Research Laboratories & Centers

Humans have been using plants, mushrooms, and other organisms as medicines since ancient times. In fact, many medicines have been developed from natural compounds produced by plants, fungi, bacteria, and other microorganisms. Thus, natural compounds are the resources for drug discovery.

We conduct research to find natural product that can be used as resources for drug discovery, or to create them using natural compounds as motifs. In addition, we aim to use the substances obtained as seed compounds for the development of pharmaceuticals, as well as for the development of substances useful for life science research.

On the other hand, as a result of the vigorous search for natural compounds, new natural compounds are being depleted. Therefore, it is not possible to conduct innovative drug discovery research by simply searching for natural compounds in the conventional way. Therefore, we will actively explore new resources for drug discovery.

1.Exploitation of new resources for drug discovery using diversity-oriented synthesis

Diversity-oriented synthesis is a synthetic method for producing a large number of compounds with different molecular skeletons from a single starting material. In particular, "diversity-enhanced extracts," which combine diversity-oriented synthesis with search for natural compounds, can yield a group of new compounds with structural diversity that exceeds that of natural compounds obtained from plants and microorganisms. We will conduct research to utilize these compounds as resources for drug discovery.
For example, we will perform chemical reactions directly on the extracts of medicinal plants used as crude drugs, as used in diversity-directed synthesis, to produce diversity-enhanced extracts. By separating, purifying, and structurally determining these extracts, we can construct a library of structurally diverse compounds and obtain seed compounds for drug discovery research.

2.Development of new resources for drug discovery using unexploited organisms

As a new drug discovery resource, we will focus on " unexploited organisms" which are different from conventionally used organisms, such as plants, fungi, and bacteria, for the search of natural compounds. Particularly, we will focus on protists, which are extremely diverse organisms that span multiple biological kingdoms, and utilize unexploited organisms such as cellular slime mold, oomycetes, and pelagic algae. In fact, compounds obtained from cellular slime mold have been developed as commercially available reagents for life science research. Thus, these unexploited organisms, including cellular slime mold, are considered to have great potential as new resources for drug discovery.

3.Molecular Networking Construction and Dereplication in Multi-component Systems

Extracts of plants and microorganisms are multicomponent systems containing various compounds, and it is not easy to obtain structural information and quantities of all the compounds contained. We have developed molecular networking based on compound data obtained by simultaneous multi-component analysis using LC-MS/MS, which enables visual understanding of compound profiles in multi-component systems. In addition, by efficiently eliminating known compounds (dereplication), we are able to rapidly discover new compounds and estimate their structures. By applying this analytical platform, for example, we are searching for new compounds produced by cyanobacteria, determining the quality of crude drugs, and analyzing compound-compound interactions in multicomponent systems.

Prevention of lifestyle-related diseases such as obesity, hyperlipidemia, arteriosclerosis, diabetes, and hypertension is a urgent issue for the public health of our nation. Aiming at the prevention of lifestyle-related diseases through diet, we are carried out to research from various angles.

Humans harbor over 100 trillion bacteria in the distal intestine. These commensal bacteria have long been appreciated for the benefits they provide to the host, the most obvious being their capacity to metabolize indigestible food components to small metabolites that are utilized as nutrients by host cells. Moreover, it is now clear that the presence of commensal bacteria contributes to shape the gut immune system though promoting the development of gut-associated lymphoid tissues (GALTs), the largest collection of secondary lymphoid organs, which are necessary for induction of mucosal IgA responses. To evoke the mucosal immune response, antigens on the mucosal surface must be transported across the epithelial barrier into GALT such as Peyer's patches. This function, called 'antigen transcytosis', is mediated by specialized epithelial M cells. We are currently conducting the studies to understand the molecular machinery by which intestinal M cells facilitate antigen transcytosis.

Certain enteric bacteria also facilitate differentiation of Th17 and Treg cells, both of which are major T cell populations in the intestinal mucosa. Thus, host-microbe interactions establish immunological homeostasis in the gut, which further raises the important question: how do commensal bacteria affect the host immune system? The intestinal microbiota constitutes a considerable bioreactor that ferments indigestible food substances (e.g., soluble dietary fibers and resistant starches) into various metabolites such as short-chain fatty acids (SCFAs). Notably, butyrate, a major SCFA, exert histone deacetylase (HDAC) inhibitory activity. We have shown that intestinal microbiota-derived butyrate contributes to establishing intestinal symbiosis by inducing Treg cells via the epigenetic mechanisms. Our laboratory aims to explore the epigenetic regulation of the immune system by intestinal microbiota, and also to elucidate the biological significance of this epigenetic regulation in immunity and metabolism.

Kimura I. et al., Science 367: eaaw8429, 2020.
Nagai M. et al., Cell 178: 1072-1087, 2019.
Furusawa Y. et al., Nature 504: 446-450, 2013.

Our research objectives are: (1) to reveal structural mechanisms of proteins critical for life functions at atomic level, (2) to establish novel strategies for drug developments based on the mechanisms, and (3) to create compounds to regulate the life functions. Proteins playing important roles physiological processes are analyzed at an atomic resolution by nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography.

The major focus of this laboratory is a disease-oriented basic neuroscience research. Although recent progress in the neuroscience field begins to shed light on complicated interactions between genetic and epi-genetic (environmental) control in the nervous system, fundamental brain functions such as learning/memory, attention, sleep, movement control are largely still enigmatic.
Neurodegenerative diseases are adult-onset and slowly progressive disorders affecting the central and peripheral nervous system. One of the major causes of the diseases is known to be aging. With the growth of elderly population, risks of suffering from these diseases are rapidly increasing and making them heavy social burden.
The main goals of our research are to elucidate physiological and pathological roles of cholinergic neurons in neurologic/psychiatric diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS) and schizophrenia, and ultimately develop better pharmacological interventions to these devastating conditions.
We are looking forward to working with motivated students who have high interest in basic research for uncovering hidden mysteries of brain functions and their disorders.

Our laboratory aims to elucidate the molecular mechanism underlying DNA double-strand break (DSB) repair, which is critical for maintaining genome integrity. Defects in DSB repair lead to severe mutations, including deletions and chromosomal translocations, which cause cell death. Introducing such severe mutations is important for killing cancer cells via radio/chemotherapy. In addition, DSB repair and signaling is involved in many biological events such as tumorigenesis, immunity, protection against virus, and biological development. We have recently attempted to visualize a repair event at a single DSB using super-resolution microscope 3D structured-illumination microscopy (SIM) in combination with next generation sequence techniques such as ChIP-seq and ATAC-seq.

Our final goal is to contribute to the development and improvement of cancer therapy by exploiting the knowledge of DNA repair research. We are currently focusing on the immune responses after DNA damage induction during cancer treatment.

Transcription associated DSB repair in G1 Yasuhara et al., Cell Rep, 2022
HR initiation at transcription active loci Yasuhara et al., Cell, 2018
DSB repair pathway choice in G1 Biehs et al., Mol Cell, 2017
53BP1 dephosphorylation promotes pro-HR environment Isono et al., Cell Rep, 2017
MRE11-dependent initiation of resection Shibata et al., Mol Cell, 2014
DSB repair pathway choice in G2 Shibata et al., EMBO J, 2011

DNA damage promotes HLA class I presentation Uchihara et al., Mol Cell, 2022
BER deficiency upregulates PD-L1 expression Permata et al., Oncogene, 2019
DSB-dependent ATR/Chk1 upregulates PD-L1 expression Sato et al., Nat Comm, 2017

Pharmaceutics is a discipline to pursue the optimal delivery of drug substance to target site of patient's body through the best scientific knowledge and technology, so that patients are released from diseases and disorders. The ultimate goal of our research is "Individualized Pharmaceutical Care".

For realizing such an object, two projects are currently carried out ;

Students to be welcomed are those who have interest in pharmaceutics and its clinical application. During the stay at our laboratory, students will acquire a vast knowledge of pharmaceutics and its meaningfulness for better clinical drug use. Through collaboration with other research units, students will have the opportunity to brush up their skills of international communication.

In recent years, there has been increasing attention on the ability of immune checkpoint inhibitors to activate immune cells against cancer cells. However, there are still some patients who cannot be cured with these drugs.

Our laboratory focuses on developing effective immunotherapies for cancers that are resistant to immune checkpoint inhibitors, such as pancreatic cancer, castration-resistant prostate cancer, and multiple myeloma. Specifically, we are conducting preclinical research aimed at elucidating the molecular mechanisms and applying them to therapy, focusing on immunogenic cell death (ICD), where cancer cells are effectively recognized by immune cells while undergoing cell death when certain drugs are added. Moreover, we are developing genetically modified T cell therapies, also known as "living drugs," using T cell receptor genes specific to antigens highly expressed in cancer cells.

These studies are conducted through translational research, where the results of basic research are applied to clinical practice, and reverse translational research, where questions arising from clinical practice are addressed through basic research.

Our research targets are mainly on metabolic diseases necessary for keeping our homeostasis, especially on the diseases of gastroenterology, liver, muscle, adipose tissues and also cancers. Recently, we focus on epigenetics and microRNAs in the understanding of mechanism in these diseases. Our goal is to develop new therapeutic strategies for these diseases and we always think about the bench-to-bed utility. Our laboratory is always open to everyone who has a high motivation to create a new concept of pharmacotherapeutics. If you have interested in our department, why not join us?

The educational target of our laboratory is to turn out researchers and pharmacists who have wide range of pharmaceutical view and knowledge, and is able to solve various clinical problems in pharmaceutical care. We consider that a good practitioner should be able to systematically organize a wide range of pharmaceutical knowledge and such ability can be acquired during pharmaceutical research.
Therefore, our research field is clinical pharmacy based on a variety of fields such as pharmacokinetics, pharmacodynamics, cell biology, information technology, and others. Especially, we aim to solve clinical problems, as mentioned below, for marketed drugs to create pharmaceutical evidences for proper and effective use of medicines.

Drug information based on sciences and reliable clinical evidences is required for proper use of drugs. On the other hands, there is a tendency of "information overflow", even on a single drug, in different style, quality and quantity.
The objective of our laboratory is to explore the mean and way for rational and proper use of drug information so that medical professionals can give patients evidence-based, safe, and effective drug therapy. The areas of our research covered are information retrieval, critical appraisal, effective provision, and the application of information, etc.

Following research projects are currently ongoing;

Students joining to our research group are expected to acquire the research oriented way of thinking and proper insight on quality information of drugs. We expect that students will be able to play an active role in clinical fields, the pharmaceutical industry, and the government and the related organization after graduation.
Students to be welcomed are, such as, those with interest in proper and effective usage of drugs in clinical phase.

The Division of Pharmacodynamics conducts research, aiming to establish new pharmacotherapy options by evaluating drug efficacy or the therapeutic and adverse effects of drugs.
To maximize their effectiveness while avoiding related adverse events as much as possible, the division analyses influencing factors, and clarifies optimal drug options and administration methods for each patient.
It also establishes new treatment methods by identifying new drug activities and developing new dosage forms. Furthermore, with a view to obtaining evidence that is useful for medical services, it identifies issues to be addressed (such as drug-drug interactions), and expands clinical and basic research.
The division aims to nurture clinical pharmacists to truly contribute to medical services and researchers with the ability to develop drugs needed in such services through research activities.

Figure. Voriconazole (VRCZ) trough concentration and logistic regression model for hepatotoxicity.
The estimated probability of hepatotoxicity at VRCZ trough concentrations of 2mg/L and 4mg/L was 1.6% and 21.6%, respectively

Figure. Relationships for Acinetobacter baumannii ATCC 19606 between the log10CFU/thigh at 24 h and the pharmacokinetic/pharmacodynamic indices.
Sulbactam showed time-dependent bactericidal activity, and was sufficiently bactericidal when an fT>MIC of >60% against A. baumannii thigh infection was achieved.

The responsibility of our group is to give undergraduate students the training of fundamental chemistry or biology for pharmaceuticals and pharmacy, such as analytical chemistry, pharmacology, biochemistry, hygiene chemistry and organic chemistry, so that students in Faculty of Pharmacy can have the ability to comprehend the modern and progressing life sciences. We are also responsible for managing the introductory and fundamental laboratory training at our Faculty of Pharmacy. We develop the program for laboratory experiment and execute it for undergraduate students during their second and third year.
In parallel, our group is active in conducting research within the above premise. Our current research subjects are;

The Basic Education Course is a course that supports students behind the scenes as they conduct their research and enter the workforce. Scientific-Medical English, mathematics, and statistics are indispensable tools for students to acquire in order to understand more information in their daily research, to improve and develop their own research, and to present their research. We provide students with in-depth practical knowledge and skills so that they can lead a more fulfilling student life in the School of Pharmacy.

The faculty in the Basic Education Course belong to Hiyoshi Campus, where pharmacy students spend their first year of education. By carefully monitoring and supporting the students' daily lives from the time they enter school, we strive to ensure that all students can begin their university life efficiently, comfortably, and without apprehension.

Development of methods for determining the environmental radionuclides, and study evaluating the effect of environmental radiation on the human body.

In the environment, not only natural radionuclides such as radon, but also trace amounts of radionuclides resulting from nuclear testing in the past are present. On the other hand, radiation has been used in medical treatment. Furthermore, small amount of radiation is emitted from some product containing minerals.

To date, we have developed accurate methods for measuring radon and applied successfully to the determination of the radon activity in natural water and indoor air, and presented the resultant distribution of radon in natural water and indoor air. Further work to establish the suitable system for measuring the radionuclide in the outdoors is in progress. Based on the modified measuring system, we measure the radionuclide in various kinds of food and products, and estimate the absorbed dose due to the environmental radionuclide, and the effect of environmental radiation on the human body.