, this review provides reliable theoretical basis for clinical decision marking regarding abnormalities

Language: Английский

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Autophagy pathways in autoimmune diseases

Journal of Autoimmunity, Journal Year: 2023, Volume and Issue: 136, P. 103030 - 103030

Published: March 29, 2023

Language: Английский

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Sonodynamic Therapy of NRP2 Monoclonal Antibody‐Guided MOFs@COF Targeted Disruption of Mitochondrial and Endoplasmic Reticulum Homeostasis to Induce Autophagy‐Dependent Ferroptosis

Advanced Science, Journal Year: 2023, Volume and Issue: 10(30)

Published: Sept. 3, 2023

The lethality and chemotherapy resistance of pancreatic cancer necessitates the urgent development innovative strategies to improve patient outcomes. To address this issue, we designed a novel drug delivery system named GDMCN2,which uses iron-based metal organic framework (Fe-MOF) nanocages encased in covalent (COF) modified with cancer-specific antibody, NRP2. After being targeted into tumor cells, GDMCN2 gradually release sonosensitizer sinoporphyrin sodium (DVDMS) chemotherapeutic gemcitabine (GEM) simultaneously generated reactive oxygen species (ROS) under ultrasound (US) irradiation. This can overcome reduce its toxicity non-targeted cells tissues. In mechanistic cascade, ROS activates mitochondrial transition pore (MPTP), leading Ca2+ induction endoplasmic reticulum (ER) stress. Therefore, microtubule-associated protein 1A/1B-light chain 3 (LC3) is activated, promoting lysosomal autophagy. process also induces autophagy-dependent ferroptosis, aided by upregulation Nuclear Receptor Coactivator 4 (NCOA4). mechanism increases sensitivity drugs DNA damage. findings demonstrate potential as new avenue for therapeutics.

Language: Английский

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Luteolin inhibits triple-negative breast cancer by inducing apoptosis and autophagy through SGK1-FOXO3a-BNIP3 signaling

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: June 6, 2023

Background: Triple-negative breast cancer (TNBC) is one of the most prominent neoplasm disorders and lacks efficacious treatments yet. Luteolin (3',4',5,7-tetrahydroxyflavone), a natural flavonoid commonly presented in plants, has been reported to delay progression TNBC. However, precise mechanism still elusive. We aimed elucidate inhibition molecular regulation luteolin on Methods: The effects biological functions TNBC cells were first evaluated using corresponding assays for cell counting kit-8 assay, flow cytometry, wound-healing transwell migration respectively. was then analyzed by RNA sequencing verified RT-qPCR, Western blot, transmission electron microscopy, etc. Finally, vivo mouse tumor models constructed further confirm TNBC.Results: dramatically suppressed proliferation, invasion, while favoring apoptosis dose- time-dependent manner. In treated with luteolin, SGK1 AKT3 significantly downregulated their downstream gene BNIP3 upregulated. According results 3D modeling, direct binding superior that AKT3. promoted FOXO3a translocation into nucleus led transcription both vitro vivo, eventually facilitating interaction between autophagy protein. Furthermore, upregulation SGK1, induced attenuated Conclusion: inhibits inducing through SGK1-FOXO3a-BNIP3 signaling.

Language: Английский

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Hydrogels for ameliorating osteoarthritis: Mechanical modulation, anti‐inflammation, and regeneration

BMEMat, Journal Year: 2024, Volume and Issue: 2(2)

Published: March 1, 2024

Abstract Osteoarthritis (OA) is a chronic and degenerative disease with limited clinical options for effective suppression. Recently, significant endeavors have been explored to reveal its pathogenesis develop treatments against OA. Hydrogels, designed striking resemblance the extracellular matrix, offer biomimetic interaction biological tissues, presenting promising avenue OA amelioration. As result, biocompatible hydrogels erected incorporating on‐demand bioactivities optimize intra‐articular microenvironment, thereby alleviating symptoms fostering eventual regeneration of articular joints. This review highlights collaborative objectives underlying establishment this tissue encompassing mechanical modulation, anti‐inflammation, regeneration. Specifically, we consolidate recent advances in hydrogel‐based biomaterials, serving as engineering scaffolds replicate lubrication properties natural joints or bioactive agent‐loaded vehicles combat localized inflammation. Additionally, function cell facilitate maintenance cellular homeostasis contribute advancement cartilage Finally, outlines prospective directions hydrogel‐mediated therapies.

Language: Английский

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Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(7), P. 2815 - 2853

Published: April 24, 2024

Regulated cell death (RCD) is a controlled form of orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, modulating immunity. Accumulating evidence has recently revealed that evasion frequently the primary cause tumor survival. Several have garnered attention promising cancer therapies due their ability induce regression prevent relapse, comparable apoptosis. Moreover, they offer potential solutions for overcoming acquired resistance tumors toward drugs. With an increasing understanding underlying mechanisms governing these subroutines, growing number small-molecule compounds targeting single multiple pathways been discovered, providing novel strategies current therapy. In this review, we comprehensively summarized regulatory emerging mainly including autophagy-dependent death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic NETotic lysosome-dependent immunogenic (ICD). Furthermore, focused on discussing related compounds. brief, insightful findings may provide valuable guidance investigating individual collaborative approaches towards different ultimately driving discovery target significantly enhance future therapeutics.

Language: Английский

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Polymeric Polylactic Acid–Glycolic Acid-Based Nanoparticles Deliver Nintedanib Across the Blood–Brain Barrier to Inhibit Glioblastoma Growth

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 443 - 443

Published: Jan. 7, 2025

The aim of this study was to investigate the inhibitory effect nintedanib (BIBF) on glioblastoma (GBM) cells and its mechanism action optimize a drug delivery strategy overcome limitations posed by blood-brain barrier (BBB). We analyzed inhibition GBM cell lines following BIBF treatment explored autophagy pathway. cytotoxicity assessed using CCK-8 assay, further techniques such as transmission electron microscopy, Western blotting (WB), flow cytometry were employed demonstrate that could block autophagic pathway inhibiting fusion autophagosomes lysosomes, ultimately limiting proliferation cells. Molecular docking surface plasmon resonance (SPR) experiments indicated specifically binds autophagy-associated protein VPS18, interfering with function normal progression autophagy. However, application in therapy is limited due restricted penetration across BBB. Therefore, utilized poly-lactic-co-glycolic acid (PLGA) nanocarriers system significantly enhance efficiency vivo. In vitro cellular vivo animal model validation demonstrated PLGA-BIBF NPs effectively overcame BBB, enhanced antitumor activity BIBF, improved therapeutic efficacy BALB/c-Nude model. This exerted significant effects binding VPS18 Combined PLGA nanocarrier system, permeability anti-tumor enhanced. Targeting BIBF-VPS18 optimizing through nanotechnology may represent new for treatment, providing innovative clinical ideas theoretical basis patients GBM.

Language: Английский

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Neutrophil Engulfment in Cancer: Friend or Foe?

Cancers, Journal Year: 2025, Volume and Issue: 17(3), P. 384 - 384

Published: Jan. 24, 2025

Neutrophils, the most abundant circulating white blood cells, are essential for initial immune response to infection and injury. Emerging research reveals a dualistic function of neutrophils in cancer, where they can promote or inhibit tumor progression. This dichotomy is influenced by microenvironment, with capable remodeling extracellular matrix, promoting angiogenesis, alternatively inducing cancer cell death enhancing responses. An intriguing yet poorly understood aspect neutrophil–cancer interactions phenomenon neutrophil engulfment which has been observed across various cancers. process, potentially mediated LC3-associated phagocytosis (LAP), raises questions about whether it serves as mechanism evasion contributes through pathways like ferroptosis. review examines current knowledge on development, their roles mechanisms LAP cells. We discuss how manipulating impacts progression may represent therapeutic strategy. also explore neutrophils’ potential delivery vehicles agents. Understanding complex functions tumor-associated (TANs) molecular underlying open new avenues effective interventions mitigate risks.

Language: Английский

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