The optimal pharmacokinetics (PK) of orally administered nanoparticles (NPs) varies depending on their application (e.g., drug delivery, adsorbent, and adjuvant). Therefore, engineering NPs to achieve optimal PK is essential for the development of drug designs. Some studies have demonstrated that individual NP factors change the intestinal absorption of NPs; however, no technology has been established to control the biodistribution of orally administered NPs. In this study, a database about the influence of NP characteristics on biodistribution after oral administration was provided. A library of N-isopropylacrylamide polymer NPs with various characteristics that could influence the biodistribution after oral administration, such as size, flexibility, hydrophobicity, surface charges, and surface chemistries, were prepared. NPs with various sizes were synthesized by tuning the surfactant concentration only during synthesis, whereas NPs with different flexibility, hydrophobicity, surface charge, and surface chemistry were synthesized by feeding the corresponding functional monomer. The total amount of NPs accumulated in the organs decreased with increasing NP size, rigidity, hydrophobicity, electric potential (whether positive or negative), and polyethylene glycol modification. The results indicated that the absorption of orally administered NPs can be controlled by optimizing the characteristics of NP such as size, flexibility, hydrophobicity, surface charge, and surface chemistry. The results of this study will provide useful information to design NP formulations.

Selenium (Se) is an essential micronutrient for animals. Various chemical forms of Se exist in nature, each with distinct physiological, nutritional, and toxicological properties. In this study, we aimed to determine whether dimethyldiselenide (DMDSe, a monomethylated Se (MMSe) compound) and dimethylselenide (DMSe, a dimethylated Se compound), known gut bacterial metabolites, could serve as Se sources in rats. DMDSe could be utilized for selenoprotein biosynthesis and was metabolized into urinary selenometabolites. By contrast, DMSe was not utilized for selenoprotein biosynthesis but was further methylated to trimethylselenonium ion (TMSe), one of the urinary Se metabolites. Our findings indicate that dimethylated Se is not readily available as an Se source in rats, unlike MMSe. Selenoprotein biosynthesis requires selenide, an unmethylated form of Se, in the metabolic pathway. Our observations support the hypothesis that demethylation occurs on MMSe as a reversible methylation step but not on dimethylated Se. This suggests that the second methylation step is crucial for inactivating Se and plays a significant role in metabolism to maintain Se homeostasis in animals. Gut microbiota, which can synthesize both DMDSe and DMSe, may contribute to host Se metabolism through methylation processes.

Mineralocorticoid receptor (MR) blockers reduce cardiovascular complications as MRs play a crucial role in cardiovascular regulation. Diabetic cardiovascular complications are caused by vascular endothelial dysfunction. This study used a type 2 diabetic mouse model (DM) to investigate whether esaxerenone (ESAX), an MR blocker, ameliorates vascular endothelial dysfunction. ESAX (3 mg/kg/d) was administered via diet to KK-Ay mice or C57BL/6J mice, a nondiabetic control (Control), for 8 weeks, and metabolic parameters and blood pressure were measured. Vascular responses of the aortic segments were analyzed with acetylcholine, sodium nitroprusside, UK14304, or phenylephrine (PE). The other aortas were used for Western blot analysis. DM mice exhibited higher plasma glucose, insulin, metabolic parameters, and blood pressure levels than those of the Control mice. Parameters that did not include blood pressure were unaltered by DM or ESAX-administered DM (DM + ESAX). However, DM impaired UK14304-induced endothelial-dependent relaxation and nitric oxide production and elevated PE-induced contraction. ESAX administration ameliorated endothelial dysfunction and improved the protein kinase B (Akt) phosphorylation under α₂-agonist UK14304 stimulation in the aorta from DM mice compared with that of the Control mice. However, ESAX did not recover the increased G protein-coupled receptor kinase 2 (GRK2) expression and activity in the DM aorta. Furthermore, the DM-induced phosphorylation of serum and glucocorticoid-regulated kinase 1 (SGK1) was inhibited by ESAX. Overall, ESAX attenuates the development of DM-induced endothelial dysfunction by reducing SGK1 activity and enhancing Akt activity without affecting the GRK2 pathway. These results suggest that the vascular protective effects of ESAX could be employed for diabetic vascular complications.

Elastic fibers, which contribute to the flexibility of tissues such as the skin, alveoli, and arteries, have a long half-life and are not regenerated once formed during the fetal stage. Consequently, the degradation of elastic fibers due to aging or inflammation can significantly impact tissue function. In the dermis, degeneration of elastic fibers is characterized by degradation in photoaging, driven by UV radiation, and structural abnormalities of elastic fibers in intrinsic aging. However, the mechanisms driving the abnormalities associated with intrinsic aging remain incomplete. This study aimed to identify the factors involved in the elastic fiber abnormalities associated with intrinsic aging of the dermis. Through a comprehensive analysis of gene expression, this study focused on microfibril-associated protein 5 (MFAP5) as a candidate gene responsible for the elastic fiber abnormalities associated with intrinsic aging. Immunofluorescence staining revealed that aged fibroblasts highly expressed MFAP5 and strongly localized it to aggregated elastic fibers. Furthermore, the elimination of MFAP5 expression suppressed elastic fiber aggregation. The exogenous addition of MFAP5 induced thickening and disorganization of elastic fibers, effects that were not observed with the overexpression of MFAP5 in young fibroblasts, which merely express MFAP5. Moreover, MFAP5 inhibited the interaction between latent transforming growth factor β binding protein 4 and fibulin-5, which are crucial for elastic fiber formation. These results suggest that excess MFAP5 expression associated with aging causes abnormalities in elastic fibers. Understanding the role of MFAP5 in elastic fiber abnormalities highlights its potential as a therapeutic target for mitigating intrinsic dermal aging and improving skin elasticity.

One of the side effects of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporin A (CsA), is intestinal mucosal damage leading to ulceration and bleeding. However, it remains to be elucidated whether these side effects are direct effects of calcineurin inhibitors on intestinal epithelial cells (IECs). To determine whether IECs are directly damaged by calcineurin inhibitors, we analyzed the effects of calcineurin inhibitors on the intestinal barrier in Caco-2 cells, a human intestinal cell line. Treatment of Caco-2 with calcineurin inhibitors such as FK506, CsA, and deltamethrin inhibited expression of zonula occludens-1, a tight junction protein, and increased permeability of Lucifer Yellow. These effects were observed in confluent cells, but not clear in subconfluent cells. Our findings suggest that calcineurin inhibitors can directly damage IECs.