Familial Mediterranean fever (FMF) is an auto-inflammatory disease characterised by periodic inflammatory attacks. We investigated changes in monocyte-granulocyte derived S10012A and chitotriosidase in both the attack and silent period of FMF for better estimation of inflammation. Endogenous resolvin was determined for utility to restrict inflammation. This study included 29 FMF patients (15 M/14 F) and 30 healthy controls (15 M/15 F). Serum levels of highly sensitive C-reactive protein, serum amiloid A (SAA), S100A12, chitotriosidase, and resolvin D1 were measured. Age, sex, body mass indexes, and lipids were similar between patients and controls. Biomarkers including hs-CRP, SAA, S100A12, chitotriosidase, and resolvin D1 were higher in the attack period of FMF patients compared to controls (P < 0.001). When FMF patients in the silent period were compared with their attack period, hs-CRP, SAA, and chitotriosidase were found elevated in the attack period (P < 0.001, P < 0.001, and P = 0.02 respectively). Serum levels of SAA, S100A12, chitotriosidase, and resolvin D1 in the silent period of FMF patients were still found elevated compared to healthy controls, indicating subclinical inflammation (P < 0.001, P < 0.001, P = 0.009, and P < 0.001 respectively ). In subgroup analysis, patients with M694V homozygote and heterozygote mutations had higher S10012A and hs-CRP compared to other mutation carriers. Our findings indicate that chitotriosidase and S10012A are useful in diagnosis and detection of subclinical inflammation and/or assessment of disease activity in FMF patients. They could be more informative for inflammation in various disease states compared to hsCRP and SAA. Resolvin D1 is elevated in both the attack and silent periods of FMF. It may be helpful to restrict inflammation.
Adult ; Biomarkers ; Docosahexaenoic Acids/*blood ; Familial Mediterranean Fever/*blood/*diagnosis ; Feasibility Studies ; Female ; Hexosaminidases/*blood ; Humans ; Male ; Reproducibility of Results ; S100A12 Protein/*blood ; Sensitivity and Specificity

Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-beta1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-beta1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-beta1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-beta1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-beta1 could be an alternative approach that selectively inhibits TGF-beta1-stimulated fibrotic tissue response while preserving major physiological function of TGF-beta1. Recent studies from our laboratory revealed that TGF-beta1 crosstalk with epidermal growth factor receptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays a critical role in the development or progression of pulmonary fibrosis. In addition, chitotriosidase, a true chitinase in humans, has been identified to have modulating capacity of TGF-beta1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-beta1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-beta1 plays a significant role.
Animals ; Drug Design ; Hexosaminidases/antagonists & inhibitors/metabolism ; Humans ; Lung/*drug effects/metabolism/pathology ; Molecular Targeted Therapy ; Pulmonary Fibrosis/*drug therapy/metabolism/pathology ; Receptor Cross-Talk ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Receptors, Transforming Growth Factor beta/antagonists & inhibitors/metabolism ; Signal Transduction ; Transforming Growth Factor beta1/*antagonists & inhibitors/metabolism

BACKGROUND: Chitotriosidase is an accepted marker of macrophage activation. In this study, we investigated serum chitotriosidase levels in pulmonary tuberculosis (PTB). METHODS: Forth-two patients with PTB and 30 healthy subjects were enrolled in the study. The radiological extent of PTB, radiological sequela after treatment, and the degree of smear positivity were assessed. Chitotriosidase levels were measured by a fluorometric method. RESULTS: The serum chitotriosidase levels of the PTB patients were significantly higher than those of the control subjects (39.73+/-24.97 vs. 9.63+/-4.55 nmol/mL/h, P<0.001). After completion of the standard 6-month antituberculous treatment, chitotriosidase levels in PTB patients significantly decreased (10.47+/-4.54 nmol/mL/h, P<0.001). Chitotriosidase levels correlated significantly with the radiological extent of PTB, degree of smear positivity, and post-treatment radiological sequela score (r=0.439, r=0.449, and r=0.337, respectively). CONCLUSIONS: This study demonstrated that serum chitotriosidase levels increase in PTB; therefore, chitotriosidase can be used as a marker of disease activity, severity, and response to treatment.
Adult ; Antitubercular Agents/therapeutic use ; Biological Markers/blood ; Fluorometry ; Hexosaminidases/*blood ; Humans ; Male ; ROC Curve ; Severity of Illness Index ; Tuberculosis, Pulmonary/drug therapy/*enzymology/radiography ; Young Adult

OBJECTIVEChitotriosidase (CT) is a plasma biomarker for Gaucher disease (GD), the enzyme activity is usually markedly elevated in plasma of Gaucher patients, and it was reported that levels of plasma chitotriosidase activity was mildly-moderately increased in patients with Niemann-Pick disease (NPD). The aim of this study was to compare chitotriosidase activity using 4-methylumbelliferyl-β-D-N, N', N″-triacetyl-chitotrioside (4MU-C3) with 4-methylumbelliferyl 4-deoxy-β-D-chitobiose (4MU-4dC2) as substrates, and apply chitotriosidase activity measurement to help clinical determination of GD and NPD, and to monitor therapy in GD patients.

METHODPlasma of 45 healthy individuals, 31 patients with GD and 9 patients with NPD type A/B was collected from outpatient clinics of the Department of Pediatric Endocrinologic, Genetic and Metabolic Diseases, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. Plasma chitotriosidase activity was measured with the substrates 4MU-C3 and 4MU-4dC2 respectively. Determinations were based on the methods described by Hollak et al and Rodrigues et al. Meanwhile, common mutation dup24 of the human chitotriosidase gene was detected.

RESULT(1) Chitotriosidase activity when measured with 4MU-4dC2 gave higher values than 4MU-C3. In the healthy controls chitotriosidase activity was increased 3.7-fold when the 4MU-dC2 was used as substrate as compared with the 4MU-C3 (Z = -4.703, P < 0.001). In the untreated GD patients, the median value was increased 794-fold and 610-fold of the control subjects (Z = -3.823, P < 0.001) when the enzyme was measured with two substrates respectively. In the GD patients during therapy, chitotriosidase activity was increased 134-fold and 79-fold, and after changing therapeutic dose chitotriosidase activity was increased 215-fold and 118-fold of the controls (Z = -2.521, P < 0.05). In the NPD patients chitotriosidase activity was increased 8-fold and 14-fold of the controls (Z = -1.604, P = 0.109). (2) Consistent with the results of chitotriosidase activity, 30 of 85 (35.3%) individuals were homozygotes of dup24 mutation, which are completely chitotriosidase enzyme deficiency. Among GD patients with wild-type and heterozygotes for the dup24 mutation, chitotriosidase activity highly increased in the plasma compared with the controls.

CONCLUSIONThe use of 4MU-4dC2 as substrate makes chitotriosidase activity measurement more sensitive. The determination of plasma chitotriosidase activity is a useful tool to assist the clinical identification of Gaucher disease, and to monitor enzyme replacement therapy (ERT) of non-chitotriosidase deficient GD patients. Chitotriosidase activity determination has no value in the clinical identification of NPD.

Adolescent ; Adult ; Blood Chemical Analysis ; methods ; Case-Control Studies ; Child ; Child, Preschool ; Female ; Gaucher Disease ; blood ; enzymology ; genetics ; Genotype ; Heterozygote ; Hexosaminidases ; blood ; genetics ; metabolism ; Humans ; Infant ; Male ; Middle Aged ; Mutation ; Niemann-Pick Diseases ; blood ; enzymology ; genetics ; Polymerase Chain Reaction ; Sensitivity and Specificity ; Young Adult

PURPOSE: Urinary excretion of N acetyl-beta-D glucosaminidase (NAG) and beta2-microglobulin (beta2-M) was increased in the presence of proximal tubular damage. Based on these urinary materials, we investigated the ability of expecting renal function in chronic glomerular diseases. In this study, we evaluated the relationship between glomerular filtration rate (GFR) urinary NAG, and urinary beta2-M. METHODS: We evaluated 52 children with chronic kidney disease at the Chung-Ang University Hospital between January 2003 and August 2009. We investigated the 24-hour urinalysis and hematologic values in all 52 patients. Serum creatinine, creatinine clearance (Ccr), serum cystatin C, urinary beta2-M and urinary NAG were measured. RESULTS: Out of 52 patients, there were 13 children with minimal change in disease, 3 children with focal segmental glomerulosclerosis, 17 children with immunoglobulin A nephropathy, 15 children with Henoch-Schonlein purpua nephritis, 3 children with poststreptococcal glomerulonephritis, and 1 child with thin glomerular basement membrane disease. In these patients, there were significant correlation between the Ccr and urinary NAG (r=-0.817; P<0.01), and between the GFR (as determined by Schwartz method) and urinary NAG (r=-0.821; P<0.01). In addition, there was a significant correlation between the GFR (as determined by Bokencamp method) and urinary NAG (r=-0.858; P<0.01). CONCLUSION: In our study, there was a significant correlation between the GFR and urinary NAG, but there was no correlation between the GFR and urinary beta2-M, suggesting that the GFR can be predicted by urinary NAG in patients with chronic glomerular disease.
Child ; Creatinine ; Cystatin C ; Glomerular Basement Membrane ; Glomerular Filtration Rate ; Glomerulonephritis ; Glomerulonephritis, IGA ; Glomerulosclerosis, Focal Segmental ; Hexosaminidases ; Humans ; Nephritis ; Proteinuria ; Renal Insufficiency, Chronic ; Urinalysis

PURPOSE: Gaucher disease is caused by a beta-glucocerebrosidase (GBA) deficiency. The aim of this study is to investigate the clinical and genetic characteristics according to subtypes of Gaucher disease in the Korean population. METHODS: Clinical findings at diagnosis, GBA mutations, and clinical courses were reviewed in 20 patients diagnosed with Gaucher disease. RESULTS: Eleven patients were diagnosed with non-neuronopathic type, 2 with acute neuronopathic type, and 7 with chronic neuronopathic type. Most patients presented with hepatosplenomegaly, thrombocytopenia, and short stature. In the neuronopathic group, variable neurological features, such as seizure, tremor, gaze palsy, and hypotonia, were noted at age 8.7+/-4.3 years. B cell lymphoma, protein-losing enteropathy, and hydrops fetalis were the atypical manifestations. Biomarkers, including chitotriosidase, acid phosphatase, and angiotensin-converting enzyme, increased at the initial evaluation and subsequently decreased with enzyme replacement treatment (ERT). The clinical findings, including hepatosplenomegaly, thrombocytopenia, and skeletal findings, improved following ERT, except for the neurological manifestations. L444P was the most common mutation in our cohort. One novel mutation, R277C, was found. CONCLUSION: Although the clinical outcome for Gaucher disease improved remarkably following ERT, the outcome differed according to subtype. Considering the high proportion of the neuronopathic form in the Korean population, new therapeutic strategies targeting the central nervous system are needed, with the development of a new scoring system and biomarkers representing clinical courses in a more comprehensive manner.
Acid Phosphatase ; Biomarkers ; Central Nervous System ; Cohort Studies ; Gaucher Disease ; Glucosylceramidase ; Hexosaminidases ; Humans ; Hydrops Fetalis ; Lymphoma, B-Cell ; Muscle Hypotonia ; Neurologic Manifestations ; Paralysis ; Protein-Losing Enteropathies ; Seizures ; Thrombocytopenia ; Tremor

PURPOSE: Gaucher disease is caused by a beta-glucocerebrosidase (GBA) deficiency. The aim of this study is to investigate the clinical and genetic characteristics according to subtypes of Gaucher disease in the Korean population. METHODS: Clinical findings at diagnosis, GBA mutations, and clinical courses were reviewed in 20 patients diagnosed with Gaucher disease. RESULTS: Eleven patients were diagnosed with non-neuronopathic type, 2 with acute neuronopathic type, and 7 with chronic neuronopathic type. Most patients presented with hepatosplenomegaly, thrombocytopenia, and short stature. In the neuronopathic group, variable neurological features, such as seizure, tremor, gaze palsy, and hypotonia, were noted at age 8.7+/-4.3 years. B cell lymphoma, protein-losing enteropathy, and hydrops fetalis were the atypical manifestations. Biomarkers, including chitotriosidase, acid phosphatase, and angiotensin-converting enzyme, increased at the initial evaluation and subsequently decreased with enzyme replacement treatment (ERT). The clinical findings, including hepatosplenomegaly, thrombocytopenia, and skeletal findings, improved following ERT, except for the neurological manifestations. L444P was the most common mutation in our cohort. One novel mutation, R277C, was found. CONCLUSION: Although the clinical outcome for Gaucher disease improved remarkably following ERT, the outcome differed according to subtype. Considering the high proportion of the neuronopathic form in the Korean population, new therapeutic strategies targeting the central nervous system are needed, with the development of a new scoring system and biomarkers representing clinical courses in a more comprehensive manner.
Acid Phosphatase ; Biomarkers ; Central Nervous System ; Cohort Studies ; Gaucher Disease ; Glucosylceramidase ; Hexosaminidases ; Humans ; Hydrops Fetalis ; Lymphoma, B-Cell ; Muscle Hypotonia ; Neurologic Manifestations ; Paralysis ; Protein-Losing Enteropathies ; Seizures ; Thrombocytopenia ; Tremor

M1-type macrophages are capable of inducing lysis in various types of cancer cells, but the mechanism of action is unclear. It has been noted that an "unknown protein" produced together with protease by activated macrophages is responsible for this action. Activated M1 macrophages have been recently reported to produce family 18 chitinases, all of which have been named chitotriosidase. Our experiments have demonstrated that family 18 chitinases work together with proteases and can damage various cancer cells both in vitro and in vivo. Thus, in this article, we suggest that the 50-kDa chitotriosidase is the reported "unknown protein". In addition, we discuss how to properly stimulate activated M1 macrophages to produce 50-kDa chitotriosidases and proteases for destroying cancer cells. Because family 19 chitinase has recently been reported to kill cancer cells, we also discuss the possibility of directly using human family 18 chitotriosidase and the humanized plant family 19 chitinase for cancer treatment.
Animals ; Antineoplastic Agents, Alkylating ; pharmacology ; Chitinases ; metabolism ; Cyclophosphamide ; pharmacology ; Hexosaminidases ; metabolism ; Humans ; Immunosuppressive Agents ; pharmacology ; Macrophage Activation ; immunology ; Macrophages ; classification ; enzymology ; immunology ; pathology ; Neoplasms ; immunology ; pathology ; Peptide Hydrolases ; metabolism ; T-Lymphocytes, Regulatory ; metabolism ; Th1 Cells ; metabolism ; Th2 Cells ; metabolism

OBJECTIVETo investigate the effect of Qingkailing injection (QKLI) on complement and RBL-2 H3 cells in virto.

METHODThe mixture of human serums and QKLI were incubated for 30 min in vitro and then the content of SC5 b-9 in the mixture was determined by ELISA. RBL-2 H3 cells were cultured and treated by QKLI. Beta-heosaminidase release rate was measured by coloration method. The content of histamine in supernatant was tested by ELISA.

RESULTThe QKLI can reduce the content of SC5 b-9 (P<0.05) and promote the release of beta-heosaminidase and histamine significantly (P<0.05).

CONCLUSIONQKLI didn't induce the complement activation, but induced the release of beta-heosaminidase and histamine directly. Therefore, the clinical adverse reactions of QKLI in clinic may be pseudoallergy which had no relation with the activation of complement system.

Adolescent ; Adult ; Animals ; Cell Degranulation ; drug effects ; Cell Line, Tumor ; Chemistry, Pharmaceutical ; Complement System Proteins ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; pharmacology ; Hexosaminidases ; secretion ; Histamine Release ; drug effects ; Humans ; Injections ; Rats ; Young Adult

PURPOSE: This study assessed the environmental lead exposure in patients with chronic kidney disease (CKD) and the relationship between lead exposure and renal function indices. METHODS: Seventy-one patients with CKD and 40 control subjects without known renal disease were included. Blood lead was measured by atomic absorption spectrophotometry and tibial lead was measured via 109Cd-based K-shell X-ray fluorescence. Blood urea nitrogen (BUN), serum creatinine, urine creatinine and urine N-acetyl-beta glucosaminidase (NAG) were also measured. Blood lead was corrected with hematocrit (female: 35%, male: 42%) to adjust for differences in anemic status of patients compared with control subjects. RESULTS: The mean level of hematocrit-adjusted blood lead was significantly higher in patients with CKD (4.18+/-1.74 microg/dL) compared with that in control subjects (3.00+/-0.92 microg/dL); the mean tibial lead level tended to be higher in patients with CKD (3.38+/-9.93 microg/g) than that in control subjects (1.28+/-7.92 microg/g), but no statistical significance was observed. In a multivariate regression analysis after adjusting for gender, age, and drinking and smoking status, adjusted blood lead was a significant predictor of increases in BUN and serum creatinine, but not of the level of urine NAG or creatinine. In contrast, no significant association between tibial lead and renal indices was observed in the multivariate regression analysis. CONCLUSION: These results suggest that environmental lead exposure may compromise renal function.
Blood Urea Nitrogen ; Creatinine ; Drinking ; Fluorescence ; Hematocrit ; Hexosaminidases ; Humans ; Renal Insufficiency, Chronic ; Smoke ; Smoking ; Spectrophotometry, Atomic