Does administration of hydroxychloroquine/amiodarone affect the efficacy of enzyme replacement therapy for Fabry mice?

As a standard therapy for Fabry disease, enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (α-Gal) has been successfully used, and the instructions for this drug state that "it should not be co-administrated with cationic amphiphilic drugs such as hydroxychloroquine (HCQ) and amiodarone (AMI), since these drugs have the potential to inhibit intracellular α-Gal activity". However, there would be cases in which HCQ or AMI is required for patients with Fabry disease, considering their medical efficacy and application. Thus, we examined the impact of HCQ/AMI on recombinant human α-Gal by in vitro, cellular, and animal experiments. The results revealed that HCQ/AMI affected the enzyme activity of α-Gal incorporated into cultured fibroblasts from a Fabry mouse when the cells were cultured in medium containing these drugs and the enzyme, although their direct inhibitory effect on the enzyme is not strong. These lysosomotropic drugs may be trapped and concentrated in lysosomes, followed by inhibition of α-Gal. On the other hand, no reduction of α-Gal activity incorporated into the organs and tissues, or acceleration of glycoshingolipid accumulation was observed in Fabry mice co-administered with HCQ/AMI and the enzyme, compared with in the case of usual ERT. As HCQ/AMI administered are catabolized in the liver, these drugs possibly do not affect ERT for Fabry mice, different from in the case of cultured cells in an environment isolated from the surroundings.

The incorporation of extracellular vesicle markers varies among vesicles with distinct surface charges.

Extracellular vesicles (EVs) are important mediators of intercellular communication. However, the methods available for distinguishing the heterogeneity of secreted EVs and isolating and purifying them are limited. This study introduced a HiBiT-tag to detect various EV markers, including CD63, CD9, Epidermal Growth Factor Receptor (EGFR), Flotilin1, and Syndecan-1, and investigated whether these marker-containing vesicles were capable of binding to differently charged column carriers. Four column carriers, Diethylaminoethyl (DEAE), Capto Adhere, Blue and Heparin, showed affinity for CD63 containing EVs, but their elution patterns varied. Furthermore, we observed that the elution patterns of the EV markers differed among vesicles with distinct surface charges when a DEAE column was used. This suggests that the incorporation of EV markers varied between these vesicles. The markers showed different subcellular localizations, indicating that the site of vesicle formation may contribute to the production of vesicles with varying charges and marker incorporation. These findings may have implications for the development of methods to purify homogeneous EVs, which could be useful in EV-mediated drug delivery systems.

Changes in the Structure and Corrosion Protection Ability of Porous Anodic Oxide Films on Pure Al and Al Alloys by Pore Sealing Treatment.

It is well known that corrosion protection of pure Al is enormously improved by the formation of porous anodic oxide films and by pore sealing treatment. However, the effects of anodizing and pore sealing on corrosion protection for Al alloys are unclear, because the alloying elements included in Al alloys affect the structure of anodic oxide films. In the present study, porous anodic oxide films are formed on pure Al, 1050-, 3003- and 5052-Al alloys, and pore sealing was carried out in boiling water. Changes in the structure and corrosion protection ability of porous anodic oxide films on pure Al and the Al alloys by pore sealing, were examined by scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS). SEM observation showed that anodic oxide films formed on pure Al have a smooth surface after pore sealing, and that cracks are formed in anodic oxide films on 1050-, 3003- and 5052-aluminum alloys, after pore sealing. Corrosion protection after pore sealing increased with anodizing time on pure Al, but only slightly increased with anodizing time on the Al alloys.

Effective Photosensitization in Excited-State Equilibrium: Brilliant Luminescence of TbIII Coordination Polymers Through Ancillary Ligand Modifications.

Invited for this month's cover are the collaborating groups of Yuichi Kitagawa, Yasuchika Hasegawa, Tetsuya Taketsugu, and co-workers at Hokkaido University. The cover picture shows a photosensitizer that has a long excited-state lifetime and provides strong emissions for TbIII coordination polymers. The photosensitization ability can be considerably altered by changing the ancillary ligands in the TbIII coordination polymers. The results provide new insights on the design of photosensitizers for improving the properties of photo-functional materials. More information can be found in the Research Article by Y. Kitagawa, Y. Hasegawa, and co-workers.

Effective Photosensitization in Excited-State Equilibrium: Brilliant Luminescence of TbIII Coordination Polymers Through Ancillary Ligand Modifications.

Molecular photosensitizers provide efficient light-absorbing abilities for photo-functional materials. Herein, effective photosensitization in excited-state equilibrium is demonstrated using five TbIII coordination polymers. The coordination polymers are composed of TbIII ions (emission center), hexafluoroacetylacetonato (photosensitizer ligands), and phosphine oxide-based bridges (ancillary ligands). The two types of ligand combinations induces a rigid coordination structure via intermolecular interactions, resulting in high thermal stability (with decomposition temperatures above 300 °C). Excited-triplet-state lifetimes of photosensitizer ligands (τ=120-1320 µs) are strongly dependent on the structure of the ancillary ligands. The photosensitizer with a long excited-triplet-state lifetime (τ≥1120 µs) controls the excited state equilibrium between the photosensitizer and TbIII , allowing the construction of TbIII coordination polymer with high TbIII emission quantum yield (≥70 %).

Does administration of hydroxychloroquine/amiodarone accelerate accumulation of globotriaosylceramide and globotriaosylsphingosine in Fabry mice?

Drug-induced lysosomal storage disease (DILSD) caused by cationic amphiphilic drugs (CADs), which exhibits toxic manifestations and pathological findings mimicking Fabry disease (α-galactosidase A deficiency), has attracted the interests of clinicians and pathologists. Although the affected region is lysosomes in both the diseases, DILSD is characterized by intralysosomal accumulation of phospholipids and Fabry disease that of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). However, it is unknown whether administration of CADs affects the catabolism of Gb3 and Lyso-Gb3 in Fabry disease. In this study, we independently administered hydroxychloroquine/amiodarone to wild-type and Fabry mice and examined the effects of the drugs on the enzyme activity and substrates accumulated in organs and tissues. The results revealed that the administration of the drugs induced accumulation of phosphatidylcholine in both the wild-type and Fabry mice. However, reduction of α-galactosidase A activity in the organs and tissues of the wild-type mice was not found, and the storage of Gb3 and Lyso-Gb3 was not accelerated by these drugs in the Fabry mice. This suggests that hydroxychloroquine/amiodarone do not have any significant impact on the catabolism of Gb3 and Lyso-Gb3 in organs and tissues of both wild-type and Fabry mice.