iPSC technology has enabled us to accurately model the pathology of human diseases. Previous studies have identified the abnormal central nervous development, impaired synaptic functions and impaired neural circuit functions as the causes of psychiatric and neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders, however, much remains unknown about the molecular and cellular etiology of these disorders. We have been focusing on disease-associated rare variants with high penetrance for analyzing the molecular and cellular etiology of psychiatric and neurodevelopmental disorders. We established iPSCs from patients with these disorders for which there is existing clinical information and differentiated these iPSCs into neurons. We identified impaired developmental and mature neural functions in the iPSC neurons from patients with rare variants with high penetrance, which provide important insights into the cellular basis of psychiatric and neurodevelopmental disorders. Patients'-derived iPSC neurons together with the patients' clinical information are versatile for understanding the molecular and cellular etiology of psychiatric and neurodevelopmental disorders and developing therapeutics for these disorders.

Technological innovations in the field of cell differentiation from iPS cells has made it possible to induce dopamine neurons, inhibitory GABA neurons, and even excitatory glutamate neurons, as well as peripheral neurons such as sensory and motor neurons. Thus, we have been able to analyze the mechanisms of disease in specific cells that are targets for disease. In addition, DNA recombination systems such as the Cre-loxP system can be used to control target gene expression specifically in the rodent brain. By connecting human disease-specific iPS cell research and in vivo neuroscience research, we may be able to elucidate the mechanisms of the onset of intractable neurologic diseases which have not yet been clarified. In the present study, we focused on genetic and sporadic intractable neurologic diseases and applied these techniques to the analysis of disease mechanisms. In this symposium, we will present our recent findings on the pathological mechanisms of familial Parkinson's disease and fibromyalgia. Furthermore, we will discuss the outlines and practice of "reverse translational neuroscience research", which is useful for applying a patient's information to basic neuroscience research.

We are exposed to numerous xenobiotic electrophiles on a daily basis through living environment, lifestyle, and dietary habits. Such reactive substances are reported to covalently modify protein thiols, resulting in formation of protein adducts. We found that xenobiotic electrophiles activate a variety of redox signaling pathways through selective modification of sensor proteins at low dose and cause disruption of the signaling and toxicity through non-selective and extensive modification of cellular proteins at high dose. We also found that reactive sulfur species (e.g., cysteine persulfide, glutathione (GSH) persulfide, hydrogen sulfide) are able to capture xenobiotic electrophiles, leading to formation of their sulfur adducts, thereby inactivating these electrophiles. Furthermore, it was demonstrated that nuclear factor-erythroid 2-related factor 2 (Nrf2) and cystathionine gamma-lyase (CSE) are involved in decreased risk of electrophilic stress in parallel through GSH and sulfur adduct formation, respectively. By the way, the concept of "exposome", which is the totality of exposure, has been proposed and has become a hot topic. In this symposium, I introduce the methodology using environmental electrophiles as a model of restricted exposome.

Natural antibodies (NAbs), essentially antibodies (Abs) of the IgM isotype present in the circulation of mammalian species, are mainly produced by B-1 lymphocytes independently of external antigenic stimulation. NAbs provide immediate protection against pathogens and play an important role in the host defense mechanism against various stresses. Most of NAbs are poly-reactive (multi-specific or cross-reactive) in nature and recognize specific molecular patterns with no apparent structural similarity. It has been demonstrated that the modified self-proteins, such as oxidized low-density lipoproteins, are important targets of Nabs. In addition, based on the findings that these modified proteins have several properties different from native proteins, including an elevated electronegative potential due to modification of the positively charged amino acid residues, we have proposed that the electronegative potential of antigens might be involved, at least in part, in the recognition by Nabs. In this symposium, I provide a summary of NAbs as a safeguard against covalently modified proteins generated in association with exposome.

Pattern recognition receptors (PRRs) play an important role in elimination of pathogenic microbes as well as damaged tissue debris by activating innate inflammatory responses. Membrane-bound PRR Toll-like receptors (TLRs) produces inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) as well as type I interferons. Cysteine persulfide (CysSSH) and polysulfides (CysS[S]nH, n > 2) are cysteine derivatives having sulfane sulfur atoms bound to cysteine thiol. Cysteine persulfide exist as a component of glutathione (GSH) as GSH persulfide (GSSH) and as protein-bound persulfide. Those cysteine persulfides act as reactive sulfur species because of their high chemical properties like antioxidative and nucleophilic activities. We found that reactive sulfur species contribute to the negative regulation of TLR signaling via inhibition of NF-kappaB pathway (Cell Chem Biol, 2019). We also found recently that reactive sulfur species down regulate inflammasome signaling (unpublished data). In this seminar, regulation of PRR signaling by reactive sulfur species will be discussed.

Functions of many proteins are regulated by posttranslational modifications. Lysine residue in proteins contains an amino group that is targeted for chemical modifications such as acetylation. Histones are the most famous lysine acetylated proteins, which regulate epigenetic gene expression and thereby determines cell fate. On the other hand, it has recently revealed that lysine residues undergo various acyl modifications including long-chain fatty acylation. These acyl modifications on lysine residues are induced by endogenous carboxylic acids such as fatty acids through chemical reactions in vivo. However, are lysine residues modified by only endogenous carboxylic acids in the body? We are exposed daily to various compounds including carboxylic acids. For example, there are more than 100 types of carboxylic acids in food additives. These exogenous carboxylic acids may be also added to lysine residues of proteins such as histones in the body. In this presentation, we would like to introduce our research on lysine acyl modifications including especially long-chain fatty acylations in transcriptional factors and discuss possible influences of exposure of exogenous carboxylic acids to a living organism from the perspective of lysine adduct exposome.

Diabetic kidney disease is an important diabetic complications as a causative disease for the progression of dialysis. However the current therapeutic option has not been fully satisfied for completely suppressing the progression of renal injury. One of the reasons is that the model animals are limited that exhibit progressive renal injury similar to those of patients such as advanced urinary protein excretion, glomerular sclerosis, renal interstitial fibrosis and decreased glomerular filtration rate. And also, this is one of the important factors that pathophysiology of diabetic kidney disease has not yet been fully clarify.

SGLT2 inhibitors are medicines that promote the excretion of glucose into the urine by suppressing the reabsorption of glucose from the renal proximal tubule and induce a blood glucose lowering effect. In order to verify the effect of SGLT2 inhibitors on diabetic complications, we examined the effects of luseogliflozin using two kind of animals expressing the progressive renal injury including the advanced features of diabetic kidney disease similar to patients. Luseogliflozin and combination therapy with ACE inhibitor prevented the progression of renal injury in these animals, and it suggests that SGLT2 inhibitors could be a candidate of therapeutic option for diabetic kidney disease.

The prevalence of chronic kidney disease (CKD) is increasing worldwide, with primarily diabetic kidney disease (DKD), being a major public health concern. Although the detailed mechanisms of CKD progression are not fully understood, the transition to kidney failure has been suggested to occur via a final common pathway, which is thought to be associated with oxidative stress and inflammation as important factors.

The Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) pathway is a key regulator of anti-oxidative and anti-inflammatory response. A number of reports have described the association between this pathway and kidney diseases in animal studies.

Bardoxolone methyl, a semi-synthetic triterpenoids, is known to be a potent Nrf2 activator. Importantly, previous clinical trials demonstrated that bardoxolone methyl increases not only estimated glomerular filtration rate (eGFR) but measured GFR, which is a true indicator of kidney function, using the inulin clearance method in patients with DKD. A Japanese Phase 3 study is currently ongoing to assess the efficacy and safety of bardoxolone methyl in more than 1,000 patients with stages G3 and G4 DKD.

This presentation summarizes available knowledge on the therapeutic potential of bardoxolone methyl for treatment of DKD.

Tolvaptan is a selective vasopressin V₂ receptor antagonist that blocks binding of arginine vasopressin (AVP) to V₂ receptors in collecting duct of kidney, thereby inducing water diuresis (aquaresis) without depletion of electrolytes. Tolvaptan was firstly approved as an aquaretic agent for treatment of hyponatremia including syndrome of inappropriate secretion of antidiuretic hormone and for treatment of fluid volume overload in heart failure and cirrhosis.

Tolvaptan was also approved for ADPKD. ADPKD is the most common genetic kidney disease and caused by mutations in PKD1 or PKD2. Fluid-filled cysts develop and enlarge in both kidneys, eventually leading to kidney failure. Several signaling pathways have been demonstrated in the pathogenesis of ADPKD. cAMP plays an important role in cyst growth by promoting cell proliferation and fluid secretion. Antagonism of AVP by tolvaptan suppressed AVP-induced cAMP production and renal cyst growth. In some animal models, tolvaptan showed suppression of cyst growth and renal injury, and delayed the onset of end-stage renal disease.

In the Phase 3 clinical trial in ADPKD patients (TEMPO 3:4), 3-year treatment with tolvaptan slowed the disease progression including increase of kidney volume and decline in renal function. The therapeutic efficacy of tolvaptan in patients with late-stage ADPKD was confirmed in another 1-year Phase 3 REPRISE trial.

Tolvaptan is a first and only approved drug for treatment of ADPKD and it provides therapeutic option to suppress both cyst growth and decline of kidney function across the globe.

Cancer patients often suffer from physical pain by cancer itself and side effects of anticancer drugs. Also, they suffer from psychological, social and spiritual pain. To get rid of such pain, it is important to deal with this total pain.

We are conducting research from the basics to clinical practice to improve the quality of life of cancer patients. If there is no drug that can relieve the patient's symptoms, it is necessary to develop new drugs or apply an existing drug to other symptoms, so called drug-repositioning. Among them, we are focusing on "Japanese Kampo medicines" introduced from China and developed according to the constitution of Japanese people. We now are conducting research to improve side effects that occur with anticancer drugs by using Kampo medicines as drug-repositioning.

Cancer patients who receive anti-cancer drugs or radiation therapy frequently develop stomatitis. This stomatitis adversely affects the basic life of "eating, drinking, and speaking." In basic research and clinical trials, we have shown that one of the Kampo medicine hangeshashinto promotes early treatment of stomatitis basically scientific evidence-mediated manner.

Medical staff such as doctors, pharmacists and nurses want to employ drugs with scientific evidence. On the other hand, patients also want to use "drugs that have been found to be effective." If a nurse working at front line of patients can tell the patients exactly why the drug works and why it is needed, and if the results can be scientifically fed back, the palliative care team contributes to patients.

Today, I would like to highlight the "a Kampo medicine used for stomatitis" and introduce the importance of understanding scientific mechanism of action of drugs and communicating them accurately and gently to cancer patients.

In recent years, collaborative medical care has progressed, and pharmacists have more opportunities to participate in clinical research. The main research subject that pharmacists are involved in is TDM research, which is one of the personalized medicines. In TDM studies, it may be necessary to collect blood over time, and the timing and storage status are often important. In addition, it is not uncommon to obtain patient information necessary for selecting, analyzing, and considering subjects according to the patient's condition not only from medical records but also from nursing records. Therefore, in advancing this type of research, it is thought that the quality of the research will be improved if the content and intention of the research are shared with nurses and other multidisciplinary medical staff. In this symposium, we would like to discuss the usefulness of multidisciplinary collaboration in advancing clinical research, citing cases and research that we have recently experienced.

Extravasation of antineoplastic agents is cited as a cause of ulceration, blistering, and induration. Delays in detecting extravasation can lead to severe skin damage, making detection as early as possible crucial. Clinical identification has previously been based on patients' accounts of pain and nurses' observations of erythema and swelling around the tip of the catheter. However, because pain and erythema may also occur as a result of drug-induced irritation of the vessel walls, cases are sometimes difficult to identify accurately. This research focused on the use of thermography as a method of identifying the presence of extravasation objectively. Extravasation was defined as swelling around the infusion site during administration or as subcutaneous hemorrhage, erythema, pigmentation, induration, blistering, or epidermal loss occurring at any time before the next visit. Of 257 patients who received chemotherapy through peripheral veins, extravasation was identified in 26. Thermography was performed every 15 to 30 minutes during the infusions. A low-temperature region with a gradual decrease in temperature from the infusion site margin was seen in the extravasation group. Sensitivity, specificity, positive predictive value, and negative predictive value using thermography were 85%, 95%, 65%, and 98%, respectively. This study showed that thermography offers an accurate method of identifying extravasation. Use of devices based on nursing science and engineering contributes to the development of new nursing technology.

The management of intravenous therapy is an important task for nurses.Extravasation of drugs is an adverse event of infusion therapy that can occurwith a variety of drugs. The frequency of extravasation of anticancer drugsranges from 0.01% to 6.5% in Europe and the United States and from 0.14% to10.8% in Japan. Although the frequency has decreased over the years,extravasation of anticancer drugs classified as vesicants, can cause necrosisand other skin injuries, thereby increasing the patient's suffering. To treatextravasation, a nurse can administer cold or hot compresses. Cooling is used tolocalize the drug, and heating is used to promote drug absorption. Hotcompresses are recommended for some drugs. However, in an experimental study onlaboratory animals, we found that heating may exacerbate skin disorders.Meanwhile, cooling may reduce (or not exacerbate) skin injuries. Therefore, wecontinue investigating the effective cooling temperature and duration againstskin injury caused by extravasation, with the aim of establishing the safety ofcompresses and providing care that brings comfort to patients. In thispresentation, we would like to share the results of our study on skin injuriescaused by extravasation.

COVID-19 pandemic from spring, 2020 changed pharmacological education. To reveal its actual status, the Physiology Society of Japan and the Japanese Pharmacological Society jointly conducted nationwide emergency survey on the response to COVID-19 pandemic and the change of educational environment in universities and colleges from August 26 to September 15, 2020. Here, we demonstrated the results from the Department of Pharmacology in Medical, Dental and Veterinary School. Response rate was high around 90%. How to do the lecture and the practice were changed in 80% and 70%, respectively. Instead of face-to-face teaching, online methods were widely utilized. Live and on-demand streaming used around 30% each and mixed streaming around 40% in the lecture, while live and mixed streaming used around 25% each and on-demand streaming around 45% in the practice. Online methods were also adopted in attendance confirmation and conduct of examination. There are several problems to do online methods such as "unstable network environment", "lack of the reality for students" and "difficulty in the check of their understanding". On the other hand, there are unexpected benefits in online methods such as "anytime and repeatable learning", "an increase in questions from students" and "concentration of learning". 60% of responders insist they will utilize the changed methods in the future. In this part, we would discuss on "new normal" pharmacological education from this survey results.

The pandemic of Covid-19 has drastically changed the education program in universities. An on-demand lecture is one of the common approaches, which are employed to prevent the infection form spreading in the classroom. On-demand lectures generally have a good reception of the students for the reason that they could repeatedly play back the video when needed and attend the class in a relaxed attitude as they like. On the other hand, we often have some concerns about their understanding of the lecture because we could not get the feedback during the preparation of the video lectures. In addition, majority of us, beginners of on-demand lectures, have to overcome the difficulties in utilizing various tools to support them.

Here, I would like to introduce some tips of on-demand lectures. One, who delivers a chalk talk, should obtain a good pen tablet and a suitable video recording software. Because video lectures with a large data size interrupt the comfortable views of the students, the video files should be compressed using a special software. Approachable Q&A systems should greatly enhance the learning efficiency and open the door to the flip teaching. The on-demand lecture should remain a workable alternative after the pandemic ending.

Laboratory work is an essential part of science education since they provide students with hands-on experience of practical scientific research. In laboratory work in pharmacology, students analyze effects of drugs using laboratory animals to learn physiological and biochemical mechanisms of the drugs. Actual experience with hands and eyes is an important factor in the laboratory work. Under the COVID-19 epidemic, however, we were forced to conduct the laboratory work online. For the laboratory work using isolated organs, we used simulation software, in which students can examine effects of a range of drugs on the smooth muscle within the guinea pig ileum. The advantage of the simulation software is that students are proactively involved in the laboratory work. Through a series of voluntary trials and errors, they elucidated the mechanism of drug action and identified the pharmacological effects of unknown drugs. For the laboratory work of observing and analyzing animal behavior, students watched videos of mice given drugs to learn the drug actions on the central and autonomic nervous system. In this symposium, we will share our challenges to online laboratory work.

The role-play for pharmacological education has been developed by Yanagita et al. since 2010. This case and communication based active learning course provides the fundamental skills for pharmacotherapy including appropriate drug prescriptions and communication to achieve behavioral modification in patients, through a role playing of medical professionals and patients in simulated clinical settings. The conventional role-play requires a face-to-face environment to run the course based on direct communication and interaction between students. However, COVID-19 forces us to transit from on-campus classes to off-campus online courses from April 2020. We performed an online role-play for the first time at Tohoku Medical and Pharmaceutical University Faculty of Medicine during the state of emergency in Japan. In this presentation, we will describe the course design, preparation, and operation of the online role-play for pharmacological education. We will explain how it was transformed and developed from the conventional composition to the online setting. We will also describe the differences, advantages, and disadvantages of the online setting. Finally, we give examples of on-going challenges to the effective use of the online role-play as a core curricular model of pharmacological and pharmacotherapeutic education.

Changes in the number of postsynaptic AMPA receptors are believed to underlie long-term potentiation and long-term depression in cellular models of learning and memory. Furthermore, dysfunctions in AMPA receptors leading to imbalances between excitatory and inhibitory synapses are thought to underlie certain neuronal disorders such as epilepsy, Alzheimer's disease, depression and schizophrenia. Despite an accumulation of basic research on AMPA receptors suggesting substantial potential of these receptors as a therapeutic target, clinical translation has been limited. This could be attributed to the lack of technology to visualize AMPA receptors in the living human brain. Thus, there is a need for a technology to visualize AMPA receptors in the living human brain to further elucidate the molecular and circuit bases of neuronal diseases and to develop novel diagnostic and therapeutic options. PET is widely used in clinical diagnosis. Although several compounds have been developed as potential PET tracers for AMPA receptors, there is currently no radiotracer suitable for in vivo PET imaging of AMPA receptors. Here we developed a new AMPA receptor PET tracer named [11C]K-2, which is suitable for visualizing AMPA receptors in the human brain.

A brain function is produced by the cooperative work of some brain areas responsible for the function. Since the breakdown of this mechanism induces the pathological conditions in neuropsychiatric disorders, it is important to identify the affected function by manipulating the specific brain regions. Designer receptors exclusively activated by designer drugs (DREADDs) are one of the chemogenetic technologies that afford a remotely reversible control of the activity of a target neural population expressing a "designer receptor" by an agonist compound. The most widely used DREADDs are muscarinic-based such as hM3Dq (excitatory) and hM4Di (inhibitory), which can be activated by clozapine-N-oxide (CNO). CNO has some concerns that the effect is slow because CNO has a modest brain penetrability, and the systemic administration may produce off-target actions because CNO is metabolized to clozapine, an antipsychotic drug that acts on numerous endogenous receptors. We solved these issues by developing a new compound, deschloroclozapine (DCZ). DCZ has a higher affinity and greater agonist potency than CNO with reduced off-target action and can rapidly modulate the neuronal activity and behavior with muscarinic-based DREADDs in living animals. Given the potential shortcomings of CNO, DCZ offers clear benefits to many users of muscarinic-based DREADD, with increased reliability by removing concerns about potential off-target responses.

Damage to the central nervous system (CNS) causes severe neurological conditions, such as sustained sensory, motor, cognitive dysfunction and compromise work capacity and self-care. Few pharmacological intervention that could foster recovery and complement current rehabilitation has yet been established as eective. Restoration of motor impairment after CNS damage is considered to be the result of compensative neural plasticity in spared neural circuit, and the Experience-dependent synaptic AMPA (α-amino-3-hydroxy-5- methyl-4-isoxazole-propionic-acid) receptor (AMPAR) delivery underlies behaviors that require neural plasticity such as learning. We found that a small compound, edonerpic-maleate (also known as T-817MA), facilitated experience-driven synaptic glutamate AMPA receptor delivery and resulted in the acceleration of motor function recovery after cortical or spinal cord cryoinjury. Edonerpic bound to collapsin-response-mediator-protein 2 (CRMP2), a downstream molecule of semaphorin, and is thought to be related to synaptic plasticity and learning. Furthermore, we detected CRMP2- dependent activation of ADF/colin by edonerpic maleate in the plasticity- inducing condition. Indicating edonerpic could facilitate synaptic AMPAR delivery through the regulation of actin dynamics. Thus, edonerpic-maleate, a neural plasticity enhancer, could be a clinically potent small compound to accelerate rehabilitation after damage of CNS.

It is suggested that spatiotemporal dynamics of molecular activities such as locality and timing are important as well as simple ON / OFF system in the living cells. On the other hand, the physiological significance of these activities and the extent of their contribution to the in vivo　remain largely unknown. Recently, live imaging has been used as a method to approach these issues. Although imaging technique has revealed the correlation between molecular and cellular dynamics and biological phenomena, new methods are needed to elucidate the causal relationship between them. The CALI (chromophore-assisted light inactivation) is one of the optical technologies for molecular inactivation by using photosensitizers that release reactive oxygen species upon irradiation. Such locally and temporally inactivation of target molecules by light is effective in elucidating the spatiotemporal properties of molecules, which are difficult to approach by genome manipulation. Our new CALI method is attracting a lot of attention as a next-generation technology for neuroscience (Humeau Y et al. Nat. Neurosci. 2019, Frank JA et al. Nat. Biotechnol. 2019, Paoletti P et al. Nat. Rev. Neurosci. 2019 etc.). In this presentation, we will first introduce the elemental technology of our highly efficient and versatile CALI methods. In addition, the application of the CALI method to novel molecules will be introduced in detail, including our recently reported work on elucidating the memory mechanism using the CALI method (Takemoto K et al. Nat. Biotechnol. 2017).

Fms-like tyrosine kinase 3 (FLT3) mutations have been found in about 30% of acute myeloid leukemia (AML) cases, and the most common form of FLT3 mutation is internal tandem duplication (ITD) in the juxtamembrane domain, which is associated with poor prognosis.

In non-clinical studies, quizartinib clearly inhibited FLT3 signaling pathways in FLT3-ITD–mutated human AML cells, leading to potent growth inhibition. When quizartinib was given to mice bearing human FLT3-ITD AML MV4-11 cells, the tumor regression was observed. In addition, quizartinib inhibited the viability of the on midostaurin-resistant human FLT3-ITD AML MOLM-14 cells, and exerted potent in vivo anti-tumor activity.

Quizartinib showed clinical benefit in patients with FLT3-ITD–mutated relapsed/refractory AML in phase III QuANTUM-R trial (NCT02039726). Quizartinib significantly prolonged median survival time compared with salvage chemotherapy (6.2 months vs 4.7 months; HR = 0.76 [95% CI, 0.58–0.98; P = 0.0177]). The most common TEAEs were thrombocytopenia, nausea and anemia. A phase III QuANTUM-First trial (NCT02668653) in patients with newly diagnosed FLT3-ITD–mutated AML is now ongoing.

Non-clinical and clinical profile of quizartinib suggests its potential for further clinical investigation of optimum treatment sequence with FLT3 inhibitors for the AML patients.

Multiple myeloma (MM) is a hematological malignancy that originates from bone marrow plasma cells. In Japan, MM is the second most common hematological malignancy and the number of patients are increasing year by year due to the aging population. In addition to the proliferation of monoclonal neoplastic plasma cells, MM presents with a variety of systemic symptoms termed CRAB manifestations, namely bone lesions, hypercalcemia, anemia, and renal involvement.

The selections of anti-myeloma therapy should be based on the patient's condition, such as newly diagnosed multiple myeloma (NDMM), relapsed and/or refractory multiple myeloma (RRMM), the indication for transplantation, and the presence or absence of organ damage due to myeloma. Therefore, the strategy of anti-myeloma therapy should be determined taking account of the patient's individual organ function.

In recent years, those drugs with various mechanisms of action, such as proteasome inhibitors (PI), immunomodulatory drugs (IMIDs), anti-CD 38 monoclonal antibodies, and anti-SLAMF7 antibodies, have emerged and improved the prognosis of MM patients. On the other hand, MM is still difficult to cure, and it relapses repeatedly and gradually becomes resistant to treatments. Therefore, the development of more promising drugs is expected in the future.

In this symposium, the pathology, current treatment strategy, and new drug development status for MM will be outlined

CAR-T therapy to target CD19 on malignant B cells is in the limelight owing to its high therapeutic efficacy. Many advanced researchs are accelerating worldwide to clarify the characteristics of CAR-T cells, such as the mechanism of cytotoxic activity, the optimization of the CAR signal domain structure, and the qualitative effects on T cell populations.

Tisagenlecleucel (Kymriah^®) is consists of CAR-T cells cultured and proliferated after ex vivo transduction with the CAR encoding gene using a lentiviral vector to patient's own T cells collected from blood. In recent years, CD19 CAR-T therapy has been developed as a treatment option for r/rDLBCL, particulary tisagenlecleucel is approved in Japan.

CAR-T therapy is an effective therapy for malignant lymphoma. However, there are still some challenges we have to conquer, which include the relapse and the management of adverse reaction such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

This presentation is to share basic knowledge on the development of CAR-T therapy based on the development experience of tisagenlecleucel for DLBCL and frontline scientific information obtained to date. Thus, we would like to discuss the current status and problems of CAR-T therapy in malignant lymphoma and the future direction of development.

Skeletal muscle has the capacity to regenerate myofibers in response to muscle injury. Upon a variety of stimuli including mechanical stretch, muscle-resident stem cells called muscle satellite cells (MuSCs) are committed to become myoblasts that can fuse with each other to regenerate myofibers. The rigidity of the microenvironment is thought to regulate regeneration of myofibers, but the molecular entity of the stiffness sensor that determines the function of MuSCs remains to be elucidated. In this session, we will present our recent data showing that PIEZO1, a Ca²⁺-permeable mechanosensitive ion channel that is activated by membrane tension, plays a crucial role in the function of MuSCs. Conditional deletion of the Piezo1 gene in MuSCs leads to delayed myofiber regeneration after muscle injury, at least in part due to a growth defect of MuSCs caused by a reduced formation of actomyosin. Thus, we propose the novel mechanism: Ca²⁺ influx in response to mechanical stimulation may be involved in adjustment of cellular stiffness that is essential for the MuSC function.

The living tissues have an optimized stiffness to perform their proper functions. It has been reported that stiffness of the extracellular environment plays major roles in determining cell fate in various cell types. To understand how cells recognize and respond to non-uniform stiffness of tissue, integrated analysis and characteristics of a series of stiffness sensing receptors are required. However, only a few stiffness responsible receptors have been identified, and it is still mostly unclear how cells recognize non-uniform stiffness through coordination of stiffness sensing receptors. G protein-coupled receptors (GPCRs) are a major class of transmembrane receptors which are responsible to various types of extracellular ligands. Recently, we found that several GPCRs can be activated by the differences of extracellular substrate stiffness. Using GPCR expression plasmid library, we identified seven GPCRs that are activated by soft substrate such as PDMS. These receptor show permanent calcium oscillation under soft substrate without receptor desensitization. In this talk, we introduce activation properties of stiffness sensing GPCRs and discuss their physiological and pathophysiological meaning.

Hemodynamic stress and extracellular matrix stiffness provide essential information for homeostatic regulation and functional adaptation on the physiological and pathological remodeling of myocytes. Previously, we have reported that transient receptor potential cation channel vanilloid-family type 2 (TRPV2) is a candidate of myocyte mechanosensor, and crucial for the maintenance of cardiac structure and function. Here, we show the role of TRPV2 in the physiological and pathological remodeling of myocytes. TRPV2-deficient neonatal cardiomyocytes exhibited no sarcomere formation, reduced Ca²⁺ contents of sarcoplasmic reticulum, or spontaneous beating, suggesting that TRPV2-dificiency affects myocyte maturation. The elimination of TRPV2 from juveniles showed the reduction of myofilaments and mildly chamber dilation in adult stage. Isolated myocytes from these mice showed the impaired Ca²⁺ handling with excitation-contraction coupling and contractile dysfunction. In hypertrophic response, increased actin-myosin cross-bridge formation enhance passive cardiomyocytes stiffness in the transverse direction. However, TRPV2-deficent hearts showed no change of myofilament protein expression and severe cardiac dysfunction to pressure-overload. Thus, TRPV2 is critical for compensate hypertrophic response to mechanical stress.

Sound evokes sub-nanoscale vibration within the cochlear sensory epithelium. The epithelium contains not only immotile cells but also contractile outer hair cells (OHCs) that actively shrink and elongate synchronously with the sound. However, the in-vivo motion of epithelial cells have remained undetermined. As a first step for determining in vivo cellular stiffness, we performed high resolution and accuracy vibrometry in live guinea pigs with an SC-introduced spectral-domain optical coherence tomography system (SD-OCT). Our study achieved the optimization of a SD-OCT system for high-resolution in-vivo vibrometry in the cochlear sensory epithelium, termed the organ of Corti, in mammalian cochlea. By introducing a supercontinuum (SC) light source and reducing the total acquisition time, we improve the axial resolution and overcome the difficulty in recording the low reflective cells in the presence of biological noise. The high power of the SC source enables the system to achieve a spatial resolution of 1.72 ± 0.00 μm on a mirror and reducing the total acquisition time contributes to the high spatial accuracy of sub-nanoscale vibrometry. Our findings reveal the various cells in the sensory epithelium.

Mechanism of excitation-contraction (EC) coupling in immature hearts are considered to be different from those in the adults because of the structural immaturity of the sarcoplasmic reticulum (SR), an intracellular Ca²⁺ store, and the different expression of Ca²⁺-regulatory proteins. However, the detailed molecular mechanism is not completely understood. In the present study, we identified neuronal Ca²⁺ sensor-1 (NCS-1), an EF-hand Ca²⁺ binding protein that is important for neuronal functions, also functions as a novel regulator of EC coupling in young hearts. We found that NCS-1 is highly expressed in immature hearts, and its deletion decreased their contractile functions. NCS-1 enhances Ca²⁺ signals mainly by promoting the IP₃ receptor functions, followed by CaMKII signaling, which results in a large increase in the SR Ca²⁺ content that enhances SR-dependent EC coupling. In addition, NCS-1 expression increases in the early stages of hypertrophy and promotes progression of hypertrophy at least in part through IP₃R-dependent elevation of nuclear Ca²⁺ signaling. Our results reveal a previously unrecognized mechanism of EC coupling in young heart and the progression of cardiac hypertrophy. We propose that the proteins involved in NCS-1-mediating Ca²⁺ signaling can be novel therapeutic targets for cardiac diseases in immature hearts.

The treatment of pediatric heart failure (PHF) is a long-standing unmet medical need because of a great variety of its pathogenesis and pathophysiology rendering large-scale clinical trials difficult. In order to overcome this issue, we conducted basic experiments and found that cardiac AT₁ angiotensin receptors (AT₁R) and their downstream β-arrestin 2 play a prosurvival role in the pre-weaning period of mice. Specifically, angiotensin II activated L-type Ca²⁺ channels through the AT₁R/β-arrestin 2 pathway in murine cardiac myocytes (CM) before weaning. A peptidyl β-arrestin-biased AT₁R agonist (BBA), TRV027 significantly increased the peak twitch Ca²⁺ transients in mouse neonatal CMs as well as human iPS cell-derived CMs with fetal to neonatal phenotype. TRV027 evoked a characteristic, strong, long-lasting positive inotropic effect (～8 h) in pre-weaning mice without little increasing heart rate, cardiac oxygen consumption, ROS production, and aldosterone secretion. Finally, daily administration of TRV027 but not an AT₁R antagonist from postnatal day 1 significantly improved the survival rate of knock-in mice bearing a genetic mutation causing human congenital dilated cardiomyopathy. In this symposium, we will refer to these and other lines of evidence indicating that PHF before weaning should be treated with BBA but not ARB.

Zebrafish is an excellent animal model for human diseases due to its high genetic homology to human, and easy genetic manipulation. To monitor the expression of Muscle RING-finger protein-1 (MuRF1) gene, which is one of marker molecules of muscle atrophy, a transgenic zebrafish line was created with microinjection of murf1 promoter-EGFP cDNA construct using tol2 transposon system.

During early development in the transgenic fish (murf1:EGFP) line, EGFP signals were observed in skeletal muscle and heart from 1 day post-fertilization (dpf). RT-PCR analysis confirmed that the murf1 gene expression was corresponded with EGFP expression after 1 dpf. In the adult transgenic fish, murf1 expression corresponding with EGFP were mainly observed in skeletal muscle and heart. Treatment with dexamethasone solution at 4 dpf for 24 hours induced up-regulation of EGFP expression in murf1:EGFP zebrafish. These results indicated that the murf1 expression could be monitored using the murf1:EGFP fish. Using the murf1:EGFP fish, we have screened 1,280 drugs to discovery chemicals to reduce the expression of zebrafish murf1, and five candidate chemicals were identified.

Our murf1:EGFP fish line might be excellent tool to evaluate the expression of murf1 and is useful to therapeutic drug screening for muscle atrophy.

Objective: COX inhibitors targeting smooth muscle cell (SMC) contraction represent the only pharmacological treatment for patent ductus arteriosus (PDA), but >30% patients are resistant to the current therapies. Intimal thickening (IT), occurs in the subendothelial region of DA to bring anatomical DA closure. We investigated the role of fibulin-1 in DA anatomical closure to seek a new IT-inducing pharmacological therapy.

Approaches and results: Microarray analysis demonstrated that fibulin-1 was the most up-regulated gene by stimulation of EP4 in DA-SMCs. EP4-induced fibulin-1 expression was mediated through the phospholipase C-protein kinase C-noncanonical nuclear factor-kappa B pathway. We performed FACS analysis and found that fibulin-1 binding protein versican was derived from DA-endothelial cells. Immunofluorescence demonstrated that fibulin-1 and versican V0/V1 were co-expressed at the IT of wild-type DA. In the DA of EP4-deficient mouse (Ptger4^-/-), fibulin-1was largely attenuated and showed PDA. All of fibulin-1-deficient mice exhibited PDA with hypoplastic IT, and fibulin-1 protein administration restored IT formation of Ptger4^-/-. Furthermore, 30% of versican deleted mice lacking a hyaluronan binding site displayed PDA.

Conclusions: Fibulin-1 contributes to DA closure by forming an environment favoring directional SMC migration toward the subendothelial region in combination with versican and hyaluronan. Targeting fibulin-1 upregulation may provide the basis for therapeutic strategies for inducing anatomical DA closure.

I received PhD at Department of Pharmacology, School of Pharmaceutical Sciences in Kyushu University in the area of Ca₂⁺ signaling in vascular biology. To further develop my research, I applied a post-doc position in the lab which was world famous for Angiotensin II receptor signaling in vascular smooth muscle cells (VSMCs) in USA. During post-doctoral fellow, I demonstrated "for the first time" that reactive oxygen species (ROS) function as second messengers to mediate G protein-coupled receptor signaling in VSMCs. This paper and several related publications helped me to develop my career in the field of ROS (redox) signaling in endothelial cell biology and angiogenesis, a process of new vessel formation. To become independent from the mentor was the most difficult when we need the help from mentor and department head to develop own research projects for applying own federal grants. At this stage, we should be independent from mentor regarding having new own ideas and writing grants and papers. After several failure, I obtained my own NIH R01 grant which gave me the opportunity to apply faculty position in USA. I received several offers and choose the institution which had many excellent faculties with NIH grants. Moving to different institution was important, because I could learn new research area and made new collaborators. Once we get NIH R01 grant, we just need to continue obtaining many grants with new and innovative research idea by finding new collaborators in the same and different institutions, which will lead to becoming successful independent investigator in USA.

When considering one's career path, it can be difficult to select the right pathway for yourself. Young scientists will especially have difficulties deciding whether to pursue academia or industry. The presentation will introduce the author's experiences in both academia and industry in two different countries; Japan and the US, and the topics will include i)

differences in career opportunities between Japan and the US; ii) advantages

and disadvantages of scientists in the academia and industry; and iii) what it

is to be like a principal investigator in the US. By this discussion, it is the author's will to broaden and enlighten the minds of young scientists about his or her career paths that there are countless opportunities in the future.

Japanese pharmacy education has shifted to six-year program since 2006, and the curriculum focuses　more on clinical pharmacy education. Pharmacy educational curriculum in the U.S. established useful tools and programs which are helpful for the Japanese six-year pharmacy education program.

I studied abroad to obtain Pharm.D. degree and to learn the advanced pharmacy education and practice in the University of Iowa College of Pharmacy. Then, I completed a two-year post-graduate training (1^st year training was for general pharmacy practice and 2^nd year was for cardiology specialized training) in the University of Kentucky Hospital to become a clinical pharmacist in the U.S. I currently work as a clinical faculty who gets involved in four main areas: clinical service, general service, education, and research in the West Virginia University School of Pharmacy.

During my presentation, I will introduce my career pathway as a clinical pharmacist/clinical faculty in the U.S. Then, I will discuss strategies and methods to become a clinical pharmacist in the U.S. Third, I will also highlight the key differences in pharmacy practice and education between the U.S. and Japan. I hope to share some insights and useful information for students/learners who want to become clinical pharmacists in the U.S. and/or to learn advanced pharmacy education and practice in the U.S.

The new coronavirus infection COVID-19, which was declared a pandemic in March 2020, has changed not only our lives and working styles, but also the landscape of the world, and it is still in full swing. The new coronavirus has a great impact on the education, research, and management of universities on which many researchers rely. In particular, as a response to education, online classes at universities have spread all at once to reduce the risk of infection, and it can be said that one of the concerns for university reform has progressed at once. Online lessons are, in a sense, an opportunity to innovate in university education and are an effective way for knowledge-giving lessons. However, opportunities for dialogue between teachers and students, or between students, are lost, and there remains a problem in clarifying the class gap between teachers.

Pharmacology education is important --- Many people would agree with this phrase, but something remains unexplainable. In the first place, what is indeed pharmacological education? What is pharmacological education; so to speak, that is to be taught by whom, what and how? Now, pharmacology has changed a great deal in terms of its standing and presence. The discipline of pharmacology has become multifaceted as a result of innovations in experimental techniques and measurement techniques, and the diversification and interdisciplinary nature of science. As the integration of disciplines is actively encouraged, the boundaries between disciplines have become blurred. This fact means that modern pharmacology education needs to change its teaching methods and subject matter from time to time according to its purpose. In other words, the ability of pharmacology educators to respond flexibly and appropriately to the detailed demands of the educational field is being questioned. In order to meet these demands, the Japanese Pharmacological Society established a "Pharmacology Educator Certification System" last year. This system is given to teachers who are in a position to teach young students the orthodox principles and concepts of pharmacology traditionally rooted in the Japanese Pharmacological Society, after a rigorous review, to guarantee their qualifications and educational skills. It is hoped that this accreditation system will contribute to the realization of what pharmacology should be in the future.

The Physiological Society of Japan (PSJ) has been focusing on education, especially at medical schools due to the historical background. However, because of the dramatic progress in life science and technology and changes in social conditions of the modern society, PSJ must consider for physiology education in according with such changes. The era with Corona unintendedly makes us face what we had to do ahead of time, but have been procrastinating. I list three issues that PSJ should tackle in the future as my personal opinion.

1. Commitment to primary and secondary education: So far, PSJ has been mostly focusing on physiology education in higher education, but we need to realize that it is the social mission of PSJ to participate in more primary and secondary education to improve the literacy for medicine and like science in people.

2. Providing digital educational content: PSJ has created training books, workbooks, and glossaries in paper media. We are now thinking of providing digital educational content by utilizing digital technology and the Internet environment.

3. Fostering quality physiology educators: PSJ considers it important to train educators as an academic society, and we established the educator system on 2012, and currently 378 educators are registered. Because the "roof tile method" could be also useful to develop this system, we are considering qualifying physiology instructors who can train educators in future.

As mentioned above, all the issues have been raised from the viewpoint that education is not just a way to provide knowledge, but to acquire the physiological "thinking".

One of the purposes of the academic society, which is a collection of knowledge about medicine, is to educate its members. In this regard, social networking services (SNS) such as Facebook and Twitter have been attracting attention in recent years as more effective than traditional methods. The American Heart Association (AHA) and the European Society of Cardiology (ESC) have 300,000 and 100,000 official Twitter followers, respectively, for slide sharing and discussion. In short, Twitter is not a toy for young people; it is a New Core Competency for Education, Teaching and Personal Branding.

In Japan, however, there are very few medical societies with more than 1,000 followers. Therefore, the Japanese Society of Cardiology established a new Information and Communication Committee (chaired by a speaker) and set up an official Twitter account, @JCIRC_IPR, to introduce various medical information, guidelines, official journals, and noteworthy papers from abroad, and to disseminate the content of the sessions at the congresses on official Twitter. As a result, as of November 2020, the number of followers has increased to nearly 10,000 (the largest of any medical society in Japan), and the number of twitter viewers during the conference has increased to 72 million. Discussions on presentations are also active on Twitter, and "Tweet the Meeting" has become a reality in Japan as well. Cluster analysis of relationships between followers and data mining of tweets has enabled us to answer the question "Who and What wants to learn". We are also pleased to hear that members who are raising children or recuperating from illness who are unable to attend the meetings can also study. It is clear that the educational effects of the program have exploded.

I would like The Japanese Pharmacological Society to have the official Twitter account, which is not a toy for young people, but a New Core Competency aimed at education, teaching, and personal branding.

Monitoring neuronal activity at the local and global levels has led to the identification of several important brain areas, such as the basolateral amygdala, in emotional control; however, the underlying mechanisms remain to be fully elucidated. Here, using Arc-dVenus reporter mice, we investigated the brain-wide neuronal activation patterns following restraint stress or social defeat stress, both of which induce anxiety-related behaviors. A supervised classification of these brain-wide activation patterns showed that neuronal activation in the claustrum prominently contributes to discrimination in stressed brains. Interregional correlation analysis indicated that the Pearson correlation coefficients are prominently increased in the claustrum, infralimbic area and nucleus accumbens in both mouse models. In addition, we monitored the calcium signals from the claustrum in freely moving mice using a head-mounted miniature fluorescent microscope, and found that activity patterns of claustral neurons are different from those of previously reported amygdala neurons, during the elevated-plus maze test. Thus, monitoring neuronal activation locally and globally helps us understand the detailed mechanisms of anxiety.

We are surrounded by various appetitive stimuli that positively motivate us to behave and aversive stimuli that negatively motivate us not to behave. In order to take action in a conflict situation where we face both appetitive and aversive stimuli, we need a willpower: an ability to make an effort to overcome difficulties to achieve goals. However, neural mechanisms of willpower are not well understood.

We set up a behavioral paradigm in which mice needed to explore an experimental context where they might receive electric shocks in order to obtain sucrose solution. Fiber photometry using Ca²⁺-sensitive fluorescent protein GCaMP6 showed that neuronal pathway from the medial prefrontal cortex (mPFC) to the periaqueductal gray (PAG) was activated when mice started moving to obtain sucrose solution. Optogenetic activation and inhibition of the mPFC-PAG pathway shortened and prolonged the latency to obtain sucrose in a conflict situation, respectively. Interestingly, in a no-conflict context where mice could obtain sucrose solution without fear of being shocked, optogenetic activation and inhibition of the mPFC-PAG pathway had no effect on the latency to obtain sucrose. These results suggest that the mPFC-PAG activity promotes animals to seek rewards in a conflict context.

Social emotions such as envy and jealousy are often observed in group-living primates including human beings. Such emotions necessarily depend on others' rewards, but neural mechanisms of reward processing for self and other in the brain remain unraveled. To address this issue, we devised a social Pavlovian conditioning procedure for pairs of monkeys. Despite being constant in amount and probability, the subjective value of forthcoming self-rewards, as indexed by licking and choice behaviors, decreased as partner-reward probability increased. We performed multisite neural recordings in three brain regions involved in processing of social and reward information: the medial prefrontal cortex (MPFC), the dopaminergic midbrain nuclei (DA), and the lateral hypothalamus (LH). MPFC neurons selectively monitored self-reward or partner-reward information, whereas DA neurons integrated this information into a subjective value. LH neurons first encoded a subjective value with bidirectional responses and changed their coding manner similarly to the MPFC. A causality analysis revealed that neural information flowed predominantly in the MPFC-to-DA/LH directions. These findings delineate dedicated pathways for subjective reward evaluation in social environments, which may be neural underpinnings of social emotions.

For efficient and accurate information processing in cerebral cortex, neural population dynamics must be spatially and temporally regulated with great precision. Medial prefrontal cortex (mPFC) of rodents has been shown important for various types of learning and memory, including fear memory. However, it has been challenging to understand the computational architecture in the mPFC, of which major problems are the complexity and heterogeneity of the prefrontal computation. We investigate this by chronic two-photon Ca2+ imaging from populations of neurons in mouse mPFC in vivo, which allows us to record activities simultaneously from large number of neurons at the single cell resolution, and investigate changes of neuronal responses over the learning process. We investigated the change in responses of mPFC neurons during Pavlovian fear conditioning (tone + aversive stimulus) and memory retrieval using a new device to perform them with a head fixed mouse. In the presentation, I will discuss how individual neurons and the neural population encode the fear memory.

Smurf2 belongs to the E3 ubiquitin ligase family. Although the role of Smurf2 in glioblastoma has been investigated previously, here we show that phosphorylation of Smurf2 at Thr249 plays an essential role in maintenance of stemness of glioma-initiating cells (GICs). Infection Smurf2 T249A mutant in GICs resulted in a significantly increase of tumorigenesis and stemness related genes, in contrast Smurf2 WT has reverse effect on GICs. Mechanistically, we demonstrated that Smurf2 regulates the TGFBR1 degradation through its ubiquitylation. Indeed, knockdown of TGFBR1 with shRNA markedly rescued the tumorigenesis observed in GICs infected with Smurf2 T249A mutant. Furthermore, phosphorylation of Smurf2 at Thr249 significantly decreased in human glioblastoma. These finding highlight the importance of phosphorylation of Smurf2 in maintenance of stemness of GICs.

In recent years, the number of non-alcoholic steatohepatitis (NASH) patients, who develop fatty liver in an alcohol-independent manner and progress to cirrhosis and liver cancer in the future, has been increasing, and there are more than approximately 10 million patients and their preps in Japan. The three-dimensional organoid culture method has been attracting attention because it enables us to culture epithelial cells and epithelial stem cells in a three-dimensional manner for a long period of time by culturing them in a special culture medium containing factors that enhance the stem cell nature and maintain the original characteristics of the tissue, such as heterogeneity and polarity. Recently, we have developed a new three-dimensional organoid culture model for recapitulating liver fibrosis by focusing on the liver tissue from a mouse model of NASH.

Six-week-old C57/BL mice were fed a NASH-inducing diet for 4, 8, and 12 weeks, and different stages of NASH progression (NASH A, NASH B, and NASH C) were cultured in NASH model mice. In the liver tissues of the NASH model mice at each stage, fibrosis of the liver, deposition of fatty droplets, and elevated markers of liver damage were observed with prolongation of the feeding period, while epithelial and mesenchymal transition (EMT)-like epithelial tissue structures were observed in the NASH C organoids, with accumulation of collagen and activated star cell markers, such as -SMA expression was found to be up-regulated in organoids. Furthermore, we identified several genes that were specifically up-regulated in organoids of each pathological stage and genes that were highly expressed in organoids of all stages (JP 2019-230780). These results indicate that liver-derived organoids from mouse models of NASH at different stages of progression recapitulate the fibrotic pathology of NASH on culture dishes. In addition, our results suggest that genes up-regulated in NASH organoids may become novel biomarkers in the future

Canstatin, a cleaved product of type IV collagen α2 chain, was firstly identified as a potent endogenous anti-angiogenic factor. Although type IV collagen α2 chain is a major component of basement membrane in cardiomyocytes, expression and physiological role of canstatin in heart remain unclear. We previously showed canstatin has a variety of biological activities in cardiac cells. Here, we report the altered expression and cardioprotective effects of canstatin in experimental rat models for cardiac diseases. Canstatin was highly expressed in myocardium while it was decreased in the infarcted area after myocardial infarction. Administration of canstatin to the myocardial infarction model exerted protective roles by promoting scar tissue formation and inhibiting cardiac remodeling including hypertrophy and fibrosis in non-infarcted area. Canstatin attenuated ischemia/reperfusion-induced ventricular arrhythmia. Plasma canstatin concentration was decreased in monocrotaline-induced pulmonary hypertensive rat which was negatively correlated with the increase of right ventricular weight. Canstatin administration exerted protective effects against monocrotaline-induced right ventricular remodeling. These findings may contribute to the development of innovative drug and biomarker targeting canstatin for cardiac diseases.

Interleukin-19 (IL-19) is a member of the IL-10 family and is an anti-inflammatory cytokine produced mainly by macrophages, epithelial cells, and vascular smooth muscle cells. In addition, receptors for IL-19, IL-20 receptor 1 and IL-20 receptor 2, are also expressed in the cells mentioned above. The last 10 years from the finding of IL-19, investigations underline the anti-inflammatory role of IL-19 in the human diseases such as psoriasis, asthma, arteriosclerosis, and inflammatory bowel disease. If it is a pro-inflammatory cytokine, therapeutic applications may include the use of neutralizing antibodies, but because IL-19 exhibits anti-inflammatory effects, recombinant products may be useful in therapeutic applications. However, the therapeutic applications of IL-19 for human disease has not yet made progress. In this symposium, we will present the new findings on the preventive and therapeutic effects of IL-19 on various mouse disease models. Increased knowledge about mouse disease models will increase the feasibility of future human disease applications.

Renal and cardiac functions have close and complementary interconnections, and the communication between kidney and heart through a variety of bidirectional pathways causes significant pathological changes. The patients with heart failure with preserved ejection fraction (HFpEF) have multiple comorbidities, including chronic kidney disease (CKD) that is one of the prognostic risks for these patients. The link between functional kidney disease and HFpEF remains incompletely understood. We focused on diabetic cardiomyopathy, which is characterized by early onset of left ventricular (LV) diastolic dysfunction. Clinical data and our preclinical studies in mouse model of diabetes suggested that the dysregulation of Ca²⁺ signaling and the impairment of NO-cGC-PKG pathway are crucial for the development of LV diastolic dysfunction. Furthermore, several renal factors including erythropoietin, inflammatory cytokines, amphiregulin and circulating miRNAs underlie the association between CKD and LV diastolic dysfunction. Recent studies suggest SGLT2 inhibitors ameliorate not only CKD but also HFpEF. In this symposium, we would like to review the late-breaking findings on the mechanism underlying the homeostasis of cardiac function through cardio-renal interactions and its failure in diabetic cardiomyopathy.

The sympathetic nervous system plays an important role in cardiovascular regulation. Brain is critically involved in determining sympathetic activity. Accumulating evidence suggests that the activated renin-angiotensin system (RAS) and the inflammation within the brain contribute to the pathogenesis of hypertension and cardiac dysfunction through sympathoexcitation. In the brain RAS, renin is the rate-limiting enzyme and type 1 angiotensin II receptor (AT1R) is a major player, as well as the systemic RAS. Activation of AT1R in the brain causes stimulating presympathetic neurons and subsequent sympathoexcitation. Brain perivascular macrophages and microglia, which are located in the perivascular space surrounding vessels and in the brain parenchyma, respectively, are major cell types of brain immune system, and are involved in brain inflammation. The prostaglandin E2 produced by brain perivascular macrophages and the pro-inflammatory cytokines released from microglia can cause neuronal activation in the presympathetic neurons. In this presentation, the roles of brain RAS and immune system in cardiovascular regulation through the sympathetic nervous system will be reviewed and discussed to understand "brain-heart interaction".

Exercise tolerance is limited in patients with heart failure (HF), and the limited exercise tolerance is an independent determinant of poor prognosis. It is known that skeletal muscle abnormalities are important factors for limited exercise tolerance. The cause of skeletal muscle abnormalities in HF is unclear.

Recently, skeletal muscle is considered as an endocrine organ that secretes hormones, and the research is progressing. Various hormones secreted from skeletal muscle are called myokine, and it has been reported that they regulate not only skeletal muscle function but also distant organ function. Brain-derived neurotrophic factor (BDNF) is abundant in the hippocampus and is known to be involved in the survival, growth, and synaptic function of nerve cells, and its decline is associated with pathological condition such as depression. We found that BDNF was a myokine secreted by skeletal muscle. We also found that blood BDNF was decreased in patients with HF, that BDNF is closely related to exercise tolerance, and that low BDNF is a predictor of the prognosis of HF. In addition, BDNF expression was decreased in the skeletal muscle of HF model mice. Treatment with human recombinant BDNF improved skeletal muscle abnormalities and exercise capacity in HF mice. On the other hand, BDNF hetero-deficient mice had the decreased skeletal muscle BDNF levels, skeletal muscle abnormalities, and decreased exercise capacity.

In this symposium, we will introduce the significance of BDNF, which is a type of myokine, for skeletal muscle abnormalities in HF.