Neuropeptide Y (NPY) is a neurotransmitter that is widely expressed in the brain and peripheral nervous system. Various immune cells express the receptor for NPY, Y1 receptor. NPY modulates these cells via its Y1 receptor, and involvement of NPY in the pathophysiology of bronchial asthma, has been reported. Increased plasma levels of NPY in asthmatic patients have been reported. NPY polymorphisms are associated with an increased risk for asthma in overweight subjects and young adults. We and other researchers have reported that using murine models of allergic airway responses, NPY and Y1 receptor play critical roles for the development of allergic airway inflammation and airway hyperresponsiveness. Therefore, manipulating NPY-Y1 pathway represents a novel therapeutic target to control allergic airway responses, and might be beneficial for treatment of bronchial asthma.

Non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play important roles in normal and diseased cell functions. A small GTPase RhoA is a key protein of bronchial smooth muscle (BSM) contraction, and an up-regulation of RhoA has been demonstrated in BSMs of experimental asthma. Our previous study also demonstrated that RhoA translation was controlled by a miRNA, miR-133a, in BSMs. In human BSM cells (hBSMCs), an up-regulation of RhoA was observed when the function of endogenous miR-133a was inhibited by its antagomir. Treatment of hBSMCs with interleukin-13 (IL-13) caused an up-regulation of RhoA and a down-regulation of miR-133a. In a murine experimental asthma, increased expression of IL-13 and RhoA and the BSM hyperresponsiveness were observed. Interestingly, the level of miR-133a was significantly decreased in BSMs of the diseased animals. These findings suggest that RhoA expression is negatively regulated by miR-133a in BSMs, and that the miR-133a down-regulation causes an up-regulation of RhoA, resulting in an augmentation of the contraction. Recent studies also revealed an inhibitory effect of lncRNA Malat1 on the miR-133a function. Thus, lncRNAs/miRNAs might be key regulators of BSM hyperresponsiveness, and provide us a new insight into the treatment of airway hyperresponsiveness in asthmatics.

In recent decades, many patients have been suffering from allergic rhinitis including Japanese cedar pollinosis, which is becoming a national disease in Japan. There is other upper airway intractable disease, called eosinophilic sinusitis. The elucidation of the pathogenesis of upper airway intractable disease is demanded for the development of novel therapies. Many researches about allergic pathogenesis have focused on IgE-mast cells pathway, however, there are the patients with allergic symptoms induced by non-IgE mediated mechanisms. The patients who show allergic rhinitis-like symptoms, such as sneezing, nasal discharge, and nasal clotting, without allergen-specific IgE, are diagnosed as non-allergic rhinitis. The precise mechanisms of non-allergic rhinitis are totally unclear. We have investigated the non-IgE mediated nasal symptoms, because the elucidation of non-IgE mediated mechanisms might lead to the elucidation of other upper airway intractable disease. We established antigen-specific Th2 cells transfer model and revealed the novel allergic mechanisms induced by Th2 cells, macrophages and endotoxin. Although Th2 cells play important roles in allergic diseases, the main function of Th2 cells are thought to produce Th2 cytokines, such as interleukin (IL)-4, IL-5, IL-13. We revealed the new functions of Th2 cells in allergic diseases. In addition, we found the novel histamine production mechanisms using in vitro macrophages and Th2 cells co-culture model. Both macrophages and Th2 cells produced histamine by the interaction through antigen. Our observations suggested the existence of the novel allergic mechanisms distinct from IgE-mast cells pathway.

Bronchial asthma is a complex disease involving various inflammatory cells and tissue constituent cells. The spread of inhaled corticosteroids is changing asthma into a controllable disease, though the existence of intractable patients implies new mechanisms for the development and deterioration of asthma. Based on the difference in the pathological condition (phenotypes) and molecular mechanism (endotypes), subdivision of disease understanding is recently progressing. Accordingly, various T cell subsets other than Th2 cells, which have been considered to play a major role for many years, are being implicated in the pathogenesis of asthma. Therefore, we aimed to deepen the understanding of the complex mechanisms of intractable asthma by reviewing the characteristics of allergic inflammation mediated by each T cell subset and the trend of therapeutic strategies targeting their representative functional molecules. Among them, recently identified Th9 cells were reported to induce asthma-like eosinophilic inflammation with bronchial hyperresponsiveness (BHR). These phenotypes resemble to Th2 cells-mediated airway inflammation, though we found that Th9 but not Th2 cell-dependent asthma model develops eosinophil-independent and steroid-resistant BHR. Here, we would like to introduce our recent findings and an approach to elucidate a new mechanism of BHR, based on antigen-specific T cell subset-transferred mouse models we have established.

Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and relatively low efficacy. Recent studies reveal that the NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant depressed patients. Despite the unique antidepressant efficacy, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks, such as abuse potential and psychotomimetic/dissociative effects. The molecular and neuronal mechanisms underlying the antidepressant actions of ketamine have been intensively studied to pave the way for the development of novel, rapid and more efficacious antidepressants with fewer side effects than ketamine. Preclinical studies demonstrate that ketamine produces antidepressant effects through rapid release and/or expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and stimulation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex and hippocampus. We have recently found that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects, and that the antidepressant effects of RvD1, RvD2 and RvE1 require mTORC1 activation. These findings suggest that resolvins could be promising targets for the development of novel rapid antidepressants with fewer side effects than ketamine because they are endogenous lipid mediators that play an important role in homeostasis.

Food allergy is an immune-mediated adverse reaction to food. The patients with food allergy are increasing year by year. Since the mechanisms of food allergy are largely unknown, there are still no standardized diagnosis and treatment methods. Authors have investigated the role of prostaglandin D₂ in food allergy and find some new insight that contribute to reveal the mechanisms of the onset and progression of food allergy. In this paper, I introduce our novel findings and recent understanding of basic mechanisms underlying food allergy.

The current therapeutic drugs for major depression mainly modulate monoaminergic signaling. Since they are not effective for all patients, the development of novel therapeutic target is required. Recently, it has been reported that inflammation-related molecules are increased in the blood from patients with major depression. Therefore, neuroinflammation is a possible cause of these disorders. However, we still do not know whether neuroinflammation induces depression. Since social and environmental stress is a risk factor for mental illnesses, repeated social defeat stress is employed as an animal model of depression. We found that prostaglandin E₂ (PGE₂) suppresses mesocortical dopaminergic pathway to induce behavioral changes and cyclooxygenase-1 (COX-1), a key enzyme for PGE₂ production, is essential for repeated stress-induced PGE₂ production and behavioral changes. Based on the finding that COX-1 is expressed in microglia in the brain, we are wondering if microglia plays an important role in stress-induced behavioral changes. We revealed that Toll-like receptor (TLR) 2 and 4 in prefrontal microglia are crucial for repeated stress-induced behavioral changes. Our results indicate that repeated social defeat stress induces microglial activation through TLR2 and 4, thereby leading to neuronal and behavioral changes through proinflammatory cytokines such as TNFα and IL-1α. These findings revealed the essential role and molecular basis of neuroinflammation. In addition, we developed the drug screening platform which targets neuroinflammation for neurodegenerative disease such as amyotrophic lateral sclerosis. Our findings pave the way for the development of therapeutic drugs for major depression targeting neuroinflammation which causes neurological disorders.

In normal condition, vasculature transports only small molecules such as nutrients across vascular wall. When inflammation occurs, inflammatory stimuli increase the permeability of vessel, which induces the extravasation of molecules larger than 40 kDa including plasma proteins. These extravasated molecules cause further inflammation by promoting the infiltration of inflammatory cells and the production of inflammatory mediators. Although it is known that vascular hyper-permeability plays an important role in inflammation, the detailed mechanism of vascular permeability regulation is still unclear. It is known that vascular permeability is controlled by two types of cells: endothelial cells and vascular mural cells. Endothelial cells cover the luminal side of vascular wall in a single layer and form endothelial barrier. Vascular mural cells regulate the blood flow volume of the downstream tissue by contracting or relaxing vascular wall. Endothelial barrier enhancement and vasocontraction suppress the vascular permeability, while endothelial barrier disruption and vasorelaxation promote it. Vascular permeability is regulated by the balance between the response of endothelial cells and vascular mural cells. Prostanoids are cell membrane-derived lipid mediators which bind to each specific G protein-coupled receptor (GPCR), prostanoid receptors. Recently, several studies showed that prostanoids regulate vascular permeability by acting on endothelial cells and/or vascular mural cells. In this review, we would like to describe the role of each prostanoid in vascular permeability by focusing on the characteristics of each specific receptor.

Drug-induced liver injury (DILI) is the major reason for the discontinuation of new drug development and the withdrawal of drugs from the market. Hence, the evaluation systems which predict the onset of DILI in the pre-clinical stage are needed. To date, many researchers have conducted the mechanism of DILI, but the DILI prediction is poor because of the complexity of DILI. In this regard, based on the information obtained from basic research and clinical case, several pharmaceutical companies have been developed DILI prediction methods with high sensitivity and specificity by combining multiple targets. Another reason for low predictability is derived from the conventional culture method which causes a rapid decrease in hepatocyte function. To overcome these problems, the construction of a high-level in vitro evaluation system has been developed and applied to DILI evaluation. On the other hand, these in vitro evaluation methods require a lot of labor and cost so, in silico prediction methods have also been constructed in recent years. Based on this point, this article reviews the trends in DILI prediction systems in the non-clinical stage.

Lisdexamfetamine dimesylate (hereinafter referred to as “lisdexamfetamine”; brand name, Vyvanse^®), was developed for the treatment of attention-deficit/hyperactivity disorder (ADHD). This drug, which is classified as a central nervous system (CNS) stimulant for once-daily oral administration, received marketing approval in March 2019 and was launched in December 2019 in Japan. Lisdexamfetamine is a prodrug that is hydrolyzed to its active form d-amphetamine in the blood following oral administration. Pharmacologically, d-amphetamine competitively inhibits the dopamine transporter (DAT) and the noradrenaline transporter (NAT) to increase dopamine (DA) and noradrenaline (NA) concentrations in the synaptic cleft. In addition to inhibiting the reuptake of DA and NA, d-amphetamine has also an effect in promoting the release of these neurotransmitters by being taken up into neuronal cells and then acting on the vesicular monoamine transporter. The mechanisms of action by which d-amphetamine exerts a therapeutic effect on ADHD may be based on the above-described effects. Clinical studies conducted in Japan and overseas have demonstrated the efficacy of lisdexamfetamine over placebo in the treatment of pediatric ADHD patients. The most of the adverse events with a higher incidence than in the placebo were mild, and long-term administration of the drug was not associated with an increase in the incidence of adverse events or the rate of treatment discontinuation. Lisdexamfetamine, which is designated as raw material for stimulants and therefore requires strict distribution control in Japan, is expected to be effective in the treatment of ADHD patients with inadequate responses to existing therapeutic agents.

In Jan 2020, dotinurad (URECE^® tablets) was approved for gout and hyperuricemia therapy in Japan. We developed a novel hypouricemic agent because benzbromarone, a commercially available uricosuric agent, has several problems, such as drug-induced liver injury or drug-drug interaction caused by CYP2C9 inhibition. In transporter-overexpressing cells, dotinurad potently inhibited URAT1 which is localized in the renal proximal tubules and functions as a urate reabsorption. On the contrary, dotinurad hardly inhibited urate secretion transporters, ABCG2 or OAT1/3. In Cebus monkeys, dotinurad dose-dependently decreased plasma urate levels at low doses compared with benzbromarone. Inhibitory effect of dotinurad on mitochondria was weaker than that of benzbromarone and there was no observation suggesting a risk of drug-induced liver injury taking into consideration the clinical dose or exposure. Dotinurad weakly inhibited CYPs and further analysis indicated there was no drug-drug interaction risk in the clinical dose. In clinical pharmacology studies, there was no difference among sex and age. Furthermore, dosage and administration are equal even in hepatic impairment patients (mild to severe) and renal impairment patients (mild to moderate). In confirmatory phase II and long-term studies, dotinurad decreased serum urate levels at low doses and almost patients using maintenance dose (2 or 4 mg) achieved a serum urate level ≤ 6.0 mg/dL. Moreover, there was no finding to raise safety concern including liver injury. In conclusion, dotinurad, a selective urate reabsorption inhibitor (SURI) could be a therapeutic option because of its more effective hypouricemic action at low doses than those of commercially available uricosuric agents.