Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis and emphysema, and current drug treatments is limited to symptomatic therapy. Thus, there is an urgent need for development of new treatments to repair alveolar destruction. To regenerate the destroyed alveoli, we focused on the differentiation of alveolar epithelial progenitor cells into type I or type II alveolar epithelial cells that constitute the alveoli. Our concept of alveolar regeneration therapy is based on developing a drug delivery system (DDS) and dry powder inhalation that can efficiently deliver new alveolar regeneration drugs, which were discovered using human alveolar epithelial progenitor cells, to stem cells present on the surface of the alveoli of COPD patients, thereby inducing alveolar regeneration. This review article summarizes our data on the discovery of the synthetic retinoid Am80 as a candidate drug for alveolar regeneration, the construction of a DDS that utilizes a biological mechanism that enhances its effect on alveolar regeneration, and the formulation design of a dry powder inhalation.

Notable advances have recently been achieved in drug therapies for renal cell carcinoma (RCC). Several tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have been approved for metastatic RCC (mRCC). The current first-line treatment for mRCC involves combination therapies using TKIs and ICIs. However, there is no consensus on which TKI+ICI therapy is best or how to select the appropriate therapy for individual patients with RCC. The kidney expresses various metabolic enzymes, including CYP and uridine diphosphate glucose (UDP)-glucuronosyltransferase (UGT). Although information on CYP and UGT expression in the kidney is limited compared to our understanding of liver expression, the main CYP and UGT subtypes expressed at high levels in the kidney are estimated to be CYP2B6, CYP3A5, CYP4A11, CYP4F2, UGT1A6, UGT1A9, and UGT2B7. In RCC, the expression profiles and levels of these enzymes are somewhat altered compared with normal kidney. The main known subtypes of CYP and UGT in RCC are CYP1B1, CYP3A5, CYP4A11, UGT1A6, UGT1A9, UGT1A10, and UGT2B7. High CYP expression has been reported in several cancers, possibly conferring resistance to anti-cancer drugs including TKIs, due to extensive drug metabolism. Additionally, CYP and UGT expression levels may possibly affect cancer prognosis by metabolizing endogenous substrates, regardless of their role in anti-cancer drug metabolism. In this review, I discuss CYP and UGT expression level profiles in RCC based on previously published papers, including ours, and examine possible relationships between these enzyme expression profiles and treatment outcomes for patients with RCC.

Functional foods have attracted increasing attention. To prevent diseases using functional foods, various unhealthy conditions must be addressed, such as blood lipids, blood sugar, and blood pressure. However, there are insufficient functional ingredients available to address these unhealthy conditions. For example, five main ingredients (such as γ-aminobutyric acid) currently predominate in foods with functional claims, and account for approximately 38.2% of the total registered products in Japan. These data suggest that some functional and safe ingredients are widely used. From this perspective, enhancing the lineup of functional ingredients is necessary to address unhealthy conditions and develop various functional foods in the future. Flavoring agents are attractive ingredients. However, studies on flavoring agents have focused only on psychological functions, such as relaxation. In this study, we discuss the potential use of flavoring agents as functional ingredients.

Food-derived components with physiological effects have been attracting attention in recent years, and studies have comprehensively analyzed these components. In this study, we sought to identify food components with functional properties for the prevention and improvement of metabolic syndrome. We performed a luciferase reporter assay using fatty acid synthase (FAS) and low-density lipoprotein receptor (LDL) receptor gene promoters. Naturally occurring isothiocyanate sulforaphane impaired FAS promoter activity and reduced sterol regulatory element-binding protein (SREBP) target gene expression in human hepatoma Huh-7 cells. Sulforaphane reduced SREBP proteins by promoting the degradation of the SREBP precursor. Furthermore, we screened LDL receptor promoter effectors and observed that extract from sweet cherry peduncles induces LDL receptor gene promoter activity. Several analytical and chemical methods revealed that chrysin 7O-β-D-glucopyranoside in cherry peduncle extract stimulated LDL receptor gene promoter activity. Thus, this comprehensive search for components that alter the expression of genes associated with lipid metabolism led to the discovery of new functions of food components.

In an aging society, there is a growing interest in functional foods that offer anti-aging benefits. Food-derived bioactive compounds such as carotenoids and polyphenols can enhance skin elasticity and delay aging. However, the mechanisms by which these orally ingested compounds directly impact the skin are not fully understood. Recent studies on exosomes have suggested significant physiological functions, including their potential for intercellular communication. Similar to mammalian exosomes, plant-derived exosomes are known for their functional roles, including cross-kingdom communication, and their ability to target specific organs in animal models as delivery vehicles. The authors have been investigating the anti-aging effects of kale and have previously reported its benefits on cognitive function and skin aging in mouse models. Long-term oral administration of glucoraphanin-enriched kale suppresses the senescence symptoms in skin and hair and increases type I collagen and antioxidant enzyme expression in skin tissues, indicating its role in promoting skin health. Exosome-like nanoparticles (ELNs) from glucoraphanin-enriched kale appear to modulate the expression of extracellular matrix-related genes. Kale-derived ELNs exhibit great potential for ameliorating skin aging, suggesting their ability to promote skin health through targeted cellular mechanisms and supporting their use as an active natural compound in nutraceuticals and functional beverages.

In recent years, functional foods have attracted increasing attention due to growing health consciousness. When functional food ingredients are poorly water-soluble, they largely fail to be absorbed due to their low solubility in the digestive tract, limiting their ability to exert their functions. To develop poorly water-soluble compounds into viable functional food ingredients, it is important to increase their gastrointestinal absorption so that they can fully exert their functions, and to ensure their safety and efficacy through ADMET research. β-Carotene exerts physiological activities including antioxidant effects, and functions as a source of vitamin A, but it is completely insoluble in water, so it is poorly absorbed from the digestive tract, rendering it difficult to use efficiently as a functional food ingredient. To overcome this problem, we are conducting research on drug delivery system to improve β-carotene solubility and thereby improve its digestive absorption by applying our unique amorphous solid dispersion production technology. To date, we have produced amorphous solid dispersions with dramatically improved water solubility by adding polymers and emulsifiers to β-carotene and kneading these mixtures under heat. The resultant amorphous solid dispersion showed unprecedentedly high gastrointestinal absorption, enhanced inhibition of allergic dermatitis, and enhanced amelioration of cognitive impairment. No major safety issues associated with long-term continuous administration were observed. In this paper, we introduce our efforts to effectively deliver poorly water-soluble compounds such as β-carotene in functional foods.

Pre-eclampsia, a type of hypertensive disorders of pregnancy (HDP), is characterized by hypertension and organ dysfunction that develops or worsens after 20 weeks of gestation. Although symptomatic management using antihypertensive medications has been adopted, definitive treatments other than pregnancy termination remain unavailable to halt disease progression. Research on heme oxygenase (HO)-1, a molecule with anti-inflammatory and antioxidative properties, has shown that a pharmacological increase in placental HO-1 expression and activity may ameliorate this condition; therefore, HO-1 is a promising therapeutic target for this disorder. Medications with properties that can be used during pregnancy are strong candidates for repurposing. In this article, I discuss the potential applications of proton pump inhibitors in the prevention or treatment of preeclampsia by presenting our foundational research and subsequent observational and interventional clinical studies.

The placenta, which acts as an interface between fetal and maternal circulations, is an indispensable organ for fetal growth in mammalian pregnancy. It mediates the transportation of nutrients, the exchange of gases such as oxygen and carbon dioxide, and the excretion of waste products between the fetus and mother. The surface of placental villi is covered by two layers of mononuclear undifferentiated cytotrophoblasts (CT) and multinucleated syncytiotrophoblasts (ST). The formation of the multinucleated ST layer via fusion of CT is referred to as syncytialization, which is a well-characterized morphological sign of terminal differentiation. STs function not only as the placental barrier to separate maternal blood from fetal tissue but also as the main source of human chorionic gonadotropin (hCG) and progesterone (P4) during pregnancy. The significance of appropriate differentiation and fusion of CTs to form STs is demonstrated by the finding that disturbance of these processes is linked to the pathogenesis of pregnancy-associated complications such as hypertensive disorders of pregnancy (HDP) and fetal growth restriction (FGR). In this review, we focused on trophoblast differentiation, cell fusion and microvilli formation, and showed the role of short-chain fatty acid butyrate and progesterone receptor membrane component 1 (PGRMC1) in these processes. Furthermore, we described the evaluation of placental function and its prospects utilizing a quantitative trophoblast cell fusion system and microfluidic device.

The use of Japanese herbal medicines (Kampo medicines), rooted in centuries of traditional practice, lacks extensive Western scientific validation regarding their safety. Concerns include potential risks such as placental dysplasia, miscarriage, teratogenicity, and fetotoxicity when administered to pregnant women. Therefore, scientific safety evaluations are crucial for the appropriate use of Kampo medicines during pregnancy. Critical physiological processes such as implantation, invasion into the endometrium, placentation, and fetal development are vital for establishing a successful pregnancy. The placenta, forming from implantation until birth, is essential for fetal growth and nutrition. Proper placental function relies on the regulated differentiation and development of specific trophoblast cell lineages. If Kampo medicines impact these cell lineages, there may be increased risks of fetal developmental issues and pregnancy complications. current studies often neglect evaluating placental function or formation, focusing primarily on fetal toxicity and teratogenicity. Thus, assays for placental function and placentation toxicity are needed. This review consolidates existing knowledge on the effects of Kampo medicines, herbs and herbal medicines on pregnancy and placentation, emphasizing the necessity for scientific safety assessments to guide their use during pregnancy. Ensuring accurate information and safety of Kampo medicines, herbs and herbal medicines for pregnant women is essential to safeguard the health of the mother, fetus, and placenta.

Pemetrexed is a folate analog inhibitor for the treatment of non-small-cell lung cancer (NSCLC). Prophylactic supplementation with vitamin B₁₂ and folic acid reduces hematotoxicity associated with pemetrexed. Metformin, the antidiabetic agent, has been associated with the potential side effect of vitamin B₁₂ deficiency. This retrospective observational study aimed to evaluate the effect of concomitant metformin use on hematologic adverse events in patients with NSCLC undergoing pemetrexed-based chemotherapy using the Medical Data Vision Database. Patients with stage III or higher NSCLC who received pemetrexed from April 2008 to May 2021 were categorized into metformin-treated (MTF) and non-metformin-treated (non-MTF) groups. The primary outcome was the proportion of granulocyte colony-stimulating factor (G-CSF) administration during cycle (C) 1 to C2 or C2 to C3 of pemetrexed therapy. Propensity score matching (PSM) was used to balance the baseline characteristics between the groups. A total of 1174 patients met the inclusion criteria (54 in MTF and 1120 in non-MTF). After PSM, 52 patients were included in each group. The median metformin dosage in the MTF group was 500 mg/d before and 625 mg/d after PSM. There were no significant differences between the MTF and non-MTF groups in G-CSF administration (15.4 vs. 21.2%, p=0.446). Multivariate logistic regression analysis also showed that metformin use did not significantly affect hematologic toxicity (odds ratio: 1.208, 95% CI: 0.554–2.634). This suggests that the concomitant use of a relatively low dose of metformin is unlikely to significantly increase the risk of hematotoxicity in Japanese patients with NSCLC receiving pemetrexed-based chemotherapy.

The relationship between the concomitant use of immune checkpoint inhibitors (ICIs) and elevated prothrombin time-to-international standard ratio (PT-INR) in patients receiving warfarin remains unclear. In the present study, 26 patients treated with ICIs during warfarin therapy were examined for increases in PT-INR within 60 d of ICI administration. Of these patients, 13 developed Grade 2 or higher PT-INR elevations, 5 of which required the immediate administration of vitamin K. The increased risk of bleeding and the impact on the continuation of cancer drug therapy are significant burdens for patients. Immune-related adverse events caused by ICIs have been suggested as one of the reasons for increases in PT-INR, and patients taking warfarin and ICIs need to be managed in consideration of the risk of elevated PT-INR by frequently checking the blood coagulation capacity.