Contribution of syndecans to lipoplex-mediated gene delivery

Letoha, Tamás; Kolozsi, Csongor; Ékes, Csaba; Keller-Pintér, Anikó; Kúsz, Erzsébet; Szakonyi, Gerda; Duda, E.; Szilák, László

doi:10.1016/j.ejps.2013.05.022

Cited by 24 publications

(48 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Syndecan 4 on alveolar epithelial cells acts as a receptor for the MTB mycobacterial heparin-binding hemagglutinin adhesin [42]. Activation of syndecan 4 stimulates signaling pathways such as RhoG and Rac1, leading to micropinocytosis [45]. Previous studies have reported effects of smoking on Rac1 activation [46, 47] or GTPase mediated pathways [43].…”

Section: Discussionmentioning

confidence: 99%

Water-pipe smoke condensate increases the internalization of Mycobacterium Bovis of type II alveolar epithelial cells (A549)

et al. 2017

View full text Add to dashboard Cite

BackgroundTuberculosis (TB) is a major global health problem, and there is an association between tobacco smoke and TB. Water pipe smoking has become an increasing problem not only in Middle Eastern countries but also globally because users consider it as safer than cigarettes. The presence of high levels of toxic substances in water-pipe smoke may be a predisposing factor that enhances the incidence of pulmonary disorders. For example, uncontrolled macropinocytosis in alveolar epithelial cells following exposure to water-pipe smoke may predispose subjects to pulmonary infection. Here, we studied the effects of water-pipe condense (WPC) on the internalization of Mycobacterium Bovis BCG by macropinocytosis in the alveolar epithelial cell line A549.MethodsA549 cells were exposed to WPC (4 mg/ml) for 24, 48, 72 and 96 h. Cell viability was studied using the methyl thiazolyldipenyl-tetrazolium bromide (MTT) reduction assay and proliferation by bromodeoxyUridine (BrdU) incorporation. Cells were exposed to FITC-Dextran (1 mg/ml) (as a control) and FITC-BCG (MOI = 10) for 20 min at 37 °C before cells were collected and the uptake of BCG-FITC determined by flow cytometry. Similar experiments were performed at 4 °C as a control. The Rho-associated protein kinase (ROCK) inhibitor Y-27632 (1 μM) was used to assess the mechanism by which WPC enhanced BCG uptake.ResultsWPC (4 mg/ml) increased the uptake of BCG-FITC after 72 (1.3 ± 0.1 fold, p < 0.05) and 96 (1.4 ± 0.05 fold, p < 0.05) hours. No effect on BCG-FITC uptake was observed at 24 or 48 h. WPC also significantly increased the uptake of FITC-Dextran (2.9 ± 0.3 fold, p < 0.05) after 24 h. WPC significantly decreased cell viability after 24 (84 ± 2%, p < 0.05), 48 (78±, 3%, p < 0.05), 72 (64 ± 2%, p < 0.05) and 96 h (45 ± 2%, p < 0.05). Y-27632 completely attenuated the increased uptake of BCG by WPC. Cell proliferation showed a decreasing trend in a time-dependent manner with WPC exposure.ConclusionWPC exposure increased epithelial cell endocytosis activity and death as well as enhancing their capacity for macropinocytosis. Our in vitro data indicates possible harmful effects of WPC on the ability of lung epithelial cells to phagocytose mycobacterium.

show abstract

Section: Discussionmentioning

confidence: 99%

Water-pipe smoke condensate increases the internalization of Mycobacterium Bovis of type II alveolar epithelial cells (A549)

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The evolutionarily highly conserved syndecans (SDCs) are the only transmembrane HSPG family and possess essential roles in cell interactions, adhesion, migration and signaling [40][41][42] . SDCs share a similar structure: a one-span and highly conserved transmembrane domain (TM) and a relatively short cytoplasmic domain (CD) 43,44 . The extracellular domain (ectodomain) of SDCs is more diverse, containing HS attachment sites with glycosaminoglycan (GAG) side chains 45,46 .…”

Section: Development Of E Cient Therapeutics Against Covid-19 Is Hampmentioning

confidence: 99%

“…Members of the SDC family show tissue-speci c expression: SDC1 is expressed on epithelial and plasma cells, SDC2 on endothelial cells, SDC3 in the neurons, while SDC4 is more ubiquitous 43,44,53,57 . The BioGPS gene expression database (http://biogps.org) indicates a high expression of SDC4 in human lung cells 53,58 .…”

Section: Development Of E Cient Therapeutics Against Covid-19 Is Hampmentioning

confidence: 99%

“…Our research group has been focusing on the exploration of SDCs' drug delivery and therapeutic potential. Our related studies with non-viral drug delivery agents, including cell-penetrating peptides (CPPs) and cationic liposomes, contributed to the understanding of SDCs' capacity to deliver bioactive macromolecules into the cells 43,44,64 . Moreover, we also revealed that SDCs contribute to the seeding and prion-like spreading of pathological protein aggregates, the major molecular culprits responsible for the onset of neurodegenerative disorders 45,46 .…”

Section: Development Of E Cient Therapeutics Against Covid-19 Is Hampmentioning

confidence: 99%

“…Deletion mutant Si4 possesses a truncated SDC4 extracellular domain made of only the short signal sequence (Si), while mutant CBD has a mutated ectodomain containing only the cell-binding domain (CBD) and Si, but no HS attachment (HSA) site and HS chains [43][44][45][46] . We also applied the deletion mutant HSA with an ectodomain comprising the HSA site and HS chains (and also the Si), but no CBD [43][44][45][46] . To readily detect their expression, all of the SDC4 mutants -along with WT SDC4 -were tagged with GFP and expressed in K562 cells [43][44][45][46] .…”

Section: ]) Colocalization Studies Revealed a Signi Cant Degree Of Cmentioning

confidence: 99%

See 2 more Smart Citations

Contribution of syndecans to the cellular entry of SARS-CoV-2

Hudák

Szilák

Letoha

2020

Preprint

Self Cite

View full text Add to dashboard Cite

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology significantly hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans facilitate the cellular entry of SARS-CoV-2. Among syndecans, syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake, yet overexpression of other isoforms, including the neuronal syndecan-3, also increased SARS-CoV-2 internalization. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus’s interactions with syndecans. Besides the polyanionic heparan sulfate chains - the established binding sites for several viruses - other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Among these inhibitors, a peptide compromising the spike protein’s heparin-binding PRRAR motif significantly reduced SARS-CoV-2 cellular uptake, highlighting the need to go beyond the ACE2 paradigm for developing efficient therapeutics against SARS-CoV-2. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offers molecularly precise, yet simple strategies in overcoming the complex nature of SARS-CoV-2 infection.

show abstract

A Comparison of Cellular Uptake Mechanisms, Delivery Efficacy, and Intracellular Fate between Liposomes and Extracellular Vesicles

Gandek

Koog

Nagelkerke

2023

Adv Healthcare Materials

View full text Add to dashboard Cite

A key aspect for successful drug delivery via lipid‐based nanoparticles is their internalization in target cells. Two prominent examples of such drug delivery systems are artificial phospholipid‐based carriers, such as liposomes, and their biological counterparts, the extracellular vesicles (EVs). Despite a wealth of literature, it remains unclear which mechanisms precisely orchestrate nanoparticle‐mediated cargo delivery to recipient cells and the subsequent intracellular fate of therapeutic cargo. In this review, internalization mechanisms involved in the uptake of liposomes and EVs by recipient cells are evaluated, also exploring their intracellular fate after intracellular trafficking. Opportunities are highlighted to tweak these internalization mechanisms and intracellular fates to enhance the therapeutic efficacy of these drug delivery systems. Overall, literature to date shows that both liposomes and EVs are predominantly internalized through classical endocytosis mechanisms, sharing a common fate: accumulation inside lysosomes. Studies tackling the differences between liposomes and EVs, with respect to cellular uptake, intracellular delivery and therapy efficacy, remain scarce, despite its importance for the selection of an appropriate drug delivery system. In addition, further exploration of functionalization strategies of both liposomes and EVs represents an important avenue to pursue in order to control internalization and fate, thereby improving therapeutic efficacy.

show abstract

Contribution of syndecans to lipoplex-mediated gene delivery

Cited by 24 publications

References 37 publications

Water-pipe smoke condensate increases the internalization of Mycobacterium Bovis of type II alveolar epithelial cells (A549)

Water-pipe smoke condensate increases the internalization of Mycobacterium Bovis of type II alveolar epithelial cells (A549)

Contribution of syndecans to the cellular entry of SARS-CoV-2

A Comparison of Cellular Uptake Mechanisms, Delivery Efficacy, and Intracellular Fate between Liposomes and Extracellular Vesicles

Contact Info

Product

Resources

About