Internalization of benzylisoquinoline alkaloids by resting and activated bone marrow-derived mast cells utilizes energy-dependent mechanisms

Alam, Syed Benazir; Kulka, Marianna

doi:10.1007/s00011-021-01526-2

Cited by 4 publications

(3 citation statements)

References 40 publications

(53 reference statements)

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“…Mast cells are a tissue-resident innate immune cell that mediate tissue homeostasis but also facilitates inflammatory disease 21 . Unlike lymphocytes, mast cells are large, granular and extremely difficult to transfect using conventional non-viral strategies 22 , 23 . We hypothesized that Apos may facilitate the internalization of cationic LNPs into terminally differentiated mouse bone marrow-derived mast cells (BMMC).…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into bone marrow-derived mouse mast cells

Alam

Wang

Qian

et al. 2023

Sci Rep

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Mast cells (MCs), are hematopoetically-derived secretory immune cells that release preformed as well as de novo synthesized inflammatory mediators in response to activation by several stimuli. Based on their role in inflammatory responses, particularly in the lung and skin, MCs provide an effective target for anti-inflammatory therapeutic strategies. Drug-delivery of lipophilic payloads to MCs can be challenging due to their functionally distinct intracellular structures. In the present study, pH-sensitive cationic lipid-based nanoparticles (LNPs) composed of DODMA, DODAP or DOTAP lipids that encapsulated a GFP or eGFP plasmid were constructed using non-turbulent microfluidic mixing. This approach achieved up to 75–92% encapsulation efficiency. Dynamic light scattering revealed a uniformly sized and homogeneous dispersion of LNPs. To promote cellular internalization, LNPs were complexed with apolipoproteins, amphipathic proteins capable of binding lipids and facilitating their transport into cells. Cryo-TEM analysis showed that LNP structure was differentially modified when associated with different types of apolipoproteins. LNP preparations made up of DODMA or DODMA, DODAP and DOTAP lipids were coated with seven apolipoproteins (Apo A1, B, C3, D, E2, E4 and H). Differentiated bone-marrow derived mouse mast cells (BMMCs) were exposed to apolipoprotein-LNP and internalization was measured using flow cytometry. Out of all the apolipoproteins tested, ApoC3 most efficiently facilitated cellular internalization of the LNP into BMMCs as determined by GFP fluorescence using flow cytometry. These effects were confirmed in a less differentiated but also interleukin-3-dependent model of mouse mast cells, MC/9. ApoC3-LNP enhanced internalization by BMMC in a concentration-dependent manner and this was significantly increased when BMMC were pre-treated with inhibitors of actin polymerization, suggesting a dependence on intracellular shuttling. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) decreased ApoC3-LNP internalization and reduced the expression of apolipoprotein E receptor 2 (ApoER2), suggesting that ApoC3-LNP binding to ApoER2 may be responsible for its enhanced internalization. Furthermore, ApoC3 fails to facilitate internalization of LNPs in Lrp8−/− KO BMMC that do not express ApoER2 on their cell surface. Altogether, our studies reveal an important role of ApoC3 in facilitating internalization of cationic LNPs into MCs.

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Section: Introductionmentioning

confidence: 99%

Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into bone marrow-derived mouse mast cells

Alam

Wang

Qian

et al. 2023

Sci Rep

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“…2C). We have demonstrated that BBR internalizes into resting and IL-3-activated BMMC by utilizing energy-dependent active transport mechanism that is dependent upon glucose metabolism and temperature [40]. Moreover, internalization of BBR into metabolically active BMMC is time-dependent.…”

Section: Internalization Of Berberine Into Cellsmentioning

confidence: 92%

Unravelling the Effects of Berberine on Metabolic Activity, Apoptosis and Proliferation of Transformed Cells

Alam¹,

Kulka²,

Wang³

2023

Preprint

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Berberine (BBR) is an isoquinoline that inhibits the proliferation of transformed cells in vitro, but due to its poor solubility and bioavailability, it has only moderate therapeutic potential in vivo. Increasing evidence indicates that BBR specifically targets several metabolic, signaling and gene transcription events in transformed cells, altering their progression through the cell cycle and decreasing their metabolic rate and proliferation. In order to further develop BBR as a therapeutic, its mode of cellular internalization and localization within the cell needs to be further examined. BBR’s molecular targets and interactions with kinases, transcription factors and some enzymes are discussed in an attempt to better understand BBR’s role in these important pathways and how they may lead to changes in metabolism. Lastly, this review examines some of the benefits and challenges of using BBR as an inhibitor in cancer cell proliferation in breast cancer and glioblastoma, as two examples. BBR is a potent drug with multiple targets and it is this multiplicity of function that makes BBR such a promising drug for targeting cell metabolism and proliferation.

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“…Mast cells are a tissue-resident innate immune cell that mediate tissue homeostasis but also facilitates in ammatory disease [21]. Unlike lymphocytes, mast cells are large, granular and extremely di cult to transfect using conventional non-viral strategies [22,23]. We hypothesized that Apos may facilitate the internalization of cationic LNPs into terminally differentiated mouse bone marrow-derived mast cells (BMMC).…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into terminally differentiated bone marrow-derived mouse mast cells

Alam

Wang

Qian

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Mast cells (MCs), are hematopoetically-derived secretory immune cells that release preformed as well as de novo synthesized inflammatory mediators in response to activation by several stimuli. Based on their role in inflammatory responses, particularly in the lung and skin, MCs provide a convenient and effective target for anti-inflammatory therapeutic strategies. Drug-delivery of lipophilic payloads to MCs can be challenging due to their functionally distinct intracellular structures. In the present study, pH-sensitive cationic lipid-based nanoparticles (LNPs) composed of DODMA, DODAP or DOTAP lipids that encapsulated a GFP or eGFP plasmid were constructed using non-turbulent microfluidic mixing. This approach achieved up to 75-92% encapsulation efficiency. Dynamic light scattering revealed a uniform and homogeneous size distribution of LNPs.To promote cellular internalization, LNPs were complexed with apolipoproteins, amphipathic proteins capable of binding lipids and facilitating their transport in the bloodstream and into cells. Cryo-TEM analysis showed that LNP structure was differentially modified when associated with different types of apolipoproteins. LNP preparations made up of DODMA or DODMA, DODAP and DOTAP lipids were coated with seven apolipoproteins (Apo A1, B, C3, D, E2, E4 and H). Terminally differentiated bone-marrow derived mouse mast cells (BMMCs) were exposed to Apolipoprotein-LNP mixture and internalization was measured using flow cytometry. Out of all the apolipoproteins tested, ApoC3 most efficiently facilitated cellular internalization of the LNP into BMMCs as determined by GFP fluorescence using flow cytometry. These effects were confirmed in a less differentiated but also interleukin-3-dependent model of mouse mast cells, MC/9. ApoC3-LNP enhanced internalization by BMMC in a concentration-dependent manner and this was significantly increased when BMMC were pre-treated with inhibitors of actin polymerization, suggesting a dependence on intracellular shuttling. Activation of peroxisome proliferator-activated receptor gamma (PPAR) decreased ApoC3-LNP internalization and reduced the expression of apolipoprotein E receptor 2 (ApoER2) , suggesting that ApoC3-LNP binding to ApoER2 may be responsible for its enhanced internalization. Altogether, our studies reveal an important role of ApoC3 in facilitating internalization of cationic LNPs into MCs.

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Internalization of benzylisoquinoline alkaloids by resting and activated bone marrow-derived mast cells utilizes energy-dependent mechanisms

Cited by 4 publications

References 40 publications

Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into bone marrow-derived mouse mast cells

Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into bone marrow-derived mouse mast cells

Unravelling the Effects of Berberine on Metabolic Activity, Apoptosis and Proliferation of Transformed Cells

Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into terminally differentiated bone marrow-derived mouse mast cells

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