Neurodegenerative diseases such as dementia and Alzheimer’s disease are caused by liquid-liquid phase separation (LLPS) proteins. LLPS is a phenomenon in which a dense liquid phase of proteins is formed in a liquid phase in which proteins are dispersed at a low concentration. The concentrated proteins enable highly efficient chemical reactions, but at the same time, there is a risk of forming insoluble aggregates that cause diseases. In fact, neurodegenerative disease-related proteins form insoluble aggregates, which cause great damage to nerves, resulting in memory and motor disorders. Drug discovery requires the design of drug candidates that can strongly bind to the intrinsically disordered region of a phase-separated protein and control the phase-separated state. This paper mainly introduces our research on peptide design that binds to phase-separated proteins. For peptide drug discovery, it is necessary to efficiently search for drug candidates among a huge number of peptides. As an efficient search method for peptides that control phase-separated proteins, we searched for amino acids that can control liquid-liquid phase separation, and devised a method for designing peptides containing effective amino acids. It was demonstrated that this method can be used to control the LLPS and solid aggregate formation of the neurodegenerative disease-related protein FUS. Furthermore, we devised a method for rationally designing a peptide that binds complementarily to the intrinsically disordered region of the target, and demonstrated the functional control of the cancer disease-related protein p53. Finally, we discuss the possibility of peptide drug discovery for disease-related LLPS proteins.

The synucleinopathies are neurodegenerative disease caused by abnormal accumulation of the 140-amino acid-containing protein α-synuclein (αSyn), including Parkinson’s disease (PD), diffuse Lewy body dementia (DLBD), and multiple system atrophy (MSA). In patients with PD and DLBD, αSyn is misfolded in neurons, and its aggregation forms Lewy bodies (LB) and Lewy neurites (LN). On the other hand, in patients with MSA, αSyn accumulates primarily in oligodendrocytes (OLGs) and forms glial inclusion bodies (GCIs), a typical pathological feature of MSA. We recently demonstrated a making complex between αSyn and fatty acid-binding proteins (FABPs) in synucleinopathies and received wide attention. Fatty acid-binding protein 3 (FABP3) in dopamine nerves, and fatty acid-binding protein 7 (FABP7) in glial cells promoted αSyn accumulation and aggregation, respectively and caused cell death. Here, we introduced the current studies about the role of αSyn and FABP7 in MSA and novel therapeutic approach targeting for FABP7.

With the advent of a super-aging society, overcoming age-related neurological diseases and developing fundamental therapeutic agents are urgent issues. In Lewy body diseases such as Parkinson’s disease and dementia with Lewy bodies, the accumulation and aggregation of α-synuclein in the neuronal cells, called Lewy bodies, are known as pathological features. Intracellular accumulation of the causative protein α-synuclein in the central nervous system requires an uptake process into neurons. Type 3 fatty acid-binding protein (FABP3) is highly expressed in dopaminergic neurons and has the ability to bind dopamine receptors, particularly dopamine D2 long type (D2L) receptors, which are abundantly localized on caveolae structures in the plasma membrane. We found that dopaminergic neurons do not take up α-synuclein in FABP3 knockout or D2L receptor-selective knockout mice. Next, we found that the C-terminal deletion of α-synuclein reduces the uptake ability. α-Synuclein has a FABP3 binding site in its C-terminal region. On this point, exposure to the C-terminal peptide reduced α-synuclein uptake into dopaminergic neurons. Based on these findings, this article describes the unique mechanism of the propagation and uptake process of α-synuclein, focusing on the physiological significance of FABP3 and dopamine D2 receptors. Additionally, we will review the development status of therapeutic peptide candidates for Lewy body diseases, and then discuss the novel pathogenic mechanism of Lewy body disease as well as the potential of fundamental therapeutics targeting the uptake process of α-synuclein.

Among the fields of medical treatments, pharmacological therapy is most the therapy that nurses are most concerned in. Under the clinical practical scenes, nurses are required to have high specialized knowledge and proper judgment ability. In the basic education of nursing care, in clinical pharmacology, we learn pharmacological therapy in terms of principal pharmacological efficacy and adverse effects, methods of administrations, and management methods of management. As pharmacology for nursing care, we lean comprehensive understanding of diseases, life style, and psychological situations. Under the actual nursing education following clinical scenes, in addition to these issues, we are required to learn knowledge and skill of performing safety pharmacological treatment of patients. It is important that we improve high specialized knowledge and proper judgment ability and we guarantee the quality of pharmacological treatments in accordance with patients safety. Especially in the university hospitals, Drug treatment using anti-cancer drugs and agents having serious side effects, and high-level clinical test drugs, are performed. Nurses are involved in the pharmacological treatment of patients as team with doctors and pharmacist. Therefore, the guarantee of pharmacological treatment is almost identical to the guarantee of quality of nursing care. In order that nurses are able to perform pharmacological treatments to patients safely, and obtain treatment efficacy, in addition to systematic and practical education, the promotion of communication of personnel interchange between clinical fields to a faculty is very useful, leading to establishment of motivation of continual education.

In 2015, accreditation system for Japanese midwives was started by Japan Institute of Midwifery Evaluation. In the present practice, midwives are not able to acquire advanced competencies. Because of Japan’s declining birth rate and uneven distribution of work places for midwives, opportunities for midwives to experience midwifery practice are decreasing and proficiency cannot be enhanced easily. The Japanese Nursing Association realized the need for strategic enhancement of midwifery practice, and consequently developed the Clinical Ladder of Competencies for Midwifery Practice (CLoCMiP) to be made available wherever it was needed. Five midwifery-related associations (Japanese Nursing Association, Japanese Midwives Association, Japan Academy of Midwifery, Japan Society Midwifery Education, and Japan Institute of Midwifery Evaluation) each shared a sense of crisis that the current situation hindered the ability of midwives to improve their ability and performance, so they decided to establish a certification system based on CLoCMiP. CLoCMiP evaluates midwifery core competencies and comprises 5 levels from Novice to Level IV to provide midwifery care autonomously. To be linked to this, designation rules of midwifery education was changed by Ministry of Health, Labor and Welfare. It increases from 28 credits to 31 credits, and applied from 2022. It should be strengthened in perinatal mental health, clinical judgment skills, and comprehensive support for the child-rearing in the community. Then, we reviewed our midwifery program and created core curriculum in preferred midwifery education by Japan Society Midwifery Education. It is important for midwives to collaborate interprofessional and continuing Education.

Cancer chemotherapy outcomes have improved markedly after the introduction of cytotoxic anticancer drugs, molecular target medicines, and immune checkpoint inhibitors (ICIs) into clinical practice. Chemotherapy regimens are specified treatment plans that include the dose of each anticancer drug, duration of treatment, and other supportive care drugs such as antiemetics. A chemotherapy regimen leads to the standardization of cancer pharmacotherapy, leading to medical safety and efficiency. Most molecular target medicines and ICIs have companion diagnostic agents (CDxs) that predict the treatment effect based on the gene variant (driver gene) and its expression level. In addition, oncogene panel tests have recently become covered by health insurance in Japan. However, there are some strict regulations and problems with their clinical use. Most molecular target medicines and ICIs have various side effects that are different from those of cytotoxic anticancer drugs. To provide more effective care and nursing to patients receiving cancer chemotherapy, clinical nurses need to understand the basic pharmacologic characteristics of each cancer medicine and provide patients with information about side effects and potential effects on daily life.

Sepsis is one of the leading cause of death worldwide. Recently, several studies suggested that free-hemoglobin and heme derived from hemolysis are important factors which may be associated with severity of septic patients including COVID-19. In other words, hemolysis-derived products enhance the inflammatory responses as damage-associated molecular patterns (DAMPs) in both intravascular and extravascular space. In addition, hemoglobin has vasoconstrictive activity by depleting nitric oxide, whereas heme or Fe²⁺ produce reactive oxygen species (ROS) through Fenton reaction leading to tissue injury. At present, we have no therapeutic options against sepsis-related hemolysis in clinical settings, however, there might be two therapeutic strategies in this regard. One is supplemental therapy of depleted scavenging proteins such as haptoglobin and hemopexin, the other is activation of the internal scavenging system including macrophage-CD163 pathway. These novel targets against sepsis are also critical for the next pandemic. In this review, we summarize the current issues regarding sepsis-related hemolysis including COVID-19, as well as for future perspectives.

Histidine-rich glycoprotein (HRG) is a plasma glycoprotein produced mainly in the liver. We have shown that HRG replacement therapy has a marked therapeutic effect on sepsis, in which high mobility group box 1 (HMGB1), one of the representative damage-associated molecular patterns (DAMPs), is known to play an important role in the disease progression. The mechanisms of action are diverse, including inhibition of immune thrombus formation and inhibition of ROS production. In addition, HRG has been shown to neutralize the toxicity of heme, a type of DAMPs, and neutralize the activity of LPS, a type of pathogen-associated molecular patterns (PAMPs), and to inhibit the translocation of HMGB1 from the nucleus of vascular endothelial cells to the extracellular space. Since DAMPs/PAMPs are known to play a central role in the pathogenesis of not only sepsis but also many inflammatory diseases, HRG has wide therapeutic applications and is considered to be a very promising seed for drug discovery.

Advanced Glycation End Products (AGEs) are produced through a non-enzymatic reaction between reducing sugar and biomolecules. These molecules are suggested to stimulate several receptors and activate inflammatory reactions. Because the accumulation of AGEs was found to be associated with hyperglycemia and/or aging, these molecules should be contributed to the pathogenesis of inflammatory diseases related to these conditions. Interestingly, possible receptors to engage AGEs are common to endogenous proinflammatory factors called damage-associated molecular pattern molecules (DAMPs). This raised the possibility that the action mechanism of AGEs and DAMPs is closely correlated. Previously, we found that AGEs interacted with high mobility group box-1 (HMGB1), a representative DAMP, and that this interaction activated the proinflammatory activity of HMGB1. These findings suggested that exacerbation of inflammation induced by HMGB1 was caused by the condition accumulating AGEs. In addition, AGEs were found to change the action of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) through their direct interaction. TWEAK is called a multifunctional cytokine, and is suggested to regulate tumor necrosis factor-α (TNF-α) induced inflammatory reactions. We found that coexistence of AGEs and TWEAK inhibited this action of TWEAK, suggesting that accumulation of AGEs induces exacerbation of inflammation induced by TNF-α. Furthermore, we found ribosomal protein L9 (RPL9) as a novel AGE-binding protein. RPL9 inhibited HMGB1-induced inflammatory reaction, suggesting that RPL9 is the endogenous regulator for DAMPs. These findings suggested that there is a novel mechanism to regulate inflammatory reactions through the interaction among AGEs, DAMPs, and/or cytokines.

Fear memory has an important role in survival, but excess fear memory could be cause to fear-related disorders such as post traumatic disorder (PTSD). People who undergo a fearful event do not always develop PTSD, suggesting that there are vulnerable factors to develop the disorder. It is believed that sex, in particular female, is one of the factors as it is known that the prevalence rate of PTSD is higher in women than in men. However, the biological mechanisms underlying the sex differences in their prevalence rate remain unclear. Because previous studies reported that patients with fear-related disorders show an impairment of fear extinction, investigation of sex differences in fear extinction may be useful for understanding the greater vulnerability of women to fear-related disorders. Although number of papers investigating sex differences in fear extinction, these reports have increased recently. This review introduces fear extinction, sex differences in fear extinction is low, and the molecular mechanisms of sex differences in fear extinction. In the molecular mechanisms, we focused brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) receptor signal which has been investigated by independent research groups.

Central nucleus of the amygdala (CeA) has been known as an output region of emotional processing, such as fear emotion. However, recent development of technology allows us to dissect CeA neurons to find the additional role of CeA in feeding behavior, anxiety behavior and pain regulation. On the other hand, neuropeptide B/W receptor 1 expressing neurons (NPBWR1 neurons) have been known to localize in the CeA, but their physiological role is still unclear. In this review, I will introduce the recent findings about the variety of neurons in the CeA and explain the role of NPBWR1 neurons in the regulation of social behavior.

It has been known that a number of tyrosine hydroxylase (TH)-positive neurons, which are regarded as dopaminergic (DA) neurons, exist in the dorsal raphe (DR). These DA neurons in the DR and periaqueductal gray (PAG) region (DA^DR-PAG neurons) are thought to belong to the A10 cluster, which is known to be heterogeneous. This DA population projects to the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) and has been reported to modulate various affective behaviors. The DA transporter (DAT) neurons, which are well overlapping with DA neurons, in the DR-PAG region are also expected to be heterogeneous. However, even though the heterogeneity of DA/DAT^DR-PAG neurons has been suggested, the characteristics of each DA/DAT^DR-PAG neuron subpopulation are not well investigated. In this paper, we summarize the previous reports investigating the heterogeneity of DA/DAT^DR-PAG neurons and the functional importance of DA/DAT^DR-PAG neurons on various affective behaviors and introduce our recent findings that DAT^DR-PAG neurons consist of two subpopulations: TH+/vasoactive intestinal peptide (VIP)− putative DA neurons and TH-/VIP+ putative glutamatergic neurons.

The delta opioid receptor (DOP) belongs to the G protein-coupled receptor family and is abundant in the limbic system. In recent years, consistent with their distribution, they have been suggested to be involved in the regulation of emotional behavior. In particular, DOP agonists have been shown to exhibit antidepressant and anxiolytic-like effects, and clinical trials are underway as targets for the development of new psychotropic drugs with mechanisms of action different from those of existing monoamine drugs. In this article, we review the roles and mechanisms of DOP in emotion regulation that are being elucidated in basic studies using rodents, and also introduce the current status of its clinical application.

Alzheimer’s disease (AD) is one of the most common causes of dementia in the world. Neurodegeneration, gliosis, and misfolded proteins such as amyloid plaques and tau tangles are neuropathological hallmarks in AD. In vivo imaging of these neuropathological lesions would be good biomarkers to understand pathophysiology as well as surrogate markers for clinical trials. We developed THK tau radiotracers including [¹⁸F]THK-5351 and tested them in humans. Validations studies identified monoamine oxidase-B (MAO-B) as the off-target binding substrate of [¹⁸F]THK-5351. Since the elevation of MAO-B, which is highly expressed in reactive astrocytes, were observed in various neurological conditions, MAO-B would be a promising target for imaging reactive astrogliosis. In fact, [¹⁸F]THK-5351 PET studies demonstrated that high tracer uptake in site susceptible regions to occur astrogliosis in various neurological disorders. However, the lack of binding selectivity affects the interpretation of PET images. Therefore, we performed lead optimization from [¹⁸F]THK-5351 generating a selective and reversible MAO-B PET tracer, [¹⁸F]SMBT-1. These translational and reverse translational studies, from the development of PET tracers to validation of PET images, led to the generation of new biomarkers. In this review, we will introduce the development of [¹⁸F]THK-5351, identification of off-target binding substrates, imaging-autopsy validations, new tracer development ([¹⁸F]SMBT-1), and finally recent clinical studies of [¹⁸F]SMBT-1.

Since the first monoclonal antibody was approved by FDA in 1986, numerous therapeutic antibodies have been developed along with advances in antibody engineering and finally, the number of approved therapeutic antibodies by FDA exceeded 100 in 2021. Although therapeutic antibodies were thought to be safer than conventional small molecule drugs, non-clinical safety evaluations of antibodies become more important because antibody-specific toxicity has been found. The depletion of target molecules for antibody drugs is a problem due to the limited number of promising targets. However, to overcome this, some technologies which can enhance the activity of antibodies and enable to add new functions to antibodies have been developed. In particular, bispecific antibodies and antibody-drug conjugates are considered to be attracting technologies as the next-generation antibody modalities. Several drugs applying these technologies have been approved in a recent decade. On the other hand, there is still plenty of room for improvement in these technologies which sometimes occur unexpected toxicity, so the safety of drugs applying these technologies should be carefully evaluated. Here some important considerations for the non-clinical safety evaluations of bispecific antibodies and antibody-drug conjugates are discussed based on a literature review of these types of antibody drugs (approved or terminated due to toxicity).

Cerebral vasospasm occurs within 4 to 14 days from the onset of aneurysmal subarachnoid hemorrhage (aSAH) in 40 to 70% of patients. Of patients with cerebral vasospasm, 17 to 40% experience delayed ischemic neurological deficits and about half of them develop cerebral infarction. Although the mechanism of the onset of cerebral vasospasm has not been fully elucidated, one of mechanisms is considered that after the onset of aSAH, the level of endothelin, a potent and sustained vasoconstriction substance, increases by production induced by oxyhemoglobin and release from erythrocytes and thus cerebral vasospasm develops via endothelin (ET)_A receptor. PIVLAZ I.V. Infusion liquid 150 mg (clazosentan sodium) is an endothelin receptor antagonist with a binding affinity for ET_A receptor approximately 1,000 times higher than that for ET_B receptor. In the clinical study, the incidence of cerebral vasospasm-related morbidity and all-cause mortality was significantly decreased by clazosentan compared with the placebo. The marketing approval was obtained for the indication of “Prevention of cerebral vasospasm, and vasospasm-related cerebral infarction and cerebral ischemic symptoms after aSAH securing” in January 2022. It is expected to contribute to reducing the risk of sequela and improving quality of life in patients with aSAH.