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Abstract Melanocortin 4 receptor gene-knockout (MC4R-KO) mice are known to develop obesity with a high-fat diet. Meanwhile, daisaikoto, one of Kampo medicines, is a drug that is expected to have therapeutic effects on obesity. Here, we report the efficacy of daisaikoto in MC4R-KO mice. Eight-week-old MC4R-KO male mice (n = 12) were divided into three groups as follows: the SD group, which is fed with a standard diet; the HFD group, fed a high-fat diet; and the DSK group, fed with a high-fat diet containing 10% of daisaikoto. After the four-week observation period, mice in each group were sacrificed and samples were collected. The body weights at 12 weeks were significantly higher in the HFD group than in the other groups, indicating that daisaikoto significantly reduced body weight gain and fat deposition of the liver. The metabolome analysis indicated that degradation of triglycerides and fatty acid oxidation in the liver were enhanced by daisaikoto administration. In MC4R-KO mice, the cytoplasm and uncoupling protein 1 expression of brown adipose tissue was decreased; however, it was reversed in the DSK group. In conclusion, daisaikoto has potentially improved fatty liver and obesity, making it a useful therapeutic agent for obesity and fatty liver.

This research developed an easy-to-use, reproducible pancreatic cancer animal model utilizing pancreas-targeted hydrodynamic gene delivery to deliver human pancreatic cancer-related genes to the pancreas of wild-type rats. KRASG12D-induced pancreatic intraepithelial neoplasia lesions showed malignant transformation in the main pancreatic duct at 4 weeks and developed acinar-to-ductal metaplasia, which led to pancreatic ductal adenocarcinoma within 5 weeks, and the gene combination of KRASG12D and YAP enhanced these effects. The repeat hydrodynamic gene delivery of KRASG12D + YAP combination at 4 weeks showed acinar-to-ductal metaplasia in all rats and pancreatic ductal adenocarcinoma in 80% of rats 1 week later. Metastatic tumors in the liver, lymph nodes, and subcutaneous lesions and nervous invasion were confirmed. KRASG12D and YAP combined transfer contributes to the E- to N-cadherin switch in pancreatic ductal adenocarcinoma cells and to tumor metastases. This pancreatic cancer model will speed up pancreatic cancer research for novel treatments and biomarkers for early diagnosis.

Serotonin (5-HT) is one of the key bioamines of nonalcoholic fatty liver disease (NAFLD). Its mechanism of action in autonomic neural signal pathways remains unexplained; hence, we evaluated the involvement of 5-HT and related signaling pathways via autonomic nerves in NAFLD. Diet-induced NAFLD animal models were developed using wild-type and melanocortin 4 receptor (MC4R) knockout (MC4RKO) mice, and the effects of the autonomic neural axis on NAFLD physiology, 5-HT and its receptors (HTRs), and lipid metabolism-related genes were assessed by applying hepatic nerve blockade. Hepatic neural blockade retarded the progression of NAFLD by reducing 5-HT in the small intestine, hepatic HTR2A and hepatic lipogenic gene expression, and treatment with an HTR2A antagonist reproduced these effects. The effects were milder in MC4RKO mice, and brain 5-HT and HTR2C expression did not correlate with peripheral neural blockade. Our study demonstrates that the autonomic liver-gut neural axis is involved in the etiology of diet-induced NAFLD and that 5-HT and HTR2A are key factors, implying that the modulation of the axis and use of HTR2A antagonists are potentially novel therapeutic strategies for NAFLD treatment. This article has an associated First Person interview with the first author of the paper.

The etiology of non-alcoholic fatty liver disease (NAFLD) consists of various factors, including neural signal pathways. However, the molecular mechanisms of the autonomic neural signals influencing NAFLD progression have not been elucidated. Therefore, we examined the involvement of the gut-liver neural axis in NAFLD development and tested the therapeutic effect of modulation of this axis in this study. To test the contribution of the gut-liver neural axis, we examined NAFLD progression with respect to body weight, hepatic steatosis, fibrosis, intestinal tight junction, microbiota and short-chain fatty acids in NAFLD models of choline-deficient defined L-amino-acid and high-fat diet-fed mice with or without blockades of autonomic nerves from the liver. Blockade of the neural signal from the liver to the gut in these NAFLD mice models ameliorated the progression of liver weight, hepatic steatosis and fibrosis by modulating serotonin expression in the small intestine. It was related to the severity of the liver pathology, the tight junction protein expression, microbiota diversity and short-chain fatty acids. These effects were reproduced by administrating serotonin antagonist, which ameliorated the NAFLD progression in the NAFLD mice models. Our study demonstrated that the gut-liver neural axis is involved in the etiologies of NAFLD progression and that serotonin expression through this signaling network is the key factor of this axis. Therefore, modulation of the gut-liver neural axis and serotonin antagonist ameliorates fatty and fibrotic changes in non-alcoholic fatty liver, and can be a potential therapeutic target of NAFLD. This article has an associated First Person interview with the first author of the paper.

Despite a large body of research on response properties of neurons in the inferior temporal (IT) cortex, studies to date have not yet produced quantitative feature descriptions that can predict responses to arbitrary objects. This deficit in the research prevents a thorough understanding of object representation in the IT cortex. Here we propose a fragment-based approach for finding quantitative feature descriptions of face neurons in the IT cortex. The development of the proposed method was driven by the assumption that it is possible to recover features from a set of natural image fragments if the set is sufficiently large. To find the feature from the set, we compared object responses predicted from each fragment and responses of neurons to these objects, and search for the fragment that revealed the highest correlation with neural object responses. Prediction of object responses of each fragment was made by normalizing Euclidian distance between the fragment and each object to 0 to 1 such that the smaller distance gives the higher value. The distance was calculated at the space where images were transformed to a local orientation space by a Gabor filter and a local max operation. The method allowed us to find features with a correlation coefficient between predicted and neural responses of 0.68 on average (number of object stimuli, 104) from among 560,000 feature candidates, reliably explaining differential responses among faces as well as a general preference for faces over to non-face objects. Furthermore, predicted responses of the resulting features to novel object images were significantly correlated with neural responses to these images. Identification of features comprising specific, moderately complex combinations of local orientations and colors enabled us to predict responses to upright and inverted faces, which provided a possible mechanism of face inversion effects. (292/300).

BACKGROUND AND AIM:Awareness of eosinophilic esophagitis (EoE) has gradually increased in Japan, therefore the characteristics of this disease in the Japanese patient population need to be elucidated. This study aimed to investigate the features of EoE in the Japanese population. METHODS:During a 2-year period, all gastrointestinal endoscopies were performed with maximum attention being paid to identify EoE through endoscopic findings. Clinical features and findings were analyzed among this population. RESULTS:Among a total of 8589 patients (general gastrointestinal endoscopy, performed for evaluation of symptoms or disease follow-up: 3669; medical check-up endoscopy, routinely performed in asymptomatic patients: 4920), 17 patients (0.20%) were diagnosed with esophageal eosinophilia (mean age ± standard deviation: 44±11.9 years; 1 female). Only 6 patients with esophageal eosinophilia were diagnosed by general gastrointestinal endoscopy; among them, 3 patients had dysphagia and 3 were asymptomatic. The remaining 11 patients were diagnosed by medical check-up endoscopy. All patients were treated with a proton pump inhibitor (PPI); 5 were diagnosed with EoE and 12 with PPI responsive esophageal eosinophilia. Chronological endoscopy analysis showed that EoE findings could be observed for a mean of 6.1 years prior to diagnosis, and the disease did not significantly progress in severity. CONCLUSIONS:Most Japanese patients with EoE have mild and slowly progressing disease, which can be diagnosed when close attention is paid to the endoscopic findings. Medical check-up endoscopy in Japan could be a great opportunity for the early diagnosis of EoE.