Effects of cyclodextrins on GM1-gangliosides in fibroblasts from GM1-gangliosidosis patients

Maeda, Yuki; Motoyama, Keiichi; Higashi, Taishi; Horikoshi, Yuka; Tanaka, Takeo; Nakagata, Naomi; Kurauchi, Yuki; Katsuki, Hiroshi; Ishitsuka, Yoichi; Kondo, Yuki; Irie, Tetsumi; Furuya, Hirokazu; Era, Takumi; Arima, Hisatomi

doi:10.1111/jphp.12405

Cited by 16 publications

(7 citation statements)

References 26 publications

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“…as constituents of microdomains in the Golgi complex 47 , as GPI-linked signalling complexes, or as key regulators of endocytic tubule formation that mediate cell entry of bacterial toxins including Shiga toxin 17,18,23,24,25,28 . Acute cholesterol depletion has been demonstrated before to perturb the transport of complex glycosphingolipids such as GM1 60 akin to our results reported here. We, thus, hypothesize that defective cholesterol export to the TGN affects complex glycosphingolipids at the level of the Golgi complex, where they are synthesized.…”

Section: Discussionsupporting

confidence: 91%

Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites

Malek

Wawrzyniak

Koch

et al. 2020

Preprint

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Vesicular traffic and membrane contact sites between organelles enable the exchange of proteins, lipids, and metabolites. Recruitment of membrane tethers to contact sites between the endoplasmic reticulum (ER) and the plasma membrane is often triggered by calcium. In contrast, we reveal here a function for calcium in the repression of cholesterol export at membrane contact sites between the ER and the Golgi complex. We show that calcium efflux from ER stores induced by inositol-triphosphate [IP3] accumulation upon loss of the inositol 5-phosphatase INPP5A or sustained receptor signaling triggers the depletion of cholesterol and associated complex glycosphingolipids from the cell surface, resulting in a blockade of clathrin-independent endocytosis (CIE) of bacterial toxins. This phenotype is caused by the calcium-induced dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing membrane contact sites. Our findings reveal a crucial function for INPP5A-mediated IP3 hydrolysis in the control of lipid exchange at membrane contact sites.

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Section: Discussionsupporting

confidence: 91%

Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites

Malek

Wawrzyniak

Koch

et al. 2020

Preprint

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“…Recently, CyDs and their derivatives are expected as APIs against various diseases such as Niemann-Pick disease type C (NPC), [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] Alzheimer's disease, [53][54][55][56][57][58] leukemia, 59) cerebral ischemic injury, 60) chronic renal failure, 61) hyperlipidemia, 62) atherosclerosis, 63) AIDS, 64,65) diabetic kidney disease, 66) influenza, 67) sterility, [68][69][70] peripheral artery disease, 71) bacterial growth, 72) solid cancers, [73][74][75][76][77][78] GM1-gangliosidosis, 79) septic shock, [80][81][82] α-synucleinopathy, 83) hypervitaminosis, 84) and transthyretin-related familial amyloidotic polyneuropathy (FAP).…”

Section: Cyclodextrin-based Molecular Necklace As Antitumor Drugmentioning

confidence: 99%

“…87) We have developed a CyD-based antitumor drug, namely folate appended-methyl-β-CyD (FA-M-β-CyD), thus far. 75,76,78) FA-M-β-CyD induced mitophagy after uptake into folate receptor-overexpressing tumor cells, leading to tumor-selective antitumor activity. 78) More recently, to improve tumor selectivity, blood retention, and safety of FA-M-β-CyD, we newly prepared a molecular necklace (polyrotaxane) consisting of FA-M-β-CyD (Fig.…”

Section: Cyclodextrin-based Molecular Necklace As Antitumor Drugmentioning

confidence: 99%

Cyclodextrin-Based Molecular Accessories for Drug Discovery and Drug Delivery

Higashi

2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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Recently, active pharmaceutical ingredients (APIs) have been dramatically expanding from low-molecular weight drugs to peptides, proteins, antibodies, genes, oligonucleotides, cells, and machines. Therefore to develop pharmaceutical technologies and drug delivery systems (DDS) for these APIs, advanced molecules and novel concepts are needed. In this review, we introduce cyclodextrin-based supramolecular accessories such as molecular necklace, molecular earring, and intelligent molecular necklace, and describe their application for pharmaceutical technology and DDS. In addition, we also introduce utility of supramolecular accessories as antitumor drugs. Finally, we propose a new concept in pharmaceutical sciences termed as "supramolecular pharmaceutical sciences," which combines pharmaceutical sciences and supramolecular chemistry. This concept could be useful for developing new ideas, methods, hypotheses, strategies, materials, and mechanisms in pharmaceutical sciences.

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“…Cytotoxicity Cytotoxicity was assayed by the WST-1 method, as reported previously. 22) Briefly, Npc1-trap-CHO cells (5×10 4 cells/96-well microplate) were incubated with 150 µL of DMEM containing R8-β-CyD (1, 10 or 100 µM) or Tween 20 for 24 h at 37°C. After washing twice with phosphate-buffered saline (PBS; pH 7.4) to remove R8-β-CyD, 100 µL of fresh Hanks' balanced salt solution (HBSS; pH 7.4) and 10 µL of WST-1 reagent (Cell Counting Kit, Wako Pure Chemical Industries, Ltd., Osaka, Japan) were added.…”

Section: Methodsmentioning

confidence: 99%

Cholesterol-Lowering Effect of Octaarginine-Appended β-Cyclodextrin in <i>Npc1</i>-Trap-CHO Cells

Motoyama

Nishiyama

Maeda

et al. 2016

Biological & Pharmaceutical Bulletin

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Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder, which is an inherited disease characterized by the accumulation of unesterified cholesterol in endolysosomes. Recently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) has been used for the treatment of NPC, and ameliorated a hepatosplenomegaly in the patients. However, to obtain the treatment efficacy, a high dose of HP-β-CyD was necessary. Therefore, the decrease in dose by using active intracellular delivery system of β-CyD to NPC cells is expected. In this study, to efficiently deliver β-CyD to NPC-like cells, we newly synthesized octaarginine (R8)-appended β-CyD with a spacer of γ-aminobutyric acid (R8-β-CyD) and evaluated its cytotoxicity, intracellular distribution, endocytosis pathway and cholesterol-lowering effect in Npc1-trap-Chinese hamster ovary (CHO) cells, cholesterol-accumulated cells through the impairment of NPC1 function. R8-β-CyD did not show cytotoxicity in the cells. In addition, Alexa568-labeled R8-β-CyD was actively internalized into Npc1-trap-CHO cells, possibly through micropinocytosis. Notably, R8-β-CyD significantly decreased intracellular cholesterol content compared with HP-β-CyD. These results suggest that R8-β-CyD may be a promising therapeutic agent for ameliorating cholesterol accumulation in NPC.

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Effects of cyclodextrins on GM1-gangliosides in fibroblasts from GM1-gangliosidosis patients

Abstract: CyDs may have the potential as drugs for GM1-gangliosidosis, although the mechanism should be thereafter clarified.

Cited by 16 publications

References 26 publications

Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites

Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites

Cyclodextrin-Based Molecular Accessories for Drug Discovery and Drug Delivery

Cholesterol-Lowering Effect of Octaarginine-Appended β-Cyclodextrin in <i>Npc1</i>-Trap-CHO Cells

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