The author retired from Iwate Medical University in March 2025 upon reaching mandatory retirement age. On this milestone occasion, I was given the opportunity to write a review article for Yakugaku Zasshi. This review primarily outlines research conducted under Professor Hiroshi Okamoto (now Professor Emeritus, Tohoku University) at the Department of Biochemistry, Graduate School of Medicine, Tohoku University, where I was affiliated before joining the Faculty of Pharmaceutical Sciences at Iwate Medical University. CD38 synthesizes cyclic adenosine diphosphate (ADP)-ribose using nicotinamide adenine dinucleotide (NAD) as a substrate, inducing insulin secretion from pancreatic β-cells via an increase in cytoplasmic calcium ion (Ca2+) concentration. Conversely, DNA damage to pancreatic β-cells activates poly (ADP-ribose) polymerase (PARP), promoting poly (ADP-ribosyl) ation. This depletes intracellular NAD, leading to pancreatic β-cell necrosis. Here, inhibiting PARP activity allows PARP to function as a transcription factor, enhancing the expression of the regeneration/proliferation factor RegI, leading to pancreatic β-cell regeneration and proliferation. Thus research findings from the Okamoto Laboratory suggest that in pancreatic β-cells, cell death, function, and regeneration/proliferation are closely interlinked, with NAD at the center. While NAD's role as a coenzyme is well-established, its physiological significance as a substrate for proteins such as sirtuins, CD38, and PARP, and its link to aging, have also been proposed. The Okamoto Laboratory's research on pancreatic β-cell function, death, and regeneration/proliferation centered on NAD represents pioneering work demonstrating NAD's critical importance in the living organism.
This study aimed to clarify the current status of dispensing assistance and support tasks performed by nonpharmacists and to provide recommendations on quality assurance for these activities. The survey targeted Japanese pharmacists and nonpharmacist dispensing assistants/support staff, thereby collecting information on their demographics, workplaces, the content of dispensing assistance tasks at their facilities, and dispensing-related training. Pharmacists responded to 25 items, whereas nonpharmacist dispensing assistants/support staff responded to 21 items. Nonpharmacist dispensing assistants/support staff participated in dispensing-related tasks at 70% of the surveyed facilities, and only approximately 20-30% of them held registered sellers of OTC drug qualifications. With respect to training frequency, the most common response from pharmacists was "at employment and after near-miss incidents" (237 respondents, 41.4%), followed by "at employment only" (96 respondents, 16.8%). For nonpharmacist dispensing assistants/support staff, "at employment and after near-miss incidents" was also most common (110 respondents, 35.9%), followed by "at employment only" (77 respondents, 25.2%). Among the respondents, 423 pharmacists (73.8%) and 222 nonpharmacist dispensing assistants/support staff (72.5%) indicated that no regular training program existed. These findings suggest the need to review educational systems in various countries and to develop a structured training framework for nonpharmacist dispensing assistants/support staff in Japan that is tailored to local needs. Such efforts could support discussions on appropriate task delegation and ensure quality in dispensing support services.
Extracellular vesicles (EVs), secreted by virtually all cell types, are instrumental in intercellular and intertissue communication; their membranes are characterized by a phospholipid bilayer that is structurally analogous to the cellular plasma membrane. They encapsulate diverse cargo, including nucleic acids, such as microRNAs and various proteins. Recent studies have highlighted the multifaceted biological functions of EVs phospholipid bilayers. For instance, certain lymphoma cells have been observed to exploit secretory phospholipase A2 (sPLA2) to generate lysophospholipids, thereby actively suppressing antitumor immune responses. In addition to highlighting the capacity of lysophospholipids to attenuate the rapid inflammatory reactions characteristic of cytokine storms. This lecture delves into the newly elucidated mechanisms that contribute to inflammation regulation. This presentation primarily focuses on the intricate interplay between EVs, phospholipids, and sPLA2, an enzyme crucial for phospholipid degradation, as the key components of this regulatory axis.
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Nanomaterials have unique functions due to their increased specific surface area compared to conventional materials. Various nanomaterials are already used in the production of many pharmaceuticals, cosmetics, and foods; however, this also means that, regardless of age or gender, it is now impossible to avoid exposure to these unique materials. Currently, there are concerns that nanomaterials may induce unexpected toxicities due to their small size. In addition, safety evaluations related to the exposure of pregnant women and fetuses, who are particularly vulnerable to the toxic effects of chemicals, are lacking globally; therefore, our understanding of the reproductive and developmental effects of nanomaterials is insufficient. Our group expects that understanding more about how the toxic effects of nanomaterials manifest not just in the mother and fetus but also in the placenta, an essential organ for maintaining pregnancy and fetal development, will be crucial for improving our understanding of the mechanisms that underly the reproductive and developmental toxicities of nanomaterials. Based on this, we have conducted a correlation analysis of the physicochemical properties, kinetics, and toxicities of nanomaterials, focusing on the placenta. In this review, we introduce the results of our research about effects of silica nanoparticles on trophoblast syncytial formation and placental kinetics of silica nanoparticles.
Mesenchymal stem cells (MSCs) have emerged as a leading cell source in regenerative medicine due to their multipotency and immunomodulatory capabilities. In recent years, extracellular vesicles (EVs) derived from MSCs have attracted increasing attention as a novel, cell-free therapeutic modality, exhibiting many of the biological effects similar to their parent cells. This review outlines the current status and future prospects of MSC-derived EVs, focusing on their therapeutic mechanisms, standardization efforts, and regulatory trends in Japan and overseas. We further discuss the challenges in the development of EV-based products, including scalable manufacturing, quality control strategies, viral safety, and impurity profiling. The application of Quality by Design (QbD) and single-particle analytics is also highlighted as a means to enhance product consistency and clinical reliability. MSC-EVs have the potential to revolutionize treatment paradigms for various refractory diseases, but their successful implementation will require harmonization of scientific, technical, and regulatory frameworks. This review provides a comprehensive overview of the translational pathway from basic research to clinical and commercial application of MSC-EV therapeutics.
My research has focused on optimizing drug delivery system (DDS) related gene and cell therapies. In my gene therapy research, I first developed a polyethylene glycol (PEG)-conjugated adenovirus vector (PEG-Ad) to allow modulation of adenovirus pharmacokinetics and achieve tumor targeting. Evaluating correlations between PEG-Ad blood retention, tumor tissue delivery, liver accumulation, and gene expression is an important step toward creating tumor-targeting PEG-Ad, demonstrating that a 90% PEGylation rate optimally reduced liver accumulation and improved tumor targeting via enhanced permeability and retention. To enhance tumor targeting specificity, we designed Cys-Gly-Lys-Arg-Lys (CGKRK)-PEG-Ad, in which the tumor-targeting peptide CGKRK was attached to the end of the PEG chain. Although CGKRK-PEG-Ad exhibited similarly reduced liver accumulation to that of PEG-Ad, its tumor delivery was higher than that of PEG-Ad, demonstrating its potent therapeutic efficacy against metastatic tumors. Next, I worked to optimize tumor immunotherapy by controlling immune cells in vivo dynamics. In this study, cytokines were used to activate antitumor immune cells, and chemokines were used to induce intratumoral infiltration by antitumor immune cells. While intratumoral administration of Arg-Gly-Asp (RGD)-Ad-C-C motif chemokine ligand 27 (CCL27) alone did not produce an antitumor effect against OV-HM tumors; however, co-administration with RGD-Ad-interleukin-12 (IL-12) demonstrated a stronger antitumor effect than administration of RGD-Ad-IL-12 alone. Infiltration of cluster of differentiation 3 (CD3)- and perforin-positive cells into tumor tissues was increased by combined administration of RGD-Ad-CCL27 and RGD-Ad-IL-12 compared with administration of RGD-Ad-IL-12 alone. These results demonstrate the importance of controlling the in vivo dynamics of antitumor immune cells.
It is no exaggeration to say that most biological processes are carried out by proteins. However, proteins in the cells of many animals, including humans, will be damaged by various non-physiological modifications with age. The accumulation of such damaged/abnormal proteins is thought to cause a decline in the physiological function of various tissues in aging individuals. To maintain normal physiological function, abnormal proteins must be restored to normal by repair enzymes or removed by protein degradation enzymes, and new molecules must be synthesized and replaced. However, the transcription factors responsible for inducing heat shock proteins involved in the repair of conformationally altered proteins and molecules in the proteasome involved in the degradation of damaged proteins, are altered with age as well. In other words, those proteins involved in maintaining the homeostasis of proteins are also altered themselves with age. This review summarizes the author's 44 years of research on "aging and proteostasis."
ClpP protease is a highly conserved serine protease that plays a crucial role in bacterial protein quality control alongside its partner AAA+ ATPases. ClpP assembles into a barrel-shaped tetradecamer that degrades unfolded or misfolded proteins translocated by ATP-driven unfoldases, such as ClpC, ClpX, or ClpA. Acyldepsipeptide (ADEP) antibiotics bind to the hydrophobic pockets of ClpP, mimicking the natural interaction with ATPases, thus activating ClpP in an ATP-independent manner. ADEP binding induces major conformational changes that open the axial pores, enabling ClpP to degrade large protein substrates such as the cell division protein FtsZ, ultimately causing cell death. Our recent studies revealed that in Bacillus subtilis the ClpP proteolytic system regulates the intracellular levels of nonribosomal peptide synthetases SrfAA, SrfAB, and SrfAC, which are responsible for surfactin biosynthesis. Moreover, ADEP1-activated ClpP directly degraded SrfAA and SrfAB both in cells and in vitro, identifying new physiological substrates of the ADEP1-ClpP complex. High-speed atomic force microscopy (HS-AFM) analysis visualized the stepwise oligomerization of B. subtilis ClpP from monomers to heptamers and then to tetradecamers upon ADEP1 binding, revealing dynamic assembly processes underlying its activation. These findings enhance our understanding of bacterial protein degradation mechanisms and provide a molecular basis for the rational design of ClpP-targeting antibiotics with novel modes of action.
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The blood-retinal barrier (BRB) consists of the inner and outer blood-retinal barrier (abbreviated as inner BRB and outer BRB). The inner and outer BRB's together regulate the transport of substances between the blood and neural retina via various membrane transporters. To utilize the oral administration for the pharmacotherapy of retinal diseases, it is necessary and important to understand many drug transport mechanisms in the BRB's. This review discusses the BRB transport research reported over more than a quarter of a century, particularly the development of in vitro and in vivo transport evaluation systems as well as newly discovered BRB-specific cationic drug transport mechanisms.
This study focuses on developing functional "molecules" and "reactions" aimed at controlling biomolecular functions. In the aspect of molecules, the asymmetric total syntheses of (-)-stemonamine and (-)-isostemonamine, which are stemona alkaloids isolated from Stemona japonica, were achieved. The strategy featured an intramolecular acylation to construct a seven-membered lactam and a tandem [2+2] cycloaddition/Dieckmann condensation to build the cyclopentenone ring, yielding the stemona alkaloids with high optical purity. Detailed kinetic analyses experimentally revealed, for the first time, the details of racemization and epimerization of/between stemonamine and isostemonamine. Biological assays demonstrated that (-)-isostemonamine exhibited potent antiproliferative activity against ERα-negative breast cancer cells. This synthetic methodology paves the way for the supply of stemona alkaloids whose biological activities are unknown and which have not yet been synthesized, and it is expected to greatly contribute to elucidating the biological functions hidden within their unique structures. In the aspect of reaction, a highly acid-sensitive Nazarov reaction proceeding under weakly acidic or even neutral conditions was developed. Key to this unprecedented reaction was the synergistic combination of (i) enhanced Lewis basicity of the carbonyl group, (ii) promotion of cyclization, and (iii) irreversible phenol elimination that shifts the reversible cyclization equilibrium toward the product. This system was further extended to a "molecular release reaction," enabling fluorescent dye liberation in aqueous media. While further development is still required, the methodology offers a basis for future exploration of biocompatible acid-responsive reactions and the establishment of new biochemical tools that releases molecules targeting the acidic environment within living systems.
The interactions between 4 compounds used as influenza neuraminidase inhibitors-oseltamivir, zanamivir, laninamivir, and peramivir- and influenza virus neuraminidase were analyzed using pair interaction energy decomposition analysis based on fragment molecular orbital (FMO) method, quantitatively elucidating binding characteristics of each inhibitor. Our calculations revealed that structures with common functional groups showed similar binding characteristics, whereas structures with functional groups differing in hydrophilicity/hydrophobicity showed different types of intermolecular interactions for the same amino acid residues. Such analysis is expected to be effective for precise molecular design in structure-based drug design.
The field of epitranscriptomics, an area of genetics concerning the regulation of gene expression via post-transcriptional RNA modification, is currently attracting substantial research attention. In epitranscriptomics, proteins, collectively termed writers, erasers, and readers, enter into complex interactions that contribute to modifying RNA, thereby maintaining biological homeostasis. However, abnormalities in the expression or function of these proteins can lead to the onset and progression of cancers and neuropsychiatric disorders. Using prostate cancer clinical specimens, I cloned a novel gene, prostate cancer antigen-1 (PCA-1), containing a domain similar to the 2-oxoglutarate, iron(II) [Fe(II)]-dependent oxygenase domain of the Escherichia coli AlkB protein and characterized by enzymatic activity associated with the demethylation of methylated RNA. This was accordingly designated AlkB homolog 3 (ALKBH3). I demonstrate that ALKBH3 is highly expressed in tumor cells in prostate, pancreatic, lung, and other cancers, and its activity is correlated with a poor prognosis. In addition, I developed novel compounds that inhibit the RNA demethylase activity of ALKBH3, thereby providing a basis for developing a first-in-class cancer therapeutic. I also succeeded in cloning the ALKBH8 gene. High ALKBH8 expression was also observed in bladder cancer cells. Furthermore, abnormalities in development and behavior were noted in the generated Alkbh8 knockout mice. On the basis of the experience gained from ALKBH3 drug discovery research, I have established a foundation system for supporting academic drug discovery research. In this review, I describe the pathway followed in integrating the findings of basic pharmaceutical and drug discovery research and further developments.
Although still controversial in some aspects, the human papillomavirus (HPV) vaccine is widely recognized as a tool for preventing cervical cancer. However, Japan has historically struggled with vaccine hesitancy due to misinformation and public concerns about side effects. This cross-sectional preliminary study investigated an emerging social media trend, the "praise movement," in which users on X (formerly Twitter) commend individuals for receiving the HPV vaccine. Although the data collection period was short in 17 d and limited volume of posts were included in the analysis (n=70), we identified the movement when the term "HPV vaccination" appeared on Japan's trending list on X. Through sentiment analysis and content categorization of posts, we found that the majority of posts (91.4%) exhibited positive sentiment, whereas 5.7% were negative. While previous studies have documented negative reactions to HPV vaccination on social media, this study highlights a shift toward positive reinforcement. The praise movement may reflect a broader shift in public attitudes toward HPV vaccination, influenced by both grassroots advocacy and official efforts, including the catch-up vaccination program. Given this study is just a snapshot of a short period and a small volume of trend, a further in-depth study should be warranted. Nevertheless, our findings suggest that online communities can play a meaningful role in influencing public health behaviors, providing insights into potential strategies for improving vaccine uptake. This study offers valuable perspectives on digital health communication and its implications for addressing vaccine hesitancy in Japan and beyond.
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As human pharmaceuticals are physiologically active substances, it is essential to assess their potential risk to ecosystems after being released into the environment. In Japan, the "Guidance on the Environmental Risk Assessment in New Pharmaceutical Development" (hereafter referred to as "the guidance") was issued in 2016. The guidance includes the environmental risk assessment (ERA) workflow, in which novel pharmaceuticals subjected to ecotoxicity testing are selected based on n-octanol/water partition coefficient (log Kow), action limit (0.01 µg/L), and predicted environmental concentration (PEC). However, for the ERA workflow, neither the action limit has been completely validated nor a method to calculate PEC has been sufficiently established. The objective of this study was to demonstrate the effectiveness and issues of the ERA workflow in the guidance. Using data accumulated from ecotoxicity studies and measured environmental concentration (MEC) data of human pharmaceuticals, we evaluated the validity of the action limit and PEC values. The action limit was found to be sufficiently on the safe side, and the PEC values (to median or 95th percentile MEC values) were generally on the safe side for the evaluated pharmaceuticals. Conversely, issues were also identified, which included a need to establish exemption rules for some specific pharmaceuticals with toxicological concerns at a concentration below the action limit and to refine the PEC calculation method based on the consideration of drug metabolism and environmental fate. The endeavor to address these issues will increase the reliability and effectiveness of the workflow.
In recent years, cancer chemotherapy has been administered in an outpatient setting; therefore, patient self-management of adverse events is an important issue. Pharmaceutical interventions were performed by pharmacists at the following 3 time points: before the physician consultation, after the physician consultation, and during multidisciplinary conferences at the Ibaraki Prefectural Central Hospital Cancer Chemotherapy Center. In this study, prescription proposals and their effectiveness for adverse events, were investigated. Of the 338 cases in which pharmaceutical interventions were performed, 280 were accepted by physicians, and the acceptance rates were 77% in conference, 89% before physician consultations, and 85% after physician consultations. Pharmaceutical interventions for the management of nausea and vomiting were most frequently accepted (96 cases), with improvement observed in 58 cases (60%). Improvement rates for hypertension and skin disorders were 76% and 56%, respectively, and improvement rates for peripheral neuropathy and dysgeusia were 33% and 22%, respectively. Of all interventions made by pharmacists, 68% were for the 1st 5 courses, with proposals continuing beyond the 6th course, suggesting that there is demand for long-term intervention. Pharmacists collecting patient information and implementing pharmaceutical interventions may contribute to the management of adverse events. As the degree of improvement varies according to the type of adverse event, it will be necessary to establish optimal pharmaceutical interventions in the future.
Targeted protein degradation (TPD) is an emerging approach that selectively eliminates specific proteins using synthetic molecules, such as proteolysis-targeting chimeras (PROTACs). It has attracted increasing attention in medicinal chemistry and chemical biology, with several PROTACs being tested in clinical settings. Unlike traditional small molecules, such as enzyme inhibitors and receptor antagonists, PROTACs exhibit a fundamentally different mechanism. Conventional drugs block enzymatic activities or receptor interactions, whereas PROTACs induce the degradation of target proteins, decreasing their cellular levels and abolishing all associated functions. PROTACs targeting enzymes in protein complexes disrupt both their catalytic activity and involvement in complex formation. In some cases, they also degrade other proteins in complexes, facilitating the elimination of entire assemblies. Our study leverages these unique features of TPD. We are currently developing various PROTACs targeting the enzymes responsible for lysine acetylation or methylation in proteins. Recently, the TPD concept has been extended beyond proteins to include nucleic acids, and ribonuclease-targeting chimeras (RIBOTACs) that selectively degrade RNA have been developed. We are also actively exploring new RNA-targeted degradation strategies. Herein, we highlight our recent work on TPD-inducing small molecules and provide an overview of RIBOTACs, which represent an area of growing research interest.