Significant association between HLA-B*35:01 and onset of drug-induced liver injury caused by Kampo medicines in Japanese patients.

AIM: Drug-induced liver injury (DILI) is a severe and life-threatening immune-mediated adverse effect, occurring rarely among treated patients. We examined genomic biomarkers in the Japanese population that predict the onset of DILI after using a certain class of drugs, such as Kampo products (Japanese traditional medicines). METHODS: A total of 287 patients diagnosed as DILI by hepatology specialists were recruited after written informed consent was obtained. A genome-wide association analysis and human leukocyte antigen (HLA) typing in four digits were performed. RESULTS: We found a significant association (p = 9.41 × 10-10 ) of rs146644517 (G > A) with Kampo product-related DILI. As this polymorphism is located in the HLA region, we evaluated the association of HLA types and found that 12 (63.2%) of 19 Kampo-DILI patients contained HLA-B*35:01, whereas only 15.2% were positive for this HLA among healthy volunteers. The odds ratio was 9.56 (95% confidence interval 3.75-24.46; p = 2.98 × 10-6 , corrected p = 4.17 × 10-5 ), and it increased to 13.55 compared with the DILI patients not exposed to Kampo products. The individual crude drug components in the Kampo products, including Scutellaria root (ougon in Japanese), rhubarb (daiou), Gardenia fruit (sanshishi), and Glycyrrhiza (kanzou), were significantly associated with HLA-B*35:01. CONCLUSIONS: HLA-B*35:01 is a genetic risk factor and a potential predictive biomarker for Kampo-induced DILI in the Japanese population.

Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in cultured mouse myotubes, chronic liver disease rats and humans.

Background: Hepatic sarcopenia is one of many complications associated with chronic liver disease (CLD) and has a high mortality rate; however, the liver-muscle axis is not fully understood. Therefore, few effective treatments exist for hepatic sarcopenia, the best of which being branched-chain amino acid (BCAA) supplementation to help increase muscle mass. Our aim was to investigate the molecular mechanism(s) of hepatic sarcopenia focused on bile acid (BA) composition. Methods: The correlation between serum BA levels and psoas muscle mass index (PMI) was examined in 73 CLD patients. Gastrocnemius muscle phenotype and serum BA levels were assessed in CLD rats treated with BCAA. Mouse skeletal muscle cells (C2C12) were incubated with lithocholic acid (LCA), G-protein-coupled receptor 5 (TGR5) agonist or TGR5 antagonist to assess skeletal muscle hypertrophy. Results: In human CLD, serum LCA levels were the sole factor positively correlated with PMI and were significantly decreased in both the low muscle mass group and the deceased group. Serum LCA levels were also shown to predict patient survival. Gastrocnemius muscle weight significantly increased in CLD rats treated with BCAA via suppression of protein degradation pathways, coupled with a significant increase in serum LCA levels. LCA treated C2C12 hypertrophy occurred in a concentration-dependent manner linked with TGR5-Akt pathways based upon inhibition results via a TGR5 antagonist. Conclusions: Our results indicate LCA-mediated skeletal muscle hypertrophy via activation of TGR5-IGF1-Akt signaling pathways. In addition, serum LCA levels were associated with skeletal muscle mass in cirrhotic rats, as well as CLD patients, and predicted overall patient survival. Funding: This research was supported by JSPS KAKENHI Grant Number 22K08011 and 21H02892, and AMED under Grant Number JP21fk0210090 and JP22fk0210115. Maintaining cirrhotic rats were partially supported by Otsuka Pharmaceutical Company.

Complement complex 1 subunit q-mediated hepatic stellate cell activation with connective tissue growth factor elevation is a prognostic factor for survival in rat and human chronic liver diseases.

Complement complex 1 subunit q (C1q) has multiple functions, including cell migration, in addition to its traditional complement-activating effect. Research shows C1q is a ligand for frizzled receptors (FZDs). FZD-induced yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) alternate Wnt signaling activation induces connective tissue growth factor (CTGF) production and hepatic stellate cell (HSC) activation. However, no study exists in which C1q directly induces CTGF in HSCs. Here, we investigated the role of C1q in HSC activation. Human HSCs (LX2) were incubated with C1q to assess HSC activation. C1q and fibrotic markers were assessed using immunohistochemistry, immunoblotting, and quantitative reverse-transcription polymerase chain reaction in cirrhotic rats administered CCl4 for 21 weeks. Serum C1q, liver function, and fibrosis score were measured in 91 patients with chronic liver disease. The correlations between serum C1q and liver function, fibrosis score, and survival prognosis were examined. C1q-activated LX2s showed morphologic changes, up-regulation of CTGF, tissue inhibitors of metalloproteinases (TIMP-1), and alternate Wnt signal genes FZD2, TAZ, and cysteine-rich angiogenic inducer 61 (Cyr61). Cirrhotic rat liver C1q expression correlated with the Azan-positive area and expression of CTGF, TIMP-1, hyaluronan synthase (HAS)1, HAS3, and CD44. Expression of C1q protein and C1q, CTGF, and TIMP-1 genes were higher in deceased cirrhotic rat livers compared to surviving rats. Human serum C1q levels increased in liver cirrhosis compared to chronic hepatitis and correlated with liver fibrosis and functional markers. Ten patients suffered liver-related death over a 66-month observation period. The C1q cut-off value (11 mg/dl) showed patients with serum values < 11 mg/dl had longer rates of survival compared to C1q ≥ 11 mg/dl. Conclusion: C1q-mediated HSC activation in liver fibrosis is associated with CTGF elevation. Additionally, serum C1q may be diagnostic for survival in human chronic liver diseases.

Development of a New Index to Distinguish Hepatic Encephalopathy through Automated Quantification of Globus Pallidal Signal Intensity Using MRI.

Hyperintensities within the bilateral globus pallidus on T1-weighted magnetic resonance images were present in some liver cirrhosis patients with hepatic encephalopathy. The symptoms of covert hepatic encephalopathy are similar to those of mild dementia. We aimed to develop a new diagnostic index in which to distinguish hepatic encephalopathy from dementia. The globus pallidus signal hyperintensity was quantified using three-dimensional images. In addition, the new index value distribution was evaluated in a cohort of dementia patients. Signal intensity of globus pallidus significantly increased in liver cirrhosis patients with hepatic encephalopathy compared to those without hepatic encephalopathy (p < 0.05), healthy subjects (p < 0.05) or dementia patients (p < 0.001). Only 12.5% of liver cirrhosis patients without hepatic encephalopathy and 2% of dementia patients exceeded the new index cut-off value of 0.994, which predicts hepatic encephalopathy. One dementia patient in our evaluation had a history of liver cancer treatment and was assumed to have concomitant hepatic encephalopathy. The automatic assessment of signal intensity in globus pallidus is useful for distinguishing liver cirrhosis patients with hepatic encephalopathy from healthy subjects and liver cirrhosis patients without hepatic encephalopathy. Our image analyses exclude possible cases of hepatic encephalopathy from patients with neurocognitive impairment, including dementia.

Frequency of null genotypes of glutathione S-transferase M1 and T1 in Japanese patients with drug-induced liver injury.

AIM: Previous reports suggest that the null genotype (*0/*0) of glutathione S-transferase (GST) M1 and/or GSTT1 could be risk factors for drug-induced liver injury (DILI). However, multi-institutional pharmacogenetic research with various suspected drugs has rarely been performed in Japan. Therefore, the aim of this study was to investigate the role of GSTM1 and GSTT1 null genotype in the occurrence of DILI in Japanese patients. METHODS: Blood samples of 270 DILI patients from 23 hospitals throughout Japan collected between 2010 and 2018 were subjected to genotyping of null genotypes of GSTM1 and GSTT1 using the SmartAmp-2 method. We also collected information on DILI types, time to onset of DILI, pharmacological classification of suspected drugs and Digestive Disease Week-Japan score, as well as genotypes of GSTM1 and GSTT1 in each patient with DILI. RESULTS: The distribution of a combination of null genotypes of GSTM1 and GSTT1 in Japanese patients with DILI was significantly different from that reported in the general Japanese population. Notably, the incidence of the GSTM1 null genotype in patients with DILI was significantly higher than that of the control population. A significant relationship between the frequency of GSTM1 and GSTT1 null genotypes and pharmacological classification of suspected drugs, clinical laboratory data for liver function, time to onset of DILI, and Digestive Disease Week-Japan scores was not observed. CONCLUSIONS: The GSTM1 null genotype was associated with an increased incidence of DILI in Japanese patients.

A new detection system for serum fragmented cytokeratin 18 as a biomarker reflecting histologic activities of human nonalcoholic steatohepatitis.

Caspase-generated fragmented cytokeratin 18 (fCK18) is recognized as a useful noninvasive biomarker in the diagnosis of nonalcoholic fatty liver disease (NAFLD), particularly nonalcoholic steatohepatitis (NASH). However, fCK18 measurement is not applied clinically due to widely variable cut-off values under the current enzyme-linked immunosorbent assay platform. Therefore, we developed a highly sensitive chemiluminescent enzyme immunoassay using newly developed monoclonal antibodies against fCK18 and investigated its relevance in NASH diagnosis. Serum fCK18 levels were measured in the derivation and validation cohort. The correlation between serum fCK18 levels and NAFLD activity score (NAS), fibrosis stage, and liver function was examined. Serum fCK18 levels were significantly correlated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase. Serum fCK18 levels were significantly associated with NAS, Brunt's grade/stage, Matteoni's classification, portal inflammation, and fat accumulation in the liver. Notably, hepatocyte ballooning was the only independent variable significantly associated with serum fCK18 in the multivariate linear regression analysis. Serum fCK18 levels were significantly elevated in patients with NAFLD and nonalcoholic fatty liver (NAFL) compared to healthy individuals. They were also significantly elevated in patients with NAFL compared to NASH defined by NAS or Matteoni's classification, with area under the curve values being 0.961 (NAFLD vs. healthy), 0.913 (NAFL vs. healthy), 0.763 (NASH vs. NAFL), and 0.796 (NASH type 3-4 vs. NAFL type 1-2). These results were confirmed by a validation cohort. Notably, changes over time in serum fCK18 levels were significantly correlated with changes in ALT, AST, and the fibrosis-4 index in 25 patients who underwent lifestyle modification. Serum fCK18 levels were significantly correlated with liver damage associated with NASH pathology. Serum fCK18 levels are accurate in distinguishing patients with NAFL or NASH from healthy individuals and may be useful to monitor NASH over time.

Extracellular vesicles from pancreatic ductal adenocarcinoma endoscopic ultrasound-fine needle aspiration samples contain a protein barcode.

BACKGROUND: The survival rate of pancreatic ductal adenocarcinoma (PDAC) is very poor because early detection is difficult. Extracellular vesicles (EVs) are released from cells associating with the cellular condition and circulated in the blood. We aimed to identify EV proteins from endoscopic ultrasound-fine needle aspiration (EUS-FNA) biopsy samples in order to develop novel biomarkers for PDAC. METHODS: Extracellular vesicles were isolated from EUS-FNA samples of 40 PDAC patients and six autoimmune pancreatitis (AIP) patients to be used as a control. EV proteins were identified using nanoLC-MS/MS. RESULTS: Intact EVs approximately 200 nm in diameter were detected from EUS-FNA samples. We identified 2059 or 1032 EV proteins in PDAC or AIP, respectively, and 1071 EV proteins were detected only in PDAC. One hundred and fifty-three EV proteins were significantly different between PDAC and AIP: 64 proteins were down-regulated in PDAC whereas 89 EV proteins were up-regulated in PDAC including mucins, keratins, Ras-related proteins, and olfactomedin-4, which proteins have been reported to be elevated in PDAC tissue/blood, or cultured pancreatic cancer cell lines. Notably, in the 89 up-regulated PDAC EV proteins we identified novel proteins including ADP-ribosylation factor 3, CD55, pyruvate kinase, and lipopolysaccharide-induced tumor necrosis factor. Out of 89 proteins, a total of 13 proteins including Ras-related proteins were significantly elevated in PDAC stages II-IV compared to PDAC stage I, including Ras-related proteins, moesin, and CD55. CONCLUSIONS: The EV proteins obtained from EUS-FNA samples contain a PDAC-specific protein barcode. The EV proteins identified from EUS-FNA samples include promising biomarkers for the diagnosis and clinical staging of PDAC.

Accuracy of carbohydrate-deficient transferrin as a biomarker of chronic alcohol abuse during treatment for alcoholism.

AIM: Clinical evaluations are generally used to verify the effectiveness of detoxification treatments for alcohol dependence, but new objective biomarkers are essential for accurate diagnosis. We aim to assess the accuracy of carbohydrate-deficient transferrin (%CDT) in a cohort of Japanese patients admitted to a psychiatric hospital specializing in alcohol dependence. In addition, we investigated the kinetics of %CDT during alcohol moderation or cessation. METHODS: The study cohort consisted of 126 alcohol-dependent patients. The levels of serum %CDT were assessed by the N Latex CDT direct immunonephelometric assay. RESULTS: Alcohol consumption was significantly correlated with %CDT. The only independent predictive factor of alcohol consumption was %CDT, with glutamyltranspeptidase (GGT) and albumin-bilirubin score proving insufficient. The cut-off value of %CDT was 1.9% with high sensitivity and specificity in detecting alcohol abstinence beyond 30 days (68.6% sensitivity, 91.8% specificity) and excessive alcohol drinking (77.9% sensitivity, 77.1% specificity). The %CDT levels were significantly decreased at 30 days of abstinence when compared with baseline. Notably, %CDT values were significantly changed even in the light alcohol drinking cohort (p = 0.0009), whereas GGT levels were not significantly changed. CONCLUSIONS: Our results indicate that %CDT is an accurate and specific biomarker of alcohol consumption and is useful in detecting alcohol abstinence even in a low alcohol intake patient cohort. These results suggest that %CDT could be a useful objective biomarker of chronic alcohol abuse during clinical treatment for alcoholism.

Clinical utility of endoscopic submucosal dissection using the pocket-creation method with a HookKnife and preoperative evaluation by endoscopic ultrasonography for the treatment of rectal neuroendocrine tumors.

BACKGROUND: Various endoscopic methods have been developed to remove small rectal neuroendocrine tumors (NETs). This study aimed to evaluate the clinical utility of endoscopic submucosal dissection using the pocket-creation method (ESD-PCM) with a HookKnife, following preoperative evaluation by endoscopic ultrasonography (EUS), for the treatment of rectal NETs. METHODS: We analyzed retrospectively consecutive patients who underwent ESD-PCM with a HookKnife for the removal of rectal NETs, with a size less than 10 mm, at Mie University Hospital between June 2015 and December 2019. All the rectal NETs were resected by ESD-PCM with a HookKnife. The R0 resection rate, procedure time, adverse event rate, diagnostic accuracy of tumor size and invasion depth evaluated by preoperative EUS, and follow-up outcome were evaluated retrospectively. RESULTS: The study group comprised 12 patients with 12 resected lesions. The median tumor size of the resected specimens was 5 mm and the size and invasion depth of each tumor was approximately equal to that predicted by preoperative EUS. R0 resection was achieved in all cases, without adverse events. The median procedure time was 50.5 min, which did not differ from previous studies. No recurrence was observed during the median follow-up period of 34.4 months (range, 5.2-60.0 months). CONCLUSIONS: ESD-PCM with a HookKnife provides a favorable clinical utility for removing rectal NETs, with high R0 resection rate and good follow-up outcome. In addition, EUS is useful for evaluating preoperatively the size and invasion depth of rectal NETs.

Update on blood-based biomarkers for chronic liver diseases prognosis: Literature review and institutional experience.

Liver cirrhosis is the final stage of chronic liver disease (CLD) and is associated with high morbidity and mortality. Various complications such as portal hypertension, ascites retention, hepatic encephalopathy, and hepatorenal syndrome deeply affect patient outcome. The most common tools to predict the outcome of a CLD patient include the following: assessing severity of portal hypertension; scoring systems such as the model of end-stage liver disease and Child-Pugh score and blood biomarkers related to complications and/or survival rate. In this article, we summarize recent studies of noninvasive markers for predicting impending complications related to CLD and discuss the clinical value of currently available blood biomarkers based on evidence from the literature. In addition, noninvasive blood biomarker assays for different prognostic functions were validated on 113 liver cirrhosis patients at our institution using Kaplan-Meier curve analysis to confirm that these markers can satisfactorily predict CLD-related patient death.

Serum Copeptin and Zinc-α2-glycoprotein Levels Are Novel Biomarkers of Tolvaptan Treatment in Decompensated Cirrhotic Patients with Ascites.

Objective The efficacy of tolvaptan, an orally active vasopressin V2-receptor antagonist, has recently been reported in patients with massive ascites unresponsive to conventional diuretics. However, the effect of tolvaptan varies among patients. Recently, the prognostic role of the tolvaptan response in cases of decompensated liver cirrhosis (LC) has been attracting increasing attention. Using serum copeptin (vasopressin precursor), zinc-α2-glycoprotein (ZAG), cystatin C (renal biomarker), neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP), we explored which factors portend a good response to tolvaptan in LC patients with ascites. Methods We enrolled 113 LC patients and divided them into the tolvaptan treatment group and non-treatment group. Tolvaptan (3.75 or 7.5 mg/day) was administrated to 38 LC patients with ascites, and a follow-up assessment was performed after a 7-day tolvaptan treatment regimen. Results We determined the predictive ability for kidney and/or liver damage of serum copeptin, ZAG, cystatin C, NGAL and L-FABP levels in all patients. After 7-day tolvaptan treatment, 19 patients had lost more than 1.5 kg of body weight (Responders), while 19 showed no marked change in their body weight (Non-responders). Basal blood urea nitrogen (BUN) (p=0.0014), serum copeptin (p=0.0265) and serum ZAG levels (p=0.0142) were significantly higher in the Non-responders than in the Responders. BUN (odds ratio 7.43, p=0.0306), copeptin (odds ratio 9.12, p=0.0136) and ZAG (odds ratio 7.43, p=0.0306) were determined to be predictive factors of drug responsiveness using a multivariate logistic regression analysis. Conclusion Serum BUN, copeptin and ZAG levels predict the patient response to tolvaptan, even when measured prior to treatment.

A novel noninvasive formula for predicting cirrhosis in patients with chronic hepatitis C.

Evaluating liver fibrosis is crucial for disease severity assessment, treatment decisions, and hepatocarcinogenic risk prediction among patients with chronic hepatitis C. In this retrospective multicenter study, we aimed to construct a novel model formula to predict cirrhosis. A total of 749 patients were randomly allocated to training and validation sets at a ratio of 2:1. Liver stiffness measurement (LSM) was made via transient elastography using FibroScan. Patients with LSM ≥12.5 kPa were regarded as having cirrhosis. The best model formula for predicting cirrhosis was constructed based on factors significantly and independently associated with LSM (≥12.5 kPa) using multivariate regression analysis. Among the 749 patients, 198 (26.4%) had LSM ≥12.5 kPa. In the training set, multivariate analysis identified logarithm natural (ln) type IV collagen 7S, ln hyaluronic acid, and ln Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA+-Mac-2 BP) as the factors that were significantly and independently associated with LSM ≥12.5 kPa. Thus, the formula was constructed as follows: score = -6.154 + 1.166 × ln type IV collagen 7S + 0.526 × ln hyaluronic acid + 1.069 × WFA+-Mac-2 BP. The novel formula yielded the highest area under the curve (0.882; optimal cutoff, -0.381), specificity (81.5%), positive predictive values (62.6%), and predictive accuracy (81.6%) for predicting LSM ≥12.5 kPa among fibrosis markers and indices. These results were almost similar to those in the validated set, indicating the reproducibility and validity of the novel formula. The novel formula scores were significantly, strongly, and positively correlated with LSM values in both the training and validation data sets (correlation coefficient, 0.721 and 0.762; p = 2.67 × 10-81 and 1.88 × 10-48, respectively). In conclusion, the novel formula was highly capable of diagnosing cirrhosis in patients with chronic hepatitis C and exhibited better diagnostic performance compared to conventional fibrosis markers and indices.

Utility of the narrow-band imaging international colorectal endoscopic classification for optical diagnosis of colorectal polyp histology in clinical practice: a retrospective study.

BACKGROUND: Narrow-band imaging (NBI) highlights the surface structures and vessels of colorectal polyps and is useful for determining the polyp histology. The narrow-band imaging international colorectal endoscopic (NICE) classification is a diagnostic tool for determining colorectal polyp histology based on NBI without optical magnification. In this study, we aimed to investigate the value of each type of the NICE classification for determining colorectal polyp histology using endoscopy data accumulated in a clinical setting. METHODS: Endoscopy data for 534 colorectal polyps (316 patients) treated at our facility were retrospectively analyzed. First, we investigated the diagnostic performance of each type of the NICE classification for the optical diagnosis of colorectal polyp histology. The procedures were performed by experienced endoscopists using high-definition colonoscopy without optical magnification. Second, inter-observer and intra-observer agreements were assessed after providing experts and non-experts with a short lecture on the NICE classification. Using 50 fine NBI images of colorectal polyps without optical magnification, the inter-observer and intra-observer agreements between five experts and five non-experts were assessed. RESULTS: The sensitivity, specificity, and accuracy values were 86.0%, 99.6%, and 98.5% for NICE type 1 lesions; 99.2%, 85.2%, and 97.8% for NICE type 2 lesions; and 81.8%, 99.6%, and 99.3% for NICE type 3 lesions, respectively. The inter-observer and intra-observer agreements ranged from substantial to excellent for both experts and non-experts. CONCLUSIONS: The NICE classification had good diagnostic ability in terms of determining the polyp histology and demonstrated a high level of reproducibility among experts and non-experts. Thus, the NICE classification is a useful clinical tool that can be used without optical magnification.

Efficacy of a small-caliber colonoscope for pain in female patients during unsedated colonoscopy: a randomized controlled study.

Background and study aims Female sex has been identified as a factor increasing patients' pain during colonoscopy. The aim of this randomized controlled study was to investigate the efficacy of a small-caliber colonoscope, PCF-PQ260 L, for limiting pain in women during unsedated colonoscopy. Patients and methods Women who underwent unsedated colonoscopy were randomly allocated to either the small-caliber or standard colonoscope group. The primary outcome was overall pain and secondary outcomes were maximum pain and procedural measures. In addition, the effects of colonoscope type were analysed using analysis of covariance and logistic regression with adjustment for stratification factors, age and prior abdomino-pelvic surgery. Results A total of 220 women were randomly assigned to the small-caliber (n = 110) or standard (n = 110) colonoscope groups. Overall and maximum pain scores were significantly lower in the small-caliber colonoscope group than the standard colonoscope group (overall pain, 20.0 vs. 32.4, P < 0.0001; maximum pain, 28.9 vs. 47.2, P < 0.0001). The small-caliber colonoscope group achieved a superior cecal intubation rate (99 % vs. 93 %, P = 0.035). The rate of patient acceptance of unsedated colonoscopy in the future was higher in the small-caliber colonoscope group than in the standard colonoscope group (98 % vs. 87 %, P = 0.003). In addition, the small-caliber colonoscope was superior with respect to reducing pain and improving the rate of patient acceptance of unsedated colonoscopy with adjustment. Conclusions This study demonstrates the efficacy of the small-caliber colonoscope for reducing pain in women and improving their rate of acceptance of unsedated colonoscopy.

Protein Composition of Circulating Extracellular Vesicles Immediately Changed by Particular Short Time of High-Intensity Interval Training Exercise.

INTRODUCTION/PURPOSE: High-intensity interval training (HIIT) promotes various biological processes and metabolic effects in multiple organs, but the role of extracellular vesicles (EVs) released from a variety of cells is not fully understood during HIIT exercise (HIIT-Ex). We investigated the changes in circulating number and proteomic profile of EVs to assess the effect of HIIT-Ex. METHODS: Seventeen young men (median age, 20 years) were enrolled in the study. Total duration of the HIIT-Ex was 4 min. Blood samples were collected from before HIIT-Ex (pre-HIIT-Ex), at the immediate conclusion of HIIT-Ex (T0), at 30 min (T30), and at 120 min after HIIT-Ex. The pulse rate and systolic blood pressure were measured. Circulating EVs were characterized, and EV proteins were detected via nano liquid chromatography tandem mass spectrometry. RESULTS: The pulse rate and systolic blood pressure at T0 to pre-HIIT-Ex were significantly higher. Circulating EV number was significantly altered throughout the HIIT-Ex, and the source of circulating EVs included skeletal muscle, hepatocytes, and adipose tissue. Proteomic analysis identified a total of 558 proteins within isolated circulating EVs from pre-HIIT-Ex, T0, and T30. Twenty proteins in total were significantly changed at pre-HIIT-Ex, T0, and T30 and are involved in a variety of pathways, such as activation of coagulation cascades, cellular oxidant detoxification, and correction of acid-base imbalance. Catalase and peroxiredoxin II were increased at T0. CONCLUSION: The circulating EV composition can be immediately changed by particularly a short time of HIIT-Ex, indicating that EVs may intercommunicate across various organs rapidly in response to HIIT-Ex.

Rifaximin ameliorates intestinal inflammation in cirrhotic patients with hepatic encephalopathy.

Rifaximin (RFX) treatment can attenuate not only hyperammonemia but also Enterococcus faecalis translocation and 10-7G values, suggesting that RFX treatment may improve intestinal inflammation and result in better overall survival.

Increased Reflux Esophagitis after Helicobacter pylori Eradication Therapy in Cases Undergoing Endoscopic Submucosal Dissection for Early Gastric Cancer.

BACKGROUND: The role of Helicobacter pylori in the pathogenesis of reflux esophagitis is controversial. This study investigated the frequency of reflux esophagitis before and after H. pylori eradication in patients having endoscopic submucosal dissection for early gastric cancer. METHODS: This study included 160 patients that fulfilled the study's criteria. Endoscopy was performed before and after H. pylori eradication, and reflux esophagitis was evaluated during the follow-up period. RESULTS: Seropositivity for H. pylori in patients with early gastric cancer was 68.8%, 101 of them received eradication therapy. During the follow-up period, the incidence of reflux esophagitis increased from 3.1% to 18.8% in the successful eradication group but no case of reflux esophagitis was observed in the failed eradication group. The univariate and multivariate analyses showed a significant correlation between successful H. pylori eradication rate and the development of reflux esophagitis. CONCLUSIONS: This study demonstrated that a successful H. pylori eradication therapy is a risk factor for newly developed reflux esophagitis in patients with endoscopic submucosal dissection for early gastric cancer.

Branched-chain amino acids protect the liver from cirrhotic injury via suppression of activation of lipopolysaccharide-binding protein, toll-like receptor 4, and signal transducer and activator of transcription 3, as well as Enterococcus faecalis translocation.

OBJECTIVES: Branched-chain amino acids (BCAAs) are used as nutritional support and for improving prognosis in liver cirrhosis. Here we investigate the molecular mechanisms of BCAA treatment and liver damage focused on pathways related to lipopolysaccharide-binding protein (LBP). METHODS: Serum LBP levels were measured in cirrhotic patients and in cirrhotic rats treated with BCAA to examine the correlation between liver function and survival. In cirrhotic rats, liver damage, Enterococcus faecalis translocation, serum capsular polysaccharide, and intestinal tight junction levels were assessed. Damaged HepG2 cells were cultured with BCAA-supplemented, BCAA-deficient, or control amino acid medium, followed by examination of LBP expression. RESULTS: Serum LBP levels were significantly increased in deceased patients individuals with liver cirrhosis. The survival rate in patients with lower serum LBP (<3.48 µg/mL) was significantly improved. In BCAA-treated rat liver samples, protein expression of LBP, toll-like receptor 4 (TLR4), and phosphorylated signal transduction and activator of transcription 3 (STAT3) were significantly reduced. Also in BCAA-treated rats, intestinal zonula occludens gene expression was increased, whereas hepatic translocation of E. faecalis and serum capsular polysaccharide levels were reduced. In damaged HepG2 cells, lipopolysaccharide-induced elevation of LBP expression was rapidly and strongly repressed in BCAA-enriched medium. CONCLUSIONS: Serum LBP level is a prognostic biomarker in liver cirrhosis. BCAA treatment reduced translocation of E. faecalis through intestinal tight junction recovery and reduced LBP expression in the liver, which repressed activation of LBP, toll-like receptor 4, and signal transduction and activator of transcription 3. Our findings suggest that BCAA supplementation protects the liver from damage via multiple pathways.