Tsumura Research Institute (Japan)

The presence of treatment-resistant patients underscores the need for novel therapeutic options for affective and anxiety disorders. Kamikihito (KKT), a traditional kampo medicine used to treat mental anxiety and neurosis, has recently attracted attention because of its unique mechanism of action as an oxytocin-activating drug. However, the underlying mechanism remains unclear. In particular, for the optimal use of KKT in clinical practice, clarifying whether KKT affects the monoaminergic system, which is the primary target of first-line antidepressants for these disorders, is essential. By evaluating monoaminergic transporter activity in vitro, we found that KKT inhibited the noradrenaline transporter (NAT). In addition, in the tail suspension test, KKT shortened the duration of immobility posture, indicative of behavioral despair, in lipopolysaccharide-injected mice, similar to desipramine, a NAT inhibitor. Furthermore, a reduction in the immobility time following KKT administration was not observed in mice pretreated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a noradrenergic neurotoxin, indicating that the antidepressant-like effect of KKT is mediated through the noradrenergic system. To identify the ingredients of KKT that are transferred into the blood and brain, we analyzed the blood and brain tissues of mice after KKT administration using mass spectrometry. Geniposide and formononetin were identified and puerarin, gardoside, 3',7-dihydroxy-4'-methoxyisoflavone 7-O-glucoside, and kazonol N were estimated as ingredients that distribute both in the blood and brain. Although these ingredients did not exhibit NAT inhibitory activity, the information presented in this pharmacokinetic study will be a valuable resource for future studies on the molecular mechanisms of KKT action.

Dai-kenchu-to is used to prevent and relieve ileus post-gastrectomy; however, it has been reported to cause hepatobiliary injury in 0.3% of patients, and knowledge regarding its risk in this context is limited. In this study, we aimed to evaluate the effect of dai-kenchu-to, a representative traditional Japanese herbal medicine, on the risk of hepatobiliary injury in patients with gastric cancer who underwent gastrectomy, using real-world data from acute care hospitals. The diagnosis procedure combination data of patients admitted with gastric cancer who underwent gastrectomy between April 2008 and May 2019 were analyzed. The collected data included sex, age, comorbid injuries and illnesses at admission, medication records during hospitalization, and tumor node metastasis classifications. The primary outcome, occurrence of hepatobiliary injury, was identified using records of the use of hepatoprotective agents or cholagogues. The odds ratios of dai-kenchu-to for predisposition to hepatobiliary injury after gastrectomy were estimated using multivariate logistic regression analysis. Herein, 33137 gastric cancer patients who underwent gastrectomy were included in the analysis. The incidences of hepatobiliary injury among patients in the dai-kenchu-to-exposed and non-exposed groups were both 5.9%. The multivariate odds ratio of dai-kenchu-to exposure for hepatobiliary injury was 0.97 (95% confidence interval, 0.73-1.29; p = 0.847). In this study, no risk of moderate-to-severe hepatobiliary injury due to the postoperative administration of dai-kenchu-to was noted in patients with gastric cancer who had undergone gastrectomy. These results provide information regarding the safety of dai-kenchu-to use after gastrectomy in patients with gastric cancer.

Genetic truncation or mutation of the gene encoding band 4.1, ezrin, radixin, and moesin (FERM) domain protein containing 4A (FRMD4A) is associated with brain developmental diseases, including microcephaly with global developmental delay. It has also been identified as a risk factor for Alzheimer’s disease. By analogy with other FERM domain-containing proteins, FRMD4A is believed to regulate cell morphogenesis and/or cell polarization in central nervous system (CNS) cells; however, it remains unclear whether and how dysfunction of FRMD4A and/or its closely homologous protein FRMD4B causes abnormal morphogenesis in neuronal cells. Here, we describe for the first time the roles of FRMD4A and FRMD4B in process elongation in neuronal cells. Knockdown of Frmd4a or Frmd4b using specific RNA-targeting clustered regularly interspaced short palindromic repeat (CRISPR) and Cas13-fitted gRNAs led to decreased process elongation in primary cortical neurons. Similar decreases in neuronal marker expression were observed in the N1E-115 cell line, a model of neuronal differentiation. Furthermore, hesperetin, an aglycone of the citrus flavonoid hesperidin known to promote neuroprotective signaling, recovered the decreased process elongation induced by the knockdown of Frmd4a or Frm4b. Hesperetin also stimulated phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs), which could help promote neuronal processes. These results suggest that FRMD4A and FRMD4B regulate process elongation through a possible signaling pathway linked to the sustained phosphorylation of MAPKs/ERKs. Crucially, this study reveals that, at the molecular and cellular levels, hesperetin can restore normal phenotypes when FRMD4A protein or FRMD4B protein is impaired.

Fecal incontinence (FI) significantly impairs patient quality of life and creates substantial distress not only for affected individuals but also for nurses and caregivers. The prevalence of FI among older adults is estimated at up to 20%, although the sensitive nature of the condition often prevents active reporting by patients. This article reviews risk factors and pharmacotherapies for FI, emphasizing the therapeutic potential of Daikenchuto (DKT). The etiology of FI is multifactorial and lacks a singular definition. Currently, no prescription drugs specifically approved for FI are available, leaving treatment options limited. Nonetheless, major clinical guidelines have identified several viable pharmacological approaches. Strongly recommended treatments include the antidiarrheal agent loperamide and stool bulking or solidifying agents, such as dietary fiber and polycarbophil. Other therapeutic options include ramosetron, a 5-HT3 receptor antagonist; amitriptyline, a tricyclic antidepressant; and sodium valproate and diazepam, which are GABAergic neuromodulators. Recently, research has explored the efficacy and mechanism of action of DKT, a traditional Japanese medicine Kampo. Historically used for abdominal symptoms like bloating and known for promoting intestinal motility, emerging evidence suggests DKT may also effectively manage FI.

Glycyrrhiza uralensis Fischer (Fabaceae), an important medicinal plant widely used in traditional Japanese and Chinese medicine, contains bioactive compounds, such as glycyrrhizin and flavonoids, which exhibit pharmacological activities, including antispasmodic and antitussive effects. Overharvesting has depleted wild populations, making the cultivation of G. uralensis necessary to stabilize its supply; however, the content of bioactive compounds tends to decrease in cultivated plants. In this study, we investigated the genetic inheritance (heritability) of medicinal compound contents in G. uralensis by analyzing clonal lines propagated from stolons. Broad-sense heritability was estimated for seven medicinal compounds using 26 clonal lines, revealing high heritability for glycyrrhizin and several flavonoids. In addition, correlation analyses between seed-derived and stolon-derived roots demonstrated strong genetic inheritance of these compounds. Furthermore, the effects of plant age and cultivation year on compound content were examined. Our results show high correlations between compound content and genotype across plant age (one- and two-year-old plants), suggesting the feasibility of early selection in breeding programs. While environmental variations influenced absolute compound levels, the relative rankings among genotypes remained stable. These results indicate the high heritability of compound contents and the strong effectiveness of selective breeding. We conclude that there is strong potential for selective breeding to enhance the medicinal quality of G. uralensis by targeting high-yielding genotypes with superior compound profiles and that this potential may also apply to the sustainable cultivation of other high-quality medicinal plant resources.

AimsPostoperative delirium (PD) is a common and severe complication in older adult patients undergoing invasive cancer resections. This study explored the plasma metabolome associated with PD and evaluated the efficacy of Yokukansan (YKS), a traditional Japanese Kampo medicine, in preventing PD.MethodsAn ancillary study was conducted alongside a double‐blind, placebo‐controlled randomized clinical trial involving patients 65 years and older, focusing on patients older than 75 years as a primary analysis population. Plasma samples were analyzed using targeted and nontargeted metabolomics. An in vivo study using aged mice assessed the effects of YKS on plasma and brain metabolites.ResultsA total of 83 patients, including 21 patients older than 75 years, were enrolled. Patients with PD had lower levels of several lipid mediators, free fatty acids, and phospholipids. YKS administration led to increased nine phospholipids and four hydrophilic metabolites in patients older than 75 years, including phosphatidylcholine (40:7) and phosphatidylcholine (42:8), which were also altered in delirium patients. In the patients older than 65 years, only two metabolites increased in the YKS administration group. In aged mice, YKS elevated plasma phospholipids, similar to findings in patients older than 75 years, and influenced brain citrulline and creatine, which related to oxidative stress and cognitive function. Correlation analyses revealed associations between plasma and brain metabolite changes.ConclusionOur findings suggest that the plasma metabolome provides insight into the pathophysiology of PD and the potential mechanism underlying the preventive effect of YKS against PD.

The genus Priestia, formerly referred to as Bacillus, is capable of growing under abiotic stresses in the ecosystem. We now report the complete genome sequence of Priestia aryabhattai KC-6A, which was obtained from culture soil utilizing peatland as an agricultural material.

嗅覚障害は症候名であり, さまざまな原因疾患により発生し, 原因として多いのは慢性鼻副鼻腔炎, アレルギー性鼻炎などの鼻副鼻腔疾患である. 今回, レセプトデータベースである JMDC Claims Databases を用いて, これらの疾患の経年的動向を探索するとともに, 嗅覚障害の特徴, 嗅覚検査の実施状況ならびに投与された薬剤の年次変化を観察した. 2005年から2022年の間に嗅覚障害, アレルギー性鼻炎の患者率は漸増し, 慢性鼻副鼻腔炎患者率は変化を認めなかった. 嗅覚障害患者は30歳代から50歳代までは男性よりも女性に多く, 全体でも女性が男性の1.3倍を示した.2010年から2019年までの10年間に, 嗅覚障害の病名で最も多く処方された薬剤はカルボシステインを主とする去痰薬・酵素製剤であり, 抗ヒスタミン薬, ステロイド点鼻薬も薬剤処方例の半数以上に処方されていた. 10年間で処方率の著明な増加を示したのは, ロイコトリエン受容体拮抗薬と漢方薬であり, 漢方薬の半数以上を当帰芍薬散が占めていた. 一方, マクロライド系抗菌薬, ステロイド点鼻薬, ビタミン B12 製剤は減少を示した. 処方数の増減は, 患者数の推移を反映するとともに, 嗅神経性嗅覚障害に対する当帰芍薬散や嗅覚刺激療法など有効性を示す治療法の出現により, 病態に基づいた治療が行いやすくなったことの表れであると思われた.

Key messageHerein, a method has been proposed for selecting optimal cross pairs based on the genetic potential of progeny in interpopulation crosses, considering different genetic effects among populations.In the breeding programs for self-pollinating plants, genetic improvements in multiple traits can be challenging when relying solely on a single biparental population, and interpopulation crosses are employed to integrate favorable alleles from multiple biparental populations to overcome this limitation. In this context, it is crucial to consider distinct genetic effects in different populations. In this study, we used a selection method based on the usefulness criterion (UC) to identify cross pairs suitable for interpopulation crosses. We expanded this approach to enhance breeding programs by accounting for varying genetic backgrounds within the genomic selection framework. Using the medicinal plant perilla as the study material, we performed simulations to compare the efficacy of selection based on the estimated genotypic values with that of selection based on UC. Our findings demonstrate that the proposed method is effective in facilitating the simultaneous improvement of multiple traits, particularly by considerably increasing the genetic gains among the top-performing individuals in the population. Furthermore, we provide guidelines for implementing interpopulation crosses, including recommendations for the optimal generation for crossing and an appropriate reference generation for calculating UC. The results obtained in this study offer valuable insights for small-scale breeding programs aimed at simultaneously enhancing multiple traits through interpopulation crosses and can be applied to a wide range of crops, including neglected and underutilized species.