Argininemia is a rare, autosomal recessive, metabolic disorder caused by an hereditary deficiency of hepatocytes arginase due to ARG1 gene defect. Arginase is the final enzyme in the urea cycle, catalyzing the hydrolysis of arginine to ornithine and urea. Research advances in the clinical manifestations, diagnosis, treatment, prenatal diagnosis and genetics of argininemia were reviewed in this paper. The clinical manifestations of patients with argininemia are complicated and nonspecific so that clinical diagnosis is usually difficult and delayed. Progressive spastic tetraplegia, seizures and cerebella atrophy are common clinical features of the disease. Blood amino acids analysis, arginase assay and ARG1 gene analysis are important to the diagnosis of argininemia. Early diagnosis and a protein-restricted diet with citrulline and benzoate supplements can contribute a lot to improve patient prognosis. With the application of liquid chromatography-tandem mass spectrometry in selective screening and newborn screening for inborn errors of metabolism, an ever-increasing number of patients with argininemia are detected at the asymptomatic or early stages.
Arginase ; genetics ; Humans ; Hyperargininemia ; diagnosis ; genetics ; therapy ; Molecular Biology ; Prognosis

OBJECTIVE: To explore the genetic basis for an infant with early-onset argininemia. METHODS: Potential variant was detected with an Ion Torrent semiconductor sequencer using a gene panel for inherited diseases. Suspected variants were verified by Sanger sequencing. RESULTS: Genetic testing indicated that he has carried c.560+2T>C and c.811T>C compound heterozygous variant of the AGR1 gene, which were inherited from his father and mother, respectively. Among these, c.560+2T>C was suspected to be pathogenic, while c.811T>C was of unknown clinical significance, and both were not reported previously. CONCLUSION The c.560+2T>C and c.811T>C compound heterozygous variants of the AGR1 gene probably underlies the argininemia in this child. Above finding has enriched the variant spectrum of the AGR1 gene.
Arginase ; genetics ; Female ; Genetic Testing ; Humans ; Hyperargininemia ; genetics ; Infant ; Male

The effect of taxol on the production of nitric oxide(NO) and reactive oxygen radicals(O2- and H2O2)and on the function of phagocytic activity of murine microglial cells were investigated. Stimulated cells also showed increased production such reactive oxygen radicals as surperoxide and hydrogen peroxide measured by luminometer after stimulated with phorbolmyristate acetate(PMA). Taxol alone had only being small effect on NO synthesis, whereas taxol in combination with rIFN-gamma synergistically increased NO synthesis in a dose dependent manner. The production of NO by taxol plus rIFN-gamma was reduced by such L-arginine analogues as N(G)-mono-metyl-L-arginine Monohydrate(N(G)MMA), and N-amino-L-arginine(NAA) and arginase which decomposes L-arginine. Collectively, the data illustrate the potential for taxol to activate microglia-mediated anticancer mechanisms in the brain in addition to its better characterized effects on ovarian, beast, and lung cancer.
Arginase ; Arginine ; Brain ; Hydrogen Peroxide ; Lung Neoplasms ; Oxygen ; Paclitaxel* ; Reactive Oxygen Species

OBJECTIVETo explore the effect of storage time on arginase level, and the possible source of arginase in suspended red blood cells (RBC).

METHODSThe arginase and myeloperoxidase (MPO) levels in suspended RBC and control plasma were detected by ELISA. The free hemoglobin level in suspended RBC and control plasma were detected by colorimetric method. The relationship between arginase level, MPO level and free hemoglobin level in suspended RBC was analyzed by the related methods.

RESULTSThe arginase and free hemoglobin levels in suspended RBC were higher than those in control plasma. Otherwise, MPO level was not significantly different between suspended RBC and control plasma. All of them did not increase along with prolonging of storage time. There was not a significant correlation between arginase level and free hemoglobin level in suspended RBC of different storage time (r = 0.03), but arginase level positively correlated with MPO level in the suspended RBC of different storage time (r = 0.76).

CONCLUSIONThe arginase level in suspended RBC storaged for different time increases significantly, but not along with prolonging of storage time. The main possible source of arginase in the suspended RBC is the residual white blood cell, especially neutrophils.

Arginase ; chemistry ; Blood Preservation ; Erythrocytes ; enzymology ; Humans ; Peroxidase ; chemistry ; Plasma ; enzymology ; Time Factors

To better understand the role of macrophages in early stages of experimental autoimmune myocarditis (EAM), we compared the expression of inducible nitric oxide synthase (iNOS) and arginase-1, markers for classically activated M1 and alternatively activated M2 macrophages, respectively, in the hearts of EAM-affected and control rats. Immunohistochemical evidence revealed that both iNOS-positive and arginase 1-positive macrophages were found in EAM lesions, while some cells were co-localized with both markers. This finding suggests that the increased level of arginase-1, which is partly from M2 macrophages, contributes to the modulation of EAM, possibly through the reduction of nitric oxide in the lesion.
Animals ; Arginase ; Heart ; Macrophages* ; Myocarditis* ; Nitric Oxide ; Nitric Oxide Synthase Type II ; Rats*

In this study, the effect of phorbol ester on the synthesis of nitric oxide(NO) in murine microglial cells was examined. Phorbol 12-myristate 13-acetate(PMA), a protein kinase C(PKC) activator, alone had no effect, whereas PMA with recombinant interferon-gamma(rIFN-gamma) synergistically increased NO synthesis in murine microglial cells. The maximal effect of PMA in the increase of NO synthesis always fit with the range for rull activation of PKC in these cells. The increase of NO synthesis was reflected as increased amount of inducible NO synthase(iNOS) mRNA by Northern blotting. Treatment of PKC inhibitors such as staurosporine(STSN) or polymxin B decreased rIFN-gamma plus PMA-stimulated NO synthesis. Further, prolonged incubation of the cells with PMA, which down regulate PKC activity, abolished synergistic cooperative effect with IFN-gamma. N(G)-monomethyl-L arginine monohydrate(NGMMA), an analogue of L-arginine, and arginase inhibited rIFN-gamma plus PMA-induced NO production in murine microglial cells. On the basis of these observations we conclude that PKC might not be involved in the expression of iNOS, but instead, might be involved in the post-transcriptional modification of iNOS mRNA.
Arginase ; Arginine ; Astrocytes ; Blotting, Northern ; Microglia ; Myristic Acid* ; Nitric Oxide Synthase Type II ; Nitric Oxide* ; Protein Kinase C ; Protein Kinases ; RNA, Messenger

Arginine deprivation is a novel antimetabolite strategy for the treatment of arginine-dependent cancers that exploits differential expression and regulation of key urea cycle enzymes. Several studies have focused on inactivation of argininosuccinate synthetase 1 (ASS1) in a range of malignancies, including melanoma, hepatocellular carcinoma (HCC), mesothelial and urological cancers, sarcomas, and lymphomas. Epigenetic silencing has been identified as a key mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine. More recently, dysregulation of argininosuccinate lyase has been documented in a subset of arginine auxotrophic glioblastoma multiforme, HCC and in fumarate hydratase-mutant renal cancers. Clinical trials of several arginine depletors are ongoing, including pegylated arginine deiminase (ADI-PEG20, Polaris Group) and bioengineered forms of human arginase. ADI-PEG20 is furthest along the path of clinical development from combinatorial phase 1 to phase 3 trials and is described in more detail. The challenge will be to identify tumors sensitive to drugs such as ADI-PEG20 and integrate these agents into multimodality drug regimens using imaging and tissue/fluid-based biomarkers as predictors of response. Lastly, resistance pathways to arginine deprivation require further study to optimize arginine-targeted therapies in the oncology clinic.
Arginase ; Arginine ; Argininosuccinate Lyase ; Argininosuccinate Synthase ; Biomarkers ; Carcinoma, Hepatocellular ; Drug Combinations ; Epigenomics ; Glioblastoma ; Humans ; Kidney Neoplasms ; Lymphoma ; Melanoma ; Sarcoma ; Urea ; Urologic Neoplasms

PURPOSE: Immunotherapy is one of the treatment strategies for breast cancer, the most common cancer in women worldwide. In this approach, the patient's immune system is stimulated to attack microscopic tumors and control metastasis. Here, we used interferon γ-induced protein 10 (IP-10), which induces and strengthens antitumor immunity, as an immunotherapeutic agent. We employed Leishmania tarentolae, a nonpathogenic lizard parasite that lacks the ability to persist in mammalian macrophages, was used as a live delivery system for carrying the immunotherapeutic agent. It has been already shown that arginase activity, and consequently, polyamine production, are associated with tumor progression. METHODS: A live delivery system was constructed by stable transfection of pLEXSY plasmid containing the IP-10-enhanced green fluorescent protein (IP-10-egfp) fusion gene into L. tarentolae. Then, the presence of the IP-10-egfp gene and the accurate integration location into the parasite genome were confirmed. The therapeutic efficacy of IP-10 delivered via L. tarentolae and recombinant pcDNA-(IP-10-egfp) plasmid was compared by determining the arginase activity in a mouse 4T1 breast cancer model. RESULTS: The pcDNA-(IP-10-egfp) group showed a significant reduction in tumor weight and growth. Histological evaluation also revealed that only this group demonstrated inhibition of metastasis to the lung tissue. The arginase activity in the tissue of the pcDNA-(IP-10-egfp) mice significantly decreased in comparison with that in normal mice. No significant difference was observed in arginase activity in the sera of mice receiving other therapeutic strategies. CONCLUSION: Our data indicates that IP-10 immunotherapy is a promising strategy for breast cancer treatment, as shown in the 4T1-implanted BALB/c mouse model. However, the L. tarentolae-(IP-10-EGFP) live delivery system requires dose modifications to achieve efficacy in the applied regimen (six injections in 3 weeks). Our results indicate that the arginase assay could be a good biomarker to differentiate tumoral tissues from the normal ones.
Animals ; Arginase ; Breast Neoplasms ; Chemokine CXCL10 ; Female ; Genetic Therapy* ; Genome ; Humans ; Immune System ; Immunotherapy ; Interferons ; Leishmania ; Lizards ; Lung ; Macrophages ; Mice ; Neoplasm Metastasis ; Parasites ; Plasmids ; Transfection ; Tumor Burden

Advanced age is one of the risk factors for vascular diseases that are mainly caused by impaired nitric oxide (NO) production. It has been demonstrated that endothelial arginase constrains the activity of endothelial nitric oxide synthase (eNOS) and limits NO generation. Hence, arginase inhibition is suggested to be vasoprotective in aging. In this study, we examined the effects of intravenous injection of Piceatannol, an arginase inhibitor, on aged mice. Our results show that Piceatannol administration reduced the blood pressure in aged mice by inhibiting arginase activity, which was associated with NO production and reactive oxygen species generation. In addition, Piceatannol administration recovered Ca²⁺/calmodulin-dependent protein kinase II phosphorylation, eNOS phosphorylation and eNOS dimer stability in the aged mice. The improved NO signaling was shown to be effective in attenuating the phenylephrine-dependent contractile response and in enhancing the acetylcholine-dependent vasorelaxation response in aortic rings from the aged mice. These data suggest Piceatannol as a potential treatment for vascular disease.
Administration, Intravenous* ; Aging ; Animals ; Arginase* ; Blood Pressure ; Injections, Intravenous ; Mice* ; Nitric Oxide ; Nitric Oxide Synthase Type III ; Phosphorylation ; Protein Kinases ; Reactive Oxygen Species ; Risk Factors ; Vascular Diseases ; Vasodilation

Caesalpinia sappan (C. sappan) is a medicinal plant used for promoting blood circulation and removing stasis. During a screening procedure on medicinal plants, the ethylacetate extract of the lignum of C. sappan (CLE) showed inhibitory activity on arginase which has recently been reported as a novel therapeutic target for the treatment of cardiovascular diseases such as atherosclerosis. CLE inhibited arginase II activity prepared from kidney lysate in a dose-dependent manner. In HUVECs, inhibition of arginase activity by CLE reciprocally increased NOx production through enhancement of eNOS dimer stability without any significant changes in the protein levels of eNOS and arginase II expression. Furthermore, CLE-dependent arginase inhibition resulted in increase of NO generation and decrease of superoxide production on endothelium of isolated mice aorta. These results indicate that CLE augments NO production on endothelium through inhibition of arginase activity, and may imply their usefulness for the treatment of cardiovascular diseases associated with endothelial dysfunction.
Animals ; Aorta ; Arginase ; Atherosclerosis ; Blood Circulation ; Caesalpinia ; Cardiovascular Diseases ; Endothelium ; Kidney ; Mass Screening ; Mice ; Nitric Oxide ; Nitric Oxide Synthase Type III ; Plants, Medicinal ; Superoxides