Chronic inflammation plays an important role in the pathogenesis of obesity and metabolic disorders. In obesity, pattern-recognition receptors in innate immune system, such as Toll-like receptor 4 (TLR4), cause chronic inflammation through prolonged activation by various endogenous ligands, including fatty acids and its metabolites. Gangliosides and other glycosphingolipids are important metabolites of fatty acids and saccharides. GM3, the simplest ganglioside comprising α2,3-sialyllactose, is expressed in insulin-sensitive peripheral tissues such as liver and adipose tissue, and furthermore secreted abundantly into serum. It has been shown that GM3 regulates the signal transduction of insulin receptor in adipose tissue as a component of membrane microdomains, and elevation in GM3 level causes insulin resistance. However, the homeostatic and pathophysiological functions of extracellularly secreted GM3 are poorly understood. We recently reported that GM3 species with differing fatty acid structures act as pro- and anti-inflammatory endogenous TLR4 ligands. GM3 with very long-chain fatty acid (VLCFA) and α-hydroxyl VLCFA strongly enhanced TLR4 activation. Conversely, GM3 with long-chain fatty acid (LCFA) and ω-9 unsaturated VLCFA inhibited TLR4 activation, counteracting the VLCFA species. GM3 interacted with the extracellular complex of TLR4 and promoted dimerization/oligomerization. In obesity and metabolic disorders, VLCFA species were increased in serum and adipose tissue, whereas LCFA species was relatively decreased; their imbalances were correlated to disease progression. Our findings suggest that GM3 species are disease-related endogenous TLR4 ligands, and “glycosphingolipid sensing” by TLR4 controls the homeostatic and pathological roles of innate immune signaling.
There is a need for an effective and efficient way to incorporate and establish evidence-based interventions in daily healthcare. Dissemination and implementation (D&I) research seeks to obtain generalized knowledge to promote that. Implementation science methodologies can be used to scientifically analyze and generalize the themes previously consid-ered as D&I activities. In this article, the author introduces D&I research, and describes its current status and future perspective in Japan. The promotion of community-based integrated care can help explore the opportunities for pharmacists to play an active role in D&I research, and conduct research using implementation science methodologies to improve the quality of healthcare.
Evidence-based medicine (EBM) has led to the development of evidence-based guidelines. The quality of guidelines has been improved by measuring their quality with The Appraisal of Guidelines for Research and Evaluation II (AGREE II) and Grading of Recommendations, Assessment, Development and Evaluation (GRADE). However, evidenced by guidelines not implemented in clinical practice or society, the evidence-practice gap has become apparent. The dissemination and implementation research, which studies methods to solve this problem, has attracted the attention of both clinicians and clinical researchers in recent years. In hypertension and diabetes, it is possible to prevent complications by maintaining good blood pressure and blood glucose levels. However, it is difficult for patients to maintain good laboratory values over the long term, and there has been no solution to this problem. Recently, it has been reported that pharmacists in the U.S. and Canada can improve patient outcomes over the long term by using pharmacies to treat these diseases. This review describes the results of the COMPASS study (diabetes) and the COMPASS-BP study (hypertension), which are the first cluster randomized controlled trials conducted in pharmacies in Japan. In addition, it discusses the possibility of implementation in pharmacies in Japan.
In collaboration with community pharmacists, we have conducted research including drug utilization reviews since 2009 and patient registry and long-term follow-up since 2013. The results of these projects have influenced the establishment of healthcare policies and pharmacists' roles. Moreover, the number of clinical studies using electronic medical records by hospital pharmacists has increased. Findings from real-world clinical practice provide useful evidence to improve the quality of patient care provided by clinical pharmacists. When comparing research between community and hospital pharmacists, differences are observed in the efficiency of using patients' information. In hospitals, patients' medical records are important for sharing information among healthcare providers. However, in communities, the importance of maintaining patients' information tends to follow dispensing medications and counseling. This practice results in a lack of data for clinical research. Studies in community pharmacies would deepen our understanding of the needs for patient records and improve the quality of patient care.
Our pharmacy, with a sterile dispensary, is a support center for home-care dispensing; we are actively participating in a regional collaboration in combination with medical treatment, nursing, and social care. We have supported about 1000 home care patients so far: most of these have been elderly people living at home, but roughly two dozen were pediatric patients. Although the primary diseases of the children varied, they shared in common both a high dependence on medicine, and great difficulty in moving them. With our pediatric patients, a caregiver had to be in constant attendance because the child's medical care was intermittent. In addition, at the pharmacy, due to the volume of medication for these pediatric patients, caregivers have had to wait a long time for prescription fulfillment, and often receive so much medicine they need a cart to carry it home. Through providing pharmacist-led home guidance on medicines, we are able to offer some support in the pharmacotherapy of children with extreme symptoms who remain under the supervision of a doctor from an advanced medical institution, even after returning home. Through my experience visiting both elderly people and children under home care, I have keenly realized the importance of a community pharmacist's research in improving pediatric formulation and home medical care systems. We must aim to reduce the burden of medication management for both patients and caregivers, and to improve a patient's “comprehensive quality of life, including (his or her) family”.
Regarding the Separation of Dispensing and Prescribing (SDP) in Japan, there are some negative opinions that the value of separating these services has not been commensurate with the cost. On the other hand, there is substantial data showing the current state of SDP and its merits, which has been collected and published in academic journals. In 2019, the Japan Pharmaceutical Association searched for articles on this subject in domestic academic journals published over the past five years, and found that there were more than 300 articles that evaluated efforts to contribute to therapeutic efficacy and safety at pharmacies. Among these, some addressed the roles required of pharmacies in a community-based integrated care system, such as efforts toward coordinated medicine management of patients who visit multiple medical institutions, follow-up with patients receiving drug therapy, utilization of patient test values at pharmacies, and home medical care. These research results can be utilized in healthcare policy making. However, even with this volume of existing research, it is hard to determine whether such research is sufficient to connect these findings to measures that would improve policy issues. Therefore, it is necessary to identify for researchers the types of evidence that would help guide and formulate effective new SDP policies.
My research area in the pharmaceutical industry is innate immunity, especially in phagocytic cells. First, I studied the heat-stable growth factor of peripheral macrophages in tumorous ascitic fluid and found that lipoproteins are an influencing factor. Later, my colleagues and I found that lipid-containing substances, namely, oxidized low-density lipoprotein, dead neutrophils, or purified lipids that could be scavenged by macrophages, induce their growth. From the series of this study, I concluded that phagocytic substances induce macrophage growth by autocrine stimulation of granulocyte-macrophage colony-stimulating factor (GM-CSF). During the study, we found that neutrophils have growth-inhibitory effects against a variety of cells. Then, I elucidated that the primary factor is a zinc-binding protein, calprotectin, an abundant protein complex in the neutrophil cytosol. I found that calprotectin induces apoptosis in many cell types, including tumor cells and normal fibroblasts, and that the zinc-binding capacity is essential for its activity. Microscopic observations revealed that neutrophil extract contains factor-inducing three-dimensional cell aggregation of human mammary carcinoma, MCF-7. I elucidated that cathepsin G is responsible for this activity and that its effect is dependent on the activation of insulin-like growth factor-1. I believe that this modest, albeit novel, observation was crucial to my thirty-nine-year-long career researching phagocytic cells.
Neurotrophic factors have been shown to potentially be beneficial for the treatment of neurodegenerative diseases such as Alzheimer's disease, because endogenous neurotrophic factors (NGF, BDNF) have been recognized to play critical roles in the promotion of neurogenesis, differentiation, and neuroprotection throughout the development of the central nervous system. However, high-molecular-weight proteins are unable to cross the blood-brain barrier and are easily decomposed under physiological conditions. Thus, small molecules that can mimic the functions of neurotrophic factors are promising alternatives for the treatment of neurodegenerative disease. Since 1990, the author has been involved in searching for natural products with typical neurotrophic properties that can cause neurogenesis, enhance neurite outgrowth, and protect against neuronal death by using three cellular systems (PC12, rat cortical neurons, and MEB5 cells). Through these research activities on neurotrophic natural products, the author has tried to induce a paradigm shift from the discipline of natural products chemistry to science disciplines. This review focuses on our independent synthetic studies of the neurotrophic natural products discovered in the plants. The following synthetic elaborations are described: syntheses of dimeric isocuparane-type sesquiterpenes mastigophorenes A and B, macrocyclic bis-bibenzyls plagiochins A-D and cavicularin through a Pd-catalyzed Stille-Kelly reaction; the formal synthesis of merrilactone A and jiadifenin, which are seco-prezizaane-type sesquiterpenes, through intramolecular Pd-catalyzed Mizoroki-Heck and Tsuji-Trost reactions; and finally the first enantioselective synthesis of neovibsanin B, a vibsane-type diterpene, through a Pd-catalyzed cyclic carbopalladation-carbonyl tandem reaction.
The use of flame retardants, namely bis(2,3-dibromopropyl) phosphate (BDBPP) and tris(2,3-dibromopropyl) phosphate (TDBPP), in textile products such as curtains, carpets and sleeping clothes is banned in Japan under the ‘Act on the Control of Household Products Containing Harmful Substances’. Herein, we developed a GC-MS based method to quantify these compounds with greater accuracy and safety than the current official method. For accurate and sensitive quantification, deuterated compounds, BDBPP-d10 and TDBPP-d15, were used as surrogate standards. In consideration of the safety of the analyst, certain solvents and reagents used for the pretreatment that are carcinogenic or have a risk of explosion were replaced. For the extraction step, benzene was replaced by ethyl acetate, and for the methyl derivatization step, the reagent was changed from a self-prepared solution of diazomethane in ether to a solution of trimethylsilyl diazomethane in hexane, a safe and easy-to-use commercially available reagent. The calibration curves were liner in the range of 0.5-8.0 μg/mL for both methylated BDBPP (BDBPP-Me) and TDBPP. The detection limit was 0.05 μg/g for BDBPP-Me and 0.3 μg/g for TDBPP, which is sufficiently low compared to the current detection limits of 10 μg/g for BDBPP-Me and 8 μg/g for TDBPP. The recoveries in various curtain material were 66-108% and relative standard deviations were 1.2-10.2% when 5 μg BDBPP and TDBPP were added to 0.5 g of samples. Thus, the developed method is applicable to textile products of various materials.
This research paper improves the TDBPP and BDBPP analysis methods of organic phosphorus flame retardants regulated by the Act on the Control of Household Products Containing Harmful Substances Japan. The authors proposed a GC-MS analysis method instead of the GC-FPD method. The new method is performed safely without using harmful reagents in the pretreatment. Furthermore, the high-sensitive analysis is realized by surrogate correction.
In recent years, lifestyle-related diseases such as hypertension and diabetes have been on the rise. These conditions can cause serious conditions such as myocardial and cerebral infarctions. Therefore, proper control of blood pressure and blood glucose levels is important issues in preventive medicine. Traditional fermented foods have been shown to have various functions, and their effects on lifestyle-related diseases have attracted particular attention. In this study, we investigated the effects of fermented soybeans and rice bran (OE-1) and supplements containing OE-1 on blood glucose levels and weight changes. We identified an inhibitory effect on elevated blood glucose levels upon administration of OE-1, and this effect was thought to be due to digestive enzyme inhibition. These effects of foods containing OE-1 are expected to have a positive effect on the prevention and improvement of lifestyle-related diseases as health foods.
Three forms of pseudo-crystalline polymorph of thiamine chloride hydrochloride are dependent on hydration states. We investigated how the measurement environment affects the transition of the pseudo-crystalline polymorph, and aimed to establish a reliable method of identifying the forms clearly by IR spectrophotometry. We prepared three pseudo-crystalline forms and compared their IR spectra. In the IR spectra obtained by the potassium chloride (KCl) disk method, Form II was identified based on its characteristic absorption, but Forms I and III could not be distinguished clearly. Form I transformed to Form III after mixing with undried KCl powder, and Form III transformed to Form I by simply being left in the laboratory environment. These results suggested that the reversible transformation between Forms I and III occurred depending on the hydration status during the process of measurement, as measured by the shift in the absorption wavenumber of the primary alcohol stretching vibration. In addition, Forms I and III could not be distinguished clearly by the X-ray powder diffraction and their crystalline forms were similar plate crystals. However, in the IR spectra by the attenuated total reflection (ATR) method, the three forms could be identified based on each characteristic absorption. In summary, the ATR method does not require pretreatment for sample analysis, can be performed quickly, and is thus suitable to identify crystalline polymorph forms such as pseudo-crystalline polymorphs of thiamine chloride hydrochloride, which transform easily depending on the hydration status in a measurement environment.