Cooperative interaction of MUC1 with the HGF/c-Met pathway during hepatocarcinogenesis

ABSTRACT: BACKGROUND: Hepatocyte growth factor (HGF) induced c-Met activation is known as the main stimulus for hepatocyte proliferation and is essential for liver development and regeneration. Activation of HGF/c-Met signaling has been correlated with aggressive phenotype and poor prognosis in hepatocellular carcinoma (HCC). MUC1 is a transmembrane mucin, whose over-expression is reported in most cancers. Many of the oncogenic effects of MUC1 are believed to occur through the interaction of MUC1 with signaling molecules. To clarify the role of MUC1 in HGF/c-Met signaling, we determined whether MUC1 and c-Met interact cooperatively and what their role(s) is in hepatocarcinogenesis. RESULTS: MUC1 and c-Met over-expression levels were determined in highly motile and invasive, mesenchymal-like HCC cell lines, and in serial sections of cirrhotic and HCC tissues, and these levels were compared to those in normal liver tissues. Co-expression of both c-Met and MUC1 was found to be associated with the differentiation status of HCC. We further demonstrated an interaction between c-Met and MUC1 in HCC cells. HGF-induced c-Met phosphorylation decreased this interaction, and down-regulated MUC1 expression. Inhibition of c-Met activation restored HGF-mediated MUC1 down-regulation, and decreased the migratory and invasive abilities of HCC cells via inhibition of beta-catenin activation and c-Myc expression. In contrast, siRNA silencing of MUC1 increased HGF-induced c-Met activation and HGF-induced cell motility and invasion. CONCLUSIONS: These findings indicate that the crosstalk between MUC1 and c-Met in HCC could provide an advantage for invasion to HCC cells through the beta-catenin/c-Myc pathway. Thus, MUC1 and c-Met could serve as potential therapeutic targets in HCC.     

Disinfection of artificially contaminated Resilon cones with chlorhexidine and sodium hypochlorite at different time exposures.

OBJECTIVE: The aim of this study was to evaluate the efficiency of chlorhexidine (CHX) and sodium hypochlorite (NaOCl) solutions on Resilon cones that were artificially contaminated with microbial samples of Enterococcus faecalis or Candida albicans at various concentrations and time exposures. STUDY DESIGN: Resilon cones artificially contaminated with E faecalis or C albicans were left in contact with 1% NaOCl, 5% NaOCl, and 2% CHX disinfecting solutions for 1 and 5 minutes. The cones were then individually transferred to the test tubes, which contained 10 mL of thioglycollate media, and were incubated at 37 degrees C for 7 days. The antimicrobial activities of tested agents were determined by microbial growth. RESULTS: All of the Resilon cones contaminated with E faecalis or C albicans could be disinfected with 1% and 5% NaOCl for 1 and 5 minutes and with 2% CHX for 5 minutes. Three of 7 Resilon cones contaminated with E faecalis and 1 of 7 Resilon cones contaminated with C albicans could not be disinfected with 2% CHX at 1 minute of treatment. CONCLUSIONS: In conclusion, these results demonstrated that 1% and 5% NaOCl solutions are effective agents for disinfecting Resilon cones in 1- or 5-minute treatments. Two percent CHX was only effective after 5 minutes of treatment.     

Role of Melatonin in Reducing Water Avoidance Stress-Induced Degeneration of the Liver

Melatonin, a pineal secretory product, is a potent scavenger of a variety of free radicals. We investigated the role of melatonin on water avoidance stress (WAS)–induced degenerations of the liver parenchyme. Wistar albino rats were exposed to acute WAS (aWAS group) or chronic WAS (cWAS group). Before exposing animals to acute (aWAS + mel group) or chronic WAS (cWAS + mel group), 10 mg/kg melatonin was injected i.p. The liver samples were investigated under light and transmission electron microscope. Malondialdehyde (MDA) and glutathione (GSH) levels were also determined. Prominent vascular congestion and dilated sinusoids, activated Kupffer cells with prominent morphology, dilated granular endoplasmic reticulum membranes, and focal picnotic nuclei were observed in the aWAS group; these morphological changes were severe in the cWAS group. MDA level was increased and GSH level was decreased significantly in the cWAS group. The morphology of liver parenchme in both the aWAS + mel and the cWAS + mel group showed that melatonin significantly reduced the degeneration in liver; besides, a significant decrease in MDA and an increase in GSH levels were observed in the cWAS + mel group. Based on the results, melatonin treatment significantly prevented WAS-induced morphological and biochemical changes in liver parenchyma.     

Blood–brain barrier leakage and perivascular collagen accumulation precede microvessel rarefaction and memory impairment in a chronic hypertension animal model

Metabolic Brain Disease - Hypertension (HT) is one of the main causes of vascular dementia, lead to cognitive decline. Here, we investigated the relationship between cerebral microvessels,...     

Effects of normobaric oxygen and melatonin on reperfusion injury: role of cerebral microcirculation

In order to protect the brain before an irreversible injury occurs, penumbral oxygenation is the primary goal of current acute ischemic stroke treatment. However, hyperoxia treatment remains controversial due to the risk of free radical generation and vasoconstriction. Melatonin is a highly potent free radical scavenger that protects against ischemic stroke. Considering its anti-oxidant activity, we hypothesized that melatonin may augment the survival-promoting action of normobaric oxygen (NBO) and prevent brain infarction. Herein, we exposed mice to 30 or 90 min of intraluminal middle cerebral artery occlusion (MCAo) and evaluated the effects of NBO (70% or 100% over 90 min), administered either alone or in combination with melatonin (4 mg/kg, i.p.), on disseminate neuronal injury, neurological deficits, infarct volume, blood-brain barrier (BBB) permeability, cerebral blood flow (CBF) and cell signaling. Both NBO and particularly melatonin alone reduced neuronal injury, neurological deficits, infarct volume and BBB permeability, and increased post-ischemic CBF, evaluated by laser speckle imaging (LSI). They also improved CBF significantly in the ischemic- core and penumbra, which was associated with reduced IgG extravasation, DNA fragmentation, infarct volume, brain swelling and neurological scores. Levels of phosphorylated Akt, anti-apoptotic Bcl-xL, pro-apoptotic Bax and endothelial nitric oxide synthase (NOS) were re-regulated after combined oxygen and melatonin delivery, whereas neuronal and inducible NOS, which were increased by oxygen treatment, were not influenced by melatonin. Our present data suggest that melatonin and NBO are promising approaches for the treatment of acute-ischemic stroke, which encourage proof-of-concept studies in human stroke patients.     

Human herpesvirus‐6 viremia is not associated with poor clinical outcomes in children following allogeneic hematopoietic cell transplantation

HHV‐6 is an evolving pathogen in the field of AlloHCT. However, the impact of HHV‐6 on AlloHCT outcomes remains to be elucidated. We studied the incidence and clinical impact of HHV‐6 viremia in children following AlloHCT. One hundred consecutive children were monitored weekly by plasma PCR for the first 180 days following AlloHCT for HHV‐6, CMV, EBV, and ADV. HHV‐6 viremia was defined as plasma PCR >1000 viral copies/mL. The median age was nine yr. Following AlloHCT, 19% (95% CI 11.3–26.7%) of patients had HHV‐6 viremia, with the highest incidence of reactivation (14/19, 73%) occurring during day +15‐day +98. The proportion of platelet engraftment by day +180 was lower in patients with HHV‐6 viremia (58%) than in those without HHV‐6 viremia (82%), p = 0.028. Delay in neutrophil and platelet engraftment was not associated with HHV‐6 viremia in multivariate analysis. Similarly, HHV‐6 viremia was not associated with TRM in multivariate analysis (p = 0.15). In summary, HHV‐6 viremia is prevalent in pediatric AlloHCT recipients. Based on our study results, we recommend that HHV‐6 PCR should only be performed on clinical suspicion.