ionophores Besides Arg overexpression our data
Besides Arg2 overexpression, our data revealed that AGEs could decrease eNOS mRNA levels, which is considered a significant cause for attenuated NO production and vasodilation. It was found recently that AGEs significantly reduce eNOS expression levels and NO bioavailability in human carotid artery endothelial ionophores (HCAECs). The same work illustrated that high plasma concentrations of AGEs in diabetic patients could repress eNOS expression and activity in a time- and concentration-dependent manner.
Along with decreased NO bioactivity; one of the major factors contributing to endothelial dysfunction is NO quenching by superoxide. NADPH oxidases 1 and 2 (NOX 1 and 2) produced in the vascular wall lead to the production of reactive oxygen species causing endothelial dysfunction . In contrast, NOX4 protects against vascular dysfunction through hydrogen peroxide generation. Clearly in our study apocynin, a NOX1/2 inhibitor, blocked the AGEs-induced impaired vasorelaxation while AGEs produced no significant effect on Nox4 expression. These findings suggest that AGEs-impaired vasodilation might be through enhancement of NOX1/2 activity whereas it is independent of NOX4, at least at the gene expression level. Ren X et al., found that NOX activity was elevated in HCAECs treated with AGEs which underlines the mechanism of increased ROS production in these cells .
Funding and acknowledgments This project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant No. G-221-166-38. The authors, therefore, acknowledge with thanks DSR for technical and financial support.
Conflicts of interest
Introduction Arginase belongs to the ureohydrolase family of enzymes and catalyzes the hydrolysis of arginine to ornithine and urea. Arginase exists in two isoenzymes encoded by distinct genes designated as arginase-1 and arginase-2. Arginase-1 is primarily expressed in hepatocytes while arginase-2 or “extrahepatic arginase” is primarily found in kidney, small intestine, prostate and other tissues , . Recent studies have shown arginase-1 to be a very sensitive and specific marker for hepatocellular differentiation , , , , , . In normal liver, arginase-1 expression is seen only in hepatocytes and not in the bile ducts or endothelial cells. Arginase-1 expression has also been reported in macrophages and neutrophils , . Studies have shown that arginase-1 is a very sensitive marker across all differentiations for hepatocellular carcinoma (HCC) and is very helpful in distinguishing HCC from cholangiocarcinomas and other metastatic tumors to the liver , , , , , . There have been only rare cases of arginase-1 staining adenocarcinomas originating in the pancreas, breast, biliary tract and colon , . Hepatoid adenocarcinoma is a rare but important type of extrahepatic adenocarcinoma, which resembles HCC both on morphology and immunohistochemistry . Hepatoid adenocarcinoma has been most commonly identified in the stomach . It has also been reported in several other organs, including gall bladder, lung, pancreas, colon, esophagus, urinary bladder, ovary and uterus , , , , , . Hepatoid adenocarcinoma is usually but not necessarily associated with ɑ-fetoprotein (AFP) production , . It is regarded as an aggressive tumor that often shows extensive angiolymphatic invasion with frequent hepatic metastasis. Hence the distinction between HCC and hepatoid adenocarcinoma in cases where the primary tumor site is unknown can be challenging, especially when the initial diagnosis needs to be made on a liver biopsy. A number of studies have failed to identify a specific marker which can confidently distinguish HCC from hepatoid adenocarcinoma , , , , .
Materials and methods
Discussion Hepatoid adenocarcinoma was first reported in 1970 , and the term hepatoid adenocarcinoma was proposed by Ishikura et al in 1985 when they reported a series of seven AFP-producing gastric adenocarcinomas that presented with histologic features similar to HCC . Nagai et al showed that gastric adenocarcinomas with hepatoid morphology have a worse prognosis, irrespective of AFP production . In 1997, Ishikura et al also reported gastric adenocarcinoma morphologically mimicking HCC that was AFP negative . Hence, the clinicopathological entity of hepatoid adenocarcinoma was broadened to include adenocarcinomas showing morphologically hepatic or hepatoid differentiation irrespective of AFP production or expression , , .