Superiority of Intestinal Adaptation by Hepatocyte Growth Factor in the Jejunum: An Experimental Study in a Short-Bowel Rat Model.

BACKGROUND: We evaluated the effect of recombinant human hepatocyte growth factor (rh-HGF) on intestinal adaptation in a rat model of short-bowel syndrome (SBS). METHODS: Sprague-Dawley rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90 % small bowel resection. The animals were divided into 3 groups: TPN/SBS (control group, n = 7), TPN/SBS/intravenous recombinant human hepatocyte growth factor (HGF) (0.3 mg/kg/day) (HGF group, n = 7), and TPN/SBS/intravenous c-Met inhibitor (0.3 mg/kg/day) (anti-HGF group, n = 5). On day 7, rats were euthanized and histologically evaluated. Serum diamine oxidase (S-DAO) levels were evaluated using an enzyme-linked immunosorbent assay. The nutrient transporter and glucagon-like peptide-2 (GLP-2) receptor expression were evaluated using real-time polymerase chain reaction. RESULTS: The jejunal and ileal villus heights were higher and the S-DAO concentrations significantly higher (p = 0.04) in the HGF group than in the control and anti-HGF groups. The sodium-dependent glucose transporter 1 expression in the HGF group was significantly higher than in the control group and significantly suppressed in the anti-HGF group (p < 0.01). The peptide transporter 1 expression in the jejunum was higher in the HGF group than in the other groups and significantly suppressed in the anti-HGF group (p < 0.01). The GLP-2 receptor expression in the jejunum was higher in the HGF group than the other groups, and it was significantly suppressed in the anti-HGF group (p < 0.01). These jejunal results regarding nutrient transporter an GLP-2 receptor were not found in the ileum. CONCLUSIONS: The administration of rh-HGF appears to be more effective in the jejunum than in the ileum. TYPE OF STUDY: Experimental Research. LEVEL OF EVIDENCE: N/A.

Glycoprotein non-metastatic melanoma protein B expression correlates with the prognosis of acute liver injury/failure.

Background: Glycoprotein non-metastatic melanoma protein B (GPNMB) is expressed in macrophages during recovery from acute liver injury (ALI) in carbon tetrachloride (CCl4)-induced liver injury model mice. In this retrospective study, we assessed whether GPNMB levels in the serum and injured liver correlate with liver injury severity and prognosis in patients with ALI or acute liver failure (ALF). Methods: The study involved 56 patients with ALI or ALF who visited the Kagoshima University Hospital. Serum GPNMB level was measured over time, and the localization, proportion, origin, and phenotype of GPNMB-expressing cells in the injured liver were assessed. Finally, the phenotypes of human monocyte-derived macrophages and peripheral blood mononuclear cells (PBMCs) of patients with ALI and ALF were analyzed. Results: Peak GPNMB levels were significantly higher in patients with ALF and hepatic encephalopathy (HE), as well as in those who underwent liver transplantation or died, than in others. The peak GPNMB level correlated with prothrombin activity, prothrombin time-international normalized ratio, Model for End-stage Liver Disease score, and serum hepatocyte growth factor level. GPNMB was expressed in CD68-positive macrophages, and its level increased with the severity of liver injury. The macrophages showed the same polarization as M2c macrophages induced with interleukin-10 from human monocytes. Moreover, PBMCs from patients with ALF exhibited an immunosuppressive phenotype. Conclusion: We found that GPNMB levels in the serum and injured liver, which increased in patients with ALF, especially in those with HE, correlated with the severity of liver injury and prognosis of ALI and ALF. Moreover, GPNMB-positive macrophages exhibited the M2c phenotype. Our results indicate that persistently high GPNMB levels may be a prognostic marker in patients with ALI and ALF.

Potential mechanisms underlying the effect of hepatocyte growth factor on liver injury in short bowel syndrome model rats.

PURPOSE: The purpose of this study was to investigate the autophagy associated with apoptosis in hepatic damage in the short bowel syndrome rat model. METHODS: SD rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90% small bowel resection. Animals were divided into two groups: TPN plus SBS (Control group) or TPN plus SBS plus intravenous administration of HGF (HGF group). On day 7, the rats were harvested, and hepatocellular injury was evaluated. RESULTS: In an SBS rat model, hepatic steatosis and lobular inflammation were histologically suppressed in the HGF group (p < 0.01). The expression of tumor necrosis factor-α in the HGF group tend to be higher than that in the control group (p = 0.13). The gene expression of transforming Growth Factor-ß in the HGF group was suppressed compared to the control group (p < 0.01). HGF treatment may have an antiapoptotic effect via the intrinsic pathway by caspase 9. Protein expressions of Rubicon (p = 0.03) and p62 (p < 0.01) in the HGF group were found to have increased compared to those in the control group. CONCLUSION: The inhibitory effect of HGF on hepatic steatosis remains unclear, and further studies focusing on the mechanisms of fat accumulation are needed.

Usefulness of the aldehyde breath test for predicting metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharyngeal squamous cell carcinoma.

BACKGROUND: The rate of metachronous recurrence after endoscopic submucosal dissection for early-stage esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma is as high (10-15%). The acetaldehyde breath test may detect acetaldehyde dehydrogenase 2 gene polymorphisms. Therefore, we evaluated its usefulness in assessing metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. METHODS: A total of 76 patients underwent endoscopic submucosal dissection for esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma and were followed up for at least 3 years (non-recurrence group: 52 patients; recurrence group: 24 patients). The risk factors for carcinogenesis were compared between the recurrence and non-recurrence groups, and the acetaldehyde-to-ethanol ratio was assessed. The cutoff acetaldehyde-to-ethanol ratio that correlated with recurrence was established, and the cumulative recurrence rate was evaluated. RESULTS: The recurrence group had a higher acetaldehyde-to-ethanol ratio, daily alcohol consumption, and Lugol-voiding lesion grade than the non-recurrence group in the univariate analysis. The cutoff acetaldehyde-to-ethanol ratio for recurrence was 28.1 based on the receiver operating characteristic curve. The multivariate analysis revealed an acetaldehyde-to-ethanol ratio of > 28.1 and a Lugol-voiding lesion grade associated with carcinogenesis. Patients with an acetaldehyde-to-ethanol ratio of ≥ 28.1 had a significantly high recurrence rate using the Kaplan-Meier method. CONCLUSIONS: The acetaldehyde-to-ethanol ratio detected using the acetaldehyde breath test could be a novel biomarker of metachronous recurrence after endoscopic submucosal dissection in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. TRIAL REGISTRATION NUMBER: UMIN000040615.

Hepatocyte growth factor ameliorates dextran sodium sulfate­induced colitis in a mouse model by altering the phenotype of intestinal macrophages.

Hepatocyte growth factor (HGF) serves key roles in cell motility, proliferation and immunoregulatory functions. However, the effect of HGF on macrophages is unclear. The present study aimed to elucidate the effect of HGF on the phenotypic alterations of intestinal lamina propria mononuclear cells (LPMCs). Colitis was induced in a mouse model using dextran sodium sulfate (DSS). Subsequently, LPMCs were isolated from the mice with chronic colitis and the expression levels of cytokine­encoding genes in the LPMCs were determined. CD11b­positive macrophages isolated from LPMCs were cultured with HGF, and alterations in the levels of M1 or M2 markers were evaluated by reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and flow cytometry. In addition, the cytokine levels were assessed using RT­qPCR and ELISA. HGF shifted the phenotype of macrophages from M1 to M2­like, as determined by increased mRNA expression levels of arginase­1, CD206 and IL­10, and reduced mRNA expression levels of CD86 and IL­6 in mice with DSS­induced colitis. Moreover, HGF could ameliorate DSS­induced colitis owing to its immunosuppressive effect on immune cells. These findings indicated that HGF treatment may not only promote the regeneration of epithelial cells but also lead to tissue repair by phenotypic alteration of M1 macrophages to M2­like macrophages.

A case of acute liver failure due to aggressive natural killer-cell leukemia with a rapid course.

An 87-year-old man consulted a former doctor with a complaint of black stool and was admitted to hospital because of anemia and multiple gastric ulcers. The laboratory findings showed that his hepatobiliary enzyme levels and inflammatory response were elevated. Computed tomography showed hepatosplenomegaly and enlarged intra-abdominal lymph nodes. Two days later, he was transferred to our hospital due to deterioration of his liver function. Since he had low level of consciousness and his ammonia level was high, we diagnosed him with acute liver failure (ALF) with hepatic coma, and started on-line hemodiafiltration. As the cause of ALF, we suspected hepatic involvement of a hematologic tumor because of high lactate dehydrogenase and soluble interleukin-2 receptor levels and large abnormal lymphocyte-like cells in the peripheral blood. Because of his poor general condition, bone marrow and other histological examinations were difficult, and he died on the third day of hospitalization. Pathological autopsy showed marked hepatosplenomegaly and the proliferation of large abnormal lymphocyte-like cells in the bone marrow, liver, spleen, and lymph nodes. Immunostaining revealed aggressive natural killer-cell leukemia (ANKL).We herein report a rare case of the development of ALF with coma due to ANKL with a review of the relevant literature.

Successful Percutaneous Transhepatic Obliteration Plus Sengstaken-Blakemore Tube Combination Therapy for Recurrent Gastroesophageal Variceal Bleeding.

We treated a case of gastroesophageal varices due to decompensated liver cirrhosis associated with Wilson's disease. The varicose veins penetrated the paraesophageal vein. We performed endoscopic variceal ligation (EVL) on the perforating vein and endoscopic injection sclerotherapy distally. However, 5 days after treatment, the patient vomited blood. Esophagogastroduodenoscopy showed bleeding from the ulcer after EVL at the perforating vein. We performed EVL and stopped the bleeding. However, the next day, she vomited blood again and developed hemorrhagic shock. We were able to achieve hemostasis and save the patient's life with combination therapy consisting of percutaneous transhepatic obliteration and Sengstaken-Blakemore tube placement.

Early-phase prothrombin time-international normalized ratio in acute liver injury indicates the timing of therapeutic intervention and predicts prognostic improvement.

AIM: We investigated whether an early-phase prothrombin time-international normalized ratio (PT-INR) is an interventional prognostic indicator for patients with acute liver injury, including acute liver failure. METHODS: This was a multicenter retrospective observational study. We included 595 patients with alanine aminotransferase levels ≥300 U/L due to acute liver injury who were admitted to Kagoshima University Hospital or other collaborative investigation organizations between January 1, 2010, and December 31, 2015. Patients with alanine aminotransferase levels ≥300 U/L and no previous liver disease were defined as having an acute liver injury. Acute liver failure was defined by PT-INR ≥1.5 with or without hepatic encephalopathy in acute liver injury patients. Data were obtained retrospectively from case reports and analyzed. RESULTS: The PT-INR on day 1 was the most accurate independent prognosis predictor in patients with acute liver injury and acute liver failure. On day 1, the transplant-free survival rates were significantly lower in patients with PT-INR ≥1.3. The transplant-free survival rates were also significantly higher in patients with acute liver injury and acute liver failure, in whom the PT-INR had recovered from ≥1.3 on day 1 to <1.3 by day 8. CONCLUSION: Early-phase changes in the PT-INR can predict the prognosis of patients with acute liver injury and acute liver failure. Furthermore, PT-INR ≥1.3 could be an interventional marker, whereas PT-INR <1.3 after 1 week could reflect prognostic improvement.

Clinical Effect of Lenvatinib Re-Administration after Transcatheter Arterial Chemoembolization in Patients with Intermediate Stage Hepatocellular Carcinoma.

The present study clarified the prognosis of intermediate-stage hepatocellular carcinoma (HCC) patients who received lenvatinib (LEN) followed by transcatheter arterial chemoembolization (TACE) on demand. We retrospectively evaluated 88 intermediate-stage HCC patients who received LEN. The median age was 74 (range: 47-92) years old, 67 patients were male, and 82 were classified as Child-Pugh A. LEN was administered until disease progression or discontinuation due to adverse events (AEs). The mean duration of LEN treatment was 7.0 months. The response and disease control rates were 51.1% and 89.8%, respectively. The median progression-free survival and overall survival (OS) after the initiation of LEN were 6.8 months and 29.9 months, respectively. The OS in patients for whom LEN was re-administered after TACE (TACE-LEN) was better than that in patients who received other therapies (e.g., only TACE, TACE-other therapy, or only other therapy) even with propensity score matching (p = 0.008). A Cox proportional hazard analysis showed that TACE-LEN was most strongly associated with the OS (hazard ratio: 0.083, 95% confidence interval: 0.019-0.362, p = 0.001). LEN was administered for approximately 11.1 months after TACE. In intermediate-stage HCC patients who can tolerate LEN without discontinuation due to AEs, TACE-LEN may prolong the prognosis.

A case of autoimmune hepatitis with thymoma and myasthenia gravis.

A 44-year-old woman presented with cough, facial edema, and progressive fatigue. Computed tomography (CT) showed an anterior mediastinal mass, and laboratory findings showed liver injury. She was diagnosed with thymoma and scheduled for thymectomy after radiation and chemotherapy. However, she was referred to our department due to exacerbation of liver injury. Autoimmune hepatitis (AIH) was suspected based on the findings of elevated anti-nuclear antibody and immunoglobulin G levels. Histological findings of a liver biopsy confirmed the diagnosis of AIH. After oral steroid therapy initiation, she had diplopia and ptosis. Five days after steroid treatment, bulbar symptoms, such as nasal voice and dysarthria, appeared. A physical examination and electrophysiological tests confirmed myasthenia gravis (MG), and to prevent MG crisis, immunoadsorption plasmapheresis and tacrolimus were started by the neurologist. MG symptoms and liver damage gradually improved, she was then treated with chemotherapy and radiation for thymoma and underwent thymectomy, now showing no relapse of AIH or MG. We report the first case of MG developing immediately after the introduction of prednisolone for AIH complicated with thymoma.

The preventive effect of recombinant human hepatocyte growth factor for hepatic steatosis in a rat model of short bowel syndrome.

PURPOSE: Short bowel syndrome (SBS) patients require total parenteral nutrition (TPN) following massive small bowel resection (SBR), which may cause intestinal failure-associated liver disease (IFALD), a life-threatening complication. Hepatocyte growth factor (HGF) acts as a potent hepatocyte mitogen with anti inflammatory and antioxidant actions. The present study evaluated the effect of recombinant human HGF (rh-HGF) on SBR and subsequent IFALD using a parentally fed rat model of SBS. METHODS: Rats underwent jugular vein catheterization for continuous TPN and 90% SBR. They were divided into 2 groups: TPN alone (SBS/TPN group: n = 7) or TPN plus the intravenous administration of rh-HGF (0.3 mg/kg/day) (SBS/TPN+HGF group: n = 7). On day 7, their tissues and stool were harvested to evaluate the effects of HGF. RESULTS: Regarding the histological findings, based on the nonalcoholic fatty liver disease (NAFLD) activity score, the SBS/TPN+HGF group showed significantly less hepatic steatosis and inflammatory cell infiltration than the SBS/TPN group (NAFLD activity score, 4.00 ± 1.83 vs. 1.00 ± 0.82; p < 0.01). The SBS/TPN+HGF group showed a higher expression of Farnesoid X receptor in the liver and lower expression of Toll-like receptor 4 in the ileum than the SBS/TPN group. Regarding the composition of the bacterial gut microbiota, Actinobacteria, Bacteroidetes and Proteobacteria were decreased in the SBS/TPN+HGF group compared with the SBS/TPN group. CONCLUSION: In our SBS with TPN rat model, rh-HGF administration had a preventive effect against hepatic steatosis and dysbiosis. rh-HGF may therefore be a potentially effective therapeutic agent for SBS and subsequent IFALD. TYPE OF STUDY: Experimental research.

Features of patients who developed hepatocellular carcinoma after direct-acting antiviral treatment for hepatitis C Virus.

BACKGROUND: The features of hepatitis C virus patients with a sustained virologic response (SVR) who developed hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) therapy are unclear. METHODS: The study population included 1494 DAA-SVR patients without a history of HCC. The cumulative carcinogenesis rate after the end of treatment (EOT) and factors related to HCC were analyzed. RESULTS: Sixty (4.0%) patients developed HCC during a median observation period of 47.6 months. At four years, the cumulative carcinogenesis rate was 4.7%. A Cox proportional hazards analysis showed that age ≥73 years (hazard ratio [HR]: 2.148), male sex (HR: 3.060), hyaluronic acid (HA) ≥75 ng/mL (HR: 3.996), alpha-fetoprotein at EOT (EOT-AFP) ≥5.3 ng/mL (HR: 4.773), and albumin at EOT (EOT-Alb) <3.9 g/dL (HR: 2.305) were associated with HCC development. Especially, EOT-AFP ≥5.3 ng/mL was associated with HCC development after 3 years from EOT (HR: 6.237). Among patients who developed HCC, AFP did not increase in patients with EOT-AFP <5.3 ng/mL at the onset of HCC. Of these 5 factors, EOT-AFP ≥5.3 ng/mL was scored as 2 points; the others were scored as 1 point. The 4-year cumulative carcinogenesis rate for patients with total scores of 0-2, 3-4, and 5-6 points were 0.6%, 11.9%, and 27.1%, respectively (p<0.001). CONCLUSIONS: EOT-AFP ≥5.3 ng/mL is useful for predicting HCC development after an SVR. However, AFP does not increase in patients with EOT-AFP <5.3 ng/mL at the onset of HCC. The combination of EOT-AFP, age, sex, HA, and EOT-Alb is important for predicting carcinogenesis.

Serine palmitoyltransferase long chain subunit 3 is associated with hepatocellular carcinoma in patients with NAFLD.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is continuously increasing, with the proportion of patients with liver carcinogenesis due to non-alcoholic steatohepatitis (NASH) rising accordingly. Although it is important to identify individuals with hepatic carcinogenesis among patients with NAFLD, useful biomarkers have not yet been established. Previously, in a mouse model of diabetes mellitus without genetic modifications, we reported that a high-fat diet increases serine palmitoyltransferase long chain subunit 3 (SPTLC3) expression in liver tissue, accompanied by high frequency of liver carcinogenesis. Serine palmitoyltransferase (SPT) catalyzes the metabolism of fatty acids, particularly sphingolipid synthesis, and SPTLC3 has been identified as its catalytic subunit, but its role in liver disease is unclear. In the present study, the importance of SPTLC3 in NAFLD development was investigated. SPTLC3 mRNA expression was observed in a liver cancer cell line and in liver tissues from patients with NAFLD and liver cancer. In total, 99 patients with NAFLD (66 without hepatocellular carcinoma (HCC) and 33 with HCC were recruited, having been diagnosed by liver biopsy or imaging, along with 6 healthy volunteers (HVs). Serum was collected from patients and HVs, and SPTLC3 level was assessed by ELISA. SPTLC3 expression was higher in non-cancerous compared with that in cancerous liver tissues. Serum SPTLC3 levels were negatively correlated with platelet count and positively correlated with hyaluronic acid levels, suggesting an association with liver fibrosis. Moreover, SPTLC3 levels were significantly higher in the HCC group than in the HV and NAFLD groups. Multivariate analysis of HCC-related factors identified platelets, alanine transferase, albumin and SPTLC3 as independent factors associated with HCC. Furthermore, in patients with other chronic liver diseases (hepatitis B and C, and alcoholic liver disease), no significant differences in serum SPTLC3 levels were observed between patients with or without HCC. Thus, SPTLC3 expression increases specifically with the progression of NAFLD. Overall, the present results indicate that SPTLC3 may be involved in the development of liver carcinogenesis during NAFLD.

The protective effects of hepatocyte growth factor on the intestinal mucosal atrophy induced by total parenteral nutrition in a rat model.

PURPOSE: Total parental nutrition (TPN) causes gastrointestinal mucosal atrophy. The present study investigated the effects of hepatocyte growth factor (HGF) on the intestinal mucosal atrophy induced by TPN. METHODS: Rats underwent jugular vein catheterization and were divided into four groups: oral feeding (OF), TPN alone (TPN), TPN plus low-dose HGF (0.3 mg/kg/day; TPNLH), and TPN plus high-dose HGF (1.0 mg/kg/day; TPNHH). On day 7, rats were euthanized, and the small intestine was harvested and evaluated histologically. The expression of c-MET, a receptor of HGF, and nutrition transporter protein were evaluated using quantitative polymerase chain reaction. RESULTS: The jejunal villus height (VH) and absorptive mucosal surface area in the TPNHH group were significantly higher than in the TPN group (p < 0.05). The VH in the ileum showed the same trend only in the TPNHH group, albeit without statistical significance. The crypt cell proliferation rate (CCPR) of the jejunum in both HGF-treated groups was significantly higher than in the TPN group (p < 0.01). The expression of c-MET and transporter protein in all TPN-treated groups was decreased compared with that in the OF group. CONCLUSION: HGF attenuated TPN-associated intestinal mucosal atrophy by increasing the villus height, which was associated with an increase in CCPR.

Highly sensitive Lens culinaris agglutinin-reactive fraction of α-fetoprotein is a predictive marker for hepatocarcinogenesis in long-term observation of patients with chronic liver disease.

Highly sensitive Lens culinaris agglutinin-reactive fraction of α-fetoprotein (hs-AFP-L3) is a specific marker for hepatocellular carcinoma (HCC) and has been reliable in cases with a low serum α-fetoprotein (AFP) level. However, the biomarkers that contribute to hepatocarcinogenesis during the long-term observation are not yet clear. The present study reported the clinical utility of hs-AFP-L3 in the long-term observation of patients with chronic liver disease. The subjects were 106 patients with chronic liver disease without HCC or a history of HCC treatment and who had been followed for >12 months. hs-AFP-L3 was measured using cryopreserved serum. The factors contributing to hepatocarcinogenesis were examined using univariate and multivariate analyses. The median observation period was 88 months (15-132 months). The cumulative incidence of HCC was 10.5% at 5 years and 19.6% at 10 years. The univariate analysis revealed that age ≥55 years old, platelet count ≤13.1x104/µl, hyaluronic acid ≥80.8 ng/ml, alanine transaminase ≥47 U/l, AFP ≥6.3 ng/ml, hs-AFP-L3 ≥3.5% and des-γ-carboxy prothrombin (DCP) ≥25 mAU/ml were significant factors. In the multivariate analysis, platelet count ≤13.1x104/µl [hazard ratio (HR), 4.966; 95% confidence interval (CI), 1.597-15.437; P=0.006] and hs-AFP-L3 ≥3.5% (HR, 5.450; 95% CI, 1.522-19.512; P=0.009) were extracted as significant factors contributing to hepatocarcinogenesis. In addition, for cases with AFP <20 ng/ml, a multivariate analysis revealed that hs-AFP-L3 ≥4.9% (HR, 11.608; 95% CI, 2.422-55.629; P=0.002) and DCP ≥25 mAU/ml (HR, 3.936; 95% CI, 1.088-14.231; P=0.037) were significant factors contributing to hepatocarcinogenesis. hs-AFP-L3 is a useful marker for predicting hepatocarcinogenesis in the long-term observation of patients with chronic liver disease.

Increased Gene Copy Number of DEFA1A3 Is Associated With the Severity of Ulcerative Colitis.

INTRODUCTION: DEFA1A3 encodes human neutrophil peptides (HNPs) 1-3 and has multiple copy number variations (CNVs). HNPs are associated with innate immunity. Ulcerative colitis (UC), a chronic inflammatory gastrointestinal disorder, is a life-threatening condition, and predictive markers of UC severity are needed. This study investigated the relationship between DEFA1A3 CNV and UC severity. METHODS: This study enrolled 165 patients with UC. The relationship between DEFA1A3 CNV and disease severity was analyzed based on Mayo score, patient characteristics, and treatment methods. In addition, serum and stimulated neutrophil-derived HNP concentrations were also measured in patients with high and low DEFA1A3 CNV. RESULTS: DEFA1A3 CNV was significantly correlated with Mayo score and white blood cell count (R = 0.46, P < 0.0001; R = 0.29, P = 0.003, respectively), and only high copy numbers of DEFA1A3 were independent factors for severe UC (P < 0.001, odds ratio: 1.88, 95% confidence interval, 1.34-2.61). The number of severe UC patients with high DEFA1A3 CNV was significantly greater than those with low CNV. We confirmed the associations between DEFA1A3 and UC severity using a validation cohort. In addition, the HNP concentration in high-copy number patients was significantly higher after neutrophil stimulation than that in low-copy number patients. DISCUSSION: This study demonstrated that there is a correlation between DEFA1A3 copy number and severity in patients with UC. In addition, neutrophils from UC patients with higher DEFA1A3 CNV had high reactivity of secretion of HNPs after stimulation. DEFA1A3 CNV may be a novel severity marker and a potential therapeutic target for UC.

Changes in body composition and low blood urea nitrogen level related to an increase in the prevalence of fatty liver over 20 years: A cross-sectional study.

AIM: Qualitative body composition (BC) change, characterized by the combination of visceral fat gain and muscle loss, is drawing attention as a risk factor for fatty liver (FL). The present study aimed to describe trends in BC change and its association with FL in the Japanese population. METHODS: Data from medical checkups carried out on 56 639 Japanese participants every 5 years from 1997 to 2017 were analyzed. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated using body mass index and body fat percentage. Subjects were divided into two groups according to deviations from the correlation line of FMI and FFMI as the reference: FMI-predominant BC and FFM-dominant BC. Fatty liver was determined using abdominal ultrasonography. RESULTS: The prevalence of FL significantly increased from 27.3% to 42.7% in men and from 18.0% to 25.5% in women. The prevalence of FMI predominance significantly increased from 33.6% to 43.9% in men and from 29.1% to 47.0% in women. Fat mass index predominance was independently associated with FL in men and women (odds ratio: 1.96 and 1.94, respectively). Serum blood urea nitrogen level was inversely associated with FL in men and women (0.958 and 0.961, respectively) and significantly decreased from 15.8 to 14.9 mg/dl in men and from 15.1 to 14.0 mg/dl in women. CONCLUSIONS: Increasing FMI-predominant BC and decreasing serum blood urea nitrogen level could account for the increase in the prevalence of FL over 20 years. We believe that these factors stem from current lifestyle habits in Japan.

The administration of hepatocyte growth factor prevents total parenteral nutrition-induced hepatocellular injury in a rat model.

PURPOSE: Total parenteral nutrition (TPN) sometimes induces parenteral nutrition-associated liver disease (PNALD). Hepatocyte growth factor (HGF) acts as a potent hepatocyte mitogen anti-inflammatory and antioxidant actions. We aimed to evaluate the effect of HGF on PNALD in a rat model of TPN. METHODS: A catheter was placed in the right jugular vein for 7-day continuous TPN. All rats were divided into three groups: TPN alone (TPN group), TPN plus intravenous HGF at 0.3 mg/kg/day [TPN + HGF (low) group], and TPN plus HGF at 1.0 mg/kg/day [TPN + HGF (high) group]. On day 7, livers were harvested and the histology, inflammatory cytokines and apoptosis were evaluated. RESULTS: Histologically, lipid droplets were apparent in the TPN group, but decreased in the TPN + HGF (low) and TPN + HGF (high) groups. The histological nonalcoholic fatty liver disease activity scores in the TPN + HGF (low) and TPN + HGF (high) groups were significantly lower than that in the TPN group (p < 0.01). There were no significant differences in the inflammatory cytokine levels of the three groups. The caspase-9 expression levels in the TPN + HGF (low) and TPN + HGF (high) groups were significantly decreased in comparison to that in the control group (p < 0.05). CONCLUSION: The intravenous administration of HGF attenuated hepatic steatosis induced by 7-day TPN dose dependently.

Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo.

Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn's disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag-/- , Rag-/- mice lacking DR3 in all cell types (Rag-/-Dr3-/-), or Rag-/- mice lacking DR3 only on fibroblasts (Rag-/-Dr3∆Col1a2) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag-/- mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag-/-Dr3-/- demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag-/-, Rag-/-Dr3∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects.

HGF-MET Signaling Shifts M1 Macrophages Toward an M2-Like Phenotype Through PI3K-Mediated Induction of Arginase-1 Expression.

Backgrounds and Aims: Hepatocyte Growth Factor (HGF)-MET signaling is known to promote biological functions such as cell survival, cell motility, and cell proliferation. However, it is unknown if HGF-MET alters the macrophage phenotype. In this study, we aimed to study the effects of HGF-MET signaling on the M1 macrophage phenotype. Methods and Materials: Bone marrow-derived macrophages (BMDMs) isolated from mice were either polarized to an M1 phenotype by IFN-γ and LPS treatment or to an M2 phenotype by IL-4 treatment. Changes in M1 or M2 markers induced by HGF-MET signaling were evaluated. Mechanisms responsible for alternations in the macrophage phenotype and intracellular metabolism were analyzed. Results: c-Met was expressed especially in M1 macrophages polarized by treatment with IFN-γ and LPS. In M1 macrophages, HGF-MET signaling induced the expression of Arg-1 mRNA and secretion of IL-10 and TGF-ß1 and downregulated the mRNA expression of iNOS, TNF-α, and IL-6. In addition, activation of the PI3K pathway and inactivation of NFκB were also observed in M1 macrophages treated with HGF. The increased Arg-1 expression and IL-10 secretion were abrogated by PI3K inhibition, whereas, no changes were observed in TNF-α and IL-6 expression. The inactivation of NFκB was found to be independent of the PI3K pathway. HGF-MET signaling shifted the M1 macrophages to an M2-like phenotype, mainly through PI3K-mediated induction of Arg-1 expression. Finally, HGF-MET signaling also shifted the M1 macrophage intracellular metabolism toward an M2 phenotype, especially with respect to fatty acid metabolism. Conclusion: Our results suggested that HGF treatment not only promotes regeneration in epithelial cells, but also leads to tissue repair by altering M1 macrophages to an M2-like phenotype.