Cellular aging is one of the most extraordinary phenomena that mammalian cells undergo in vivo and in vitro. We have been observing their behavior for approximately 4 decades and here would like to summarize some of our salient findings. Normal cells such as human diploid cells exhibit finite growth potential in vitro as well as a set of senescent cell phenotypes. Those changes appear probabilistic and irreversible. In the search of the factor(s) to evoke the features we have observed that cellular glycosaminoglycan molecules plays significant roles in the cell physiology. Besides, CCAAT-box binding transcription factor NF-Y relates to the aging-coupled changes in gene expression, and aging of gastric mucosal cells may relate to a decrease in cytoprotection. As to the intracellular signaling, we have confirmed that the breakdown of phosphatidylinositol bisphosphate is critical for mitogenesis by using micro-injection of its antibody. Subsequently, we have discovered a novel, pivotal adaptor protein Grb2/Ash, a missing link between the receptor tyrosine kinases and their downstream target Ras. The limiting factors for the cellular life span have been considered as telomere shortening and accumulation of cellular and genomic damages. We have observed that telomerase-expressing cells exhibit expanded division potential; yet oxidative stress similarly induces senescent cell phenotypes. Herein we have demonstrated that the treatment of senescent cells with nicotinamide or related reagents elicits unique cellular responses, which might indicate the capability of the cells to recover from the aging.

Barley tea (Mugicha), commonly consumed in Japan and other East Asian countries, is prepared by decocting roasted barley (Hordeum vulgare) seed with hot or cold water. Although barley tea is commonly consumed, studies on its health benefits are limited, especially regarding its bioactivity against thrombosis. During the evaluation of functional foods and drinks, barley tea extract was found to exhibit potential fibrinolysis-enhancing activity induced by urokinase. Therefore, the aim of this study was to explore the application of barley tea as a functional food and conduct a preliminary investigation to reveal the effects of barley tea on thrombosis. Hot water extract of roasted barley was treated with pancreatin and separated via various techniques using macroporous resin and silica gel and tangential flow filtration with an ultra-filtration membrane. The low-molecular-weight fraction of the roasted barley tea extract was found to possess activity. We further purified the extract and found that the activity of each fraction decreased. Thus, the different fractions of the roasted barley extract may not exhibit the activity individually, instead additive or synergistic effects of multiple components may occur. The results suggest the potential use of barley extract as a functional food to prevent thrombosis.

Chemotherapy-induced myositis is a severe adverse event caused by chemotherapeutic agents such as immune checkpoint inhibitors (ICIs) or cytotoxic agents. We experienced a patient with gefitinib-induced myositis with symptoms of muscle cramps and stiffness in the limbs, and reported the treatment process. A 70-year-old woman received four courses of carboplatin (CBDCA)+pemetrexed (PEM)+gefitinib (intravenous CBDCA area under the curve (AUC) 5 and PEM 500 mg/m², every 3 weeks, and oral gefitinib 250 mg daily), for epidermal growth factor receptor (EGFR) mutation-positive stage IV lung cancer treatment; followed by seven courses of PEM+gefitinib, and continued gefitinib monotherapy thereafter. Myositis occurred 5 months after the initiation of gefitinib monotherapy. She developed strong limb cramps despite regular oral administration of 400 mg acetaminophen three times a day and complained of pain on a numeric rating scale of 10/10. Her creatine kinase (CK) was elevated from the second course of CBDCA+PEM+gefitinib but was stable at grade 1–2 thereafter. However, the muscle symptoms disappeared with CK normalization within a few days of gefitinib discontinuation due to disease progression. The Naranjo Adverse Drug Reaction Scale score was 6, suggesting a probable association. Osimertinib (an EGFR tyrosine kinase inhibitor)-induced myositis has been reported, but similar events were first observed with gefitinib in this case. Consequently, when treating with gefitinib, myositis, including the CK variation, should be monitored and appropriately managed with multidirectional treatment.

Unlike many researchers of natural product chemistry, I was fortunate to have the opportunity to study phytochemical metabolites and isolates of microbial origin. I began my career isolating the active compound(s) from the medicinal plants. After obtaining a Ph.D. degree from Tohoku University, I flew to Chicago, College of Pharmacy, University of Illinois, where I carried out research on the chemistry of acronycine and discovered several interesting chemical reactions regarding this alkaloid. After returning to Japan, I began to work at the Kitasato Institute, to search for novel antitumor antibiotics. During this period, 27 new antibiotics were isolated, and the new chemical structures were elucidated. After rejoining the Pharmaceutical Institute at Tohoku University, I again began to work on the phytochemical substances, mainly alkaloids. These studies continued after I moved to Aomori University and finally to Nihon Pharmaceutical University. I was interested in the biosynthesis of the alkaloids and found that all alkaloids could be classified into 16 classes based on their method of biosynthesis. I wrote a book about this in Japanese, and subsequently the book was translated into English as “ALKALOIDS—A Treasury of Poisons and Medicines.” After completing the publication of this book, I had many chances to write books, mainly concerning poisons and medicines. Totally, I have been able to publish 26 books regarding on these fascinating topics until now. I am feeling very satisfied with my natural product chemistry contributions, especially those of alkaloids and poisons.

We held lectures and practices for the regional community residents with the aim of promoting appropriate use of medications. To evaluate the usefulness of our activity, we conducted medicine-related questionnaire surveys (pre- and post-questionnaires) before and after the lectures and practices, and satisfaction with the activity questionnaire surveys (post-questionnaires) after them. We also evaluated the effect of age difference on the results by dividing the participants into elderly (age ≥65) and non-elderly (age <65), before the analysis. In the both (elderly and non-elderly) groups, the ratio of positive answers in several items of post-questionnaire regarding appropriate use of medications was higher than that of pre-questionnaire. These results suggest that the basic medicine-related knowledge improved by attending the lectures and practices, and indicate that the knowledge of the regional community residents is higher than we imagined. Furthermore, there was no difference in the ratio of positive answers between the both groups, suggesting that our activity is applicable to a wide range of age groups. Our activity benefitted the participants, and not only provided education to the regional community residents regarding appropriate drug use, but also lead to the development of regional community activity, by the coming together of the regional community residents of various age.

In this review, the authors review and explain their research on “Discovery of Bonding Active Species Containing Nitrogen Atoms” from the past to the present. The authors are interested in new chemical phenomena, especially in the activation of chemical bonds containing nitrogen atoms, and have conducted research to discover chemical bonds with new properties. The activated chemical bonds containing nitrogen atoms are the following (Fig. 1). (1) Rotationally activated C–N bonds by pyramidalization of amide nitrogen atoms (2) N–N bond cleavage ability with reduced bond strength by pyramidalization of nitrosamine nitrogen atoms (3) Transient hetero atom-N bond formation by neighboring group participation of a halogen electron to the nitrogen cation. (4) A unique carbon cation reaction involving nitrogen atoms, especially nitro groups (C–NO₂ bond) and ammonium ions (C–NH₃⁺ bond). These purely basic chemistry discoveries unexpectedly led to the creation of functional materials, especially biologically active molecules. We will explain how new chemical bonds led to the creation of new functions.

Although the need for homecare medicine for children is increasing in Japan, few studies have focused on the role of pharmacists in this area. The purpose of the present study was to clarify the practice process of pharmacists in pediatric homecare medicine and develop a practice model. Three pharmacists with experience in homecare medicine for children participated in semi-structured interviews. The data were analyzed using the modified-grounded theory approach (M-GTA). The analysis generated 8 categories and 21 concepts. The practice of pharmacists in homecare medicine for children is the pharmacotherapy management process, and it aims at “enabling the transition from hospital to home for children and continuity of their homelife with family” in collaboration with other professions. Above all, the two concepts of “optimization of prescription and device selection to enable the hospital-to-home transition” and “optimization of prescription and device selection for ensuring patient safety” form the core of clinical decision making in the pharmacotherapy management process. By integrating these two optimization concepts, the transfer of patients to home can be undertaken smoothly, leading to safer pharmacotherapy in the lives of patients and their families. Furthermore, pharmacists considered clinical decision making from two perspectives: “the child’s growth-based approach” and “homelife-based approach.” The foundation of these practice processes comprised “professional responsibilities” and “consideration of families’ feelings.”

Several good manufacturing practice (GMP) compliance issues and their associated quality problems that have been revealed since 2020 have led to large-scale recalls and supply suspensions of drug products in Japan. This paper provides an overview of the causes and countermeasures for supply disruptions of low-molecular-weight chemical pharmaceutical agents, focusing on quality-related issues. A recent increase in the use of generic drugs emphasized the importance of strengthening active pharmaceutical ingredient (API) supply chains and ensuring GMP compliance among drug manufacturers. In addition, increasing recalls in the drug products of certain marketing authorization holders due to storage stability problems strongly suggests the need to improve their development process considerably. Other measures to stabilize the supply of pharmaceuticals, including increasing stockpiles of APIs, were also discussed.

Sandhoff disease (SD) is a glycosphingolipid storage disease resulting from a genetic mutation in HEXB and associated deficiency in β-hexosaminidase activity. This defect causes abnormal accumulation of ganglioside GM2 and related glycolipids in lysosomes, resulting in progressive deterioration of the central nervous system. Hexb-knockout (Hexb^−/−) mice, an established animal model, show abnormalities similar to the severe phenotype seen in human infants. We used iPS cells derived from this mouse model (SD-iPSCs) to examine abnormal neuronal lineage differentiation and development in vitro during the asymptomatic phase of SD. Differentiation ability along the time axis appears to be altered in SD-iPSCs in which the differentiation ability of neural stem cells is promoted and differentiation into neurons is completed earlier, while the timing of differentiation into astrocytes is accelerated. This abnormal differentiation was suppressed by introducing the Hexb gene. These results indicate that the abnormal differentiation of SD-iPSCs into the nervous system reflects the pathogenesis of SD. Analysis using Hexb^−/− mice revealed that activated microglia causes astrogliosis at the early stage of development that can be ameliorated via immunosuppression. Furthermore, reactive astrocytes in the cortex of Hexb^−/− mice express adenosine A_2A receptors in the late inflammatory phase. Inhibition of this receptor resulted in a decrease in activated microglial cells and inflammatory cytokines/chemokines. These results suggest that the astrocyte A_2A receptor is important as a sensor that regulates microglial activation in the late inflammatory phase. Thus, our results provide new insights into the complex pathogenesis of SD.

Green tea components, such as catechins have been reported to provide several benefits including anti-oxidative, anti-viral/bacterial, and anti-inflammatory effects in vitro and in vivo. Catechins effectively inhibited the adsorption and replication of the influenza virus. Additionally, green tea contains theanine and vitamin C, which enhance the immunity against viral/bacterial infections. Based on these, green tea is hypothesized to have potential benefits in the prevention of influenza and other respiratory tract infections in the clinical setting. However, its specific effects in patients remain unclear. To determine the clinical significance of green tea in the prevention of respiratory tract infections, we conducted an observational study and eight interventional studies. Based on the results of three studies, consuming or gargling green tea or its components significantly aided in the prevention of influenza. Meanwhile, one study showed that green tea successfully prevented common colds. Catechin inhalation was also reported to decrease the bacterial load of methicillin-resistant Staphylococcus aureus in the sputum. Although the anti-viral/anti-bacterial effects of green tea components have been demonstrated in experimental studies, the clinical evidence remains limited. Further studies are required to confirm the clinical efficacy of green tea and its components in preventing respiratory tract infections.

The globalization of drug trade has led to the increased production of falsified medicines. In addition, poor medication adherence increases the costs of healthcare. The need to manage medication has given rise to marketing of highly functional networked digital medicine. Therefore, a growing need has emerged to ensure the traceability of pharmaceutical products from shipment to patient distribution. Microtaggant technologies that can encode individual numbers on pharmaceutical products are expected to serve achieving this goal. Taggants are a class of materials that can be applied to an object to make it identifiable, like barcodes and holograms. Since the smaller size of microtaggant make it invisible to naked eyes, it is more difficult to reverse-engineer than conventional taggants. The U.S. Food and Drug Administration (FDA) has established guidelines for the use of microtaggants. Many studies have explored the use of various analytical technologies and materials as the microtaggants. However, the advantages and disadvantages of each method have not been established yet. In this review, recent research on the use of microtaggants for anti-counterfeiting is summarized and compared to current anti-counterfeiting technologies with spectrographic methods, distribution management systems with barcodes, and medication management systems with sensor devices. We also discuss the microtaggants implementation costs and security level.

It is well-established that G protein-coupled receptors (GPCRs) transduce signals into cells using G proteins as intermediary molecules. β-Arrestins are molecules involved in regulating GPCRs; however, it has recently been reported that β-arrestins can also mediate signaling through GPCRs. Signaling through G proteins or β-arrestins can be activated selectively using specific agonists; of the latter, those that can selectively activate either G proteins or β-arrestins are called biased agonists. The clinical use of biased agonists could potentially induce fewer side effects. However, partial agonists can also explain the mechanism of G protein-biased agonists; thus, appropriate assay systems must be considered. Endogenous agonists are known to bind to orthosteric and allosteric sites in the agonist binding site, and the allosteric site is associated with the activity of biased agonists. This current review presents a detailed discussion of biased agonists.

Studies on the isolation and molecular mechanisms of phytochemicals with anti-tumor or anti-inflammatory properties are important to developing new drugs for cancer and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. In the course of a study to screen bioactive isoflavones from Erythrina poeppigiana (Leguminosae), we isolated an isoflavone with potent apoptosis-inducing activity against human leukemia HL-60 cells. It was designated erypoegin K. The studies demonstrated an enantiomer, (S)-erypoegin K, displayed selective cytotoxic activity, was a novel inhibitor of topoisomerase II, and possessed anti-tumor activity both in vitro and in vivo. We identified other apoptosis-inducing isoflavones with the ability to inhibit glyoxalase I. Dimeric acridone alkaloids, carbazole alkaloids, and coumarin and quinoline derivatives—all obtained mainly from plants in the family Rutaceae—induced apoptosis of HL-60 cells via the production of reactive oxygen species and mitochondrial dysfunction. We also identified terpenoid coumarins, carbazole quinones, rotenoid derivatives, and quinolone alkaloids with anti-inflammatory activities. These compounds reduced nitric oxide (NO) production from RAW264.7 macrophage cells stimulated with lipopolysaccharides and interferon-γ. Some of the compounds displayed neuroprotective activity by reducing NO production. This review primarily describes our recent studies on erypoegin K, and other compounds with apoptosis-inducing and anti-inflammatory activities.

This review summarizes one portion of the research for which the author received the Pharmaceutical Society of Japan Award. The complete title of the awarded research is “Pharmacological Studies on Metabolism and Functions of Biomembrane Lipids”. Because the awarded research is a very broad study, this review describes the discovery, physiological functions, and congenital defects of α-tocopherol transfer protein (α-TTP), a critical factor in determining the transport of vitamin E in the body, which has been the focus of the author's work throughout his research career.

Naldemedine (Nal) is widely used as a therapeutic drug against opioid-induced constipation. However, patients in phase III trials are limited to those with good performance status (PS). Cancer patients may have inferior PS owing to progression of symptoms and adverse events from chemotherapy. Therefore, it is important to survey the efficacy of Nal in patients with poor PS. This study aimed to evaluate Nal efficacy in patients with poor PS. We retrospectively investigated patients from July 2017 to June 2019 and compared Nal efficacy between patients with good and poor PS. The efficacy of Nal was evaluated using changes in the number of spontaneous bowel movements 7 days before and after the introduction of Nal with reference to previous reports. Multivariate analysis was performed to reveal whether poor PS affects Nal efficacy. In total, 141 patients at the Hokkaido University Hospital were analyzed. The effective rate of Nal from day 1 to day 7 of administration was 71.7% and 71.4% in the patients with good and poor PS, respectively, that from day 1 to day 2 of administration was 61.1% and 57.1%, respectively, and that from day 3 to day 7 of administration was 60.2% and 71.4%, respectively, suggesting an absence of significant differences. Furthermore, results of multivariate analysis showed that “best supportive care” and “body weight (55 kg and above)” reduced Nal efficacy. In conclusion, Nal showed similar effectiveness in patients with poor PS as that in those with good PS.

Natural medicines, including crude drugs and Kampo prescriptions, have a long history of clinical uses. An important characteristic of natural medicines is that they are multicomponent medicines. Kampo prescriptions, particularly, usually consist of several crude drugs that contain a large number of constituents. The therapeutic effects of a Kampo prescription result from the total effects of its constituents and not from the effect of a representative constituent with a strong pharmacological effect. In fact, only a few of these constituents with strong biological activity have been listed in the Japanese Pharmacopoeia as therapeutic agents. During my research career, I have observed various synergistic effects and interactions among the constituents of natural medicines. This article reviewed our researches on the biologically active constituents of natural medicines, including the analysis of the anti-inflammatory constituents of orengedokuto (a Kampo prescription). Understanding the role of each constituent with therapeutic effects in Kampo prescriptions forms a scientific basis of Kampo medicine. This will enable the better use and quality control of Kampo prescriptions. Moreover, this will aid the future development of a multicomponent mimic for a specific effect of a Kampo prescription using the appropriate mixture of active constituents in amounts found in the prescription. The above is my dream as a natural product chemist, and I believe that the mixture can do more than we anticipate!

Discovery of natural products that possess novel chemical structures and pharmaceutical activities increases opportunities of drug development. Filamentous fungi have been recognized as an attractive source for pharmaceutically beneficial natural products. Genome sequencing innovation represented by Next-generation sequencer opened fungal genomes one after another, suggesting that one fungal strain has far more biosynthetic gene clusters than that are estimated from the number of previously isolated natural products. In addition, bioinformatics analyses have indicated that most biosynthetic gene clusters are silent under laboratory culture conditions and there are a huge number of natural products hidden in the fungal genome. Therefore, we focused on those silent biosynthetic gene clusters as a potential source for novel natural products and developed methods to activate silent biosynthetic gene clusters by using low molecular weight molecules. In this review, we describe on discovery of novel natural products through activating fungal silent biosynthesis by addition of epigenetic modifiers and plant hormones.

The use of flame retardants, namely bis(2,3-dibromopropyl) phosphate (BDBPP) and tris(2,3-dibromopropyl) phosphate (TDBPP), in textile products such as curtains, carpets and sleeping clothes is banned in Japan under the ‘Act on the Control of Household Products Containing Harmful Substances’. Herein, we developed a GC-MS based method to quantify these compounds with greater accuracy and safety than the current official method. For accurate and sensitive quantification, deuterated compounds, BDBPP-d₁₀ and TDBPP-d₁₅, were used as surrogate standards. In consideration of the safety of the analyst, certain solvents and reagents used for the pretreatment that are carcinogenic or have a risk of explosion were replaced. For the extraction step, benzene was replaced by ethyl acetate, and for the methyl derivatization step, the reagent was changed from a self-prepared solution of diazomethane in ether to a solution of trimethylsilyl diazomethane in hexane, a safe and easy-to-use commercially available reagent. The calibration curves were liner in the range of 0.5-8.0 μg/mL for both methylated BDBPP (BDBPP-Me) and TDBPP. The detection limit was 0.05 μg/g for BDBPP-Me and 0.3 μg/g for TDBPP, which is sufficiently low compared to the current detection limits of 10 μg/g for BDBPP-Me and 8 μg/g for TDBPP. The recoveries in various curtain material were 66-108% and relative standard deviations were 1.2-10.2% when 5 μg BDBPP and TDBPP were added to 0.5 g of samples. Thus, the developed method is applicable to textile products of various materials.