2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) promotes mouse hepatocarcinogenesis by activating transforming growth factor-β and Wnt/β-catenin signaling pathways

The purposes of the present study were to investigate the modifying effects of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a genotoxic carcinogen produced during cooking of protein-rich foods, and elucidate underlying mechanisms in a two-stage hepatocarcinogenesis mice model. Six-week-old B6C3F1 mice were subjected to two-thirds partial hepatectomy at the beginning of the study, followed by an intraperitoneal injection of diethylnitrosamine on day 1. Starting 1 week later, they were fed diets containing IQ at doses of 30, 100, or 300 ppm for 39 weeks. A dose-dependent trend for increase in eosinophilic altered foci as well as eosinophilic hepatocellular adenomas was observed, along with significant elevation in the incidence of hepatocellular carcinomas in the 100- and 300-ppm IQ groups as compared with initiation control group. Furthermore, IQ elevated the protein expression levels of Wnt1, transforming growth factor-β (TGF-β), TGF-β receptors 1 and 2 (TβR1 and TβR2), and phosphorylated c-Jun (p-c-Jun), while suppressing those of E-cadherin and p21(WAF1/Cip1). Moreover, translocation of β-catenin to the nuclei as well as upregulated nuclear expression of c-Myc and cyclin D1, which are downstream targets of β-catenin and p-c-Jun, were detected at 100 and 300 ppm. These findings suggest that IQ exerts dose-dependent promoting effects on mice hepatocarcinogenesis by activating TGF-β and Wnt/β-catenin signaling pathways and inhibiting cell adhesion.     

CYP2C76 non-synonymous variants in cynomolgus and rhesus macaques

Cynomolgus CYP2C76, not orthologous to any human cytochrome P450, partly accounts for species differences in drug metabolism between cynomolgus macaques and humans. To discover the CYP2C76 variants, we previously surveyed cynomolgus macaque genomes and found several non-synonymous variants, including a null allele. However, the analysis was limited to cynomolgus macaques, and the number of genomes was relatively small. In this study, therefore, further screening was conducted using 74 cynomolgus and 30 rhesus macaques. A total of 18 non-synonymous variants was found, among which 7 were in substrate recognition sites, important for protein function, and 14 (74%) were shared by both macaque lineages. In cynomolgus macaques, 3 (16%) non-synonymous variants were unique to Indochinese animals, whereas all the variants found in Indonesian animals were shared by Indochinese animals. Among the 18 variants, as compared with the wild type, in progesterone 16α-hydroxylation, L65F, M310L, and N364S variants showed lower metabolic activity and lower intrinsic clearance by kinetic analysis. Molecular modeling indicated that the reduced catalytic activity of the L65F variant in progesterone 16α-hydroxylation possibly resulted from a longer distance of progesterone to the heme in the active site of the CYP2C76 protein. L65F, M310L, and N364S variants might partly influence inter-animal variations of CYP2C76 metabolic activities.     

Inhibition of Na⁺-H⁺ exchange as a mechanism of rapid cardioprotection by resveratrol

BACKGROUND AND PURPOSE Resveratrol is a polyphenol abundantly found in grape skin and red wine. In the present study, we investigated whether resveratrol exerts protective effects against cardiac ischaemia/reperfusion and also explored its mechanisms. EXPERIMENTAL APPROACH Infarct size and functional recovery in rat isolated perfused hearts subjected to no-flow global ischaemia followed by reperfusion were measured. Cultured neonatal rat cardiomyocytes were exposed to H(2)O(2) (100 μmol·L(-1)) to induce cell injury. Intracellular ion concentrations were measured using specific dyes. Western blotting was used to quantify protein expression levels. KEY RESULTS In rat isolated perfused hearts, treatment with resveratrol (20 and 100 μmol·L(-1)) 15 min before ischaemia considerably improved left ventricular functional recovery and infarct size. In cultured neonatal rat cardiomyocytes, resveratrol significantly attenuated the increase in reactive oxygen species (ROS) and loss of mitochondrial inner membrane potential. Resveratrol also suppressed the increase in intracellular concentrations of Na(+) ([Na(+)](i)) and Ca(2+) ([Ca(2+)](i)) after H(2)O(2) application; however, it did not suppress the ouabain-induced [Ca(2+) ](i) increase. By measuring changes in intracellular pH recovery after acidification, we also confirmed that acid-induced activation of the Na(+)-H(+) exchanger (NHE) was prevented by pretreatment with resveratrol. Furthermore, resveratrol inhibited the H(2)O(2)-induced translocation of PKC-α from the cytosol to the cell membrane; this translocation is believed to activate NHE. CONCLUSION AND IMPLICATIONS Resveratrol exerts cardioprotection by reducing ROS and preserving mitochondrial function. The PKC-α-dependent inhibition of NHE and subsequent attenuation of [Ca(2+)](i) overload may be a cardioprotective mechanism.     

Antifungal susceptibilities of Aspergillus fumigatus clinical isolates obtained in Nagasaki, Japan

We investigated the triazole, amphotericin B, and micafungin susceptibilities of 196 A. fumigatus clinical isolates in Nagasaki, Japan. The percentages of non-wild-type (non-WT) isolates for which MICs of itraconazole, posaconazole, and voriconazole were above the ECV were 7.1%, 2.6%, and 4.1%, respectively. A G54 mutation in cyp51A was detected in 64.2% (9/14 isolates) and 100% (5/5 isolates) of non-WT isolates for itraconazole and posaconazole, respectively. Amphotericin B MICs of ≥2 μg/ml and micafungin minimum effective concentrations (MECs) of ≥16 μg/ml were recorded for two and one isolates, respectively.     

Pathophysiology of functional dyspepsia

Functional dyspepsia is a highly prevalent and heterogeneous disorder. Functional dyspepsia involves many pathogenic factors, such as gastric motility disorders, visceral hypersensitivity, psychological factors, Helicobacter pylori infection, and excessive gastric acid secretion. The present article provides an overview of pathogenetic factors and pathophysiologic mechanisms.     

MT1-MMP plays an important role in an invasive activity of malignant pleural mesothelioma cell

Malignant pleural mesothelioma (MPM) has a poor prognosis and is a treatment resistant tumor, which is increasing in frequency throughout the world. The poor prognosis is due to the aggressive local invasiveness rather than distant metastasis. In this study, we established a cell line of malignant mesothelioma from a clinical specimen and assessed the relationship between the expression of MT1-MMP and the invasion ability of that line, as well as the cultured cells of several other lines, using the simple method that we created previously. We established a cell line from a clinical specimen from a patient with malignant mesothelioma. We assessed the invasive activities of MPM cells in an easy-to-prepare double-layered collagen gel hemisphere (DL-CGH) system that enabled us to visualize cell movements during invasion. To assess the role of MT1-MMP in the invasive activity of MPM cells, we knocked down its expression by RNA interference (RNAi). The invasion assay with DL-CGH revealed that a high expression of MT1-MMP in MPM cells was associated with aggressive invasive activity. The RNAi of MT1-MMP indicated that the expression of MT1-MMP might have a crucial role in the invasiveness of MPM cells. The MT1-MMP expression in MPM cells is related to their capacity for locally aggressive spreading into the pleura and the surrounding tissues, and MT1-MMP should be a suitable molecular target for the suppression of the invasiveness of MPM.     

A pilot trial of body weight reduction for nonalcoholic fatty liver disease with a home-based lifestyle modification intervention delivered in collaboration with interdisciplinary medical staff

Background

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome. The aim of this study was to evaluate a 6-month home-based lifestyle modification intervention delivered in collaboration with physicians, hygienists, registered dietitians, and nurses.

Methods

Outpatients with NAFLD diagnosed by abdominal ultrasonography were eligible for this study. Abdominal computed tomography (CT) scan evaluated liver fat deposition by the liver–spleen ratio (L/S ratio) and visceral fat accumulation as the visceral fat area (VFA; cm²). During the 6-month home-based lifestyle modification intervention, each patient was examined by physicians, nurses, hygienists, and registered dietitians, who provided individualized advice to the patients. Patients recorded their daily weight for self-control of weight with recommended diet and exercise regimens.

Results

Sixty-seven NAFLD patients were enrolled in this study and 22 patients (32.8%) completed the 6-month intervention. Nineteen of the 22 patients achieved significant improvements in body weight, body mass index (BMI), waist circumference, VFA, L/S ratio, and systolic blood pressure, with improved laboratory data. Overall, 39 patients withdrew from the intervention. The mean age of the patients who withdrew was 50.0 ± 11.0 years, which was significantly younger than that of the patients who were followed up (60.1 ± 10.1 years; P < 0.01).

Conclusions

The reduction in body weight achieved by NAFLD patients during the 6-month intervention was associated with improved fat deposition and liver function. This intervention offers a practical approach for treating a large number of NAFLD patients with lifestyle modification therapy.     

Clinical impact of different cut-off values in high-resolution manometry systems on diagnosing esophageal motility disorders

Journal of Gastroenterology - The values of the parameters in the Chicago classification measured by a high-resolution manometry (HRM) system with the Unisensor catheter (Starlet) are significantly...     

Epidemiological Survey of Patients With Hemodialysis Complicated by Hepatitis C in Japan

Nowadays, interferon‐free direct‐acting antiviral (DAA) treatment is the standard of care for chronic hepatitis C patients. Some DAA regimens are highly effective and safe even for those with renal dysfunction/failure including those receiving HD. However, it remains unclear to what extent HD specialists gain knowledge about advances in anti‐hepatitis C virus (HCV) treatment. To clarify the current situation and identify problems in the treatment of HD patients with chronic hepatitis C, we performed a questionnaire survey at 36 HD facilities between June 2016 and September 2017. In a total of 3418 HD patients, 179 (5.2%) were positive for anti‐HCV antibody, and among these patients, 110/125 (88.0%) were positive for serum HCV RNA. Of the latter, only 42/110 (38.2%) patients received antiviral therapy. Moreover, HCV serotyping or genotyping was performed in 23/110 (20.9%) patients. In 26/49 (53.1%) of the remaining 68 untreated patients, “HD specialists do not know any HCV‐specific treatments” and “HD specialists have no opportunity to consult with a hepatologist” were the reasons cited for the lack of anti‐HCV treatment. This epidemiological study found that some HD patients with chronic hepatitis C had not yet received antiviral treatment despite the emergence of DAAs. To overcome such undesirable circumstances, medical cooperation between HD specialists and hepatologists should be required.     

Case of rectal migratin of mesh after TVM (tension-free vaginal mesh) operation

A 64-year-old woman presented with recto-cutaneous fistula after tension-free vaginal mesh reconstruction using polypropylene mesh for pelvic organ prolapse. Eleven months after the operation, an ulcerative lesion with stools smell secretion developed in the left hip. Magnetic resonance imaging and colonoscopy revealed a migration of the left arm of the mesh and a recto-cutaneous fistula. The patient underwent excision of the infected mesh and rectal wall closure together with transient colostomy. After 8 months, colonoscopy revealed a new migration of the mesh in the rectum, which was also removed. The colostomy was closed one year later and rectal erosion has not reccurred since then. The possibility of developing a rare but severe mesh-related complication as presented here should always be kept in mind.