Serum Arginase Activity Research Articles

Measurement of Arginase Activity in Sera of Iraqi Acromegaly Patients with Diabetes

The goal of this study was to measure arginase enzyme activity in diabetic acromegaly Iraqi patients and compare it to a control group. This study included 80 participants, whose ages ranged from 25 to 65, and was conducted on forty diabetic acromegaly Iraqi patients attending the national diabetes center of Mustansiriyah University in Baghdad and forty healthy individuals (as a control group). The results showed a highly significant reduction in arginase activity and High-density lipoprotein-cholesterol (HDL-C), Urea levels were reduced not significantly, whereas a highly significant increase in levels of Growth Hormone (GH), Insulin-Like Growth Factor-1 (IGF-1), Fasting Serum glucose (FSG), Total Cholesterol (TC), Triglycerides (TG), Low-density lipoprotein-cholesterol (LDL-C), and Very low-density lipoprotein-cholesterol (VLDL-C)) compared to control. A significant positive correlation was revealed between arginase activity and FSG levels in diabetic acromegaly patients. In conclusion, diabetic acromegaly patients had a significant decreased in serum arginase activity with no significant decrease urea levels, which indicates that their bodies store more nitrogen compounds to be utilized in constructing processes.

Differential Status of Serum Arginine, Arginase and Nitric Oxide in Patients of Chronic and Advanced Stage Kidney Disease Undergoing Hemodialysis

Background: Chronic kidney disease (CKD) is characterized by deterioration of endothelial function which is associated with reduced availability of nitric oxide. The objective of the study was to assess the differential status of the serum levels of arginine, arginase, NO, urea and creatinine in CKD patients not on hemodialysis and in end stage renal disease (ESRD) patients receiving hemodialysis. Material and Methods: In this case control study, clinically diagnosed 30 CKD patients (group I), 30 ESRD patients before hemodialysis (Group II), 30 patients with ESRD after first hemodialysis (group III) and 30 patients with ESRD after second hemodialysis (Group IV) were included. 30 healthy volunteers were included for comparison. Serum arginine, arginase, nitric oxide, urea and creatinine were estimated by colorimetric and spectrophotometric methods. Results: Serum creatinine and urea levels were evaluated to determine the severity of renal dysfunction. A significantly decreased serum arginine and nitric oxide levels whereas significantly increased serum arginase levels were observed in ESRD patients when compared to levels in CKD patients. Serum creatinine levels were significantly decreased after second hemodialysis. But there was no significant change in the serum levels of arginine, arginase and nitric oxide in ESRD patients after first and second hemodialysis compared to pre-dialysis group. Conclusion: The findings of the study throw light upon the differential status of serum arginine, arginase and nitric oxide in CKD and in ESRD patients. The evaluation of decreased nitric oxide levels coupled with elevated arginase activity may help in assessing progression of CKD to ESRD along with traditional markers of kidney function. Additionally, evaluation of serum arginase activity may provide useful prognostic information, with large study group and further follow-up, in hemodialysis patients.

Determination of Serum Arginase-1 Concentrations and Serum Arginase Activity for the Non-Invasive Diagnosis of Endometriosis.

Backgroud: Endometriosis remains a diagnostic challenge, both clinically and economically, affecting 6% to 15% of women of child-bearing potential. We have attempted to determine whether testing serum concentrations and activity of arginase isoenzymes could be useful for the non-invasive diagnosis of endometriosis. Methods: This study involved 180 women (105 endometriosis subjects-study group B; 22 subjects with other benign gynaecological conditions-control group 1-K1, both undergoing surgery; and 53 healthy subjects without features of endometriosis-control group 2-K2). Results: Preoperative and postoperative arginase-1 (Arg-1) concentrations were significantly higher in patients, as compared with the control groups K1 (p < 0.0001 and p = 0.0005, respectively) and K2 (both p < 0.0001). Similarly, arginase activity was significantly higher in patients than in the control group K1 before surgery and higher than in both control groups after surgery. No significant differences in either Arg-1 concentrations or arginase activity were noted between the operated control group K1 and the non-operated control group K2. A significant postoperative decrease in Arg-1 concentration was observed within both patient (p < 0.0001) and control group K1 (p = 0.0043). Diagnostic performance was assessed using the receiver operating characteristic (ROC) method. The threshold for differentiation between endometriosis patients and healthy non-operated controls was 42.3 ng/mL, with a sensitivity of 90% and specificity of 81%. For differentiation of patients and operated controls with benign gynaecological conditions, the threshold was 78.4 ng/mL, with a sensitivity of 61% and specificity of 95%. Conclusions: We, therefore, conclude that Arg-1 serum concentrations and arginase activity could be considered potential biomarkers for endometriosis but require further studies on larger cohorts of patients.

Study of arginase activity in serum of patients with hypothyroidism and type 2 diabetes mellitus

In L-arginine metabolizing pathways, arginase and nitric oxide synthase are regulated in a reciprocal manner. In recent years, nitric oxide has been proposed as a key player in hyperthyroidism. The importance of arginase in arginine control has not yet been studied in hypothyroidism. The goal of this study was to examine the activity of arginase in in type 2 diabetic patients with and without hypothyroidism. The two most popular endocrinopathies that exist in clinical practice are thyroid disease and diabetes mellitus DM. The thyroid hormones, on the other hand, control the metabolism of carbohydrates and the pancreas activity. The study group consisted of 120 subjects divided into four groups; the first group included 30 healthy control subjects, the second group included 30 patients with both hypothyroidism and type 2 DM, the third group included 30 patients with hypothyroidism without type 2 diabetes (T2DM) and the fourth group included 30 patients with T2DM without hypothyroidism. The concentration of fasting serum glucose (FSG), total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), very low-density lipoprotein (VLDL), triiodothyronine (T3), thyroxin (T4), thyroid-stimulating hormone (TSH) were determined.

Alterations of nitric oxide homeostasis as trigger of intestinal barrier dysfunction in non-alcoholic fatty liver disease.

Changes in intestinal nitric oxide metabolism are discussed to contribute for the development of intestinal barrier dysfunction in non‐alcoholic fatty liver disease (NAFLD). To induce steatosis, female C57BL/6J mice were pair‐fed with a liquid control diet (C) or a fat‐, fructose‐ and cholesterol‐rich diet (FFC) for 8 weeks. Mice received the diets ± 2.49 g L‐arginine/kg bw/day for additional 5 weeks. Furthermore, mice fed C or FFC ± L‐arginine/kg bw/day for 8 weeks were concomitantly treated with the arginase inhibitor Nω‐hydroxy‐nor‐L‐arginine (nor‐NOHA, 0.01 g/kg bw). Liver damage, intestinal barrier function, nitric oxide levels and arginase activity in small intestine were assessed. Also, arginase activity was measured in serum from 13 patients with steatosis (NAFL) and 14 controls. The development of steatosis with beginning inflammation was associated with impaired intestinal barrier function, increased nitric oxide levels and a loss of arginase activity in small intestine in mice. L‐arginine supplementation abolished the latter along with an improvement of intestinal barrier dysfunction; nor‐NOHA attenuated these effects. In patients with NAFL, arginase activity in serum was significantly lower than in healthy controls. Our data suggest that increased formation of nitric oxide and a loss of intestinal arginase activity is critical in NAFLD‐associated intestinal barrier dysfunction.

Effects of curcumin on arginase enzyme activity, ornithine and nitric oxide levels in experimental breast cancer model

Breast cancer accounts for almost 30% of all cancer types, making it the most common type of tumor among women in the world. Arginase, an essential enzyme of the urea cycle, leads to the formation of urea and ornithine from L-arginine using the same substrate as nitric oxide synthase (NOS). Arginase has been reported to be higher in cancer patients and can be used as a useful biomarker. In this study, we aimed to investigate the effects of curcumin, an anticarcinogenic agent, on arginase enzyme activity, ornithine, and nitric oxide (NO) levels in experimental breast cancer model in mice. 43 male Balb/c mice were used, and Erhlich acid tumor model was created in the study. Mice were divided into five groups as healthy control group, curcumin treatment before tumor formation, curcumin treatment after tumor formation and cancer control groups. 100 mg/kg curcumin were given orally. Serum and tissue arginase enzyme activities, NO levels and tissue ornithine levels were determined spectrophotometrically. Increased serum arginase activity decreased with curcumin treatment, but this difference was not statistically significant. On the other hand, decreased NO levels were increased with curcumin treatment. In tumor tissue, arginase activity and ornithine levels decreased significantly with curcumin treatment and tissue NO levels increased significantly with curcumin treatment. In our study, we show that curcumin may have a protective effect on the development of breast cancer by inhibiting arginase enzyme activity and ornithine levels, which are the precursors of polyamines, as well as inducing NO production via NOS. As a promising anticancer agent, the net effects of curcumin in this mechanism should be supported by more advanced studies and new parameters.

L‐Arginase induces Vascular Dysfunction in Old Spontaneously Hypertensive Rats

BackgroundAging is a major non‐modifiable risk factor for hypertension. Structural, functional and mechanical changes occur with aging. These changes are similar to those seen in hypertension in the vasculature. Also, aging increases the vascular dysfunction that occurs in hypertension. L‐arginase is a ureohydrolase enzyme that converts L‐arginine to L‐ornithine and urea. Arginase action reduces substrate (L‐arginine) availability for the formation of nitric oxide (NO). This reduces the level of NO and leads to reduced vasodilation and ultimately, vascular dysfunction.HypothesisThis study tests the hypothesis that the age dependent vascular dysfunction in SHRs is mediated by arginase.MethodsYoung (12–14 weeks) and old (11–12 months) male Wistar and spontaneously hypertensive rats (SHR) were used in this study. Mean arterial pressure (MAP) was measured in the rats. They were then euthanized and 5ml of blood was drawn from the heart to obtain serum for the assay of arginase activity. Mesenteric resistance arteries (MRAs) and thoracic aortae were excised and placed in ice‐cold physiological salt solution (PSS). Arterial segments were either snap‐frozen in liquid nitrogen and stored for immunoblotting studies or cut into 2mm rings for reactivity studies. Cumulative concentration‐response curves to phenylephrine (PE; 10‐9‐3×10‐5M), acetylcholine (Ach; 10‐9 – 3×10‐5M) and sodium nitroprusside (SNP; 10‐12 – 3×10‐5 M) were performed in the absence or presence (30‐minute exposure) of various agents: L‐arginase, 0.05U/ML (MRA) or 0.5U/ML (aorta); Rho kinase inhibitor, Y27632 − 10‐5mmol/L; or 0.5U/ML L‐arginase + 10‐5mmol/L Y27632 (aorta). All chemicals were obtained from Sigma‐Aldrich MO, USA. Data are expressed as mean + S.E.M. of 6 rats per group. Statistical differences were calculated using Student’s t‐test and two‐way ANOVA with repeated measures followed by Bonferroni post hoc test. Significance was set at p&lt;0.05.ResultsMAP increased during aging in the SHRs (132.2±10.2 vs 166.2±1.9mmHg p&lt;0.05.) but not in the Wistar rats (104.4±3.0 vs 92.0±1.5mmHg). Arginase impaired the endothelium‐dependent relaxation responses of thoracic aortic and MRA arterial rings to Ach in the old Wistars (Emax aorta: 68.66248±1.96% vs 56.46116±3.42%) and SHRs (Emax aorta: 29.41753±2.19% vs 7.943045±1.86%). Arginase also impaired endothelium‐independent relaxation response to SNP in the old SHRs only (Emax aorta: 88.62396±4.10% vs 31.45081±10.61%). Correspondingly, arginase potentiated contractile responses of thoracic aortic and MRA arterial rings to PE in the old SHRs (Emax MRA: 25.24835±1.93mN vs 36.43248±2.99mN) which was attenuated by the Rho Kinase inhibitor (Y26732) in the presence or absence of arginase. We also observed no differences in the serum arginase activity in the four groups of rats. On the contrary, arginase activity in the thoracic aortae of young Wistar rats was reduced compared to the other groups.ConclusionsThe results of this study suggest that arginase impairs both endothelium‐dependent and –independent vasorelaxation responses, through the NO signaling pathway.Support or Funding InformationNIH

L-arginase induces vascular dysfunction in old spontaneously hypertensive rats.

Aging is a major non-modifiable risk factor for hypertension. Changes in aging are similar to those seen in hypertension in the vasculature. Also, aging increases the vascular dysfunction that occurs in hypertension. L-arginase action reduces substrate (L-arginine) availability for the formation of nitric oxide (NO). This reduces the level of NO and leads to reduced vasodilation and ultimately, vascular dysfunction. This study examines the hypothesis that age-dependent vascular dysfunction in SHRs is mediated by arginase. Young (12-14 weeks) and old (11-12 months) male Wistar and spontaneously hypertensive rats (SHR) were used. Mean arterial pressure (MAP) was measured in the rats. They were then euthanized and mesenteric resistance arteries (MRAs) and thoracic aortae were excised and placed in ice-cold physiological salt solution (PSS). Arterial segments were either snap-frozen in liquid nitrogen and stored for immunoblotting studies or cut into 2mm rings for reactivity studies. Cumulative concentration-response curves to acetylcholine (Ach: 10-9 - 3x10-5M) and sodium nitroprusside (SNP: 10-12 - 3x10-5 M) were performed in the absence or presence (30-minute exposure) of L-arginase, 0.05U/ML (MRA) or 0.5U/ML (aorta). Vessels were pre-contracted with phenylephrine (PE; 3x10-6M). MAP increased during aging in the SHRs p<0.05 but not in the Wistar rats. Arginase impaired the endothelium-dependent relaxation responses of thoracic aortic and MRA arterial rings to Ach in the old Wistars and SHRs (Emax aorta: 29.42±2.19% vs 7.94±1.86%). Arginase also impaired endothelium-independent relaxation response to SNP in the old SHRs only (Emax aorta: 88.62±4.10% vs 31.45±10.61%). We also observed no differences in the serum arginase activity in the four groups of rats. On the contrary, arginase activity in the aortae of young Wistar rats was reduced compared to other groups. Arginase impairs both endothelium-dependent and -independent vasorelaxation responses, through the NO signaling pathway.

Association analysis between ARG1 gene polymorphisms and idiopathic dilated cardiomyopathy.

The current study aimed at investigate the potential association of ARG1 polymorphisms in subjects affected by idiopathic dilated cardiomyopathy (IDCM).We have investigated 352 subjects affected by IDCM and 352 population-matched healthy controls by exploiting case-control study. The serum lipids were quantified using spectrophotometric assay, serum arginase activity was done by enzyme colorimetric assay and 2 polymorphisms (rs2781666 and rs2781667) in ARG1 were typed by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) to find out disease associate allele/haplotype segregating in subjects affected by IDCM.Significantly high arginase activity was found to be associated with IDCM subjects when compared with population-matched healthy controls (P < .0001). The higher arginase level in IDCM subjects is negatively correlated with nitrite and nitrate (r = –0.4687, and r = –0.6435, respectively) in our study. There was a significant difference in the distribution of rs2781666 and rs2781667 genotypes of ARG1 polymorphism in patients and controls (P < .0001). Similarly, variant allele T at both loci showed a significant association with the disease phenotypes (P < .0001). Haplotype TT at rs2781666G/T and rs2781667C/T also showed a significantly association (P < .0001).To our knowledge, this is the first report to show a significant involvement of ARG1 polymorphisms to produce IDCM symptoms in subjects originating in Pakistan.

A study of serum arginase activity in diagnosis of liver diseases

A study of serum arginase activity in diagnosis of liver diseases

PPARα interacts with PHD proteins on Renal Fibrosis in a Mouse Unilateral Ureteral Obstruction Model of Chronic Kidney Disease

Peroxisome proliferator activated receptor (PPAR)α and prolyl hydroxylase domain‐containing protein (PHD), “sensors” of cellular energy and oxygen have protective effects in the kidney and potentially act in a complimentary fashion but the mechanisms involved are not fully known. This study examined the effects of PPARa and its interaction with PHD in a mouse model of renal fibrosis induced by unilateral ureteral obstruction (UUO). UUO increased hydroxyl proline in PPARa WT and KO kidneys (P&lt;0.05) but to a greater extent in KO kidneys. Dimethyl oxallyl glycine (DMOG), a PHD inhibitor, markedly blunted the effect only in WT kidneys (P&lt;0.05). TGFβ expression was also increased (~ 3‐fold, P&lt;0.05) in both WT and KO kidneys. However, DMOG blunted UUO‐induced increase in TGFb expression only in WT kidneys (P&lt;0.05). Bilirubin, an index of heme oxygenase activity, was lower in KO kidneys at basal level (P&lt;0.05) and was reduced in WT kidneys (P&lt;0.05) following UUO but paradoxically increased in KO kidneys (P&lt;0.05). DMOG blunted the reduction in bilirubin in WT (P&lt;0.05) but was without effect in KO kidneys. Serum arginase activity, an index of cellular content of L‐Arginine, was increased in WT mice (P&lt;0.05) but there was no change in KO mice following UUO. DMOG abolished the effect in WT but not KO mice. These data suggest that PPARα plays a protective role against UUO that appears to be coupled to PHD proteins by mechanisms related to heme oxygenase and arginase.Support or Funding InformationThis study was supported by the National Institutes of Health grant G12MD007605.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Early Effects of Hyperbaric Oxygen on Inducible Nitric Oxide Synthase Activity/Expression in Lymphocytes of Type 1 Diabetes Patients: A Prospective Pilot Study

This study aimed at examining the early effects of hyperbaric oxygen therapy (HBOT) on inducible nitric oxide synthase (iNOS) activity/expression in lymphocytes of type 1 diabetes mellitus (T1DM) patients. A group of 19 patients (mean age: 63 ± 2.1) with T1DM and with the peripheral arterial disease were included in this study. Patients were exposed to 10 sessions of HBOT in the duration of 1 h to 100% oxygen inhalation at 2.4 ATA. Blood samples were collected for the plasma C-reactive protein (CRP), plasma free fatty acid (FFA), serum nitrite/nitrate, and serum arginase activity measurements. Expression of iNOS and phosphorylation of p65 subunit of nuclear factor-κB (NFκB-p65), extracellular-regulated kinases 1/2 (ERK1/2), and protein kinase B (Akt) were examined in lymphocyte lysates by Western blot. After exposure to HBOT, plasma CRP and FFA were significantly decreased (p < 0.001). Protein expression of iNOS and serum nitrite/nitrate levels were decreased (p < 0.01), while serum arginase activity was increased (p < 0.05) versus before exposure to HBOT. Increased phosphorylation of NFκB-p65 at Ser536 (p < 0.05) and decreased level of NFκB-p65 protein (p < 0.001) in lymphocytes of T1DM patients were observed after HBOT. Decreased phosphorylation of ERK1/2 (p < 0.05) and Akt (p < 0.05) was detected after HBOT. Our results indicate that exposure to HBO decreased iNOS activity/expression via decreasing phosphorylation of ERK1/2 and Akt followed by decreased activity of NFκB.

Disturbance of Arginase Activity and Nitric Oxide Levels in Iraqi Type 2 Diabetes Mellitus

This study is an attempt to find whether arginine metabolism dysregulation by arginase activity is related to hyperglycemia, followed by changes in nitric oxide (NO) generation in type 2 diabetic patients. This study includes 42 control subjects (Group I), and 92 Iraqi patients with type 2 diabetes mellitus (T2DM). The patient group was subdivided into two groups: Group II (54) with T2DM only and Group III (38) with T2DM and dyslipidemia (who were treating with atorvastatin along with diabetes treatment). The samples were obtained to measure arginase activity and NO levels. Serum arginase activity increased significantly in patients(groupII and groupIII) compared to control group. While serum NO level was significantly lower in diabetic patients as compared to control group, three significant correlations appeared in this study between glucose and arginase activity, glucose and NO levels, and between arginase activity and NO levels. The results also show that treatment with atorvastatin affects arginase activity and NO levels. Increasing in levels of arginase activity can be considered as an indicator of diabetic status. Endothelial dysfunctions accompanied with diabetes mellitus reverses correlation between arginase and NO in diabetic

ARG1 Gene Polymorphisms and Their Association in Individuals with Essential Hypertension: A Case-Control Study.

The purpose of this study is to investigate the association of variant alleles (rs2781666 and rs2781667) at ARG1 to be involved in the generation of essential hypertension (EH) phenotypes in human subjects. The ARG1 noncoding polymorphisms (rs2781666; Chr6:131572419-G/T and rs2781667; Chr6:131573754-C/T) were investigated in 570 subjects, including 285 individuals diagnosed with EH. Determination of serum arginase activity and concentrations of nitric oxide catabolites were detected by the colorimetric enzymatic assay. Genetic typing of the noncoding polymorphisms, in ARG1, was performed using PCR and restriction digestion strategy. A significant increase in arginase activity was observed in individuals exhibiting EH phenotypes, compared with controls (p < 0.0001). Arginase showed negative correlation with serum nitrite and nitrate (r = -0.446 and r = -0.6075, respectively). A significant difference to be claimed in the distribution of SNPotypes, in rs2781666 and rs2781667, between cases and controls (p = 0.0086 and p = 0.0232; respectively). Interestingly, variant allele T, at both loci, is tightly linked to the disease phenotypes compared to the wild-type allele (p = 0.002; and p = 0.007, respectively). To our knowledge, this report is the first ever that described arginase activity, and the ARG1 polymorphism data of individuals originated in Pakistan, segregating EH phenotypes, thus, highlighting a novel risk factor for the disease.

Disturbance of Arginase Activity and Nitric Oxide Levels in Iraqi Type 2 Diabetes Mellitus

This study is an attempt to find whether arginine metabolism dysregulation by arginase activity is related to hyperglycemia, followed by changes in nitric oxide (NO) generation in type 2 diabetic patients. This study includes 42 control subjects (Group I), and 92 Iraqi patients with type 2 diabetes mellitus (T2DM). The patient group was subdivided into two groups: Group II (54) with T2DM only and Group III (38) with T2DM and dyslipidemia (who were treating with atorvastatin along with diabetes treatment). The samples were obtained to measure arginase activity and NO levels. Serum arginase activity increased significantly in patients(groupII and groupIII) compared to control group. While serum NO level was significantly lower in diabetic patients as compared to control group, three significant correlations appeared in this study between glucose and arginase activity, glucose and NO levels, and between arginase activity and NO levels. The results also show that treatment with atorvastatin affects arginase activity and NO levels. Increasing in levels of arginase activity can be considered as an indicator of diabetic status. Endothelial dysfunctions accompanied with diabetes mellitus reverses correlation between arginase and NO in diabetic

Association of increased risk of asthma with elevated arginase & interleukin-13 levels in serum & rs2781666 G/T genotype of arginase I.

Background & objectives:High expression of arginase gene and its elevated level in serum and bronchial lavage reported in animal models indicated an association with the pathogenesis of asthma. This study was undertaken to assess the serum arginase activity in symptomatic asthma patients and healthy controls and to correlate it with cytokine levels [interleukin (IL)-4 and IL-13] and arginase I (ARG1) gene polymorphism.Methods:Asthma was confirmed by lung function test according to the GINA guidelines in patients attending Allergy and Pulmonology Clinic, Bhagwan Mahavir Hospital and Research Centre, Hyderabad, India, a tertiary care centre, during 2013-2015. Serum arginase was analyzed using a biochemical assay, total IgE and cytokine levels by enzyme-linked immunosorbent assay and genotyping of ARG1 for single-nucleotide polymorphisms (SNPs) rs2781666 and rs60389358 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.Results:There was a significant two-fold elevation in the arginase activity in asthmatics as compared to healthy controls which correlated with disease severity. Non-atopic asthmatics showed elevated activity of arginase compared to atopics, indicating its possible role in intrinsic asthma. Levels of serum IL-13 and IL-4 were significantly high in asthma group which correlated with disease severity that was assessed by spirometry. A positive correlation was observed between arginase activity and IL-13 concentration. Genetic analysis of ARG1 SNPs revealed that rs2781666 G/T genotype, T allele and C-T haplotype (rs60389358 and rs2781666) were associated with susceptibility to asthma.Interpretation & conclusions:This study indicated that high arginase activity and IL-13 concentration in the serum and ARG1 rs2781666 G/T genotype might increase the risk of asthma in susceptible population. Further studies need to be done with a large sample to confirm these findings.

The Involvement of Arginase and Nitric Oxide Synthase in Breast Cancer Development: Arginase and NO Synthase as Therapeutic Targets in Cancer.

It is well established that, during development of malignancies, metabolic changes occur, including alterations of enzyme activities and isoenzyme expression. Arginase and nitric oxide (NO) synthase (NOS) are two of those enzymes considered to be involved in tumorigenesis. The goal of this article was to study the involvement of arginase and NOS in the development of different stages of breast cancer. Our results have shown that human serum arginase activity and NO (resp., and NOS activity) and polyamines quantities increased in parallel with cancer stage progression and decreased after neoadjuvant chemotherapy. For breast cancer, the only isoenzyme of arginase expressed in serum before and after chemotherapy was in a cationic form. The data of Lineweaver-Burk plot with a Km value of 2 mM was calculated, which is characteristic for human liver type isoform of arginase. During electrophoresis at pH 8.9, the enzyme exhibited high electrophoretic mobility and was detected near the anode. The presented results demonstrated that arginase in human serum with breast cancer and after chemotherapy is not polymorphic. We suggest that arginase and NOS inhibition has antitumor effects on cancer development, as it can inhibit polyamines and NO levels, a precursor of cancer cell proliferation, metastasis, and tumor angiogenesis.

Arginine metabolic endotypes related to asthma severity.

AimsArginine metabolism via inducible nitric oxide synthase (iNOS) and arginase 2 (ARG2) is higher in asthmatics than in healthy individuals. We hypothesized that a sub-phenotype of asthma might be defined by the magnitude of arginine metabolism categorized on the basis of high and low fraction of exhaled nitric oxide (FENO).MethodsTo test this hypothesis, asthmatics (n = 52) were compared to healthy controls (n = 51) for levels of FENO, serum arginase activity, and airway epithelial expression of iNOS and ARG2 proteins, in relation to clinical parameters of asthma inflammation and airway reactivity. In parallel, bronchial epithelial cells were evaluated for metabolic effects of iNOS and ARG2 expression in vitro.ResultsAsthmatics with high FENO (≥ 35 ppb; 44% of asthmatics) had higher expression of iNOS (P = 0.04) and ARG2 (P = 0.05) in the airway, indicating FENO is a marker of the high arginine metabolic endotype. High FENO asthmatics had the lowest FEV1% (P < 0.001), FEV1/FVC (P = 0.0002) and PC20 (P < 0.001) as compared to low FENO asthmatics or healthy controls. Low FENO asthmatics had near normal iNOS and ARG2 expression (both P > 0.05), and significantly higher PC20 (P < 0.001) as compared to high FENO asthmatics. In vitro studies to evaluate metabolic effects showed that iNOS overexpression and iNOS+ARG2 co-expression in a human bronchial epithelial cell line led to greater reliance on glycolysis with higher rate of pyruvate going to lactate.ConclusionsThe high FENO phenotype represents a large portion of the asthma population, and is typified by greater arginine metabolism and more severe and reactive asthma.

Differential effects of low-dose fludarabine or 5-fluorouracil on the tumor growth and myeloid derived immunosuppression status of tumor-bearing mice

Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play a key role in the suppression of the innate and adaptive immunity. Chemotherapeutic strategies have been developed to deplete or deactivate MDSCs in different tumor models. The pyrimidine analog, 5-fluorouracil (5-FU) is found to reduce the tumor size by depleting MDSCs. Here, we asked whether the purine analog, fludarabine (Flu), could exert similar effects. Employing a lymphoma model, we demonstrated that in mice with advanced tumors (where MDSC-induced suppression was present), treatment with a single low-dose Flu (25, 50, 100mg/kg) elevated the numbers of splenic MDSCs and serum arginase activity, and simultaneously, increased the tumor growth (only the highest dose). On the other hand, in mice with palpable tumors (where the MDSC-induced suppression was in progress), treatment with Flu had no significant effects on the tumor growth or the number of splenic MDSCs. In contrast to Flu, treatment with low-dose 5-FU, irrespective of tumor stage, caused tumor regression which coincided with significant reductions in the numbers of splenic MDSCs and blood neutrophils, but increases in the ratios of splenic CD4+ T and CD8+ T cells to suppressive MDSCs. Finally, in healthy mice (where MDSC-induced immuosuppression did not exist), 5-FU, but not Flu induced significant decreases in the number of myeloid cells in the bone marrow, naturally occurring splenic MDSCs and thymocytes. In conclusion, Flu exacerbates MDSC-induced immunosuppression in a tumor stage-dependent manner, whereas 5-FU alleviates the suppressive effects of MDSC at all stages of tumor development.

The Relation of Serum Arginine Levels with Serum Arginase and Nitric Oxide Synthase Activity in Patients with Breast Cancer

The Relation of Serum Arginine Levels with Serum Arginase and Nitric Oxide Synthase Activity in Patients with Breast Cancer