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Rheumatoid arthritis (RA) is a disease that causes inflammation of joints, resulting in pain and swelling. Reduced barometric pressure induces painful symptom of RA, but there is no appropriate animal model and pharmacological evaluation. Keishinieppiittokajutsubu (KNEIJB), a Kampo medicine used to treat RA; however, its mechanism of action is not clear. Here, we found that KNEIJB suppressed the low barometric pressure (LP)-induced pain response in CFA-induced arthritic model rats. Furthermore, we found that KNEIJB reduced plasma IL-6 levels. These results suggest that KNEIJB might be beneficial in the treatment of RA or some other arthralgia induced by LP., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest regarding this research and/or publication., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We often encounter patients with congestive heart failure refractory to conventional diuretics therapy. Kampo goreisan (Tsumura &Co. Tokyo, Japan) is receiving great concern in mediating body water balance, particularly for such a cohort. However, its detailed biological mechanism remains uncertain. Patients who received goreisan to treat congestive heart failure refractory to tolvaptan-incorporated medical therapy were prospectively included and observed for one week during the therapeutic period. The change in urine biomarkers during the first 24 h was assessed as a primary concern. Baseline factors associated with an increase in urine volume during the first 24 h were investigated as a secondary concern. A total of 18 patients were included. Median age was 81 (77, 86) and 12 (67%) were men. During the first 24 h after the initiation of goreisan, urine cyclic AMP tended to decrease, urine aquaporin-2 decreased significantly, urine osmolality decreased significantly, and urine volume tended to increase. Baseline higher common logarithm of plasma B-type natriuretic peptide was associated with any increases in urine volume during the first 24 h with an odds ratio of 73.2 (95% confidence interval 1.04-5149, p = 0.048). Baseline plasma B-type natriuretic peptide level had a positive correlation with a change in urine volume between baseline and day 1 (r = 0.533, p = 0.026). Goreisan may increase urine volume even in patients with congestive heart failure refractory to tolvaptan-incorporated medical therapy by modulating aquaporin-2 systems in the collecting duct, particularly in individuals with advanced heart failure accompanying significant congestion. Goreisan may have a regulatory effect on body fluid, rather than just forcing aquaresis., Competing Interests: Declarations Conflict of interest The authors declare that they have no conflict of interest., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Multiherbal medicines are traditionally used as personalized medicines with custom combinations of crude drugs; however, the mechanisms of multiherbal medicines are unclear. In this study, we developed a novel pathway-based method to predict therapeutic effects and the mode of action of custom-made multiherbal medicines using machine learning. This method considers disease-related pathways as therapeutic targets and evaluates the comprehensive influence of constituent compounds on their potential target proteins in the disease-related pathways. Our proposed method enabled us to comprehensively predict new indications of 194 Kampo medicines for 87 diseases. Using Kampo-induced transcriptomic data, we demonstrated that Kampo constituent compounds stimulated the disease-related proteins and a customized Kampo formula enhanced the efficacy compared with an existing Kampo formula. The proposed method will be useful for discovering effective Kampo medicines and optimizing custom-made multiherbal medicines in practice., (© 2024 The Author(s). Molecular Informatics published by Wiley-VCH GmbH.)

Community-acquired pneumonia is caused primarily by bacterial infection. For years, antibiotic treatment has been the standard of care for patients with bacterial pneumonia, although the emergence of antimicrobial-resistant strains is recognized as a global health issue. The traditional herbal medicine Kampo has a long history of clinical use and is relatively safe in treating various diseases. However, the antimicrobial effects of Kampo products against pneumonia-causative bacteria remain largely uncharacterized. In this study, we investigated the bacteriological efficacy of 11 Kampo products against bacteria commonly associated with pneumonia. Sho-saiko-To (9), Sho-seiryu-To (19), Chikujo-untan-To (91) and Shin'i-seihai-To (104) inhibited the growth of S. pneumoniae serotype 3, a highly virulent strain that causes severe pneumonia. Also, the growth of S. pneumoniae serotype 1, another highly virulent strain, was suppressed by treatment with Sho-saiko-To (9), Chikujo-untan-To (91), and Shin'i-seihai-To (104). Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against these strains ranged from 6.25-50 mg/mL and 12.5-25 mg/mL, respectively. Furthermore, Sho-saiko-To (9), Chikujo-untan-To (91), and Shin'i-seihai-To (104) suppressed the growth of antibiotic-resistant S. pneumoniae isolates. Additionally, Sho-saiko-To (9) and Shin'i-seihai-To (104) showed growth inhibition activity against Staphylococcus aureus, another causative agent for pneumonia, with MIC ranging from 6.25-12.5 mg/mL. These results suggest that some Kampo products have antimicrobial effects against S. pneumoniae and S. aureus, and that Sho-saiko-To (9) and Shin'i-seihai-To (104) are promising medicines for treating pneumonia caused by S. pneumoniae and S. aureus infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Akahori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Japanese traditional (Kampo) medicines are often used for pregnant women in Japan. However, no comprehensive studies have been conducted regarding the self-reported use of these medicines during pregnancy. This study investigated the use of Kampo medicines during pregnancy in Japan using the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study)., Methods: Questionnaires were distributed to pregnant women participating in the TMM BirThree Cohort Study (July 2013 to March 2017) at approximately 12 weeks (early pregnancy) and 26 weeks (middle pregnancy). We analysed Kampo medicines use over three periods: (1) 12 months before pregnancy diagnosis, (2) the period between pregnancy diagnosis and around Week 12 of pregnancy and (3) from around Week 12 of pregnancy., Results: In total, 19 220 women were included in the analysis. The proportions using prescribed Kampo medicines were 4.1% before pregnancy diagnosis, 4.5% from diagnosis to Week 12% and 4.5% after Week 12 of pregnancy. The most frequently prescribed Kampo medicines were tokishakuyakusan (1.0%) before pregnancy diagnosis, shoseiryuto (1.3%) from diagnosis to Week 12 and shoseiryuto (1.5%) Post-week 12. Sixty of the pregnant women used Kampo medicines containing crude drugs, which should be administered cautiously during pregnancy., Conclusion: The proportion of Kampo medicines use before and during pregnancy was 4%-5%. Some pregnant women used Kampo medicines containing crude drugs that should be administered cautiously during pregnancy. Further research is required to determine the safety of Kampo medicines during pregnancy., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Even in patients who survive resuscitation through multidisciplinary treatment, minor persistent symptoms can make hospital discharge difficult. Herein, we report a case of myocardial infarction with intractable symptoms following resuscitation, which were successfully treated using Kampo medicine., Case Presentation: A 71-year-old man experienced intractable cough and hiccups following resuscitation for acute myocardial infarction. Despite successful invasive treatment for his cardiac condition, the patient's persistent symptoms hindered his recovery and discharge from hospital. The patient was diagnosed with qi and blood deficiency, qi stagnation, and fluid retention, before being prescribed the Kampo medicine "bukuryoingohangekobokuto (BRIHK)". Within days of treatment initiation, his symptoms notably improved, allowing him to be discharged., Conclusion: This case highlights the potential of Kampo medicine for addressing post-resuscitation symptoms that are refractory to conventional treatments, and emphasizes the importance of integrating Kampo medicine with Western medical practices to enhance patient care and quality of life., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Berberine (BBR), a key component in Kampo medicine, is a cationic benzylisoquinoline alkaloid whose detection plays a critical role in the quality control of these traditional remedies. Traditional methods for detecting BBR often involve complex procedures, which can be time-consuming and costly. To address this challenge, our study focuses on developing a simpler, faster, and more efficient detection method for BBR in Kampo medicine formulations., Results: We successfully developed a rapid fluorometric detection method for BBR using colloidal gold nanoparticle-based systematic evolution of ligands by exponential enrichment (GOLD-SELEX). Initially, specific single-stranded DNA (ssDNA) sequences were selected for their ability to enhance BBR's fluorescence intensity. The optimal ssDNA sequence, identified as BBR38, was further truncated to produce BBR38S, a stem-loop ssDNA that improved fluorescence upon interaction with BBR. To further enhance the fluorescence, the BBR38S aptamer underwent additional modifications, including stem truncation and nucleotide mutations, resulting in the higher fluorescence variant BBR38S-3 A10C. The final product, TetBBR38S, a tetramer version of BBR38S-3 A10C, exhibited a linear detection range of 0.780-50.0 μg mL - 1 and a limit of detection of 0.369 μg mL -1 . The assay demonstrated sufficient selectivity and was successfully applied to analyze 128 different Kampo medicine formulations, accurately detecting BBR content with high precision., Significance: This study represents an advancement in Kampo medicine research, marking the first successful application of an aptamer-based approach for BBR detection in complex matrices. The developed method is not only simple and rapid (with a detection time of 5 min) but also cost-effective, which is crucial for widespread application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rationale: The use of anti-CGRP antibody drugs as migraine preventive drugs is increasing worldwide, but there are still a certain number of cases where antibody drugs are ineffective or cannot be used due to high prices. Conventional prophylactic drugs or traditional Japanese medicine (kampo medicine) are still often used in such cases. However, to date, only limited evidence supports the efficacy of kampo medicine for headaches because these treatments have been used primarily empirically and traditionally. However, in recent years studies have begun to be published that describe the efficacy of kampo medicine for various types of headache. Here, we report the case of a patient who achieved a marked reduction in migraine frequency and severity by prophylactic therapy with the kampo drug yokukansan (TSUMURA Yokukansan Extract Granules)., Patient Concerns and Diagnoses: The patient was a 50-year-old woman. She began to experience headaches around high school age and was diagnosed with migraine without aura at 42 years of age., Interventions and Outcomes: She started prophylactic therapy with amitriptyline and topiramate and this treatment reduced the frequency of migraines for several years. However, the frequency began to increase again around 47 years, which is when she presented at our hospital. We achieved a temporary reduction in migraine frequency by adjusting the dose of drugs in her prophylactic therapy regimen, but the frequency increased again around age 49. We then tried monotherapy with the kampo medicine yokukansan, and this markedly reduced migraine frequency and severity over the following year. This therapy has remained effective to date., Lessons: We speculate that, in this case, migraine without aura was improved by prophylactic therapy with yokukansan due to its action on the glutamatergic system or serotonin system through suppression of orexin-A secretion or its anti-inflammatory effects as reported in previous animal studies. Yokukansan could be a usable kampo medicine for migraine prophylaxis in countries all over the world and should be investigated in a large clinical trial as soon as possible., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Kampo, a Japanese herbal medicine, is approved for the treatment of various symptoms/conditions under national medical insurance coverage in Japan. However, the contemporary nationwide status of Kampo use among patients with acute cardiovascular diseases remains unknown., Methods and results: Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified 2,547,559 patients hospitalized for acute cardiovascular disease (acute myocardial infarction, heart failure, pulmonary embolism, or aortic dissection) at 1,798 hospitals during the fiscal years 2010-2021. Kampo medicines were used in 227,008 (8.9%) patients, with a 3-fold increase from 2010 (4.3%) to 2021 (12.4%), regardless of age, sex, disease severity, and primary diagnosis. The top 5 medicines used were Daikenchuto (29.4%), Yokukansan (26.1%), Shakuyakukanzoto (15.8%), Rikkunshito (7.3%), and Goreisan (5.5%). From 2010 to 2021, Kampo medicines were initiated earlier during hospitalization (from a median of Day 7 to Day 3), and were used on a greater proportion of hospital days (median 16.7% vs. 21.4%). However, the percentage of patients continuing Kampo medicines after discharge declined from 57.9% in 2010 to 39.4% in 2021, indicating their temporary use. The frequency of Kampo use varied across hospitals, with the median percentage of patients prescribed Kampo medications increasing from 7.7% in 2010 to 11.5% in 2021., Conclusions: This nationwide study demonstrates increasing Kampo use in the management of acute cardiovascular diseases, warranting further pharmacoepidemiological studies on its effectiveness.

Objective: This study aimed to determine the effects of traditional Japanese (Kampo) medicines used to treat oral mucositis on nerve conduction., Methods: The effects of Kampo medicines, crude drugs, and chemical compounds on compound action potentials (CAPs) were analyzed using extracellular recordings in frog sciatic nerves., Results: Among the Kampo medicines, inchinkoto demonstrated the most significant reduction in CAP amplitude, with a half-maximal inhibitory concentration (IC 50 ) of 5.4 mg/mL. Hangeshashinto, shosaikoto, hochuekkito, and juzentaihoto also showed a significant reduction. Regarding inchinkoto, Artemisiae Capillari Spica (artemisia) was the most effective crude drug, with an IC 50 of 4.2 mg/mL for CAP amplitude reduction, whereas Gardeniae Fructus (gardenia) exerted no significant effect. However, the combined use of artemisia and gardenia reduced the CAP amplitude more effectively than artemisia alone, indicating a synergistic interaction. The chemical ingredient eugenol from artemisia administered at 1 and 3 mmol/L reduced CAP amplitude, whereas other chemical ingredients administered at 0.1 and 1 mmol/L had no significant effects., Conclusions: Inchinkoto exhibited the most effective reduction in CAP amplitude in the sciatic nerve of frogs, primarily through the action of artemisia, with potential synergistic interaction between artemisia and gardenia., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

Goblet cell hyperplasia and increased mucus production are features of airway diseases, including asthma, and excess airway mucus often worsens these conditions. Even steroids are not uniformly effective in mucus production in severe asthma, and new therapeutic options are needed. Seihaito is a Japanese traditional medicine that is used clinically as an antitussive and expectorant. In the present study, we examined the effect of Seihaito on goblet cell differentiation and mucus production. In in vitro studies, using air-liquid interface culture of guinea-pig tracheal epithelial cells, Seihaito inhibited IL-13-induced proliferation of goblet cells and MUC5AC, a major component of mucus production. Seihaito suppressed goblet cell-specific gene expression, without changing ciliary cell-specific genes, suggesting that it inhibits goblet cell differentiation. In addition, Seihaito suppressed MUC5AC expression in cells transfected with SPDEF, a transcription factor activated by IL-13. Furthermore, Seihaito attenuated in vivo goblet cell proliferation and MUC5AC mRNA expression in IL-13-treated mouse lungs. Collectively, these findings demonstrated that Seihaito has an inhibitory effect on goblet cell differentiation and mucus production, which is at least partly due to the inhibition of SPDEF., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Introduction: Dyspeptic symptoms belong to the most frequent reasons to seek medical advice and are a burden both for the individual affected and the healthcare system. In Japan, the traditional herbal Kampo prescription rikkunshito has proven benefit for this indication., Methods: In a prospective, multicentre, non-interventional study (NIS), the effectiveness, safety, and tolerability of a two-week treatment with the registered rikkunshito extract product YamatoGast was assessed in German patients with an acute episode of dyspeptic symptoms of functional origin under real-world conditions. The primary endpoint was the responsiveness to treatment assessed by the overall treatment effect (OTE) score. Secondary endpoints were the change in severity of dyspeptic symptoms and the change in quality of life (QoL). Safety evaluation was based on reported adverse drug reactions, drug compliance, and ratings of tolerability by physicians and patients., Results: Sixty-six patients were enrolled (mean age 48.9 years, 74% females). The treatment was well tolerated and highly beneficial, as expressed by pronounced responder rates of 78.9% for the primary endpoint OTE. All secondary endpoints were also met. The severity of dyspeptic symptoms significantly improved by 62-77% compared to baseline, confirmed by a remarkable improvement of QoL. Significant symptom relief started from the third day of treatment onwards., Conclusion: In this non-interventional study, two-week treatment with YamatoGast resulted in a significant improvement of dyspeptic symptoms and was associated with high patient response and satisfaction. YamatoGast was confirmed as a safe and clinically relevant therapeutic option for patients suffering upper gastrointestinal complaints in routine practice., Competing Interests: HRH has received honoraria for consulting/speaking from Ominedo Pharmaceutical Industry Co Ltd., Japan. JT and KRD are employees of G. Pohl-Boskamp GmbH & Co KG. The other authors declare no conflict of interest., (Thieme. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a progressive disease that is characterized by chronic airway inflammation. A Japanese herbal medicine, hochuekkito (TJ-41), is prominently used for chronic inflammatory diseases in Japan. This study aimed to analyze the anti-inflammatory effect of TJ-41 in vivo and its underlying mechanisms. We created a COPD mouse model using intratracheal administration of porcine pancreatic elastase and lipopolysaccharide (LPS) and analyzed them with and without TJ-41 administration. A TJ-41-containing diet reduced inflammatory cell infiltration of the lungs in the acute and chronic phases and body weight loss in the acute phase. In vitro experiments revealed that TJ-41 treatment suppressed the LPS-induced inflammatory cytokines in BEAS-2B cells. Furthermore, TJ-41 administration activated the AMP-activated protein kinase (AMPK) pathway and inhibited the mechanistic target of the rapamycin (mTOR) pathway, both in cellular and mouse experiments. We concluded that TJ-41 administration reduced airway inflammation in the COPD mouse model, which might be regulated by the activated AMPK pathway, and inhibited the mTOR pathway., (© 2024. The Author(s).)

The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m 2 or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner., Competing Interests: HO and KM were employed by Tsumura & Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Maejima, Yokota, Yamachi, Misaka, Ono, Oizumi, Mizuno, Hidema, Nishimori, Aoyama, de Wet and Shimomura.)

Gardenia jasminoides Ellis, a plant widely used in traditional medicine, is known for its array of biological activities. A key bioactive compound, geniposide (GE), an iridoid glycoside, significantly contributes to the medicinal properties of the plant, with potential side effects. Thus, a reliable and efficient method for GE detection is required to ensure the quality of medicinal-grade G. jasminoides Ellis. This study developed such a method by first synthesizing GE-bovine serum albumin conjugates to function as immunizing agents in mice. This led to the production of a monoclonal antibody (mAb 3A6) against GE from the fusion of splenocytes from immunized mice with myeloma cells (P3U1), resulting in a hybridoma that produces mAb 3A6. Thereafter, we developed a mAb 3A6-based indirect competitive enzyme-linked immunosorbent assay (icELISA). The icELISA exhibited satisfactory sensitivity (0.391-12.5 μg/ml) and repeatability (coefficients of variation <10%). The accuracy of this method was validated through a spike-recovery assay (recovery of 101-112%). Furthermore, the icELISA was employed to determine the GE content in plant and Kampo medicine samples. The GE content positively correlated with those determined by high-performance liquid chromatography-ultraviolet. The proposed icELISA is rapid, cost-effective, and reliable for high-throughput GE detection in G. jasminoides Ellis, thereby contributing to the improved quality control and standardization of this valuable medicinal plant., Competing Interests: Declaration of competing interest The authors declare no competing interests or conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Despite the widespread practice of Japanese traditional Kampo medicine, the characteristics of patients receiving various Kampo formulations have not been documented in detail. We applied a machine learning model to a health insurance claims database to identify the factors associated with the use of Kampo formulations., Methods: A 10% sample of enrollees of the JMDC Claims Database in 2018 and 2019 was used to create the training and testing sets, respectively. Logistic regression analyses with lasso regularization were performed in the training set to construct models with prescriptions of 10 commonly used Kampo formulations in 1 year as the dependent variable and data of the preceding year as independent variables. Models were applied to the testing set to calculate the C-statistics. Additionally, the performance of simplified scores using 10 or 5 variables were evaluated., Results: There were 338,924 and 399,174 enrollees in the training and testing sets, respectively. The commonly prescribed Kampo formulations included kakkonto, bakumondoto, and shoseityuto. Based on the lasso models, the C-statistics ranged from 0.643 (maoto) to 0.888 (tokishakuyakusan). The models identified both the common determinants of different Kampo formulations and the specific characteristics associated with particular Kampo formulations. The simplified scores were slightly inferior to full models., Conclusion: Lasso regression models showed good performance for explaining various Kampo prescriptions from claims data. The models identified the characteristics associated with Kampo formulation use.

Two representative Kampo formulas, keishibukuryogan and tokishakuyakusan, are frequently prescribed for patients with dysmenorrhea. We previously constructed a model that could predict which of these 2 formulas was most suitable, which is based on 4 subjective symptoms and 3 objective signs. To evaluate the prognosis of patients with dysmenorrhea using the established prediction model and assess the treatment outcomes between those treated in accordance with the prediction model and those who received various other treatments. In this retrospective, observational study, we included patients with menstrual pain who visited the Kampo Clinic at the Keio University Hospital for the first time between October 2014 and December 2020. These patients were monitored over a 90-day follow-up period. Participants were categorized into 2 groups: model-accordance and various-options. The progression of visual analogue scale (VAS) values was evaluated by determining the slopes from regression analysis between these 2 groups, with changes corroborated by the medical records. The study comprised 57 patients: 37 in the model-accordance group and 20 in the various-options group. Notably, the various-options group reported a significantly higher number of subjective symptoms (P = .03). The VAS value showed a decline, as indicated by the negative slope value of the regression line, across both groups - irrespective of their classification. There were no significant differences in the occurrence of adverse events between the 2 groups. The prognosis of patients with dysmenorrhea and the incidence of adverse events remained consistent, regardless of whether the treatment approach was in accordance with the prediction model or varied. Further studies are warranted to assess the prognosis when Kampo formulas are chosen based on the prediction model in the various-options population., Competing Interests: Tetsuhiro Yoshino was employed for the joint research program by Tsumura & Co. Kenji Watanabe and Yuko Horiba received lecture fees from Tsumura & Co. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All other authors have no competing/conflict of interest., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Kampo medicine is a traditional medicine that originated in ancient China and has since developed as a uniquely Japanese medicine. Although Kampo medicine is one of Japan's most important therapeutic modalities and numerous papers have been published recently, information on current hotspots and trends in Kampo research is lacking. This bibliometric analysis of Kampo medicine surveyed the latest research hotspots and trends., Methods: Articles on Kampo medicine were retrieved from the Web of Science Core Collection. We used medical subject headings related to Kampo medicine and searched for publications from 2013 to 2022. The retrieved articles were analyzed for countries, authors, journals, references, and keywords related to Kampo medicine using CiteSpace, VOSviewer, and SCImago Graphica., Results: A total of 1170 articles were included. The number of Kampo medicine-related publications and citations has recently increased, mainly from Japan. Author Keiko Ogawa-Ochiai published the most papers (40 papers), while Yoshio Kase had the highest frequency at 663 citations. Among the co-cited authors, Toru Kono was the most cited and had the highest total link strength. The journal with the most submissions was Evidence-based Complementary and Alternative Medicine. A comprehensive keyword and literature analysis revealed the following research hotspots: "Yokukansan and behavioral and psychological symptoms of dementia," "Ninjinyoeito and geriatric care," "Daikenchuto and postoperative gastrointestinal cancer," and "Rikkunshito and functional dyspepsia." We also identified a new research frontier by identifying an association between hochuekkito and COVID-19., Conclusions: Our findings reveal trends in Kampo medicine research, with specific hotspots and the authors and publications with the largest research impact. Collecting a large volume of literature data, analyzing the impact of studies, and identifying research hotspots, as in this study, will provide researchers with future directions for Kampo research., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Kampo medicine is widely used in Japan; however, most physicians and pharmacists have insufficient knowledge and experience in it. Although a chatbot-style system using machine learning and natural language processing has been used in some clinical settings and proven useful, the system developed specifically for the Japanese language using this method has not been validated by research. The purpose of this study is to develop a novel drug information provision system for Kampo medicines using a natural language classifier® (NLC®) based on IBM Watson., Methods: The target Kampo formulas were 33 formulas listed in the 17th revision of the Japanese Pharmacopoeia. The information included in the system comes from the package inserts of Kampo medicines, Manuals for Management of Individual Serious Adverse Drug Reactions, and data on off-label usage. The system developed in this study classifies questions about the drug information of Kampo formulas input by natural language into preset questions and outputs preset answers for the questions. The system uses morphological analysis, synonym conversion by thesaurus, and NLC®. We fine-tuned the information registered into NLC® and increased the thesaurus. To validate the system, 900 validation questions were provided by six pharmacists who were classified into high or low levels of knowledge and experience of Kampo medicines and three pharmacy students., Results: The precision, recall, and F-measure of the system performance were 0.986, 0.915, and 0.949, respectively. The results were stable even with differences in the amount of expertise of the question authors., Conclusions: We developed a system using natural language classification that can give appropriate answers to most of the validation questions., (© 2023. The Author(s).)

Reductions in brain-derived neurotrophic factor (BDNF) expression levels have been reported in the brains of patients with neurological disorders such as Alzheimer's disease. Therefore, upregulating BDNF and preventing its decline in the diseased brain could help ameliorate neurological dysfunctions. Accordingly, we sought to discover agents that increase Bdnf expression in neurons. Here, we screened a library of 42 Kampo extracts to identify those with the ability to induce Bdnf expression in cultured cortical neurons. Among the active extracts identified in the screen, we focused on the extract based on the Kampo formula daikenchuto. The extract of daikenchuto in the library used in this study was prepared using the mixture of Zingiberis Rhizoma Processum (ZIN), Zanthoxyli Piperiti Pericarpium (ZAN), and Ginseng Radix (GIN) without Koi. In this study, we defined DKT as the mixture of ZIN, ZAN, and GIN without Koi (DKT extract means the extract prepared from the mixture of ZIN, ZAN, and GIN without Koi). DKT extract significantly increased endogenous Bdnf expression by mediated, at least in part, via Ca 2+ signaling involving L-type voltage-dependent Ca 2+ channels in cultured cortical neurons. Furthermore, DKT extract significantly improved the survival of cultured cortical neurons and increased neurite complexity in immature neurons. Taken together, our findings suggest that DKT extract induces Bdnf expression and has a neurotrophic effect in neurons. Because BDNF inducers are expected to have therapeutic potential for neurological disorders, re-positioning of Kampo formulations such as daikenchuto may lead to clinical application in diseases associated with reduced BDNF in the brain., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Objectives: This is a narrative review of the integration of traditional medicine with conventional biomedicine in present day Japan, whose aging population is considered one of the largest globally. Design: It is focused on the aging population because this age group most avails of healthcare. We also tried to describe the unique Japanese medical situations, clinical outcome of Japanese traditional medicine (Kampo medicine) which may include acupuncture, and education of Kampo medicine workforce. Results: Conventional schools of medicine in Japan are required to teach Kampo medicine, and most Japanese physicians (>80%) prescribe traditional medicine, especially in primary care settings. The universal national healthcare system covers Kampo medicine prescribed by physicians and treatment by acupuncturists (they sometimes refer patients who may need evaluation by physicians), enhancing access to primary healthcare. Additionally, pharmacists who graduated from conventional schools of pharmacy also select and sell Kampo medicine as over-the-counter (OTC) medication. Kampo medicine available as prescription drugs and OTC is effective, and has been proven to be economically beneficial in several clinical settings. Conclusions: An aging population is a global concern for both developed and developing countries. Japan, having a significantly-large aging population, integrates conventional biomedicine and traditional medicine in its universal national healthcare coverage, through its biomedically-trained physicians and pharmacists who also learned traditional medicine, as well as the acupuncturists. By reviewing the current situation in Japan, the authors hope to introduce the future of the global contribution of traditional, complementary, and integrative medicine in primary care.

Compared to psychotropic drugs, the clinical use of Kampo medicines (Japanese herbal medicines) is unclear because of the difficulty in accumulating scientific evidence for various reasons. This study reviews Kampo medicines frequently prescribed in psychiatry and the principles of disorders of qi, blood, and fluid for their use, which are considered particularly important in this field. Kampo medicines are one of the preferred treatment modalities for patients with mental disorders in Japan, and we hope that these will become a treatment option for patients refractory to psychotropic drugs.

Ethnopharmacological Relevance: Ninjin'yoeito (NYT), a traditional Japanese Kampo medicine consisting of 12 herbs, has been reported to improve cognitive dysfunction, depression, and neurological recovery in patients with neurovascular diseases such as Alzheimer's disease and stroke. Several studies have reported that the NYT components exert neurotrophic, neurogenic, and neuroprotective effects. In addition, exercise enhances neuroprotection and functional recovery after stroke. Rehabilitative exercises and pharmacological agents induce neurophysiological plasticity, leading to functional recovery in stroke patients. These reports indicate that NYT treatment and exercise may promote functional recovery following stroke through their beneficial effects. However, no study has determined the effects of NYT and the possible mechanisms of neurorepair and functional recovery after stroke., Aim of the Study: This study aimed to investigate the combined effects of NYT and exercise on neuroprotection and functional recovery and the underlying mechanisms in a rat ischemic stroke model., Materials and Methods: Stroke was induced with 60-min middle cerebral artery occlusion (MCAO) followed by reperfusion in adult male Sprague-Dawley rats. After stroke, the rats were assigned to four groups: ischemia reperfusion (IR), NYT, exercise (Ex), and NYT + Ex. NYT-treated rats were fed a diet containing 1% NYT one day after stroke. Exercise was performed using a motorized treadmill for 5 days a week (8-15 m/min, 20 min/day), starting 3 days after stroke. The NYT treatment and exercise were continued for 4 weeks after the stroke. Infarct volume, neurological deficits, sensorimotor functions, expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase A (TrkA) and B (TrkB), caspase-3 activity, and the p-Akt/Akt ratio were examined by immunohistochemistry and western blotting., Results: Compared to the IR group, all treated groups indicated reduced infarct volumes. The NYT + Ex group showed significantly improved waking time and beam walking score compared with the IR group. The expression of NGF/TrkA/p-TrkA and BDNF/TrkB was significantly increased in the NYT + Ex group compared with those in the IR group, whereas the number of caspase-3 positive cells around the lesion was significantly lower in the NYT + Ex group than in the IR group. In addition, the ratio of p-Akt/Akt was significantly higher in the NYT + Ex group than in the IR group., Conclusions: This study suggests that NYT in combination with exercise provides neuroprotective effects and improves sensorimotor function by stimulating NGF/TrkA and BDNF/TrkB, and by activating the Akt pathway in ischemic stroke of rats. NYT may be an effective adjunctive agent in post-stroke rehabilitation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Myogenesis is required to generate skeletal muscle tissue and to maintain skeletal muscle mass. Decreased myogenesis under various pathogenic conditions results in muscular atrophy. Through a small screening of Japanese traditional (Kampo) medicines, hachimijiogan (HJG) was shown to promote the myogenic differentiation of C2C12 myoblasts through the upregulation of myogenin. In tumor-bearing cancer-cachectic mice, HJG was also found to have a protective effect against cancer-cachectic muscle wasting. This effect was significant when HJG was administered in combination with aerobic exercise by treadmill running. Moreover, HJG ameliorated the cellular atrophy of C2C12 myotubes induced by treatment with conditioned medium derived from a colon-26 cancer cell culture. In addition, HJG suppressed H2O2-dependent myotube atrophy, suggesting that HJG could reverse the atrophic phenotypes by eliminating reactive oxygen species.

Objective: To develop versatile and interactive model classes by generating the contents of Kampo classroom sessions that can be taught by instructors who are not familiar with Kampo medicine., Methods: In 2018, we conducted Kampo classroom sessions among fourth-year medical students at Kyushu University in which we incorporated new content. A videotaped digest edition of the classes was sent to Kampo medicine instructors in medical schools throughout Japan. An online questionnaire was given to the instructors regarding effectiveness of the class content (Q1) and whether they would introduce the content in their classes (Q2). We modified the curriculum according to survey responses and conducted revised classroom sessions again in 2019. A second online survey was given and we finalized the model classes. We compared survey responses between staff and instructors (group A) and non-specialists in Kampo medicine (group B)., Results: In 2018, there were significant differences between groups A (44) and B (52) regarding a patient's story and case report (Q1). In 2019, there were significant differences between groups A (42) and B (54) regarding the case report using e-learning(Q1) and an instructor's experience (Q2)., Conclusions: We propose that Kampo medicine classes should incorporate an instructor's experience and interactive case report presentation using e-learning.

Objective: To clarify the fetal safety of herbal Kampo medicines, including Hange-koboku-to, Koso-san, Nyoshin-san, Yokukansan, Yokukansan-kachinpi-hange, Saiko-keishikankyo-to, Keishi-karyukotu-borei-to, and Kanbaku-taisou-to, when administered to pregnant women with depression using a large healthcare administrative database., Methods: We extracted data from the JMDC Claims Database (2005-2018) for this retrospective cohort study of pregnant women aged 19 years or older admitted to obstetric clinics or hospitals for delivery. Participants were classified into four groups: those without depression, those diagnosed with depression without medication, those given Kampo medicines for depression, and those given western medicines for depression. Neonatal outcomes (congenital anomalies, low birth weight, and preterm birth) were considered as the safety outcome measures., Results: We identified 179 707 eligible mothers. The adverse outcomes did not differ significantly between participants receiving Kampo medicine and those not diagnosed with depression during pregnancy. The proportion of low-birth-weight neonates did not differ significantly between the Kampo medicine and non-depression groups (adjusted odds ratio [aOR] 1.28; 95% confidence interval [CI] 0.86-1.91), but was significantly higher in the unmedicated depression group (aOR 1.31; 95% CI 1.07-1.61) and western medicine group (aOR 1.47; 95% CI 1.18-1.83)., Conclusion: Kampo medicines are safe for treating depression during pregnancy without increasing the incidence of congenital anomalies, low birth weight, or preterm birth., (© 2022 International Federation of Gynecology and Obstetrics.)

Donepezil, an acetylcholinesterase inhibitor, is associated with gastrointestinal symptoms, such as nausea, vomiting, and anorexia, which may affect adherence to continuous therapy. Since Rikkunshi-To, a Japanese herbal medicine, activates the ghrelin signaling pathway and promotes gastrointestinal function, it is administered to prevent gastrointestinal symptoms. We herein investigated whether donepezil-induced gastrointestinal side effects in mice are ameliorated by Rikkunshi-To and if its therapeutic efficacy is mediated by ghrelin. Since pica behavior, the ingestion of kaolin, correlates with nausea and vomiting in humans, donepezil was intraperitoneally administered with or without Rikkunshi-To daily to mice, and food and kaolin intakes were monitored. The effects of donepezil on intestinal motility and a ghrelin receptor antagonist on donepezil-induced pica behavior, anorexia, and changes in intestinal motility were examined in mice treated with Rikkunshi-To. Pica behavior and anorexia were significantly induced by donepezil and significantly inhibited by Rikkunshi-To. Intestinal motility was significantly suppressed by donepezil and promoted by Rikkunshi-To. Furthermore, the therapeutic effects of Rikkunshi-To were antagonized by the ghrelin receptor antagonist. The present results support the therapeutic efficacy of Rikkunshi-To against donepezil-induced gastrointestinal side effects., Competing Interests: Conflict of interest Professor. Kouichi Yamamoto received Rikkunshi-To from Tsumura & Co. Professor Keisuke Hagihara awarded the endowed chair position established by Tsumura & Co. Professor. Yuhki Sato, Kyosuke Kirikihira, Akito Jotaki, Ayana Michihara, and Yumi Miyake declare no conflicts of interest associated with this manuscript., (Copyright © 2022 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Objective: Herb-induced liver injury due to Kampo formulae is a clinically relevant adverse effect, which may be associated with formulae containing Scutellariae Radix. We explored this incident relationship further by surveying outpatients treated with a Kampo formula containing Scutellariae Radix (KFCSR) at our clinic., Methods: We included patients who had been treated with a novel KFSCR formulation between November 2014 and October 2015. The participants underwent liver injury-related blood tests (examining the aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, and total bilirubin levels, as well as the percentage of eosinophils in the white blood cell count) before and after treatment to evaluate its efficacy., Results: In total, 43 of the 363 patients treated during the study period received KFCSRs and 37 underwent blood tests before and after treatment. Liver injury occurred in four patients (10.8%) and all patients recovered quickly after cessation of the formula., Conclusions: We found that 10.8% of patients treated with KFCSR developed liver injury, which was higher than that reported previously. We believe that herb-induced liver injury should be seriously considered as a risk factor for KFCSRs. Further investigation is warranted to verify these results.

Traditional Japanese medicines, known as "Kampo medicines", are pharmaceutical-grade multi-herbal treatments that are integrated within the modern medical system in Japan. Although basic and clinical research including placebo-controlled double-blind trials is attempting to clarify their effectiveness and mechanisms of action, such studies are seriously limited due to the multi-targeted, multi-component "long-tail" properties of Kampo medicines, which are fundamentally different from modern western therapeutics. However, recent progress in high-throughput analytical technology, coupled with an exponential increase in biomedical information on various levels from molecular biology to clinical "big" data, is enabling us to commence a multidisciplinary and comprehensive investigation of Kampo medicines based on multi-omics, bio-informatics, and systems biology. In addition to deriving an inclusive understanding of the benefits and mechanisms of Kampo medicines, "KAMPOmics" may lead to the development of new principles to control and treat diseases in a systems-oriented manner. Furthermore, elucidation of "sho" and "mibyo" - classical concepts of Kampo, which loosely approximate to the notions of "precise medicine" and "pre-symptomatic aberration", respectively - may contribute to the development of patient-oriented medicine, an area attracting enormous growth and interest in contemporary medicine., (Copyright © 2022. Published by Elsevier B.V.)

Objective: To establish a prediction model of qi stagnation referring to two existing models., Design: Prospective observational study., Setting: We recruited patients who visited the Kampo Clinic at Keio University from February 2011 to March 2013., Methods: We constructed a random forest algorithm with 202 items as independent variables to predict qi stagnation patterns using full agreement data of the physicians' diagnosis and the result of two existing scores as a reference standard. To compare the new model with the two existing models, we calculated the discriminant ratio (prediction accuracy), precision, sensitivity (recall), specificity, and F-measure of these models., Results: The number of eligible participants was 1,194, and 29.1% of them were diagnosed with qi stagnation by Kampo physicians. The discriminant ratio, precision, sensitivity, specificity, and F-measure in our new model were 0.960, 0.672, 0.911, 0.964, and 0.774, respectively. Our new model had a significantly higher discriminant ratio than the two existing models., Conclusions: We constructed a better qi stagnation prediction model than the previously established ones. Our results can be utilized to reach an international agreement on qi stagnation pattern diagnosis in traditional East Asian medicine., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The number of people with obesity is rapidly increasing worldwide. Since obesity is a critical risk factor for cardiovascular diseases and mortality, the management of obesity is an urgent issue. However, anti-obesity drugs are insufficient in current clinical settings. Bofutsushosan (BTS, Fang-Feng-Tong-Sheng-San in China) is a traditional Japanese Kampo formula for patients with obesity. Recent basic studies have indicated that BTS potentially improves the pathophysiology of obesity. However, it is still unknown whether BTS clinically reduces body mass index (BMI) in patients with obesity., Methods: We searched electronic databases, including the Medline, EMBASE, Cochrane Library, and Japanese/Chinese/Korean databases, on June 15, 2021. We conducted a meta-analysis of randomized controlled trials to evaluate the effects of BTS on BMI, waist circumference, glycolipid metabolism, and blood pressure in participants with obesity. The primary outcome was change in BMI., Results: We included seven studies and 679 participants (351 in the BTS group and 328 in the control group). In participants with obesity, BTS significantly reduced BMI relative to controls (mean difference, MD [95% confidence interval]: -0.52 kg/m2 [-0.86, -0.18], P = 0.003). There was no significant difference in waist circumference, glycolipid parameters, or blood pressure. Sensitivity analyses showed robust outcomes for the primary endpoint, although the heterogeneity was considerable. Moreover, no serious adverse events were observed in the BTS group., Conclusion: BTS showed a potential benefit in safely and tolerably improving BMI in participants with obesity., Competing Interests: Kazushi Uneda, Ryuji Saito, Takao Namiki, and Tadamichi Mitsuma have received research grant support from Tsumura & Co. In the past, Tadamichi Mitsuma also received lecture fees from Tsumura & Co. and Kotaro Pharmaceutical Co., Ltd. The funders did not have any roles in the study design, data collection, analysis, publishing decision, or manuscript preparation. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All authors contributed significantly to this article.

Background: The purpose of this study was to develop an objective, content-valid, and reliable assessment method for Kampo medicine using an objective structured clinical examination (OSCE) for the assessment of clinical competence in Kampo medicine., Methods: We developed a blueprint followed by a list of 47 assessment items and three task scenarios related to clinical competence in Kampo medicine. An eight-member test committee checked the relevance of the assessment items on a Likert scale. We calculated a content validity index and content validity ratio, and used the Angoff method to set the passing threshold. We trained a total of nine simulated patients with three assigned to each scenario. We conducted an OSCE for 11 candidates with varying medical abilities, and conducted three stations per person, which were evaluated by one evaluator in one room by direct observation. We used video recordings to test the inter-rater reliability of the three raters. We used the test results to verify the reliability of the assessment chart., Results: The inter-rater reliability (intraclass correlation coefficient [2,1]) was 0.973. The reliability of the assessment chart for each scenario (Cronbach's α) was 0.86, 0.89, and 0.85 for Scenarios 1, 2, and 3, respectively. The reliability of the assessment chart for the whole OSCE (Cronbach's α) was 0.90., Conclusions: We developed a content-valid new OSCE assessment method for Kampo medicine and obtained high inter-rater and test reliabilities. Our findings suggest that this is one of the most reliable evaluation methods for assessing clinical competence in Kampo medicine., (© 2022. The Author(s).)

Összefoglaló. A japánok hagyományos gyógymódja, a Kanpó a több ezer éves kínai gyógyító tapasztalaton alapul. A Kanpó filozófiája azonban csak részben hasonlít a hagyományos kínai orvosláshoz, bár megtartja annak több fontos alaptételét, de annak egyszerűsített, pozitivista és pragmatikus változata, amely igazodik a japán kultúrához. A Kanpó a japán egészségbiztosítási rendszer fontos része a korszerű nyugati gyógymódokkal együtt. A nyugati orvostudomány viszont kevésbé érdeklődik a Kanpó terápiás lehetőségei iránt, tekintettel arra, hogy a hagyományos kínai orvoslás és az Ájurvéda-gyógymódok széles körben elterjedtek a világban az utóbbi néhány évtizedben. A Kanpó készítményei elérhetők az internet különböző kereskedelmi honlapjain. Sajnálatos módon a készítmények összetétele általában pontatlanul van megadva. A gyógynövények fajait nem jelölik, így nemcsak félrevezető, hanem az összetevők hatása sem ismert. A dolgozat a leggyakrabban használt néhány hagyományos készítmény összetételét és hatását tárgyalja. Orv Hetil. 2022; 163(110): 386-392. Summary. Kanpo, the traditional Japanese medicine, is based on thousands of years of Chinese healing experience. Kanpo's philosophy, however, is only partially similar to traditional Chinese medicine. Although it retains several important basic tenets, it is a simplified, positivist, and pragmatic version of aligning to Japanese culture. Kanpo is an important part of the Japanese health insurance system along with modern western therapies. Western medicine, on the other hand, is less interested in Kanpo's therapeutic options, given that traditional Chinese medicine and Ayurvedic therapies have become widespread in the world over the past few decades. Kanpo's herbal preparations are available on various commercial internet websites. Unfortunately, the composition of the formulas is generally inaccurate. The species of herbs are not identified, so not only are they misleading, but the effects of the ingredients are not known either. The article discusses the composition and effects of some of the most commonly used conventional formulas. Orv Hetil 2022; 163(10): 386-392.

To elucidate the interactions between crude drugs in Kampo medicines (traditional Japanese medicines), it is important to determine the content of the constituents in a cost-effective and simple manner. In this study, we quantified the constituents in crude drug extracts using thin-layer chromatography (TLC), an inexpensive and simple analytical method, to elucidate the chemical interactions between crude drugs. We focused on five crude drugs, for which quantitative high-performance liquid chromatography (HPLC) methods are stipulated in the Japanese Pharmacopoeia XVIII (JP XVIII) and compared the analytical data of HPLC and TLC, confirming that the TLC results corresponded with the HPLC data and satisfied the criteria of JP XVIII. ( Z )-ligustilide, a major constituent in Japanese Angelica Root, for which a method of quantification has not been stipulated in JP XVIII, was also quantitatively analyzed using HPLC and TLC. Furthermore, Japanese Angelica Root was combined with 26 crude drugs to observe the variation in the ( Z )-ligustilide content from each combination by TLC. The results revealed that combinations with Phellodendron Bark, Citrus Unshiu Peel, Scutellaria Root, Coptis Rhizome, Gardenia Fruit, and Peony Root increased the ( Z )-ligustilide content. Quantifying the constituents in crude drug extracts using the inexpensive and simple TLC method can contribute to elucidating interactions between crude drugs in Kampo medicines, as proposed by the herbal-pair theory.

Aging-induced neuroinflammation, also known as neuroinflammaging, plays a pivotal role in emotional disturbances, including depression and anxiety, in older individuals, thereby leading to cognitive dysfunction. Although numerous studies have focused on therapeutic strategies for cognitive impairment in older individuals, little research has been performed on treating its preceding emotional disturbances. Here, we examined whether Kampo formulas (kososan [KS], nobiletin-rich kososan [NKS], and hachimijiogan [HJG]) can ameliorate aging-induced emotional disturbances and neuroinflammation in mice. The depression-like behaviors observed in SAMP8 mice, relative to normally aging SAMR1 mice, were significantly prevented by treatment with Kampo formulas for 13 weeks. Western blot analysis revealed that hippocampal neuroinflammation was significantly abrogated by Kampo formulas. KS and NKS also significantly attenuated the hippocampal neuroinflammatory priming induced by lipopolysaccharide (LPS, 0.33 mg/kg, i.p. ) challenge in SAMP8 mice. Hippocampal IL-1β, IL-6, and MCP-1 levels were significantly decreased in NKS-treated SAMP8 mice. KS and NKS showed significantly reduced tau accumulation in the brains of SAMP8 mice. RNA-sequencing revealed that each Kampo formula led to unique dynamics of hippocampal gene expression and appeared to abrogate hippocampal inflammatory responses. HJG significantly blocked the LPS-induced increase in serum IL-6 and MCP-1. These results suggest that Kampo formulas would be useful for treating aging-induced depression, in part by regulating neuroinflammatory pathways. This finding may pave the way for the development of therapeutic strategies for aging-related emotional disturbances, which may contribute to the prevention of cognitive dysfunction in older individuals.

Many constituents of crude drugs in Japanese Kampo formulas are thought to function as pro-drugs, whose pharmacological activity is manifested after oral administration. Proteins and peptides in crude drugs may be digested and metabolized in the digestive tract and liver. However, few studies have reported the pharmacological activity of peptides in crude drugs. Here, we applied an analysis using LC-tandem mass spectrometry (LC-MS/MS) to identify the compounds derived from six crude drugs that are assumed to have anti-inflammatory effects. To simulate in vivo protease digestion, each water-soluble fraction of the crude drug extracts was treated with proteases, including endoproteinases and exopeptidases. Amines in the resultant digests were modified by 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate and analyzed using LC-MS/MS, which demonstrated the presence of four decarboxylated amino acids (primary amines). In the digest of the hydrophilic fraction of the fruit of Ziziphus jujuba Miller var. inermis Rehder (Taiso), isobutylamine, isoamylamine, and 2-methylbutylamine were identified, which may be derived from valinyl, leucinyl, and isoleucinyl residues, respectively. Additionally, tyramine possibly derived from tyrosyl residues was identified in the digests of all the crude drugs. In primary cultured rat hepatocytes treated with interleukin-1β, all these decarboxylated amino acids suppressed the production of nitric oxide, a proinflammatory mediator. Our approach, i.e., in vitro protease digestion and LC-MS/MS analysis, suggests that decarboxylated amino acids may be formed in vivo from peptides and may be responsible for the anti-inflammatory effect of crude drugs included in Kampo medicine.

In the 1970s, the public&#8217;s need for Japanese herbal medicine increased, and the Ministry of Health and Welfare was flooded with applications for Japanese herbal extracts as OTC drugs. In 1975, the ministry of Health issued the guidebook of the approval standards for Kampo products for 210 prescriptions. But, although Kampo has already been partially incorporated into the healthcare system, this does not mean that clinical research is not being conducted or that evidence-based medicine (EBM) is being taken lightly.

Natural medicines, including crude drugs and Kampo prescriptions, have a long history of clinical uses. An important characteristic of natural medicines is that they are multicomponent medicines. Kampo prescriptions, particularly, usually consist of several crude drugs that contain a large number of constituents. The therapeutic effects of a Kampo prescription result from the total effects of its constituents and not from the effect of a representative constituent with a strong pharmacological effect. In fact, only a few of these constituents with strong biological activity have been listed in the Japanese Pharmacopoeia as therapeutic agents. During my research career, I have observed various synergistic effects and interactions among the constituents of natural medicines. This article reviewed our researches on the biologically active constituents of natural medicines, including the analysis of the anti-inflammatory constituents of orengedokuto (a Kampo prescription). Understanding the role of each constituent with therapeutic effects in Kampo prescriptions forms a scientific basis of Kampo medicine. This will enable the better use and quality control of Kampo prescriptions. Moreover, this will aid the future development of a multicomponent mimic for a specific effect of a Kampo prescription using the appropriate mixture of active constituents in amounts found in the prescription. The above is my dream as a natural product chemist, and I believe that the mixture can do more than we anticipate!

Abstract: Lymphatic malformations (LMs) are congenital malformations of the lymphatic system that cause considerable cosmetic and functional complications. In this study, we present 8 children with LM who were treated with the Kampo medicine eppikajutsuto (EKJT).Between 2001 and 2020, 8 children (male: 4, female: 4) with LMs who underwent magnetic resonance imaging (MRI) evaluation both before and after treatment or observation were selected for investigating the effect of EKJT. Two patients were observed without any treatment for 24 and 60 months. EKJT was evaluated based on percentage reduction, defined as the percentage of total lesions that decreased in size, confirmed by radiological examination after initiating treatment with EKJT or determined by observation alone. Volumetric analysis of LMs on MRI was performed using the Digital Imaging and Communications in Medicine viewer.Six patients were treated with EKJT. The mean observational period was 13.2 months (range: 6-24 months). The mean reduction in LM volume on MRI was 73.0% in treated patients and -66.3% in observed patients. Two of the 6 lesions exhibited complete reduction, 2 exhibited marked (>90%) reduction, 1 exhibited moderate reduction, and 1 exhibited a small response. The treatment was well-tolerated, with no severe adverse events.This preliminary study demonstrated the beneficial effects of EKJT. Prospective evaluations of this promising therapeutic modality are warranted based on the results of this study., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Cancer cachexia results in the discontinuation of aggressive cancer therapy, and halting its progression has a significant effect on the survival rate and quality of life of patients with cancer. Currently, there are few therapies to control or slow down the progression of cancer cachexia. Although traditional Japanese Kampo medicine is widely used to support aggressive cancer therapy, the relevant scientific evidence is limited. Additionally, Kampo medicines are based on historical experience. In recent years, there have been widespread attempts to prove the efficacy of Kampo medicines through basic research, and an increasing number of studies have clarified the mechanism of action of Kampo medicines at the molecular level. It has been proposed that the improvement of cancer cachexia by Kampo medicines might involve enhancement of feeding via the central nervous system, improvement of protein maintenance in the skeletal muscle, and suppression of inflammatory cytokine production. In particular, among Kampo medicines, tonifying formulae, called "hozai" in Japanese, have been shown to be effective in alleviating cancer cachexia. In this review, we summarize the recent progress of basic and clinical research in Kampo medicines on cancer cachexia, and introduce Kampo medicines that are expected to be attractive supportive cancer medication., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In Japan, 147 types of oral Kampo extract products are covered by the public insurance system; however, to the best of our knowledge, there are no large-scale randomized clinical trials. Therefore, the level of evidence or these products is low compared with that for medicines that have been introduced as insurance reimbursement drugs through randomized clinical trials. However, when conventional western medical treatments have not been effective or when patients desire a more effective therapy, Kampo extract products are one of the treatment options. Kampo extract products involve the adding of crude drugs and comprise a multi-component system. Therefore, it may be effective for various symptoms. I recommend that specialists use these products as complementary alternative medicines. I also introduce the "Huaier extract granule," which is an orally bioavailable traditional Chinese medicine composed of granules containing an aqueous extract of Trametes robiniophila Murr (Huaier), a mushroom found on hardwood tree trunks, with potential immune-regulating activity. Huaier has immunity enhancement activity, such as antineoplastic property, as well as immunity regulating activity against diseases, such as asthma, psoriasis, and immunoglobulin A nephritis. Therefore, for some intractable diseases, especially when the disease is thought to involve an immune disorder, Huaier can be an additional treatment option.

Patients with chronic intractable dizziness (henceforth referred to as "intractable dizziness") have a high risk of developing frailty complications. This warrants investigation of a combined treatment for intractable dizziness and frailty. Ninjin'yoeito (NYT), a traditional Japanese medicine (Kampo medicine), is reportedly effective in treating frailty and sarcopenia. Herein, we report on the results of a retrospective study that involved the combined application of NYT and dizziness rehabilitation therapy (henceforth referred to as "dizziness rehabilitation"). Of the 31 patients with intractable dizziness, 14 developed frailty, indicating a complication rate of 45.2%. This in turn was approximately 4 times higher than the previously reported rates. Eleven patients became non-frail after 6 months of the combined treatment, and their improvement rate was 78.6%. The aforementioned combination therapy not only improved dizziness but also improved frailty. Following 6 months of combined treatment, patients in the frailty group exhibited improvement in the Dizziness Handicap Inventory score, frailty symptoms, Kihon checklist score, and visual analog scale score (fatigue), and approached the pre-treatment values of those in the non-frailty group. Together, our results highlight the need to combine the treatment for intractable dizziness and frailty., (Copyright © 2021. Published by Elsevier Ltd.)

Ninjin-yoei-to (NYT), a Kampo medicine, has ameliorative effects on cognitive dysfunction via enhancing cholinergic neuron activity. To explore an efficacy of NYT administration for prevention and cure of Alzheimer's disease, here we examined the effect of NYT on amyloid β 1-42 (Aβ 1-42 )-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aβ 1-42 was intracerebroventricularly injected. Neurodegeneration in the dentate granule cell layer of the hippocampus, which was determined 2 weeks after the injection, was rescued by administration of the diet for 4 weeks. Aβ staining (uptake) was not modified in the dentate granule cell layer by pre-administration of the diet for 2 weeks, while Aβ 1-42 -induced increase in intracellular Zn 2+ was reduced, suggesting that pre-administration of NYT prior to Aβ injection is effective for reducing Aβ 1-42 -induced Zn 2+ toxicity in the dentate gyrus. As a matter of fact, Aβ 1-42 -induced neurodegeneration in the dentate gyrus was rescued by pre-administration of NYT. Interestingly, the level of metallothioneins, intracellular Zn 2+ -binding proteins, which can capture Zn 2+ from Zn-Aβ 1-42 complexes, was elevated in the dentate granule cell layer by pre-administration of NYT. The present study suggests that pre-administration of NYT prevents Aβ 1-42 -mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn 2+ toxicity induced by Aβ 1-42 .

Circadian rhythm is an approximately 24 h endogenous biological rhythm. Chronic disruption of the circadian clock leads to an increased risk of diabetes, cardiovascular disease, and cancer. Hence, it is important to develop circadian clock modulators. Natural organisms are a good source of several medicines currently in use. Crude drugs used in Japanese traditional Kampo medicine or folk medicines are an excellent source for drug discovery. Furthermore, identifying new functions for existing drugs, known as the drug repositioning approach, is a popular and powerful tool. In this study, we screened 137 crude drug extracts to act as circadian clock modulators in human U2OS cells stably expressing the clock reporter Bmal1-dLuc, and approximately 12% of these modulated the circadian rhythm. We further examined the effects of several crude drugs in Rat-1 fibroblasts stably expressing Per2-luc, explant culture of lung from Per2::Luciferase knockin mice, and zebrafish larvae in vivo. Notably, more than half of the major ingredients of these crude drugs were reported to target AKT and its relevant signaling pathways. As expected, analysis of the major ingredients targeting AKT signaling confirmed the circadian clock-modulating effects. Furthermore, activator and inhibitor of AKT, and triple knockdown of AKT isoforms by siRNA also modulated the circadian rhythm. This study, by employing the drug repositioning approach, shows that Kampo medicines are a useful source for the identification of underlying mechanisms of circadian clock modulators and could potentially be used in the treatment of circadian clock disruption., (© 2021. The Author(s).)

Kampo medicines contain many kinds of herbal drugs. Chinpi and Kippi, dried citrus peels, are components of a substantial number of Kampo medicine. They contain abundant flavonoids and studies on hesperidin, narirutin, and nobiletin as active ingredient have been conducted. Conversely, in Kagoshima prefecture, located in the southwestern part of the Japanese Islands, various citrus products are cultivated. Among them, Tankan and Daimasaki are specialies. In this study, we conducted high- performance liquid chromatography to determine the difference in flavonoid contents among Tankan, Daimasaki, Tankan related product, Chinpi, and Kippi. As a result, several active components, such as hesperidin, narirutin, nobiletin, and tangeretin, in common with crude drug, Chinpi, were detected in local citrus fruits. In addition, some active components little or not found in Chinpi, for example hesperetin and rutin, were detected in the local products. A detailed analysis of active components considering their genetic origin, the time of fruit collection, and different parts of the fruit used (peel, albedo, edible parts, and the whole) will need to be discussed to get the most out of the citrus fruits or make best use of them for health and longevity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Thirteen herbal medicines, Kakkonto (TJ-001), Kakkontokasenkyushin'i (TJ-002), Hangekobokuto (TJ-016), Shoseiryuto (TJ-019), Maoto (TJ-027), Bakumondoto (TJ-029), Hochuekkito (TJ-041), Goshakusan (TJ-063), Kososan (TJ-070), Chikujountanto (TJ-091), Gokoto (TJ-095), Saibokuto (TJ-096), and Ryokankyomishingeninto (TJ-119) were tested for human parainfluenza virus type 2 (hPIV-2) replication. Eight (TJ-001, TJ-002, TJ-019, TJ-029, TJ-041, TJ-063, TJ-095 and TJ-119) out of the thirteen medicines had virus growth inhibitory activity. TJ-001 and TJ-002 inhibited virus release, and largely inhibited genome, mRNA and protein syntheses. TJ-019 slightly inhibited virus release, inhibited gene and mRNA syntheses, and largely inhibited protein synthesis. TJ-029 slightly inhibited virus release, largely inhibited protein synthesis, but gene and mRNA syntheses were unaffected. TJ-041 only slightly inhibited virus release, the gene and mRNA syntheses, but largely inhibited protein synthesis. TJ-091 largely inhibited gene, mRNA and protein syntheses. TJ-095 largely inhibited gene synthesis, but NP and HN mRNAs were slightly detected, and protein syntheses were observed. TJ-119 inhibited gene, mRNA and protein syntheses. TJ-001, TJ-002, TJ-091, TJ-095 and TJ-119 inhibited multinucleated giant cell formation derived from cell-to-cell spreading of virus. However, in TJ-019, TJ-029 and TJ-041 treated infected cells, only small sized fused cells with some nuclei were found. TJ-019 and TJ-041 slightly disrupted actin microfilaments, and TJ-001 and TJ-002 destroyed them. TJ-041 slightly disrupted microtubules, and TJ-001 and TJ-002 disrupted them. In general, the medicines effective on common cold and bronchitis inhibited hPIV-2 replication.

Objective: To examine how Kampo education in Japanese medical schools changed between 2011 and 2019., Methods: We administered nationwide postal questionnaire surveys about current characteristics of Kampo medicine education in all 82 Japanese medical schools, directed to the persons responsible for Kampo education at each university. One survey was conducted in 2011 and one in 2019. Analysis used Welch's t-test and a chi-squared test., Results: The average class meeting time was shorter in 2019 than in 2011. The proportion of class meetings that were about Kampo saw a statistically significant increase in the third year and a significant decrease in the fourth and sixth years of medical school. Curriculum standardisation, preparation of simple textbooks, and fostering Kampo medicine instructors were the primary problems in both years. The proportion of mainstream medical education contents focusing on traditional Japanese Kampo medicine did not change over time, nor did the percentage of those considering using standardised textbooks. Other changes were statistically nonsignificant., Conclusion: In Japanese medical schools, the number of class meetings teaching Kampo medicine has increased; however, this number is not statistically significant. Persistent problems in Kampo education, including curriculum standardisation, need to be addressed.

Background/purpose: We examined the effects and mechanisms of rikkunshito (RKT) and hangeshashinto (HST) on cisplatin-induced mucosal injuries in the rat small bowel., Methods: Juvenile rats were divided into 6 groups: sham control, cisplatin injection without kampo medicines, and cisplatin injection with oral administration of low and high doses of RKT (1000 mg/kg and 2000 mg/kg) and HST (500 mg/kg and 1000 mg/kg). Fecal condition, intestinal morphological changes, enterocyte proliferation, and enterocyte apoptosis were assessed., Results: Diarrhea and atrophy of ileal villi observed in the cisplatin group were significantly improved in all kampo groups. Injury scores of the jejunum were significantly lower with RKT (2000 mg/kg) and HST (500 and 1000 mg/kg) than with cisplatin, and those of the ileum were significantly lower with HST (500 and 1000 mg/kg) than with cisplatin. Enterocyte proliferation of the jejunum was significantly increased with RKT (2000 mg/kg) and HST (500 mg/kg) compared with cisplatin, and those of the ileum were significantly increased in all kampo groups compared with the cisplatin group. Jejunal and ileal apoptosis following cisplatin administration was significantly inhibited by HST., Conclusions: RKT and HST prevented cisplatin-induced intestinal mucosal injury with increasing proliferation of intestinal epithelial cells. HST also attenuated cisplatin-induced crypt cell apoptosis., Competing Interests: Declaration of Competing Interests RKT and HST were provided by Tsumura & Co. (Tokyo, Japan). The authors have no other conflict of interest associated with this manuscript., (Copyright © 2021. Published by Elsevier Inc.)