br Concluding remarks It is clear

Concluding remarks It is clear that a disordered l-arginine homeostasis by changes in arginase, NOS and ADMA activity and expression, is not only vital in the chronic airway diseases, p-Chlorophenylalanine australia and COPD, but also seems to play an important role in many co-morbidities. Unknown, however, is whether l-arginine disbalance in the lung systemically affects other organs, thereby contributing to the development of co-morbidities. Moreover, it is not clear in how far altered l-arginine metabolism in systemic comorbidities may contribute to the severity of asthma and COPD. In the same line of reasoning, it is also largely unknown if restoring l-arginine-balance in the airways, for example by using arginase inhibitors, will alleviate symptoms of co-morbidities and vice versa. Remarkably, we recently found that the arginase inhibitor ABH inhibited airway inflammation and remodeling as well as right ventricular hypertrophy in a guinea pig model of COPD [49]. Currently, lung diseases are preferably treated locally by inhalation of nebulized drugs. In this way, low doses of drugs can be used and side-effects are reduced. In animal models of asthma and COPD, both systemic [76] and local treatment with arginase inhibitors lead to an increase in bioavailable l-arginine and reduced pulmonary symptoms [16, 49, 77]. However, most studies in this area have focused on the organ of interest instead of systemic effects of arginase inhibition. As with all treatments, caution should be paid to potential side-effects occurring during the use of arginase inhibitors, particularly with regard to ammonia detoxification in the liver. However, short-term, as well as long-term systemic treatment in animal models of hypertension and atherosclerosis did not show any toxic side-effects or induction of a compensatory enzyme upregulation [78]. Naturally, each co-morbidity requires a different approach in treatment. Nevertheless, it would be beneficial when possible treatment of asthma or COPD by arginase inhibitors, or other drugs interfering with l-arginine metabolism, could also leads to relief of symptoms in other organs.
Conflict of interest statement
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
Acknowledgement This work is part of the research programme ‘Connecting Innovators’ with project number 13547 which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO).
Introduction Hepatocellular carcinoma is the most common malignant primary tumor of the liver, which is now one of the commonest malignancies in the world and the second most frequent cause of cancer mortality, responsible for nearly 745 000 deaths in 2012 [1]. Approximately 20 000 new cases of hepatocellular carcinoma are diagnosed in the United States each year [2]. Despite the advances in imaging techniques, tissue diagnosis via a needle biopsy remains an important tool in the diagnosis of hepatocellular carcinoma in many cases, such as tumors occurring in non-cirrhotic livers [3], [4]. A tissue diagnosis of hepatocellular carcinoma is based on morphology plus the use of immunohistochemical stains. There are multiple markers of hepatocytic differentiation which are routinely used in surgical pathology. The most commonly used ones are HepPar-1, arginase-1, and glypican-3. HepPar-1 is a sensitive marker of hepatocyte differentiation that recognizes carbamoyl phosphate synthetase 1 [5], a mitochondrial enzyme involved in urea production. Arginase-1 also targets a urea cycle protein, one that catalyzes the hydrolysis of arginine to ornithine and urea. Arginase is found as two main isoforms, termed arginase-1 and arginase-2, which are encoded on separate genes and share approximately 60% amino acid sequence homology [6], [7]. Arginase-1 is present in the liver cytosol in high amounts, but is also found in lower quantities in neutrophils, blood vessels, and immune cells. Arginase-2 is located in mitochondria and has a much wider tissue distribution, including the kidney, prostate, small intestine and lactating mammary gland [8].