We performed the design, synthesis and evaluation of ligands of nuclear receptors [vitamin D receptor (VDR), retinoid receptor and a VDR mutant], stapled short helical peptides as VDR-coactivator interaction inhibitors, and estrogen receptor degradation inducers based on a protein knockdown strategy and selective estrogen receptor down-regulators. We also demonstrated the design and functionalization of helical peptides, and performed conformational analysis of peptides, as well as an in silico study on the prediction of bioactivity for the regulation of new designer drugs.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic bladder disorder of unknown etiology, characterized by pelvic and/or bladder pain accompanied by lower urinary tract symptoms such as urinary frequency and urgency. Currently, sufficiently effective pharmacological treatments are lacking. The non-selective cation channel, transient receptor potential vanilloid 4 (TRPV4), which is expressed in the bladder, responds to mechanical stretch. Its contribution to immune responses in an environment-dependent manner, positions it as a promising potential therapeutic target. I investigated the effects of TRPV4 activation on inflammatory responses and painful bladder hypersensitivity in a lipopolysaccharide (LPS)-induced IC/BPS rat model. Co-instillation of the selective TRPV4 agonist GSK1016790A (GSK) with LPS into the rat bladder alleviated LPS-induced bladder inflammation and modulated macrophage polarization. Moreover, GSK mitigated the LPS-induced increase in bladder pain-related behaviors and voiding frequency. Cytokine analysis revealed the suppression of multiple pro-inflammatory chemokines. These findings suggest that TRPV4 regulates innate immune responses in the bladder, thereby contributing to inflammation resolution and tissue protection, and underscore its potential as a novel therapeutic strategy for IC/BPS. In this review, I integrate my research findings and previous advances in the field to summarize the functional roles of TRPV4 in the bladder.

Toll-like receptors (TLRs) play a key role in initiating innate and acquired immunity, but their overactivation is also implicated in the development of autoimmune and chronic inflammatory conditions. To ensure tight regulation of TLR signaling, it is crucial to understand the expression and function of negative regulators of TLR signaling, such as mucin-1 (MUC1) and single immunoglobulin interleukin-1-related receptor (SIGIRR). Given these aspects, my research has revealed the following findings. 1) Membrane-tethered mucin glycoprotein MUC1 suppresses various TLR signaling pathways via its intracellular domain. 2) Lipopolysaccharide (LPS)-TLR4-p38 pathway suppresses SIGIRR gene expression. 3) Dominant-negative mutant of SIGIRR (Δ8-SIGIRR) reduces cell surface expression of wild-type SIGIRR in airway epithelial cells derived from cystic fibrosis (CF), characterized by chronic lung inflammation. The reduction of SIGIRR disrupts the SIGIRR/interleukin-18 receptor α (IL-18Rα) complex formation with interleukin-37 (IL-37), resulting in the impairment of the diverse anti-inflammatory activities of IL-37. 4) Enhancement of anti-inflammatory pathway via induction of SIGIRR/IL-18Rα expression and interaction. In CF cells, inhibition of histone deacetylase 3 (HDAC3) induces SIGIRR and IL-18Rα expression and restores IL-37-dependent anti-inflammatory responsiveness. To identify compounds as alternatives to IL-37, we developed a novel screening system capable of detecting SIGIRR/IL-18Rα heterodimer formation. Using this system, we discovered natural compounds that promote the interaction between SIGIRR and IL-18Rα. These findings provide fundamental insights into the treatment of inflammatory diseases and highlight the potential of MUC1 and SIGIRR as promising therapeutic targets.

In recent years, factory operations performed using linear transport technology have become a hot topic of discussion, particularly in countries in the European Union. It is widely believed that the use of this approach will cause a paradigm shift in production technology. This would therefore be a good time to promote the use of linear transport techniques in the manufacture of pharmaceuticals and other products in Japan and thus push Japan toward becoming a global production technology powerhouse. In this work, we review state-of-the-art technological information from manufacturers that provide linear systems for use in production and from manufacturers that propose and install these technologies in production plants. We then discuss the application of these systems and technologies to production plants, including a look at the manufacturing companies that operate such plants.

In recent years, production plants have shifted from the production of large quantities of the same product to more flexible production systems that respond to changing consumer needs. Flexibility in production requires both the ability to handle a wide variety of products and the agility to change production plans. Although these goals have been difficult to achieve with conventional technology, linear systems have been touted as a solution. The use of a linear system decreases downtime and increases production per unit area, thereby increasing productivity.

Linear transport systems enable shuttles carrying products to move freely, similar to the movements of robots. In contrast with conventional conveyor lines, which often require multiple machines and human intervention, a single machine can perform various processes, skip unused steps, and transport products safely and at a controlled pace to match the operator’s pace. Although required functions vary from industry to industry, linear transport systems offer intelligent control and thus outperform traditional conveyor systems in complex production tasks, mixed-product manufacturing, and equipment downsizing.

Astatine-211 (²¹¹At) has recently attracted significant attention as one of promising alpha-emitting radionuclides for targeted alpha therapy (TAT), owing to its favorable physical and chemical properties. As a halogen element located below iodine in the periodic table, ²¹¹At enables the adaptation of existing radioiodination techniques. It means potential for applications in radiotheranostics by combining ²¹¹At-labeled agents with iodine-123/124 (^123/124I)-labeled agents. Additionally, ²¹¹At has a relatively short half-life of approximately 7.2 h, making it well-suited for use with tumor-targeting small molecules or peptides that rapidly accumulate in tumors. Here, the development of a ²¹¹At-labeled peptide using arginylglycylaspartic acid (RGD) peptide as a model targeting ligand is reviewed.

Recently, targeted α-therapy (TAT) that uses radiopharmaceuticals emitting α-particles has shown high therapeutic effectiveness and has attracted global attention. Astatine-211 (²¹¹At) is one of the α-emitters applicable to TAT, and ²¹¹At-labeled agents have been actively developed. However, many ²¹¹At-labeled agents suffer from the in vivo deastatination, which causes accumulation of free astatide ([²¹¹At]At⁻) in normal tissues, such as the stomach, thyroid, spleen, and lung. The mechanism of in vivo deastatination remains unclear, and no established strategy exists for producing highly stable ²¹¹At-labeled agents. To address this problem, we have developed a novel astatination method using a neopentyl glycol (NpG) scaffold. Initially, the stability of ²¹¹At-labeled NpG scaffold was demonstrated using a low-molecular-weight model compound. We conjugated the NpG scaffold with various low-, middle-, and high-molecular-weight targeting molecules to produce ²¹¹At-labeled agents. This review summarizes the applicability and usefulness of the NpG scaffold.

Targeted α-radionuclide therapy (TAT) is a systemic therapy for cancer with cancer-targeting compounds conjugated with α-emitters. Since the linear energy transfer (LET) of α-particles are high, relative biological effectiveness is higher than low LET radiation, such as X-rays and β-particles, and the damage to the normal tissues surrounding the tumor is minimal because path length of α-particle is short (a few cells). TAT has demonstrated remarkable therapeutic effects in patients and has attracted considerable attention from physicians and researchers worldwide. In particular, a study published in 2016 showed that disseminated tumors in patients with castration-resistant prostate cancer disappeared following treatment with an actinium-225 (²²⁵Ac)-labeled prostate-specific membrane antigen ligand. What is the powerful antitumor effect of TAT? The molecular mechanisms underlying the antitumor effects of radiation have been well studied in external beam radiation therapy (EBRT). However, as EBRT and TAT are fundamentally different in terms of dose rate, irradiation uniformity, and exposure time, extrapolating the knowledge of EBRT to TAT is difficult. Compared to the research on the development of new TAT agents, studies focusing on the radiobiology of TAT are limited, and the detailed mechanisms of its antitumor effects remain poorly understood. We have developed α-emitting meta-[astatine-211 (²¹¹At)]astato-benzylguanidine ([²¹¹At]MABG) as a novel TAT agent, and investigated radiobiological responses caused by [²¹¹At]MABG using comprehensive gene expression analysis. Here, we introduce the mechanism of the antitumor effects of TAT based on our studies on [²¹¹At]MABG.

Targeted alpha therapy is gaining prominence owing to its superior therapeutic efficacy compared with conventional radionuclide therapies using beta emitters. Astatine (²¹¹At, half-life: 7.2 h) has recently emerged as a promising alpha emitter, along with actinium (²²⁵Ac) and lead (²¹²Pb). It can be produced domestically by irradiating natural bismuth targets with alpha particles using a 30 MeV cyclotron. Chemically analogous to iodine, astatine accumulates in differentiated thyroid cancer cells via the sodium/iodide symporter and demonstrated significant antitumor effects in a xenograft model. At The University of Osaka, we completed the first-in-human investigator-initiated clinical trial using [²¹¹At]sodium astatide (NaAt) in patients with metastatic thyroid cancer refractory to radioiodine (¹³¹I) therapy. The disappearance of iodine-avid lesions and a marked reduction in serum thyroglobulin levels (a tumor marker) were observed, suggesting clinical efficacy. In addition, we developed ²¹¹At-labeled compounds targeting the prostate-specific membrane antigen (PSMA), and a clinical trial is currently underway to confirm their efficacy and safety in preclinical studies. Furthermore, pan-tumor-targeting probes, including amino acid derivatives specific for L-type amino acid transporter 1 (LAT1) and antibodies targeting ephrin type-A receptor 2 (EphA2), are under active development and optimization for clinical applications. Targeted alpha therapy using astatine has great potential to significantly alter the future landscape of cancer therapy.

Pre-mRNA splicing proceeds through two successive trans-esterification reactions: cleavage of the 5′-splice site by the nucleophilic attack from the conserved branch-site adenosine (step I), followed by release of the intron via nucleophilic attack of the 3′ splice site by the phosphate group of the 5′ splice site (step II). These processes are accomplished by the spliceosome, a dynamic macromolecular complex of the U1, U2, U4, U5 and U6 small nuclear ribonucleoproteins (snRNPs). Recognition of the 5′ splice site, the branch point and the 3′ splice site is mediated by the U1 and U2 snRNPs and the U2AF protein, respectively. The binding of these factors, and thereby the splicing pattern of the pre-mRNA, is regulated by hundreds of splicing-associated proteins, which bind near putative splicing sites in response to a variety of biological situations. Our group aims to elucidate the regulation mechanism of the first splicing step, using biochemical and structural approaches. In particular, we focus on the protein–protein and protein–RNA interactions involving the constitutive factors in step I (U1, U2snRNP and U2AF complex) and several splicing regulatory factors. Here, we summarize our findings in the context of recent advances in the field.

In response to the rapid advancement of digital transformation (DX) in healthcare, pharmacists are increasingly expected to interpret and apply electronic health record (EHR) information to support clinical decision-making and patient care. Despite this shift, the integration of educational EHRs into pharmacy curricula remains limited, and their educational effectiveness is underexplored in Japan. This study implemented a structured EHR-based educational program for fourth-year pharmacy students and evaluated its impact on their clinical reasoning, interprofessional perception, and information and communications technology (ICT) literacy. Nineteen students participated in a 240-min program, featuring a pediatric Kawasaki disease case, and utilizing an educational EHR platform. The instructional design included case analysis, group discussion, role-play, and reflection. Educational outcomes were assessed using pre- and post-intervention tests; rubric-based performance evaluations; Attention, Relevance, Confidence, and Satisfaction model questionnaires; and qualitative analysis of open-ended feedback. Statistical analysis using the Wilcoxon signed-rank test revealed significant improvements in knowledge and performance metrics (p<0.05). Students reported high motivation and satisfaction, and qualitative findings highlighted the program’s effectiveness in fostering clinical thinking and team-based care perspectives. However, feedback also suggested the need for workload balance and instructional pacing refinement. These findings indicate that an EHR-based program can serve as a valuable model for developing essential competencies in pharmacy education aligned with evolving professional roles. Future iterations may benefit from incorporating flipped classroom elements, repeated exposures, and diversified assessment strategies to enhance long-term learning outcomes.

Eldecalcitol (ELD), an active vitamin D₃ analog, is extensively prescribed in Japan for the treatment of osteoporosis. However, hypercalcemia remains a significant concern, particularly in patients with impaired renal function. Data on the extent to which renal dysfunction increases the risk of hypercalcemia are limited. This retrospective study investigated the relationship between hypercalcemia and renal function in 212 ELD-treated outpatients at Matsuyama Shimin Hospital. Hypercalcemia was observed in 17.0% of the patients. A weak negative correlation was observed between follow-up serum calcium levels and estimated glomerular filtration rate (eGFR). Receiver operating characteristics (ROC) analysis identified a baseline eGFR cutoff of ≤45.9 mL/min, and propensity score matching (1 : 1) adjusted for 12 covariates, including baseline calcium, demonstrated a significantly higher incidence of hypercalcemia in patients with eGFR ≤45.9 mL/min. These findings indicate that a low baseline eGFR predisposes patients to hypercalcemia during ELD therapy. In clinical practice, patients with baseline eGFR ≤45.9 mL/min may require more frequent calcium monitoring and consideration of alternative treatments such as alfacalcidol, with close collaboration between physicians and pharmacists.

The Edmonton Symptom Assessment System-Revised (ESAS-r) is a simple, reliable, patient-reported outcome measure designed to assess nine symptoms experienced by cancer patients, including multiple myeloma (MM). While each symptom can be evaluated individually, limitations in time or resources may make it difficult to assess all items in routine practice. In such cases, asking about “well-being,” the simplest and most general item in the ESAS-r, may still provide clinically meaningful insight into a patient’s overall condition. Although “well-being” is an essential indicator of a patient’s overall health, its correlation with the other eight symptoms remains poorly understood. In this hypothesis-generating cross-sectional study, we aimed to understand the symptoms of MM patients during initial treatment using the ESAS-r and analyzed the relationship between the patient’s “well-being” and each symptom. The study included 36 patients with first-episode MM who had started induction therapy with bortezomib, lenalidomide, and dexamethasone. “Well-being” was found to be correlated with pain (rs=0.711) and anxiety (rs=0.638). In addition, pain (p=0.0053) and anxiety (p=0.0336) were also significantly associated with the clinical cutoff value. The findings of this study indicate that focusing on “well-being” can increase the likelihood of early intervention in MM patients for symptoms that are difficult to express, such as pain and anxiety. Thorough screening of “well-being” and early introduction of care as needed, even within the limited time of consultation, through multidisciplinary collaboration including pharmacists, may be significant in terms of improving the quality of life of MM patients.