In addition to direct activation by pathogens and antigens, immune cell functions are further modulated by G protein-coupled receptor (GPCR) signals that are evoked by environmental factors produced in response to immune responses. Recent studies have revealed that membrane-derived lysophospholipids are such environmental factors. When immune cells are activated, phospholipid metabolism becomes active, and under such conditions lysophospholipids are produced by the action of various phospholipases. As a result, the immune responses are regulated positively or negatively via GPCR-type receptors. These lysophospholipids include lysophosphatidic acid (LPA), lysophosphatidylserine (LysoPS), and lysophosphatidylinositol (LPI). Here, we summarize our current knowledge of the synthetic pathways, receptors signaling for these LPLs, and discuss updated findings on the immunomodulatory functions of lysophospholipids, with a particular focus on the recently identified bioactive lysophospholipid, LysoPS.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by progressive muscle atrophy throughout the body. In nearly all ALS patients, abnormal accumulation of the RNA-binding protein TDP-43 is observed in degenerating motor neurons. We have found that RNA-binding proteins such as TDP-43 and FUS are concentrated in GEM bodies, where they contribute to the integrity of the spliceosome machinery involved in pre-RNA splicing. Additionally, the most common cause of ALS, repeat expansion in the C9orf72 gene, triggers abnormal repeat-associated non-AUG (RAN) translation, leading to the accumulation of neurotoxic dipeptide repeat (DPR) proteins. We have identified that these DPR proteins may inhibit GEM body formation and contribute to ALS pathology. Furthermore, therapeutic approaches to suppress RAN translation using dCas13 technology are under development, offering promising new strategies to address abnormalities in RNA metabolism in ALS.

G-quadruplex (G4) is a unique nucleic acid structure that formed when a four-stranded structure is produced within a single-stranded guanine-rich sequence. Four guanine molecules form a square planar arrangement, termed G-quartet, which are stacked on top of each other to form the G4 structure in DNA (G4DNA) and in RNA (G4RNA). Recent studies have revealed that G4DNA and G4RNA are folded in cells, which suggested their biological and pharmacological significance in DNA replication, transcription, epigenetic modification, and RNA metabolism. In this review, I will provide an overview of G4, its identification methods, and the biological functions “G4 biology” that have been reported, as well as its relevance to the neurological diseases that we have reported. 1) we found a neuropathogenic mechanism, “G4 prionoids” in a CGG triplet repeat disease, Fragile X-associated tremor/ataxia syndrome (FXTAS). 2) G4 is a target of cognitive function therapy for ATR-X intellectual disability syndrome, in which mutations are found in a G4 binding protein ATRX. 3) 5-aminolevulinic acid is a potential candidate drug for treating some neurological diseases through the G4 binding ability.

In the motor neurons of amyotrophic lateral sclerosis (ALS) patients, excessive (G4C2)n repeats in the intronic region of the C9orf72 gene are transcribed to RNA, forming G-quadruplexes that sequester RNA-binding proteins, leading to gelation within the cytoplasm as one of the many mechanisms leading to pathogenesis. While ALS patients frequently harbor over 700 repeats, this kind of 100% GC-rich region is very difficult to clone, and past studies report the necessity to add additional sequences in the middle to clone more than a few dozen repeats. The goal of this study was the in vitro production of the longest repetitive RNA to date consisting solely of (G4C2)n repeats. T4 DNA ligase was used to connect (G4C2)10 stretches of DNA with 3nt overhangs. Then, using a heat-resistant T7 RNA polymerase, the RNA obtained contained transcripts over 100 repeats. Artificial biomimetic RNA gels generated by scaling up this synthesis method are expected to contribute to elucidating the molecular mechanisms of repetitive sequence-related pathogenesis, as well as screening for drugs that can disrupt the gel structure.

In recent years, chemical modifications of RNA, known as the epitranscriptome, have been shown to influence not only the regulation of gene expression but also diseases such as neurodegenerative disorders and viral infections. Among them, N⁶-methyladenosine (m⁶A), which is highly abundant in transcripts, has been shown to regulate RNA stability, localization, and translation and has also been implicated in development, differentiation, and cancer. However, there are limitations in understanding the role of individual m⁶As in disease and biological phenomena using enzymatic knockdown methods that alter RNA methylation levels throughout the cell; if RNA methylation states can be selectively regulated by RNA sequences, the function of RNA methylation in a variety of biological phenomena can be elucidated. With this background, systems have been developed to selectively and temporally control the methylation state of specific adenosine. Using RNA-binding proteins that can freely alter the sequence of the RNA to which they bind, we created sequence-specific demethylases and methylases and demonstrated that these artificial proteins can regulate the methylation state of adenosine near the target sequence of the RNA-binding protein. In addition, the switching of methylation and demethylation activities by external stimuli is being developed in combination with external stimulus-dependent heterodimeric systems. In this review, developments in molecular tools for the sequence-selective regulation of epitranscriptomes are presented.

Establishing a robust drug discovery ecosystem is seen as a key priority for enhancing Japan’s drug discovery capabilities. Globally, startups play a significant role in advancing drug discovery. The author’s research demonstrated that startups have recently expanded their role to late-entry drug discovery, the area where large pharmaceutical companies traditionally had strength, while maintaining their contribution to first-in-target drug discovery. Despite the growing importance of startups, Japan has faced challenges in fostering successful drug discovery startups, falling particularly behind in leveraging modality technologies. The development of promising startups requires the establishment of a robust startup ecosystem, as seen in the U.S. and certain European countries. Japan’s ecosystem for supporting drug discovery startups remains fragile due to factors such as low entrepreneurial activity, limited labor mobility, and insufficient investment capital. The author’s research has revealed that in Japan’s unlisted drug discovery startups, “being a corporate spin-off” and “having a leader in research and development with prior experience in corporate R&D” positively impact the startup’s valuation and total funding amounts. In Japan, large pharmaceutical companies still account for the majority of new drug discoveries, with a wealth of promising drug discovery seeds and experienced R&D talent accumulated within these corporations. Facilitating the creation of corporate spin-offs that utilize unexploited seeds within large companies and promoting the transfer of corporate talent to startups could strengthen Japan’s drug discovery ecosystem. This paper will also explore potential policy measures to encourage these developments.

Lemborexant, an orexin receptor antagonist (ORA), was introduced as a safer sleep medication at our hospital, but its prescription rate remained low. To address this issue, promotion of ORAs began in August 2022. This study aimed to evaluate the impact of these activities on the number of patients prescribed lemborexant. And it aimed to evaluate prescription conditions non-benzodiazepine drugs (NBDs) and delirium treatment antipsychotics (DTAs). The study spanned from August 2021 to March 2024, with August 2022 serving as the intervention point. The drugs analyzed included lemborexant, zolpidem and eszopiclone (NBDs), and risperidone and quetiapine (DTAs). Analyzed using interrupted time-series analysis, and assess changes in the number of patients prescribed these medications and the number of patients with abnormal indications. The promotion of ORAs significantly increased lemborexant prescriptions [level change 18 (95% confidence interval 0.07 to 35: p=0.049), slope change 2.7 (0.57 to 4.9: p=0.015)]. Concurrently, prescriptions for NBDs decreased [level change −56 (−86 to −25: p<0.001), slope change −30 (−54 to −5.7: p=0.017)], and the slope change for DTAs with abnormal instructions also decreased [−1.2 (−2.3 to −0.11: p=0.032)]. No significant differences were found for the other items. Promoting ORAs increased its use, and led to a reduction in the prescriptions of NBDs and DTAs with abnormal indications. Although there was no change in patient conditions, given the adverse effects associated with NBDs and DTAs these changes suggest a shift toward safer drug treatment practices.

Studies investigating pharmacy accessibility have demonstrated value for analyzing healthcare resource distribution and regional disparities. However, researchers have not yet conducted a comprehensive investigation of the geographical distribution of pharmacies. This study aimed to examine the geographic accessibility and functionality of pharmacies in Wakayama Prefecture using a geographic information system. This cross-sectional study analyzed pharmacies, hospitals, and clinics in Wakayama Prefecture from November 2024 to March 2025. The investigation was conducted at the secondary medical region level, evaluating the population percentage within pharmacy service areas. The study also collected and analyzed data on pharmacy-to-population ratios, operating hours, numbers of full-time pharmacists, and pharmacy functions. Results indicated that pharmacies were predominantly concentrated in northern and coastal regions. The Wakayama Medical Region showed the highest population percentage (69.4%) within an 800-m service radius, while the Gobo Medical Region showed the lowest (35.6%). Analysis of pharmacy functions revealed disparities exceeding 20% for 24-hour service and home dispensing services. These findings suggest that despite Wakayama Prefecture’s pharmacy density exceeding the national average, accessibility challenges persist due to regional disparities within the prefecture. The results emphasize the need to address regional disparities in pharmacy accessibility and promote equitable distribution of medical resources. Future research should include a survey tailored to the needs of local residents to identify areas for improvement.

Creosote, a derivative of coal tar, is used as a wood preservative. In Japan, regulations govern three specific polycyclic aromatic hydrocarbons (PAHs) present in creosote and creosote-treated wood: benzo[a]pyrene, benz[a]anthracene, and dibenz[a,h]anthracene. However, the existing standardized analytical methods in Japan have raised concerns regarding the safety of reagents employed and insufficient purification processes. To overcome these challenges, we developed an analytical method incorporating effective purification techniques, such as centrifugation, silica gel cartridges, and anion exchange cartridges, while eliminating the use of potentially carcinogenic dichloromethane. The validity of this method was evaluated through interlaboratory collaborative tests involving seven institutions. The analysis focused on 10 PAHs, including the three compounds regulated in Japan, across three concentration levels that encompassed current regulatory values. Validation results demonstrated that the method met the trueness and repeatability criteria, established at 70–120% and <10%, respectively. Most reproducibility data satisfied the <15% requirement. Exceptions were observed for two non-regulated compounds in Japan, as well as for samples with high matrix components spiked with the low concentrations of target analytes. The inherent difficulty of analyzing trace compounds in complex matrix components likely contributed to these unsatisfactory results. Despite these limitations, the developed method was validated as suitable for the analysis of at least three regulated PAHs in Japan.