Bempedoic acid (Nexletol®) is a novel cholesterol-lowering agent that is converted to its active CoA ester by very long-chain acyl-CoA synthetase 1 (ACSVL1), an enzyme selectively expressed in hepatocytes. The active metabolite selectively inhibits ATP citrate lyase (ACL), leading to a reduction in cytosolic acetyl-CoA levels and subsequent activation of SREBP2. This results in increased expression of LDL receptors and enhanced clearance of LDL cholesterol (LDL-C). Because ACSVL1 is not expressed in skeletal muscle, bempedoic acid is not activated in muscle tissue and is therefore less likely to cause muscle-related toxicity. Nonclinical studies have demonstrated direct ACL inhibition, suppression of hepatic lipid synthesis, and LDL-C-lowering effects with attenuation of atherosclerotic lesion progression in multiple animal models. In domestic and international clinical studies, bempedoic acid reduced LDL-C levels in patients with elevated LDL-C, regardless of their response to statin therapy. The LDL-C-lowering effect was observed from the first scheduled assessment after treatment initiation. With respect to safety, no significant safety concerns requiring special consideration were identified, and bempedoic acid was generally well tolerated. In addition, an international Phase III trial in patients with hypercholesterolemia who were statin-intolerant and had established cardiovascular disease or were at high cardiovascular risk demonstrated that bempedoic acid not only reduced and sustained reductions in LDL-C levels but also significantly reduced the risk of cardiovascular events, the primary endpoint of the study.
Anatomy is fundamental to medical education, providing the basis for understanding normal human structure and function and for learning clinical medicine. Cadaveric dissection plays a central role in anatomy education and remains the only opportunity for medical students to obtain information directly from the human body. During dissection practice, students face cadavers with sincerity and get information from the cadavers. The educational goal is not merely the memorization of anatomical knowledge, but the construction of a three-dimensional understanding of the human body and the development of scientific observational skills. Anatomy dissection practice is possible thanks to the noble spirit of Kentai donors, who donate their bodies to contribute to medical education. As such, dissection practice also provides an important opportunity for students to express respect and gratitude toward donors, to reflect on the dignity of life, and to cultivate medical ethics and professionalism. At our university, new dissection programs have been introduced in collaboration with clinical departments. These include the use of soft-embalmed cadavers for surgical training, enabling students to learn anatomy while experiencing basic clinical procedures such as tracheal intubation. Surgeons also provide special lectures with surgical videos, explaining how anatomical knowledge is useful in their fields. In addition, integrated education combining cadaveric dissection with medical image interpretation, including CT and MRI, has been implemented to enhance students' three-dimensional anatomical understanding from early medical education. Despite recent advances in virtual reality-based teaching tools, cadaveric dissection continues to be an essential cornerstone of anatomy curricula.
Pharmacology is one of the fundamental academic disciplines in the educational courses of Schools of Pharmaceutical Sciences, and practical training of pharmacology provides profound educational effects. On the other hand, the contents of practical training are increasingly forced to make several changes, which is motivated by several factors such as limitation in budget, concerns on animal welfare and experience of COVID-19 crisis. In Kumamoto University School of Pharmacy, the content of practical training of pharmacology and anatomy has been changed recently to diminish the usage of experimental animals to minimum necessary. For example, experiments on the effects of drugs on blood pressure in rats have been replaced by practical training with software-based simulations. Experiments on the effects of drugs on contraction responses of small intestines have also incorporated software-based simulations, but in addition, students have a chance to observe contraction of mouse small intestines in Magnus preparations. Several movies of pharmacological experiments using animals and isolated organs are provided to students via e-learning system. The other sets of experiments involve drug treatments and surgical operations in mice, and students are encouraged to handle mice by themselves in these experiments. We should continue efforts for improving the contents of practical training, while considering several factors including educational effects benefited from animal experiments and a purpose of Schools of Pharmaceutical Sciences in developing human resources for basic research of pharmaceutical sciences and life sciences.
During mammalian evolution, the cerebrum underwent remarkable changes: the brain surface expanded, and cortical folding increased. Neurons and astrocytes have increased in number and have acquired greater morphological complexity and functional diversity. Mice transplanted with human astrocytes show improved memory and learning abilities, suggesting that astrocyte functions were enhanced during evolution. Recently, human astrocytes have been shown to exhibit a larger cellular territory as well as morphological diversity. These findings suggest that evolutionary changes in astrocyte number, morphology, and function play an important role in the emergence of higher brain functions. However, research on astrocytes in enlarged, highly folded brains remains limited. To address this issue, we are investigating the molecular mechanisms that regulate astrocyte changes during evolution and their functional significance, using the ferret as a model system because of its well-developed brain structure. In this article, we provide an overview of our findings, focusing on the regulation of astrocyte number and its role in cortical folding.
Pharmacology department in medical schools performs an introductory practical training program where medical students first experience the medical practice of using drugs in a university setting. However, recent university budget cuts have led to a shortage of human resources, insufficient funding for practical training, and the simplification or promotion of online training due to the COVID-19 pandemic, as well as changes in student attitudes, creating a significant turning point. In this symposium, I presented the results of a survey on the current state of pharmacology laboratory courses at medical schools nationwide, discussed the challenges and difficulties faced by universities across the country. While new forms of practical training, such as joint role-play with other universities and VR practical training that is more accessible to students, have been identified, on the other hand, fewer universities are conducting practical training using animals to cultivate an understanding of the dangers of actual drugs, the importance of life, and the uncertainty of drug administration and the ability to respond to it. Reasons include the decreasing number of staff capable of conducting such experiments, the rising costs of experimental animals, and the limited participation of only some students. However, the educational and ethical benefits of such experiments remain high. Some universities show implementing various innovative training programs. It is essential to gather such insights and collaborate nationwide to develop training formats that, while efficient and rational for faculty, also benefit students in terms of ethical and humanistic development.
Etrasimod L-arginine (Velsipity® 2 mg tablets) is a small-molecule sphingosine 1-phosphate (S1P) receptor modulator with high selectivity for the S1P receptor subtypes S1P1, S1P4, and S1P5. Through its action on S1P1, etrasimod induces receptor internalization, thereby inhibiting lymphocyte egress from lymph nodes to sites of inflammation. This mechanism is considered to reduce chronic inflammation in the colonic mucosa associated with ulcerative colitis (UC). Nonclinical pharmacology studies have shown that etrasimod preferentially activates the β-arrestin pathway, while relatively weakly activating G protein pathway associated with heart rate reduction compared to other S1P modulators. In clinical trials, first-dose bradycardia was mild and transient, and the magnitude of heart rate reduction after dose titration to 2 mg was comparable to that observed when treatment was initiated directly at 2 mg. Therefore, etrasimod can be initiated at the maintenance dose of 2 mg. In domestic and global Phase III clinical trials, once-daily oral administration of etrasimod 2 mg significantly improved clinical remission and endoscopic outcomes compared with placebo at 12 and 52 weeks in patients with moderately to severely active UC, including those with an inadequate response to biologics or Janus kinase inhibitors. The safety profile was favorable, with adverse event rates comparable to placebo and most events being mild to moderate. Based on these results, etrasimod was approved in Japan in June 2025 for moderate to severe UC with inadequate response to existing therapies. With once-daily oral dosing without titration and a favorable safety profile, etrasimod represents a new therapeutic option for UC.
For the development of orally-administered drugs, quantitative prediction of drug intestinal absorption and drug-induced intestinal toxicity is one of the essential evaluation items. However, the current experimental systems have some critical problems such as large inter-species difference in animal studies and different gene expression levels between Caco-2 cells and human intact intestinal tissue. Thus, the construction of novel experimental systems which can reflect human intestinal physiology has been desired. We established stable 3D culture of intestinal stem cells in Matrigel originally isolated from surgical specimens and novel experimental systems for the prediction of intestinal absorption and toxicity with their differentiated cells. For the prediction of intestinal absorption, intestinal availability and PXR-mediated induction of pharmacokinetics-related genes could be predicted with our differentiated cells, but not Caco-2 cells due to the low expression levels of key molecules. For the prediction of intestinal toxicity, we evaluated the decrease in intracellular ATP level of intestinal stem cells by anticancer drugs to predict the risk of drug-induced severe diarrhea and serotonin release from EC (enterochromaffin) cell-rich spheroids to predict the risk of drug-induced emesis. Based on these in vitro assays, we succeeded in the prediction of the difference in the frequency of diarrhea and emesis in the clinical situation after administration of each tested drug. In this review, we summarized the major problems of current assays and usefulness of human crypt-derived intestinal stem cells and their differentiated cells for the prediction of clinical pharmacokinetics and toxicity of drugs in humans.
Myelin is increasingly recognized as a dynamic regulator of neural circuits, shifting the paradigm from a purely synaptic-centric view of brain plasticity. This report details how activity-dependent changes in myelin lipid composition optimize neural circuit synchrony during motor learning. Using a mouse model with subtle myelin structural deficits, we demonstrate that impaired myelin regulation leads to increased temporal dispersion of axonal conduction. This asynchrony reduces the signal-to-noise ratio of neural activity in the primary motor cortex, thereby hindering motor skill acquisition. Crucially, optogenetic synchronization of thalamocortical inputs rescues these learning deficits, confirming that temporal precision is vital for plasticity. Furthermore, imaging mass spectrometry revealed stage-specific shifts in myelin lipid composition during motor learning. Sphingomyelin levels rise during the early phase, while galactosylceramide levels increase during the middle-to-late stages. Targeted suppression of the galactosylceramide-synthesizing enzyme in oligodendrocytes specifically impairs late-stage learning and increases conduction asynchrony without affecting gross myelin morphology. These findings suggest that oligodendrocytes actively fine-tune the timing of information arrival by modulating the lipid composition of myelin. These dynamic changes in myelin lipid composition represent a novel perspective on white matter plasticity essential for optimizing neural circuit outputs and behavior, offering new insights into neuropsychiatric disorders characterized by impaired neural synchrony.
In pharmacology education, practical classes using animals or isolated tissues have long played an important role in helping students integrate and deepen the knowledge acquired in lectures. Recently, however, increasing emphasis on animal welfare and the 3Rs, along with personnel and financial constraints and the increasing adoption of simulator-based training, has reduced opportunities for animal-based practice. Because the specialized techniques required for such classes are difficult to rebuild once lost, re-evaluating their educational significance based on objective data is becoming increasingly important. At Kochi University, pharmacology practice involving guinea pigs, rats, and mice-focusing on intestinal motility, cardiovascular responses, and central nervous system function-has been conducted annually. This article analyzed free-text reflections voluntarily submitted by students in 2023 and 2024 using text-mining techniques to characterize learning outcomes and ethical awareness. Frequency analysis indicated that terms such as "pharmacology," "drug," and "practical exercises" frequently appeared in both years, suggesting that the practice supported students' understanding of lecture content. References to "mouse" were most common, reflecting the strong impression made by observing behavioral changes in mice. Rat practical exercise emphasized quantitative assessment of blood pressure, whereas guinea pig practical exercise highlighted organ-level responses. Co-occurrence network analysis further showed that students often linked observations of biological responses with concepts related to pharmacological understanding, medical safety, and bioethics. Overall, these findings indicate that animal-based pharmacology practice contributes not only to the deepening of scientific understanding but also to the development of ethical and clinical awareness, supporting their continued value in multifaceted pharmacology education.
To address the low predictability (92% clinical failure rate) and high costs associated with species differences in traditional animal testing, this research advocates for New Approach Methodologies (NAMs) in alignment with the US FDA Modernization Act 2.0. The central achievement presented is the development of a "human Heart-on-a-chip." This microfluidic device co-cultures human iPS-derived cardiomyocytes, fibroblasts, and vascular endothelial cells to mimic living 3D tissue structures and fluid environments. The system demonstrated superior physiological reproducibility compared to conventional methods in evaluating drug responses (e.g., nifedipine) and detecting fatal side effects like QT prolongation. In addition to the heart, applications are advancing across diverse organ and disease models, including the construction of ischemia-reperfusion injury models using kidney chips and pulmonary fibrosis models using lung chips, the evaluation of barrier functions via blood-brain barrier (BBB) chips, and the analysis of interactions between cancer cells and immune cells using cancer chips. It is concluded that these technologies enable high-precision in vitro reproduction of human physiology and pathology, thereby improving the efficiency of drug screening, reducing economic losses, and accelerating the paradigm shift toward the 3Rs (Replacement, Reduction, and Refinement) in animal experimentation.
Undergraduate education in health science professionals consists of lectures, drills, practical work, skill practice and experiments. Lectures constitute a significant portion of the curriculum, as they are the primary opportunity to introduce new fundamental knowledge and concepts to students. Drills, practical work, skill practice and experiments supplement the fundamental knowledge and concepts learned in lectures. Similar strategies are used in physiology education. Practical work in physiology education can be divided into two categories: one for deepening students' understanding of the fundamental knowledge and concepts covered in lectures, and the other for demonstrating the applicability of the fundamental knowledge to clinical practice. Practical work reinforces and deepens students' understanding of the knowledge gained in lectures, but due to time constraints, the number of topics covered in practical work is far fewer than those covered in lectures. Practical work cannot be an effective educational method if it simply supplements lectures; desirably, it should fulfill its own unique purpose independent of lectures. Health science professionals are expected to acquire fundamental skills in scientific thinking. Scientific thinking can be described as the ability to clearly distinguish between facts and opinions and to form opinions based on the facts through logical reasoning. Practical work provides the best and most unique method for cultivating scientific thinking. Practical work thus not only complements lectures, but also has distinct advantages over lectures. Practical work is an important educational method in not only reinforcing knowledge gained through lectures but also cultivating scientific thinking.
Astrocytes are essential glial cells that maintain brain homeostasis. Upon brain injury, they become reactive astrocytes with altered morphology, gene expression, and function, including dysregulated Ca2+ signaling implicated in disease development and progression. P2Y1 receptor (P2Y1R), one of Gq-GPCRs, is upregulated in reactive astrocytes across multiple brain disorders, including Alzheimer's disease, epilepsy, and stroke; however, how this upregulation contributes to pathology has remained unclear. To address this question, we generated astrocyte-specific P2Y1R-overexpressing transgenic mice. P2Y1R overexpression in astrocytes induced neuronal hyperexcitability, as evidenced by increased hippocampal neuronal firing, abnormal EEG spikes, and heightened susceptibility to pilocarpine-induced seizures. Dual-color Ca2+ imaging of neurons and astrocytes, electrophysiology, transcriptome analysis of astrocytes, immunohistochemistry, and CRISPR/Cas9-mediated astrocyte-specific knockdown revealed that P2Y1R overexpression amplified both neuron-to-neuron and neuron-to-astrocyte signaling, with astrocytes becoming hypersensitive to neuronal activity-derived ATP. Astrocyte-specific transcriptomic analysis identified insulin-like growth factor binding protein 2 (IGFBP2) as a key downstream effector. IGFBP2, a secreted protein selectively expressed in astrocytes, enhanced glutamatergic synaptic transmission. Furthermore, co-upregulation of P2Y1R and IGFBP2 was confirmed in reactive astrocytes in both kainate-induced epilepsy and middle cerebral artery occlusion stroke models. These findings identify the P2Y1R-IGFBP2 signaling axis as a common pathological feature of reactive astrocytes across brain diseases and establish IGFBP2 as a novel glial-derived factor that could promote neuronal hyperexcitability.
In neurons, fine morphological structures such as dendritic spines play a key role in maintaining synaptic input independence and enabling local, parallel signal processing, forming a fundamental basis of neuronal computation. In this context, it is well established that neuronal microstructure shapes the spatiotemporal properties of signaling. In contrast, although astrocytes, a type of glial cells, possess highly elaborate, densely ramified processes, the functional significance of their morphology has remained less clear. Astrocytic Ca2+ signals have long been described as slow and spatially diffuse, seemingly at odds with their fine structures. Recent advances in live super-resolution imaging have begun to bridge this gap by allowing direct visualization of perisynaptic astrocytic processes. Our studies suggest that astrocytic processes are not merely passive structural elements, but actively localize Ca2+ signals at individual synapses by regulating the diffusion of signaling molecules. Thus, astrocytes may, like neurons, exploit their morphology to control spatiotemporal signaling. Furthermore, such compartmentalization strategies may extend beyond the intracellular structure to the extracellular space surrounding neurons and astrocytes. The extracellular space has traditionally been examined only at a coarse, tissue-level resolution; however, advances in live super-resolution imaging have revealed a highly complex, heterogeneous geometry. This architecture is closely coupled to astrocytic microstructure and may influence local dynamics of transmitters and ions. In this review, we propose that microstructures outside neurons also contribute to shaping spatiotemporal signaling patterns through the regulation of molecular diffusion, and may even constitute the structural basis of brain information processing.
In recent years, declining success rates and rising development costs have posed major challenges in drug development, highlighting the need for more efficient and rational approaches to evaluating drug efficacy and safety. Although non-clinical studies have traditionally relied primarily on animal experiments, adverse events that are difficult to predict continue to emerge during clinical trials and post-marketing, underscoring limitations in human extrapolation. In this context, new approach methodologies (NAMs), including human cell-based models and in silico analyses, have gained increasing international attention for improving predictivity while contributing to the 3Rs principles. This review outlines international and domestic regulatory trends in NAMs and highlights recent advances in organ-specific toxicity assessment using human-relevant models. For cardiotoxicity, contractility assays using human iPSC-derived cardiomyocytes have demonstrated the ability to predict chronic contractile dysfunction and are expected to support anticancer drug safety assessment. In neurotoxicity, platforms combining rat cortical neurons and human iPSC-derived neurons with multi-electrode array system have improved sensitivity for detecting seizure risk. In hepatotoxicity, three-dimensional culture systems and hepatocytes derived from humanized liver chimeric mice have shown promise for predicting drug-induced liver injury. Future efforts should focus on defining context of use and establishing reproducibility and reliability to enable broader regulatory acceptance of NAMs. As regulatory frameworks continue to evolve worldwide, guidelines are expected to be developed or updated based on a weight-of-evidence approach integrating in vitro and in silico data.
Fatty liver disease prevalence is rising in Japan due to Westernized diets. Despite extensive efforts, treatments for metabolic dysfunction-associated steatohepatitis (MASH), which carries high cirrhosis risks, remain unapproved in Japan. A primary cause of clinical failure is the inability of animal models to accurately predict human responses. We developed the "Functional Cellular Device (FCD®)" to replicate human organ functions using 3D tissue engineering. Its first application, the "Human 3D Mini-Liver" (launched in 2023), consists of primary human hepatocytes and stellate cells. We successfully induced fibrosis in this model, observing neutral lipid accumulation and progressive fiber deposition. Transcriptomic analysis revealed an upregulation of oxidative stress and inflammation genes, followed by markers of stellate cell activation, demonstrating high pathophysiological similarity to human MASH. To validate its utility, clinical-stage MASH drugs were added to the fibrotic 3D mini-liver for 1-2 weeks. We evaluated stellate cell activation, collagen production, and fiber deposition. Integrating these phenotypic data with transcriptomic analysis enables precise efficacy prediction and mechanism of action (MOA) verification for drug candidates. Utilizing both healthy and diseased Human 3D Mini-Livers as evaluation tools facilitates drug safety and efficacy assessments based on human biology, significantly contributing to enhanced pharmaceutical R&D efficiency.
