Folia Pharmacologica Japonica最新文献

Adenosine triphosphate (ATP) is a crucial molecule which is used not only as an energy source in living organisms but also as a signaling molecule in various biochemical reactions. Real-time measurement of ATP dynamics in vivo is necessary to elucidate the physiological and pathological mechanisms involving ATP. However, conventional techniques have lacked sufficient temporal and spatial resolution to evaluate ATP dynamics in those mechanisms. To overcome this limitation, we developed the AVID (ATP visualization in vivo directly) mouse, which expresses a genetically encoded biosensor, enabling real-time monitoring of ATP dynamics across organs and cells in via in vivo imaging. In this article, we show a multiscale and millisecond-scale ATP imaging using the AVID mouse. Furthermore, we introduce previous findings using genetically encoded biosensors that have elucidated physiological ATP functions in neurons and discuss how the AVID mouse may contribute to uncovering the pathophysiological mechanisms underlying central nervous system disorders.

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that regulates lipid metabolism and inflammatory responses. Recent studies have revealed that PPARα also plays an important role in maintaining neuronal homeostasis through modulation of fatty-acid oxidation and inflammation in the brain. Our previous work using both animal models and human samples has demonstrated that PPARα is involved in the pathophysiology of schizophrenia. Ppara-deficient mice exhibit reduced prepulse inhibition, increased anxiety-like behavior, and decreased dendritic spine density with a reduction of mature spines in the prefrontal cortex. In patients with schizophrenia, decreased expression of the PPARA gene in hair-follicle cells and loss-of-function variants of PPARA have been identified, suggesting that impairment of PPARα signaling contributes to disease development. Moreover, administration of a PPARα agonist ameliorates dendritic spine abnormalities and behavioral deficits in phencyclidine (PCP)-treated model mice. Other groups have reported that prenatal treatment with PPARα agonists improves adult behavioral abnormalities and suppresses fetal cytokine elevation in maternal immune-activation models. In addition, PPARα agonists have shown beneficial effects in animal models and clinical studies of autism spectrum disorder and depression. Collectively, these findings indicate that PPARα represents a novel therapeutic target that bridges metabolic, neurodevelopmental, and neurodegenerative mechanisms, offering new opportunities for drug discovery in psychiatric and neurological disorders.

Steroid hormone receptors (SRs) play pivotal roles in the fundamental biological functions related to reproduction, development, and homeostasis. They are also closely associated with various pathophysiologies, including hormone-dependent cancers, metabolic syndromes, and neuropsychiatric disorders. SRs are ligand-dependent transcription factors belonging to the nuclear receptor superfamily. This superfamily also includes orphan nuclear receptors, such as estrogen-related receptors (ERRs) comprising three subtypes of α, β, and γ. Despite their high homology with estrogen receptors (ERs), ERRs cannot bind any endogenous steroid hormones and can activate gene transcription in a ligand-independent manner. Recently, ERRs have attracted considerable attention for their involvement in stem cell pluripotency, senescence, and other poorly understood biological processes. Although subcellular and subnuclear dynamics are crucial for SR function, how ERRs behave in living cells to activate or repress their target genes remains incompletely understood. We have investigated the behaviors of ERRs using fluorescent protein labeling, focusing on whether ERRs exhibit dynamic changes similar to SRs and whether these changes relate to their functional activity. In this review, we summarize findings from studies of molecular behavior, highlighting the coregulation of estrogen signaling by ERs and ERRs, the subnuclear movement of ERRs related to transcriptional repression, and the promotion of lactate metabolism by a novel lactate-responsive protein, LRPGC1, through interaction with ERRγ. We hope these insights contribute to elucidating fundamental biomedical processes and the pathological mechanisms linked to aberrant nuclear receptor signaling pathways.

Pharmacology role-play is a participatory learning exercise in which students take on the roles of healthcare providers and patients or family members, explaining diseases and pharmacological treatments based on presented case scenarios, and actively learning through mutual communication. Traditionally conducted face-to-face within a single university, this exercise has shifted to online formats during the COVID-19 pandemic, and more recently, attempts have been made to implement inter-university online sessions that utilize remote collaborative learning. In this study, we compared the educational outcomes of online role-play conducted independently at Kochi University and Ehime University in 2020 with those of an inter-university online role-play jointly conducted by both universities in 2021. Participants were third-year medical students at Kochi University and second-year medical students at Ehime University. After completing all assignments, students were asked to complete a post-session questionnaire. Five-point Likert scale responses were analyzed, and free-text comments were further examined using text mining with co-occurrence network analysis. The results indicated that inter-university role-play, compared with single-university sessions, facilitated the recognition of diverse perspectives and promoted deeper reflection through discussion. This experience contributed to enhanced understanding of patients' perspectives, increased motivation for becoming physicians, and improved learning attitudes. These findings suggest that inter-university online role-play is an effective educational approach for enhancing learning outcomes in pharmacology education.

Hereditary angioedema (HAE) is a rare life-threatening disease with recurrent edema. We outline the pharmacological characteristics and study results of a new drug, garadacimab (human anti-activated factor XII [FXIIa] monoclonal antibody), which has novel mechanism of action and suppresses acute HAE attacks. In HAE, excessive bradykinin production, an inflammatory mediator increasing vascular permeability, causes edema, and activation of factor XII initiates bradykinin production. Garadacimab suppresses bradykinin production by inhibiting FXIIa. HAE attacks include fatal laryngeal edema, and overall severity varies substantially among patients. There is an unmet medical need for treatment to reduce its frequency and severity. For prophylactic treatment, a convenient drug with long-administration interval is desired to reduce patients' burden. Based on results of Phase I study in healthy subjects and Phase II study of multiple doses in patients, efficacy and safety of monthly administration of 200 mg garadacimab were compared in 64 patients (ITT: 39 in garadacimab and 25 in placebo) in Phase III study. The primary endpoint, monthly attack frequency was significantly lower in garadacimab than placebo (0.27 vs. 2.01; P < 0.001), with relative reduction rate 87%. Monthly subcutaneous administration of 200 mg garadacimab showed favorable safety profile. The proportion of patients who remained attack-free during the 6-month was 62% in garadacimab and 0% in placebo, and effect after the first dose was maintained throughout the study period. Since this drug is administered subcutaneously once a month with autoinjector, reduction of patients' burden is also expected.

The treatment of recurrent or metastatic cervical cancer has entered a new era, with immune checkpoint inhibitors now being used as first-line standard of care options. Meanwhile, there is a lack of second-line and subsequent treatment options that can adapt to this changing treatment landscape, highlighting the need for the development of new treatments with novel mechanisms of action. Tisotumab vedotin (recombinant) is an antibody-drug conjugate (ADC) consisting of tisotumab, an anti-human tissue factor (TF) monoclonal antibody (IgG1κ), the microtubule inhibitor monomethyl auristatin E (MMAE), and a valine-citrulline linker. When the linker is cleaved by a protease in a tumor cell, MMAE is released to induce cell cycle arrest and apoptosis via disruption of the microtubular network. In non-clinical studies, tisotumab vedotin demonstrated concentration-dependent cytotoxic and anti-tumor activities. Tisotumab vedotin also mediated antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activities. In a global Phase III study of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer (Study SGNTV-003/innovaTV 301), the drug demonstrated higher efficacy than the investigator's choice of chemotherapy. Although some eye-related adverse events occurred as unique toxicities, the safety profile of tisotumab vedotin was generally manageable. The results of analysis in the Japanese subpopulation of the SGNTV-003 (innovaTV 301) study were consistent with those of the overall population. Based on these results, tisotumab vedotin received regulatory approval in Japan in March 2025 for the indication of "advanced or recurrent cervical cancer that has progressed after cancer chemotherapy".