Metabolically and immunologically beneficial impact of extra virgin olive and flaxseed oils on composition of gut microbiota in mice.

PURPOSE: Extra virgin olive oil (EVOO) and flaxseed oil (FO) contain a variety of constituents beneficial for chronic inflammation and cardio-metabolic derangement. However, little is known about the impact of EVOO and FO on dysbiosis of gut microbiota, intestinal immunity, and barrier. We, therefore, aimed to assess the impact of EVOO and FO on gut microbiota, mucosal immunity, barrier integrity, and metabolic health in mice. METHODS: C57BL/6 J mice were exposed to a low-fat (LF), lard (HF), high fat-extra virgin olive oil (HF-EVOO), or high fat-flaxseed oil (HF-FO) diet for 10 weeks. Gut microbiota assessment was undertaken using 16S rRNA sequencing. Levels of mRNA for genes involved in intestinal inflammation and barrier maintenance in the intestine and bacterial infiltration in the liver were measured by qPCR. RESULTS: HF-EVOO or HF-FO mice showed greater diversity in gut microbiota as well as a lower abundance of the Firmicutes phylum in comparison with HF mice (P < 0.05). The qPCR analyses revealed that mRNA level of FoxP3, a transcription factor, and IL-10, an inducer of regulatory T cells, was significantly elevated in the intestines of mice-fed HF-EVOO in comparison with mice-fed HF (P < 0.05). The mRNA level of the antimicrobial peptide, RegӀӀӀγ, was markedly elevated in the intestines of HF-EVOO and HF-FO compared with HF group (P < 0.05). CONCLUSIONS: Our data suggest that the consumption of EVOO or FO can beneficially impact gut microbiota, enhance gut immunity, and assist in the preservation of metabolic health in mice.

Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation.

BACKGROUND: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. METHODS: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. RESULTS: We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. CONCLUSIONS: The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.

Fecoflowmetric profiles in postoperative patients with Hirschsprung's disease.

PURPOSE: The objective of this study is to evaluate the anorectal function from the viewpoint of fecoflowmetry in postoperative patients with Hirschsprung's disease (HD). METHODS: This study evaluated 23 long-term follow-up patients who had undergone a radical operation for HD. Their mean age was 11 years. The types of HD included rectosigmoid colon type, 18 cases, and entire colon type, 5 cases. An anorectal manometric study was performed before fecoflowmetry. After normal saline solution was administrated as an imitation stool into the rectal cavity under pressure monitoring, the patients defecated on a fecoflowmeter. After discussing the maximum defecation flow (Flow-max), fecoflow pattern (FFP), tolerance rate (TR), anal canal pressure (AP), and Kelly's clinical scores (Kelly-Scores), the significant parameters were identified to elucidate the anorectal activity. RESULTS: (1) A close relationship was observed between the FFP and Kelly-Scores (P = .0027). (2) Flow-max, TR, and AP in patients with good Kelly-Scores were significantly higher than those in patients with fair Kelly-Scores (P < .05). (3) The Flow-max accurately reflected the TR, Kelly-Scores, and AP. Flow-max >45 mL per second, TR >70%, or AP >30 mm Hg was statistically regarded as a borderline level of fecal continence (P < .002). CONCLUSIONS: The Flow-max and FFP are considered to be useful parameters for postoperative patients with HD.

Effects of the herbal medicine Inchinko-to on liver function in postoperative patients with biliary atresia--a pilot study.

BACKGROUND/PURPOSE: A continuation of liver fibrosis after undergoing successful Kasai operation has become the important clinical issue in the long-term follow-up of patients with biliary atresia (BA). The aim of this study is to evaluate the efficacy of the herbal medicine Inchinko-to (TJ-135) on the treatment of liver fibrosis in patients with BA without jaundice, especially from the viewpoint of the long-term effects of TJ-135. METHODS: Six postoperative patients with BA ranging between 3 and 13 years of age with normal serum total bilirubin levels (total bilirubin < 1.0 mg/dL [17 micromol/L]) received TJ-135 from 2 to 4 years. The liver enzyme (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT], gamma glutamyl transpeptidase[gamma-GTP]transpeptidase[gamma-GTP] levels and hyaluronic acid (HA) levels were compared before and after the administration of TJ-135. The monthly collected data were averaged on a 1-year basis. The record of one postoperative patient with BA and a normal serum total bilirubin level was incorporated as a control. This patient showed portal hypertension and did not receive TJ-135. RESULTS: Five of the six patients who showed abnormal values for liver enzymes, exhibited a significant decrease in serum GOT, gamma-GTP, or GPT levels after a 1 to 3-year administration of TJ-135, and the improvement in these parameters persisted thereafter. Furthermore, one patient who had an abnormally high value of HA also showed a significant decrease in the serum level of HA. In the remaining patient with normal liver enzyme values, no significant change was observed during the administration of TJ-135. The control patient exhibited a chronological decrease in the serum GOT and GPT levels by 5 years of age, but the serum gamma-GTP and HA levels remained stable throughout the postoperative period. CONCLUSIONS: The long-term effectiveness of TJ-135 was only found in those patients with abnormal liver enzyme levels and HA, thereby suggesting that TJ-135 has a protective and antifibrotic effect on the liver.