Fatty liver is defined as a condition in which fat accumulates excessively in the liver. It is characterized by either more than 30% of hepatocytes being fatty or over 5% of the total liver weight attributable to fat. The mechanisms behind hepatic fat accumulation are not fully understood, and no curative treatments have been established; thus, most treatments are symptomatic. Recent studies have focused on the mechanisms involving peroxisome proliferator-activated receptors (PPARs) α and γ, which are central to most research in lipid metabolism and inflammation. However, the development of drugs targeting PPARβ/δ, another isoform, has not progressed as much as for other PPARs. PPARβ/δ is known to play a critical role in maintaining homeostasis in lipid and glucose metabolism, differentiation, and inflammation, similar to other PPAR isoforms, making it a promising target for drug discovery. This review summarizes the potential of PPARβ/δ as a therapeutic target for fatty liver treatment, suggesting that it could be a valuable drug target given its roles in fundamental regulatory mechanisms.

Pediatric drug development is a global challenge. Children undergo organ growth and exhibit different drug reactions than adults, resulting in different pharmacological responses. Therefore, it is necessary to consider children’s physiological characteristics when evaluating drug efficacy and safety in pediatric patients. We conducted drug discovery research for the treatment of pediatric heart failure, based on neonatal-specific physiological functions of angiotensin II. Pediatric heart failure is one of the most important causes of death in children, particularly neonates and infants. However, only a few therapeutic agents are available to treat pediatric heart failure. Angiotensin II binds to its receptors (angiotensin II receptor type 1: AT₁R) and regulates cellular functions through G protein and β-arrestin pathways. We previously found that the β-arrestin-biased AT₁R agonist, TRV027, induced a positive inotropic effect in the hearts of neonatal mice. Acute administration of TRV027 did not affect heart rate, oxygen consumption, or production of reactive oxygen species. The inotropic effect of TRV027 was also observed in human iPS cell-derived cardiomyocytes and a neonatal mouse model of dilated cardiomyopathy. Furthermore, chronic administration of TRV027 improved the survival rate of mice with dilated cardiomyopathy during the preweaning period. These results demonstrate that TRV027 has the potential to be a safe and effective drug for treating pediatric heart failure.

It is difficult to appropriately diagnose the severity of fetal heart failure using only ultrasonography. Biomarkers of fetal heart failure in the fetal blood, amniotic fluid, and maternal blood have not been established. Therefore, we investigated natriuretic peptides (NPs) such as Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and N-terminal proBNP (NT-proBNP) in umbilical cord blood and amniotic fluid in cases of fetuses with congenital heart disease, and investigated whether maternal serum biomarkers could diagnose fetal heart failure. The features of NPs in the umbilical cord blood and amniotic fluid provide a strong basis for their use as biomarkers of fetal heart failure. Maternal serum concentrations of tumor necrosis factor (TNF-α), vascular endothelial growth factor-D (VEGF-D), and heparin-binding epidermal growth factor-like growth factor (HB-EGF) can be used to assess fetal heart failure severity. There are no established transplacental treatments for heart failure in utero, and no animal models or experimental systems of fetal heart failure have been established. We first used an ultra-high-frequency ultrasound imaging system in utero and demonstrated that Hrt2 knockout (KO) embryos had marked left ventricular (LV) dilatation as well as worsening fractional shortening (FS) as gestation progressed, indicating that the embryos can be used as a murine model of fetal heart failure. Subsequently, we evaluated the effect of tadalafil treatment on fetoplacental circulation in Hrt2 KO embryos. LV FS was significantly higher in the tadalafil group than in the control group. Maternal administration of tadalafil improved LV systolic function without altering LV morphological abnormalities in Hrt2 KO embryos. Our findings suggest that tadalafil may effectively treat impaired fetal ventricular systolic function.

Age-appropriate pediatric formulations are needed to achieve optimal medication adherence in children. In Europe and the United States, mini-tablets (MTs) have garnered interest as a new pediatric formulation that is easier to swallow than liquid formulations (LFs). In Japan, fine granules (FGs) are also common for children. Acceptability of a medicine is likely to have significant impact on pediatric adherence. We examined the acceptability of drug-free MTs and compared it with that of FGs and LFs in children aged 6 months to 8 years who were visiting a pediatric department in Showa University Hospital. The primary endpoint was the measure of acceptability by observation of healthcare professionals according to pre-defined evaluation criteria. We compared the percentage of children who could swallow MTs without chewing with that of children who could swallow FGs or LFs without leftover. MTs showed lower swallowability compared to FGs and LFs in children aged 2–6 years, likely because children tend to chew on MTs. In contrast, significantly more children aged 6–11 months could swallow the MTs than those who could swallow all the FGs and LFs. No significant differences were observed in children aged 12–23 months. Palatability and swallowability are important for acceptability. Parents of children aged 6–23 months rated palatability after taking the three formulations. We combined the swallowability and palatability results into a new acceptability analysis. MTs did not differ significantly from FGs and LFs in acceptability for infants, but this new endpoint is useful for evaluating oral pediatric formulations.

Countercurrent chromatography (CCC) is a form of liquid–liquid partition chromatography that eliminates the solid support used in column chromatography. This allows the recovery of all samples subjected to CCC separation of bioactive components without denaturation and adsorption caused by interacting with the column matrix. The CCC apparatus requires numerous and continuous partitioning processes composed of the sufficient mixing of the two-phase solvent system, separating into two liquid phases, and moving the mobile phase. The present paper introduces my studies over 35 years on the development and improvement of CCC including the rotation behavior of the coiled column, column configuration, tube design, and two-phase solvent system followed by the application to the separation of bioactive compounds. Among the CCC instruments developed or improved in those studies, the floor-standing type of cross-axis CCC was first domestically produced and prompted the fabrication of benchtop type small-scale cross-axis CCC to achieve satisfactory separation of proteins and enzymes without loss of their bioactivity using aqueous two-phase solvent systems. The coil satellite centrifuge designed and fabricated in our laboratory enabled sufficient separation using a two-phase solvent system after adjusting the suitable rotation speed combination of the sun axis, planet axis, and satellite axis. Better partition efficiency was achieved using an eccentric coil for the analytical-scale and multilayer coil for the preparative-scale. Notably, the multilayer coil wound with long-pressed locular tubing increased the peak resolution within shortened separation times. The high-performance of the CCC apparatus developed will expand the ability to reveal the mechanisms of cell particles.

Diterpenoid alkaloids are major pharmaceutically active constituents of Aconitum plants. In phytochemical investigations on Aconitum japonicum subsp. subcuneatum, Aconitum yesoense var. macroyesoens, and Delphinium elatum cv. Pacific Giant (Ranunclaceae), the structures of isolated C₁₉- and C₂₀-diterpenoid alkaloids were elucidated. Three aconitine-type C₁₉-diterpenoid alkaloids, jesaconitine, aconitine, and mesaconitine, which are main components of A. japonicum subsp. subcuneatum, are significantly toxic to the central nervous system. However, lycoctonine-type C₁₉-diterpenoid alkaloids and C₂₀-diterpenoid alkaloids are less toxic. Several diterpenoid alkaloids from the genera Aconitum and Delphinium and their derivatives exhibited slight cytotoxic activity against several human tumor cell lines [A549 (lung carcinoma), DU145 (prostate carcinoma), MDA-MB-231 (triple-negative breast cancer), MCF-7 (estrogen receptor-positive, HER2-negative breast cancer), KB (identical to cervical carcinoma HeLa derived AV-3 cell line), and multidrug-resistant (MDR) subline KB-VIN]. In our course of studies on synthetic derivatives of the C₁₉-diterpenoid alkaloids delcosine and delpheline and the C₂₀-diterpenoid alkaloids lucidusculine, pseudokobusine, and kobusine, we found several derivatives showing significant cytotoxic activity and, thus, providing promising new leads for further development as antitumor agents. Notably, several diterpenoid alkaloids were more potent against MDR subline KB-VIN cells than the parental drug-sensitive KB cells. Among non-cytotoxic synthetic analogues, several lycoctonine-type C₁₉-diterpenoid alkaloid derivatives effectively and significantly sensitized MDR cells to three anticancer drugs, paclitaxel, vincristine, and doxorubicin.

Active vitamin D₃ (VDRAs) can cause drug-induced hypercalcemia and acute renal failure. Eldecalcitol (ELD), a VDRA, promotes bone formation more strongly than other VDRAs, such as alfacalcidol (ALF), but whether or not ELD affects serum calcium (Ca) levels and renal function more significantly than other VDRAs is unclear. In Japan, the supply of ALF was temporarily stopped in 2021, and patients at Fukuoka University Hospital who were taking ALF were either switched to ELD or discontinued ALF. We retrospectively investigated how these prescription changes affected serum Ca levels and renal function. Sixty-seven adult patients who were admitted to our hospital for at least 5 d between September 2021 and March 2022 and were taking ALF at the time of admission were divided into 3 groups: 36 patients who continued ALF (ALF-C), 12 who were switched to ELD (ELD-S), and 19 who discontinued VDRAs (DC). The changes in weekly serum Ca levels and renal function during hospitalization were compared between the groups. At the second week of observation, the change in the serum Ca level was 0.01 mg/dL in the ALF-C group, +0.45 mg/dL in the ELD-S group, and −0.37 mg/dL in the DC group, showing a significant difference among these groups. In addition, serum Ca levels were increased in all patients in the ELD-S group at Week 2. The estimated glomerular filtration rate didn’t change significantly in any group during hospitalization. These results suggest that serum Ca levels should be measured by Week 2 when ELD is newly started or changed.

Despite that the Japanese package insert for vonoprazan (VPZ) includes a precaution that the potassium ion-competitive acid blocker may potentiate the effects of midazolam (MDZ), reports on the actual effects in clinical practice are lacking. Therefore, in this study, we evaluated whether VPZ-taking patients experience clinical effects under MDZ sedation during endoscopy. The participants were outpatients who underwent upper gastrointestinal endoscopy under MDZ anesthesia between April 2021 and April 2022. Comparisons were made between the VPZ(+) and VPZ(−) groups, and the patient background was adjusted using propensity score matching. The post-examination observation time was prolonged in 16.4% of patients in the VPZ(+) group and 13.7% in the VPZ(−) group, but the difference was not statistically significant (p=0.818). The two patients groups also showed no statistically significant differences in the percentage of individuals who received oxygen administration during the examination or in post-examination oxygen saturation and blood pressure values. These results suggest that the use of MDZ for sedation during upper gastrointestinal endoscopy may have minimal clinical effects arising from drug interaction with VPZ.