Methamphetamine, a psychostimulant drug, acts on dopaminergic neuron terminals projecting from the ventral tegmental area to the nucleus accumbens, which constitutes the reward system in the brain. In addition to dependence triggered by excessive excitation of the reward system, methamphetamine induces various effects, including hallucinations, delusions, and cognitive dysfunction. This means that molecules responsive to methamphetamine are importantly involved in the brain function. This report reviews the functions of Shati/Nat8l and Piccolo, identified as methamphetamine-responsive molecules in the murine nucleus accumbens, in cognitive and psychiatric functions clarified by rodent studies. Shati/Nat8l is related to drug addiction and depression and participates in the synaptic function of the hippocampus to maintain cognitive function. Its upregulation suppresses cognitive disturbance in Alzheimer’s disease pathology. In the nucleus accumbens, Piccolo contributes to the behavioral alteration caused by methamphetamine. Piccolo downregulation in the prefrontal cortex induced schizophrenia-like behavioral and neuronal changes in mice. These findings indicate that Shati/Nat8l and Piccolo exert important functions on the brain and are potential targets for brain disorder studies. It is anticipated that understanding of brain function will be achieved through the analysis of methamphetamine-responsive molecules.

The incidence of type 2 diabetes mellitus (T2DM), a major lifestyle-related disease, is increasing worldwide. T2DM, which accounts for approximately 90–95% of all diabetes mellitus cases, is caused by deficient insulin secretion, tissue insulin resistance, or both. Many therapeutic drugs for T2DM have been developed that target the pancreas, which secretes insulin. The liver is the central organ for glucose and lipid metabolism, and failure of hepatic regulatory mechanisms leads to hyperglycemia, insulin resistance, and lipid accumulation. Here, we focused on the liver as a novel therapeutic target for T2DM. The fatty acid composition of phospholipids, a major component of biological membranes, has received considerable research attention owing to their involvement in T2DM onset and progression. Fatty acids in phospholipids are cleaved by phospholipase A to form lysophospholipids, which are subsequently remodeled back into phospholipids by lysophospholipid acyltransferases (LPLATs). LPLATs play an important role in lipid metabolism and homeostasis by regulating the abundance of various phospholipid species in multiple cell and tissue types. We investigated whether overexpression of LPLAT10, also called LPCAT4 and LPEAT2, in the liver could improve abnormalities in glucose metabolism and help treat T2DM. For overexpression, we generated an LPLAT10-expressing adenovirus (Ad) vector using an improved Ad vector named Ad-E4-122aT, which exhibited higher and longer-term transgene expression and lower hepatotoxicity than conventional Ad vectors. In this article, we review the current findings that changes in hepatic phospholipid species due to liver-specific LPLAT10 overexpression affect the pancreas and suppress postprandial hyperglycemia by increasing postprandial insulin secretion.

In recent years, the number of people suffering from lifestyle diseases such as hyperlipidemia and fatty liver disease has increased rapidly due to westernization of dietary patterns. Among fatty liver diseases, those that are not caused by alcohol are referred to as nonalcoholic fatty liver disease (NAFLD). Some NAFLD can progress to nonalcoholic steatohepatitis (NASH), and further progression of NAFLD can lead to cirrhosis and liver cancer. Although numerous studies have demonstrated the efficacy of dietary polyunsaturated fatty acids (PUFAs), particularly omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), against NAFLD, the detailed mechanisms by which these PUFAs exert their protective effects on the pathogenesis and progression of NAFLD are not well understood. Recent studies using knockout mouse models and genome-wide association studies have suggested a potential role for the enzymes responsible for the biosynthesis of PUFAs (FADS1, FADS2, ELOVL2, and ELOVL5) and their incorporation into phospholipids (LPCAT3/MBOAT5/LPLAT12 and LPIAT1/MBOAT7/LPLAT11) in the development of NAFLD. In this review, we summarize recent findings on the association of NAFLD and PUFAs with a focus on PUFA biosynthetic and metabolic enzymes to discuss the potential role of PUFAs in the prevention of NAFLD.

Neonatal malnutrition has been suggested as a factor contributing to neurological and other disorders. However, the details of this mechanism remain unclear. We focused on fibroblast growth factor 21 (FGF21), an endocrine factor produced in the liver during lactation—the main source of nutrition during the neonatal period— and analyzed its role in the brain. From the RNA-seq analysis of mouse brains, we analyzed the genes whose expression was regulated by FGF21 and their respective functions. We found that FGF21 has two functions in the neonatal brain; FGF21 induces the production of growth hormone-releasing hormone (GHRH) in the hypothalamus and is involved in isoform determination of Kalirin, a Ras homologous guanine nucleotide exchange factor, and promotes neurite outgrowth in the brain. Furthermore, the above mechanism is regulated by SH2-containing tyrosine phosphatase (SHP2) activity downstream of the FGF receptor. Additionally, the conserved intron of the SHP2 gene, Ptpn11, shows altered activity in malnourished mouse brains. In summary, FGF21 functions in neurite outgrowth and GHRH production in the neonatal mouse brain, with the mechanism being regulated by SHP2. However, SHP2 activity depends on nutritional status. Our goal was to elucidate the mechanisms by which FGF21 is involved in the maintenance of the central nervous system during the neonatal period. This study provides new insights into the role of FGF21 in diseases caused by dysfunction due to malnutrition.

Human liver organoids are expected to be a hepatocyte source for preclinical in vitro studies of drug metabolism and disposition. Although these organoids show long-term proliferation, their hepatic functions remain low. Therefore, it is necessary to enhance the hepatic functions of primary human hepatocyte (PHH)-derived organoids. Here, we propose a novel method for two dimensional (2D)-cultured hepatic differentiation from PHH-derived organoids. PHH-derived organoids were established from cryopreserved PHHs. When cultured under a 2D condition, the single cells from PHH-derived organoids were seeded on collagen type I-coated plates. Then, optimal conditions for hepatic differentiation were screened using several compounds, cytokines and growth factors. Based on the results of the screening, we determined the 2D-cultured hepatic differentiation method from PHH-derived organoids. Hepatic gene expressions in PHH-derived organoids-derived hepatocytes (Org-HEPs) were greatly increased, compared to those in PHH-derived organoids. An RNA-seq analysis showed that gene expressions related to pharmacokinetics were upregulated in Org-HEPs compared to PHH-derived organoids. The metabolic activities of CYP1A2, CYP2C8, CYP2E1 and CYP3A4 were at levels comparable to those in PHHs. We also treated Org-HEPs and PHHs with hepatotoxic drugs, such as acetaminophen, troglitazone, amiodarone and clozapine. The cell viability of Org-HEPs was almost the same as that of PHHs. These results suggested that PHH-derived organoids could be differentiated into highly functional hepatocytes in 2D culture, and Org-HEPs could be used for hepatotoxicity tests. Thus, Org-HEPs will be useful for pharmaceutical research.

Familial hypercholesterolemia (FH) is characterized by high serum low-density lipoprotein cholesterol (LDL-C) levels from birth, tendon/skin xanthomas, and premature coronary artery disease. The prevalence of FH is 1 per 300 individuals in the general population. FH is caused by a pathogenic (rare) variant in the LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. In Japan, there has been only one reported case of a family with FH caused by the known APOB p.(Arg3527Gln) variant. Those without pathogenic variants in the LDLR or PCSK9 genes account for approximately 36% of patients with FH. Novel causative genes/variants of FH have been explored in patients with FH worldwide, but no gene variants with a large effect size have been found. Polygenic hypercholesterolemia accounts for approximately 10% of patients with clinical FH. We performed whole-exome sequencing in 122 families without pathogenic variants in the LDLR and PCSK9 genes. However, we could not find novel causative genes/variants of FH via family analysis. We examined all the APOB variants and showed that the low-frequency APOB p.(Pro955Ser) variant has a moderate effect size in FH patients via functional analysis of hepatocytes. We also reported that low-frequency PCSK9 variants contribute to the severity of the FH phenotype in patients with FH harboring an LDLR pathogenic variant. Thus, the combination of low-frequency variants and age, environmental factors such as diet, or other genetic factors contribute to the severity of or variability in the FH phenotype.

Based on the perspectives of the environment, food, and health, this review reflects on previous research examining stem cells for the early detection of chemical hazards and the development of preventive health tools. The risks posed by endocrine-disrupting chemicals in the environment are investigated, including studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), phthalate esters, and bisphenol A. Building on the findings of these studies, this review identifies emerging challenges in the field of endocrine-disrupting chemical research. Moreover, this paper explores innovative testing methods aimed at accurately evaluating the impact of chemicals on human health. The key topics covered include the implementation of developmental neurotoxicity testing methods, the species-specific effects of methylmercury, nanomaterials and the application of human pluripotent cells to assess the effects of low-dose radiation. Additionally, this review highlights transformative approaches in chemical health impact assessment that integrate cell science and artificial intelligence, and addresses challenges related to the application of multi-omics technologies in environmental health and toxicology.

As I recently retired from Chiba University, I would like to describe how I began my research career, some of my accomplishments in the research field of modeling and simulation, and future prospects in this area. Here, I discuss the research topics of drug interactions, the oral absorption of drugs, analyses of between-group and individual differences in pharmacokinetics based on the theories of physiologically-based pharmacokinetics and population pharmacokinetics, and my roles in implementation of the drug interaction guideline. Furthermore, I also discuss modeling topics unrelated to pharmacokinetics, i.e., the analyses of the long-term progression of chronic diseases, such as Alzheimer’s disease, Parkinson’s disease, and chronic obstructive pulmonary disease using individual patient information; the spread of the coronavirus disease 2019 (COVID-19) pandemic; and prognostic factors of chronic heart failure with the view towards personalized medicine. After completing my Master’s course at Hokkaido University, I joined a pharmaceutical company and worked as a pharmacokinetics researcher for 21 years, while obtaining my doctoral degree. I spent the next 9 years as a hospital pharmacist focusing on scientific research at the University of Tokyo Hospital, and the last 10 years as a Professor of Clinical Pharmacology and Pharmacometrics at Chiba University. My career is, therefore, characterized by involvement in pharmaceutical sciences from many different perspectives. This description focuses rather on the background of the studies than scientific details.

In this study, we assessed the information sharing practices between pharmacists and multidisciplinary healthcare professionals such as doctors, care managers, and nurses, and others. We evaluated the effectiveness of “home medical care management guidance reports” and “home-visit drug management guidance reports” prepared by pharmacists. We also identified factors that could enhance collaborative practices. To improve the reports, we introduced a new report form with an overview column and a reply column. We used the SOAP format in the new reports. We found that the response rate for reports from X pharmacy was significantly higher than that of Y pharmacies. A survey revealed that X’s reports contained more categories (median of 3 versus 1 in Y’s reports). Pharmacy X’s reports had a smaller proportion of pharmacotherapy details, and a larger proportion of information regarding patients’ living and health conditions, as well as environmental factors. We also found that the character count in X’s assessment column was significantly greater (168.5 versus 60), and notably less in the overview sections (12 versus 22) when compared to Y’s reports. Suggestions and guidance constituted a significantly larger portion of X’s reports (29.8% compared to 10.8% in Y’s). Questionnaire feedback from other healthcare professionals to whom the subject pharmacies send reports highlighted the importance of pharmacist-provided information on health and living conditions, based on pharmacological knowledge. Based on these results, to enhance health information sharing, pharmacists should integrate assessments of pharmacotherapy with health and living conditions and effectively communicate this information to other professionals.

Ixazomib (IXA) is a convenient oral anticancer drug; however, due to its fixed dosage, IXA tolerability among elderly Japanese individuals may be reduced. Therefore, this study aimed to clarify the difference in relative dose intensity (RDI) of IXA in IRd therapy in elderly patients. Between October 2018 and September 2023, patients who underwent IRd therapy (IXA, lenalidomide, and dexamethasone combination treatment) at Ogaki Municipal Hospital were enrolled in the study and categorized into two age groups: ≥75 years (group O, n=16) and <75 years (group Y, n=6). We retrospectively analyzed RDI of IXA, in IRd therapy. In addition, we evaluated the reasons for dose reduction or delayed treatment. The median initial IXA dose was 3 mg (range: 2.3–4 mg) and 4 mg (range: 3–4 mg) in group O and Y, respectively (p=0.122). The median RDI in group O (65.8%, range: 51.1–91.7%) was significantly lower than in group Y (93.3%, range: 80.5–100.0%) (p=0.002). Among them, anorexia was more common in group O than in group Y (p=0.049). In group O, dose adjustments were made due to anorexia (n=10), diarrhea (n=5), nausea (n=2), and fatigue (n=2). In group Y, adjustments were made due to diarrhea (n=2) and thrombocytopenia (n=1). Upon IXA (4 mg) administration, the rate of dose adjustments due to gastrointestinal symptoms were 75% and 17% in group O and Y, respectively (p=0.051). Overall, RDI was lower in group O owing to gastrointestinal symptoms. This suggests that the fixed IXA dosage (4 mg) is less tolerable in older individuals.