Clioquinol was extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). SMON is characterized by the subacute onset of sensory and motor disturbances in the lower extremities with occasional visual impairments, which are preceded by abdominal symptoms. Although pathological studies demonstrated axonopathy of the spinal cord and optic nerves, the underlying mechanisms of clioquinol toxicity have not been elucidated in detail. We previously performed a global analysis of human neuroblastoma cells using DNA chips and demonstrated that clioquinol induced 1) DNA double-strand breaks and subsequent activation of ATM/p53 signaling; 2) the expression of VGF, the precursor of neuropeptides involved in pain reactions, by inducing c-Fos; 3) the expression of interleukin-8, which is reported to be involved in intestinal inflammation, optic neuropathy, and neuropathic pain, by down-regulating GATA-2 and GATA-3. We also demonstrated that clioquinol induced zinc influx and oxidation of the copper chaperone ATOX1, leading to the impairment of the functional maturation of a copper-dependent enzyme dopamine-β-hydroxylase and the inhibition of noradrenaline biosynthesis. Thus, clioquinol-induced neurotoxicity in SMON seems to be mediated by multiple pathways.

Cardiotoxicity is a serious adverse effect of anti-cancer drugs. Anti-cancer drug-induced cardiotoxicity are arrhythmia, cardiac contractile dysfunction, coronary artery disease, and hypertension, which affect to the quality of life in patients with cancer. In particular, cardiac contractile dysfunction is a life-threatening symptom leading to heart failure, suggesting that it is very important to predict the risk of developing the contractile dysfunction by anti-cancer drugs. Recently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to assess the risk of drug-induced arrhythmias. This prompts us to evaluate other cardiotoxic effects such as contractility dysfunction and structural toxicity with hiPSC-CMs. Since anti-cancer drug-induced contractility dysfunction are considered to be induced by chronic exposure, we have developed a method to assess chronic contractility dysfunction by imaging analysis of hiPSC-CMs. BMS-986094, which failed in clinical trials due to the occurrence of heart failure, was used as a positive compound. We found that chronic exposure to BMS-986094 decreased the contraction and relaxation velocity in hiPSC-CMs. Doxorubicin was observed to decrease cytotoxicity and both contraction and relaxation velocities in hiPSC-CMs. We are currently further evaluating other anti-cancer drugs with different mode-of-actions using hiPSC-CMs and assess the predictivity and utility of contractile assessment using hiPSC-CMs by comparing with real-world data. Here, we introduce our novel method to assess the chronic contractility of hiPSC-CMs by imaging analysis and discuss the future perspectives for assessing the anti-cancer drug-induced cardiotoxicity.

Pharmacogenetic testing benefits patients by predicting drug efficacy and risk of adverse drug reactions (ADRs). Pharmacogenetic biomarkers useful in clinical practice include drug-metabolizing enzyme and drug transporter genes and human leukocyte antigen (HLA) genes. HLA genes, which are important molecules involved in human immunity, have long been analyzed for associations with ADRs, such as skin rash, drug-induced liver injury, and agranulocytosis. HLA is composed of many genes, each of which has dozens of different types (alleles), and many HLA alleles associated with ADRs have been reported. The odds ratios in the association of HLA alleles range from approximately 5 to several thousand, indicating a very large impact on the risk of ADRs. Thus, HLA genetic testing prior to initiation of drug therapy is expected to make a significant contribution to avoiding ADRs, but to demonstrate the clinical utility, it is necessary to prospectively show the effects of medical interventions based on the test results. We conducted the GENCAT study, a prospective, multicenter, single-arm clinical trial to investigate the impact of a therapeutic intervention based on the HLA-A*31:01 test on the incidence of carbamazepine-induced skin rash. HLA-A*31:01-positive patients were treated with an alternative drug such as valproic acid, and the study showed an approximately 60% reduction in the incidence of carbamazepine-induced skin rash. It is expected that the genetic test, which has demonstrated clinical utility, will lead to the establishment of safer and more appropriate stratified medicine by reflecting the information in clinical practice guidelines.

During the past decade, many high-alert medications have been developed and used in clinical practice. Particularly, in the pharmacotherapy of high-alert medications with large individual differences, more attention is needed. To achieve appropriate and individualized pharmacotherapy, there are many issues to be addressed from a clinical pharmacology perspective, such as enhanced monitoring and prior risk identification. This paper is focusing on the therapeutic drug monitoring of molecularly targeted anticancer drugs, and the provision of real-world evidence based on the clinical implementation of pharmacogenetic testing.

Sepsis is defined as the body’s overwhelming and life-threatening response to infection that can lead to tissue damage, organ failure, and death. Since bacterial infection is one of the main causes of sepsis, appropriate antimicrobial therapy remains the cornerstone of sepsis and septic shock management. However, since sepsis is a multifaceted chaos involving inflammation and anti-inflammation disbalance leading to the unregulated widespread release of inflammatory mediators, cytokines, and pathogen-related molecules leading to system-wide organ dysfunction, the whole body control to prevent the progression of organ dysfunction is needed. In sepsis and septic shock, pathogen-associated molecular patterns (PAMPs), such as bacterial exotoxins, cause direct cellular damage and/or trigger an immune response in the host. PAMPs are recognized by pattern recognizing receptors (PRRs) expressed on immune-reactive cells. PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Thus, most PRRs respond to PAMPs or DAMPs by triggering activation of transcriptional factors, NF-κB, AP1, and STAT-3. On the other hand, sepsis leads to immune (lymphocytes and macrophages) and nonimmune (endothelial and epithelial cells) cell death. Apoptosis has been the major focus of research on cell death in sepsis, but autophagy, necrosis, necroptosis, pyroptosis, NETosis, and ferroptosis may also play an important role in this critical situation. The recent development in our understanding regarding the cellular pathogenesis of sepsis will help in developing new treatment of sepsis.

Acute phase proteins such as CRP, amyloid protein A, and α1-antitrypsin are produced in the liver and their plasma levels are increased during the acute inflammatory response. In contrast, there are plasma proteins whose dynamics are opposite to acute phase proteins. This group includes histidine-rich glycoprotein (HRG), inter-α-inhibitor proteins, albumin, and transthyretin. HRG binds to a variety of factors and regulates the fundamental processes; the blood coagulation, the clearance of apoptotic cells, and tumor growth. In the present review, we focus on the anti-septic effects of HRG in mice model, the actions of HRG on human blood cells/vascular endothelial cells, and the identification of a novel receptor CLEC1A for HRG, based on our recent findings. HRG appears to maintain the quiescence of neutrophils; a round shape, the low levels of spontaneous release of ROS, the ease passage through artificial microcapillaries, and prevention of adhesion to vascular endothelial cells. HRG also inhibited activation of vascular endothelial cells; the suppression of adhesion molecules and the inhibition of HMGB1 mobilization and cytokine secretion. It was shown that plasma HRG level was an excellent biomarker of septic patients in ICU for the evaluation of severity and prognosis. So far little attention has been paid to HRG in terms of a functional role in sepsis and ARDS, however, it is strongly suggested that HRG may be an important plasma factor that prevents a progress in the septic cascade and maintains the homeostasis of blood cells and vascular endothelial cells.

While sepsis mortality is reducing in developed countries due to advances in intensive care medicine, morbidity is increasing due to aging and obesity. ICU-acquired weakness (ICU-AW) is a respiratory and limb muscle weakness experienced by many sepsis survivors and is present in 50–75% of sepsis patients. ICU-AW can persist for several years, making reintegration of sepsis survivors difficult and leading to a secondary decrease in long-term survival. Exposure of septic patients to multiple muscle-damaging factors during ICU admission, including hyperglycemia, immobility, mechanical ventilation, administration of muscle relaxants, and administration of steroidal anti-inflammatory drugs, may compound the hyper cytokine, hyper nitric oxide, and hyper oxidative conditions, leading to the development of ICU-AW. However, the pathogenesis of ICU-AW remains unclear, and the pathophysiology of ICU-AW awaits further elucidation to develop therapeutic strategies. Recent ICU-AW studies have also revealed that skeletal muscle itself is a key organ in the inflammatory response and metabolic abnormalities in sepsis. In this article, we review the pathophysiology of skeletal muscle in sepsis and international trends in the development of therapeutic agents based on our research results.

Polyunsaturated fatty acids (PUFAs) are essential for brain development and function, and an imbalance of brain PUFAs is linked to mental disorders like autism and schizophrenia. However, the cellular and molecular mechanisms underlying the effects of PUFAs on the brain remain largely unknown. Since they are insoluble in water, specific transporters like fatty acid binding proteins (FABPs), are required for transport and function of PUFAs within cells. We focused on the relationship between FABP-mediated homeostasis of brain PUFAs and neural plasticity. We found that FABP3, with a high affinity for n-6 PUFAs, is predominantly expressed in the GABAergic inhibitory interneurons of the anterior cingulate cortex (ACC) in the adult mouse brain. FABP3 knockout (KO) mice show increased GABA synthesis and inhibitory synaptic transmission in the ACC. We also found that FABP7 controls lipid raft function in astrocytes, and astrocytes lacking FABP7 exhibit changes in response to external stimuli. Furthermore, in FABP7 KO mice, dendritic protrusion formation in pyramidal neurons becomes abnormal, and we have reported a decrease in spine density and excitatory synaptic transmission. Here, we introduced recent advances in the understanding of the functions of PUFAs and FABPs in the brain, focusing especially on FABP3 and FABP7, in relation to human mental disorders.

Twenty years after the concept of open innovation was first proposed, entrepreneurship and horizontal division of labor have become popular in Japan, following the global trend. However, in the life science field, the foundation for open innovation is still in its infancy due to the high degree of specialization, large scale of required investment, and low probability of success. For the five years since its opening in 2018, Shonan Health Innovation Park (Shonan iPark) has taken on the challenge of building an ecosystem to create a place where a diverse range of players can realize open innovation. The key points of the efforts are the multifaceted approach taken by the governing body, which is well versed in life sciences, and on the other hand, the fostering of a mutually supportive mechanism and culture by actively borrowing the strength of the community’s constituent members. In this article, we introduce the efforts to support diverse players, including venture companies, from the perspective of a science park that creates a place for open innovation.