In 1999, with the report “To Err Is Human: Building a Safer Health System” from the Institute of Medicine of the United States Academy of Sciences, social needs for quality assurance and improvement in medical care increased. Restructuring of clinical education and quality assurance of medical education were proposed as measures to improve the medical care delivery system and improve the quality of medical care. Outcome-based education (OBE) has become a global standard to ensure the quality of medical education. Medical education in Japan has also undergone a paradigm shift from the process-based education to OBE, in which learning outcomes are clearly indicated and achieved. An implementation of pharmacology to OBE was constructed in four steps. Step 1 is to set learning outcomes, Step 2 is to create learning strategies according to sequential performance levels for each competency, Step 3 is to create learning outcome evaluation methods, and Step 4 is to verify and improve the entire curriculum. As milestones for graduation that lead to learning outcomes, we have independently formulated the outcome of being able to safely prescribe the optimal drug (under the guidance and supervision of a preceptor) based on the treatment plan and with the patient’s and family’s explanations and consent. Learning objectives related to pharmacotherapy were extracted from the 2022 revision of the medical education model core curriculum. We created a curriculum and an evaluation method for learning outcomes, and introduced the Chiba University School of Medicine’s efforts to verify and improve the entire curriculum.

The Japan Accreditation Council for Medical Education is the organization to evaluate medical education programs at each university based on the World Federation for Medical Education Global Standards for Quality Improvement. The practice of outcome-based education is one of the most important points in the evaluation. Each university is required to clarify learning outcomes, which are the qualities and abilities that students should acquire at the time of graduation, and the curriculums and the framework of evaluations to achieve the learning outcomes. With the publicization of common achievement tests for medical students prior to clinical clerkship, medical students can perform medical treatments during clinical clerkship except for the issuance of prescriptions. However, to properly issue prescriptions as a resident soon after passing the national examination for medical practitioners, medical students should acquire the qualities and abilities not only to understand the pathophysiology of disease and the pharmacological actions of therapeutic drugs but also comprehensively to grasp the relationships between the patient, family, and society. Therefore, pharmacology is inevitably involved in many learning outcomes as a hub in the horizontal integration of basic medicine and the vertical integration of basic medicine, behavioral science, social medicine, and clinical medicine. In this paper, I look at pharmacology education at the Mie University School of Medicine from the perspective of outcome-based education and consider the role that pharmacology should play in the evaluation of medical education programs.

The Japan Accreditation Council for Medical Education has strengthened the promotion of horizontal and vertical integration of medical education, assuring the quality of medical education in Japan from an international perspective. Pharmacology plays an important role as a central hub that connects basic medical education with clinical medical education. As part of promoting horizontal integration of medical education, Tokushima University has started a joint practice with three basic medical subjects such as Biochemistry, Physiology, and Pharmacology for 2nd grade medical students in 2019. Each subject is in charge of two or four items of practice, and a total 8 of items are performed for 10 days in integrated practice every year. This joint practice has become an official subject in 2022. We introduce our experiences of unique practices based on their advantages and limitations.

As of February 1st, 2023, the Japan Accreditation Council for Medical Education (JACME) has evaluated and certified medical education programs at 70 medical schools as meeting international standards. It is required that medical schools continue to undergo this accreditation process to improve and further develop the quality of medical education. Although many medical schools have received and completed the first round of review, one of the remaining common issues is to change to an integrated curriculum based on an outcome-based education. Osaka Metropolitan University is in the process of reviewing its educational programs, including the establishment of milestones to appropriately assess the level of achievement of the competencies based on the outcome-based education. In addition, the university is continuing to revise the program to promote integrated education and active learning practices toward the set graduation outcomes. This paper introduces the devises and attempts for horizontally and vertically integrated understanding in pharmacology education based on the learning outcome-based educational system promoted by Osaka Metropolitan University.

Psychosocial stress is a risk factor for psychiatric disorders, including depression and anxiety, and chronic pain, whereas chronic pain is also closely related to the development of psychiatric disorders. However, the pathological mechanisms of stress-triggered psychiatric disorders and chronic pain are unknown, and their effective treatments have not been established. Recently, the advances in analytical techniques for fatty acids and their metabolites have made it possible to comprehensively measure changes in fatty acid composition in various cells and organs using the lipidomics approach, and to visualize the localization of phospholipids, fatty acids, and other lipid mediators using imaging mass spectrometry. Many researchers have focused on understanding the differences in the distribution of phospholipids, fatty acids, their lipid metabolites in cells and organs, and the changes of fatty acid composition in various diseases. More recently, changes in the fatty acid composition and its distribution during chronic pain and stress have also been reported. We also proposed that modulation of brain fatty acid signaling could be a new therapeutic target for stress-induced chronic pain. In this review, we summarize the latest basic and clinical findings on the role of fatty acid signaling in stress-induced psychiatric disorders and chronic pain.

The free fatty acid receptor 1 (FFAR1) is suggested to function as a G protein-coupled receptor for medium- to long-chain free fatty acids. We have previously shown that FFAR1 signaling pathway plays an important suppressive role in spinal nociceptive processing after peripheral inflammation and nerve injury, and that FFAR1 agonists might serve as a new class of analgesics for treating inflammatory and neuropathic pain. To further pursue the functional significance of central FFAR1 signaling, we investigated the possible involvement of FFAR1 in endogenous pain modulation, depressive-like behavior, and aberrant behavior induced by addictive drugs using FFAR1 agonist (GW9508), FFAR1 antagonist (GW1100), and FFAR1 gene-deficient mice. As a result, FFAR1-deficient mice were found to exhibit stronger inflammatory and peripheral neuropathic pain-like behavior as well as depressive-like behavior. In particular, we noticed that peripheral nerve injury-induced depressive-like behavior was insensitive to imipramine. Next, we employed in vivo microdialysis to investigate whether FFAR1 is actually involved in the regulation of brain monoamines (dopamine and serotonin) releases. Our findings suggest that FFAR1 indirectly regulates dopamine release by promoting serotonin release. Thus, we are currently investigating how FFAR1 is involved in behavioral changes induced by addictive drugs such as cocaine and morphine. In this review, we briefly discuss about the possible involvement of FFAR1 in cocaine-induced locomotor hyperactivity.

According to the Ministry of Health, Labour and Welfare, the treatment rate (hospitalization + outpatient) for mood disorders (including bipolar disorder) has doubled over the past quarter-century, from 48 per 100,000 population in 1996 to 94 in 2020. The impact of the COVID-19 pandemic has also contributed to an increase in the prevalence of depression and depressive symptoms across OECD member countries. In Japan, the prevalence rate was 7.9% in 2013, but it has risen to 17.3% in 2020. While the main treatments for depression have traditionally included pharmacotherapy, psychotherapy, and electroconvulsive therapy, there has been a growing body of evidence over the past decade suggesting that improvements in daily lifestyle habits such as sleep, diet, and exercise can contribute to prevention or symptom alleviation. Furthermore, there have been numerous reports highlighting the association between depression and nutrition, particularly with regard to omega-3 polyunsaturated fatty acids. Omega-3 initially gained attention in the 1970s through observational studies conducted in Greenland, focusing on its preventive and therapeutic effects on atherosclerosis. Observational and intervention studies targeting mental health, including depression, have been conducted since around 2000, gradually revealing their mechanisms through animal experiments and other research. In this article, we will present our findings and provide an overview of overseas observational and intervention studies in this field, along with their mechanisms.

Na⁺,K⁺-ATPases are essential for maintaining the membrane potential in almost all cells, and their catalytic subunits have four isoforms (α1–α4). Volume-regulated anion channel (VRAC) plays an important role in the cell death signaling pathway in addition to its fundamental role in cell volume maintenance. First, we introduce that disruption of actin filaments cause the dysfunction of VRAC, which elicits resistance to cisplatin in the cancer cells. Next, we summarize the cardiac glycosides-induced signaling pathway mediated by the crosstalk between Na⁺,K⁺-ATPase α1-isoform (α1NaK) and VRAC in the membrane microdomain of the cancer cells. In this mechanism, sub-micromolar concentrations of cardiac glycosides bind to the receptor-type α1NaK, and generate VRAC activities concomitantly with a deceleration of cancer cell proliferation. Finally, we summarize the pathophysiological function of α3NaK, which is abnormally expressed in the intracellular vesicles of cancer cells. The cancer cell can survive even under loss of anchorage because they have the avoidance mechanism for anoikis. On cancer cell detachment, we found that intracellular α3NaK is translocated to the plasma membrane and this event contributes to the survival of the cells. Interestingly, cardiac glycosides inhibited the α3NaK translocation and cell survival. Our findings may open up new opportunities for the development of cancer medicines.

Recent evidence suggests that the targeting of membrane transporters specifically activated in cancer stem cells (CSCs) is an important strategy for cancer therapy. The objectives of the present study were to investigate the ion channel expression profiles in digestive CSCs. Cells strongly expressing CSC markers, such as ALDH1A1 and CD44, were separated from the human esophageal squamous cell carcinoma, gastric cancer, and pancreatic cancer cell lines using fluorescence-activated cell sorting, and CSCs were identified based on tumorsphere formation. Messenger RNA levels of CSC markers were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to anticancer agents. The microarray analysis revealed that the expression of transient receptor potential vanilloid 2 (TRPV2), voltage-gated calcium channels (VGCCs), and voltage-gated potassium channels (VGKCs) were upregulated in esophageal, gastric, and pancreatic CSCs, respectively, compared with non-CSCs. The TRPV2 inhibitor tranilast, VGCCs inhibitors amlodipine and verapamil, and VGKC inhibitor 4-aminopyridine exhibited greater cytotoxicity in CSCs compared with non-CSCs, and their inhibitory effects were also confirmed in a xenograft model in nude mice. Taking these results, phase I/II study to investigate clinical safety and efficacy of neoadjuvant combination chemotherapy of tranilast in advanced esophageal squamous cell carcinoma (TNAC study) is ongoing. These researches identified a role of ion channels in the persistence of CSCs and suggested that their inhibitors may have potential as a therapeutic agent for digestive cancers.

The unscheduled proliferation of cancer cells outside their natural niches subjects the cells to multiple insults, such as metabolic aberrations, detachment from the extracellular matrix (ECM), hypoxia, and immune cell attacks. Oxidative stress is a hallmark of cancer because these insults can all lead to the accumulation of reactive oxygen species (ROS). However, it remained largely elusive how cancer cells are able to adapt to harsh oxidative environments. Here, we provide evidence that cancer cells co-opt the neuronal ROS-sensing channel TRPA1 to tolerate highly oxidative environments. While TRPA1 is usually expressed at sensory neurons, we found that the channel is also overexpressed in various types of human cancer. TRPA1 does not affect canonical ROS-neutralizing programs but senses ROS and upregulates Ca^2＋-dependent anti-apoptotic programs that promotes oxidative-stress tolerance. These findings offer a significant advance in our understanding of adaptation mechanisms to oxidative stress, which represents a substantial hurdle that impedes tumor initiation and progression.

Ca^2＋-activated K^＋ channels play a critical role in the proliferation, apoptosis, migration, adhesion, and metastasis of various types of cancer cells by controlling Ca^2＋ signaling and cell volumes. Their amplification correlated with a high tumor stage and poor prognosis and has the potential as tumor grade-associated markers. The amplification of the large-conductance Ca^2＋-activated K^＋ channel, K_Ca1.1 is observed in many types of cancers such as breast, colon, ovarian, prostate, pancreatic cancers and gliomas. The hypoxic tumor microenvironment (TME) promotes the anti-cancer drug resistance and stemness of solid tumors. Three-dimensional (3D) in vitro cancer spheroid models mimic the TME of human solid tumors, and are efficient tools for investigating chemoresistance and stemness. We here introduce the mechanisms underlying the post-translational modification of K_Ca1.1 and the overcome of chemo- and antiandrogen-resistance by K_Ca1.1 inhibition in 3D cancer spheroid models. K_Ca1.1 is a key modulator of chemoresistance in K_Ca1.1-positive cancer cells, indicating that targeting K_Ca1.1 is a promising therapeutic strategy for overcoming chemoresistance.

Chimeric mouse with humanized liver is an experimental animal which is produced by transplanting normal human hepatocytes into a host mouse having both of immunodeficient and liver-injured characters. PXB-mouse^®, which is developed and supplied by PhoenixBio group, is produced by utilizing cDNA-uPA/SCID mouse as a host animal and has a humanized liver containing over 70% of human hepatocytes. It has been utilized in the research fields of drug metabolism such as investigation of human-specific metabolites and pharmacokinetics, prediction of human DILI and development of anti-viral hepatitis drugs. Furthermore, it is expected that PXB-mouse will be valuable for the development of drugs of new modalities as the emerging technologies such as oligonucleotide medicine and gene therapy. Because it has an organ which consists almost entirely of human cells PXB-mouse is expected to be used in validation of efficacy or prediction of off-target effect caused by human specific nucleotide sequence. This paper introduces the character of PXB-mouse focusing on the successful achievements in these research fields.

Ozoralizumab, a novel TNF inhibitor, is the first NANOBODY^® compound in Japan for rheumatoid arthritis. This compound consists of a humanized fusion protein with a trimeric structure having two anti-human TNFα NANOBODY^® molecules and one anti-human serum albumin NANOBODY^® molecule, and has the unique structure without an Fc portion. Ozoralizumab showed an inhibitory effect on TNFα-induced cell death, and its inhibitory concentration was lower than that of etanercept, adalimumab, and infliximab. Ozoralizumab also showed inhibitory effects on human TNFα-induced cellular infiltration in the murine air pouch model and reduced the arthritis scores in a murine rheumatoid arthritis model. In addition, ozoralizumab showed distinctive pharmacological characteristics different from the traditional IgG antibodies, which may be attributed to its unique structure, such as its ability to rapidly distribute to inflamed joint tissues in a murine rheumatoid arthritis model, and its immune complexes with TNFα do not induce inflammation in a murine subcutaneous inflammation model. In clinical trials, ozoralizumab demonstrated clinical efficacy in rheumatoid arthritis patients with inadequate response to methotrexate, which was observed from day 3 of treatment. Ozolalizumab also showed improvements in clinical symptoms in rheumatoid arthritis patients without methotrexate. The safety profile of the compound was not significantly different from that of current TNF inhibitors. Based on these results, ozoralizumab was approved in September 2022. Ozoralizumab shows early improvement of clinical symptoms in patients with rheumatoid arthritis, and its characteristic structure is expected to be new treatment options for patients who have an inadequate response to current bDMARDs.