Approximately 80% of all the information we receive about the world comes through the visual pathways and visual function deterioration causes severe decline in QOL. Glaucoma is the leading cause of blindness in the world, in which visual field deficit deteriorates as the optic nerve degeneration progresses. Hence, the development of fundamental cure is needed. Our research focuses on the signaling of brain-derived neurotrophic factor (BDNF), one neurotrophic factor reduced with aging and glaucoma patients. We generated modified tropomyosin receptor kinase B (TrkB) which can be constitutively activated in the absence of its ligand BDNF. The active site of TrkB is localized to the plasma membrane, allowing for constitutive activation of intracellular signaling. Gene therapy with the modified TrkB in a mouse model of glaucoma was proven to be protective. In addition, our group reported that apoptosis signal-regulating kinase 1 (ASK1), one of the stress response factors, is related to the severity of optic neuritis and myelitis in model mice of multiple sclerosis. We generated four lines of cell type specific ASK1 conditional knockout mice and found that ASK1 in glial cells increased the severity of neuroinflammation while ASK1 deficiency in immune cells had no significant effects. Further, we found that ASK1 is required in microglia and astrocytes to cause and maintain neuroinflammation by a feedback loop between these two cell types. Our results suggest that ASK1 might be a promising therapeutic target for reducing neuroinflammation including optic neuritis.

The sensory system detects the internal and external environment of the body and the stimulus trigger feedback loops toward the set point to maintain homeostasis, but if taste sensitivity has changed, we may consume more nutrients or loss of appetite. These can lead metabolic syndrome or malnutrition, which can lead to frailty. In this review, we examined which of the five basic tastes (sweet, umami, bitter, sour, and salty) is affected by aging. Next, we summarize the effects of oral bacteria and tongue coating on taste, which can cause problems such as bad breath and aspiration pneumonia. Even healthy people can change their taste sensitivity and pose health risks if they continue to eat certain taste substances on a daily basis. Furthermore, we summarize research from the discovery of the taste of fatty acids to the present, and discuss how the involvement of taste in food intake regulation contributes to homeostasis through a literature survey. Recently, a gut-brain circuit for fat preference has been identified. In the intestine, fatty acids are sensed by the same receptors as those in the taste buds of the tongue, and nutritional information is sent to the brain via the vagus nerve. It is very interesting that nerves that convey fatty acid-specific information have been discovered. In this way, taste system of the tongue and nutrition-sensing in the digestive tract are very similar, so we think it will be very meaningful to progress research by referring to each other.

Itch is an unpleasant sense to evoke desire to scratch skin. Itch not only disturbs daily lives, but also exacerbates inflammation in case of atopic dermatitis (AD). It had been thought that both itch and pain are transduced by the same neurons; however, it is now known that neutrons transducing either itch or pain are distinct. Moreover, TRP channels, a family of calcium channels, play an important role for transducing itch as well as pain, temperature, and pressure. Development of neuroscience and molecular biology has dramatically advanced our understanding of how itch is transduced in recent years. On the other hand, development of immunology has revealed that there exist several immune types in our host defense mechanism and that type 2 immune reaction is dominant in the pathogenesis of allergic diseases including AD. Although it had been already known that type 2 cytokines contribute to the pathogenesis of AD by binding to their receptors on both immune cells and tissue resident cells, it has been recently found that several type 2 cytokines directly transduce the itch signals by binding to peripheral nerves. Due to this discovery, we can understand more deeply the itch mechanism of AD and can develop molecularly targeted drugs for AD targeting type 2 cytokines, which has dramatically changed the treatment of AD. In this review article, we describe the progress of our recent understanding of the itch mechanism and the strategy of treatment against it.

MPS is already being utilized in various aspects of drug development. This paper introduces MPS from a different viewpoint in previous reviews. First, I will introduce how the term “microphysiological systems” came to be used based on the results of the PubMed search, and show the results of an abstract analysis at the MPS World Summit 2023 held in Berlin, which quantified the organs of interest in MPS and the needs of pharmaceutical companies. Next, the author’s activities in the AMED-MPS2 (the identification and experimental validation of device or cell considerations as MPS evaluation systems) and MPS-RS (the development of CoUs suitable for guidelines) projects as MPS projects in Japan will be introduced. I am also engaged in the construction of an evaluation system using cardiac MPS. The features and results of several cardiac MPS devices that have been developed for the contraction evaluation will be introduced, including the author’s own efforts. Evaluation systems using MPS are attracting attention not only in drug discovery but also in the food and chemical industries, and while social implementation is gradually advancing, discussion groups are being created around the world to discuss how MPS should truly be utilized in society and in regulations. Countries seem to be focusing on acquiring data using useful devices that have survived the race for survival. For Japan to lead the world, it will be necessary to quickly identify useful devices and acquire enough data to discuss them.

In vitro compound evaluation using human-derived neural cells is beginning to incorporate microphysiological systems (MPS). Neural MPS includes not only microfluidic devices but has also recently recognized neural organoids as viable MPS platforms. The history of neural MPS utilizing microfluidic devices is extensive, with the development of models that control the positioning of cell bodies and neurite outgrowth, as well as models that mimic neuronal projections through the connection of heterogeneous cell types. This paper presents examples of predicting peripheral neuropathy through machine learning applied to images of cell bodies and neurites in microfluidic devices, as well as the construction of a motor neuron-skeletal muscle model. Additionally, it discusses the responses to contraindicated drugs in Dravet syndrome using brain organoids that reflect biological brain structures. In drug discovery applications of neural MPS, it is essential to develop and utilize appropriate MPS tailored to specific objectives, ensuring biological relevance and reliability for future advancements.

The tumor microenvironment (TME) includes immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, pericytes, and more. Previously, these non-cancer cells were considered inactive components in cancer pathology. However, it has become evident that these cells and their secretions play crucial roles in cancer progression. To unravel the complexity of the TME and elucidate its mechanisms, microphysiological systems (MPS) have gained attention. An MPS is defined as “a microscale cell culture platform for in vitro modeling of functional features of a specific tissue or organ of human or animal origin”, allowing for the control of the chemical or physical conditions of the TME and the analysis of the responses of cancer cells and surrounding cells. In recent years, the incorporation of vascular networks into tumor MPS has enabled more accurate assessments of the dynamics within the TME. This review provides an overview of the latest research on cancer MPS with vascular networks and the cellular and molecular dynamics within the TME.

Pregnancy can affect the absorption, distribution, metabolism, and excretion of several drugs due to pregnancy-induced physiological changes. Risperidone, a second-generation antipsychotic, is prescribed to pregnant women when the benefits outweigh the risks to the fetus. Serum concentrations of risperidone and its active metabolite paliperidone in a pregnant woman as well as her newborn were measured, and physiologically-based pharmacokinetic (PBPK) models of both drugs were developed. The effects of pregnancy on pharmacokinetic parameters of both drugs were quantitively assessed by the developed PBPK model. As a result, serum concentrations of risperidone and paliperidone decrease in the pregnant status and abruptly recover to the non-pregnant level after delivery mainly due to cytochrome P450 (CYP) 2D6 activity changes, and therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. In the 10 different models for estimating the renal function of children, the Flanders metadata equation showed the lowest absolute bias and the greatest precision in predicting paliperidone serum concentration in the neonate. PBPK model-informed approach could help with the precision dosing in special populations, such as pregnant women and neonates.

Fetal thyroid hormones (THs), essential for brain development, largely depend on maternal supply. Clinical studies have shown that TH alterations in pregnant mothers can lead to permanent neurodevelopmental effects in their children, suggesting that chemicals causing maternal TH disruption may require regulation. However, the quantitative relationship between chemical-induced maternal TH reductions and fetal brain TH disruption, as well as fetal brain developmental abnormalities, is not fully understood. Thus, there is a need for methods that can precisely, rapidly, and quantitatively evaluate TH-disrupting effects of test chemicals that may cause brain abnormalities. Currently, multiple molecular initiating events (MIEs) in the adverse outcome pathways (AOPs) of TH disruption are known, and tests using New Approach Methodologies are being developed to investigate the effects of chemicals on these MIEs. Additionally, the Comparative Thyroid Assay (CTA) is expected to be utilized to comparatively evaluate the decrease in blood TH concentrations, commonly observed as a result of actions on multiple MIEs, in maternal rats along with their offspring. Recently, due to the increasing need for more precise and efficient evaluations and the reduction of animal testing, we have worked on improving the CTA. We proposed a modified CTA that adds new test items: brain TH concentrations and heterotopia (a histological marker of brain TH deficiency), while reducing the number of animals used by 50%. Feasibility studies confirmed that it can detect approximately 20–30% TH disruption in the offspring brain. This review outlines the current efforts to develop new evaluation methods for perinatal TH disruption effects.

Pharmaceuticals used for pregnant women must be safe for the babies while therapeutic to the mothers. To ensure the safety of drugs, developmental neurotoxicity should be evaluated although it is currently not a mandatory requirement in the US and Europe at the regulatory level. Organisation for Economic Co-operation and Development (OECD) has constituted the test guideline (TG426) to assess developmental neurotoxicity. TG426 requires various assessments using animals (assuming rats), including the brain weight, neuropathology, locomotion, sensorimotor function, and learning ability of dams from the mother treated with the chemical during pregnancy. Due to the huge burden of the cost, time, and labor, the number of chemicals evaluated for developmental neurotoxicity by TG426 remains around 200. To boost the pace of the assessment, OCED has constituted a novel guideline (No. 377) adopting in vitro test batteries. OCED has also evaluated the utility of the neurobehavior of zebrafish larvae in the assessment of developmental neurotoxicity. In this review, I focus on valproic acid, a therapeutic drug to treat epilepsy and bipolar disorder and a well-known developmental neurotoxicant, and summarize the studies using zebrafish neurobehavior to assess the developmental neurotoxicity of valproic acid. The utility and validity of zebrafish neurobehavior for developmental neurotoxicity testing are discussed by comparing the findings from rodents and humans.

In recent years, the rapid development of generative AI has given rise to a variety of services such as machine translation, sentence summarization, and programming code generation. In drug discovery, generative AI and chemoinformatics have been used for seed/lead compound generation and optimization, and several successful cases were reported. The use of AI technology in drug discovery is expected to solve previously difficult problems and dramatically improve success rate in drug discovery. ITM, Inc. is a venture company established in 2004 to support drug discovery in silico using original chemoinformatics technology. Currently, ITM is developing a drug discovery support system that combines state-of-the-art AI technology and chemoinformatics technology. This paper introduces ITM's technology with a focus on the use of generative AI.

Difelikefalin (KORSUVA^® IV Injection Syringe for Dialysis) is a novel kappa opioid receptor (KOR) agonist. In September 2023, difelikefalin was approved for the treatment of pruritus in hemodialysis patients. Pruritus is a major symptom that significantly reduces the quality of life of hemodialysis patients, even with improved dialysis techniques, dialysis membranes, and dialysate solutions. The factors that contribute to pruritus include dry skin, accumulation of uremic toxins, overproduction of chemical mediators and altered immune function, and disruption of the opioid balance. In nonclinical studies, difelikefalin showed highly selective for KOR and antipruritic effects in animal models of histamine- and substance P-induced itching. It also showed anti-inflammatory effects by suppressing cytokine release in human monocyte-derived macrophages and TNFα and IL-1β induced by lipopolysaccharide administration in mice. In the phase 3 clinical trial in Japanese hemodialysis patients, difelikefalin showed significant improvement compared to placebo in the primary endpoint of the change from baseline in the weekly mean NRS score at week 4. It also improved sleep disturbance and itch-related quality of life, and the improvement in itch was sustained up to 58 weeks. Furthermore, there was no increase in adverse drug reactions with long-term treatment, and no delayed adverse events were observed. In conclusion, the novel KOR agonist difelikefalin is expected to be a new treatment option for pruritus on dialysis.

Belumosudil mesylate (REZUROCK_® Tablets hereafter belumosudil) is a novel selective rho-associated, coiled-coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 is a kinase involved in immune cell differentiation and tissue fibrosis. Belumosudil exerts its effect by decreasing the inflammation and fibrosis in various organs which are the two key features of cGVHD. In the phase III clinical study in Japan, the primary endpoint was met, best overall response rate (best ORR), defined as the percentage of patients who achieved complete response (CR) or partial response (PR), was 85.7%. Belumosudil received manufacturing and marketing approval for the treatment of chronic graft-versus-host disease (cGVHD) in patients who have insufficient response to steroid therapy in March 2024 and launched in May 2024. The Japanese MHLW has also granted orphan drug designation in May 2023 for the treatment of cGVHD.