Immunomodulatory Effects of Chitotriosidase Enzyme

Contains fulltext : 172746.pdf (publisher's version ) (Open Access)Chitotriosidase enzyme (EC: 3.2.1.14) is the major active chitinase in the human body. It is produced mainly by activated macrophages, in which its expression is regulated by multiple intrinsic and extrinsic signals. Chitotriosidase was confirmed as essential element in the innate immunity against chitin containing organisms such as fungi and protozoa; however, its immunomodulatory effects extend far beyond innate immunity. In the current review, we will try to explore the expanding spectrum of immunological roles played by chitotriosidase enzyme in human health and disease and will discuss its up-to-date clinical value

Pituitary adenylate cyclase-activating polypeptide (PACAP) in zebrafish models of nephrotic syndrome

Contains fulltext : 177235.pdf (publisher's version ) (Open Access

Nephropathic cystinosis: an update

Contains fulltext : 170199.pdf (publisher's version ) (Closed access

A simple potentiometric sensor for rhodamine B

The construction and performance characteristics of PVC electrodes for Rhodamine B (RB) are described. Different methods for electrode fabrication (modified with the ion-pair, ion pairing agent or soaking the plain electrode in the ion-pair suspension) have been used. Matrix compositions were optimized on the basis of effects of type and content of the modifier as well as influence of the plasticizers. The fabricated electrodes worked satisfactorily in the concentration range from 1×10-6 to 0.001 M with Nernstian cationic slopes, depending on the method of electrode fabrication. The ion-pair modified electrode showed the best performance (slope 56.3±2.0 mV decade-1) compared with the plain electrodes or modified with sodium tetraphenylborate (NaTPB) and fast response time of about 8 sec and adequate lifetime (4 weeks). The developed electrodes have been successfully applied as well as end point indicator electrode for the potentiometric titration of RB with high accuracy and precision. The solubility products of different RB ion-pair were determined conductometrically

Cystinosis: a review

Cystinosis is the most common hereditary cause of renal Fanconi syndrome in children. It is an autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin, transporting cystine out of the lysosomal compartment. Defective cystinosin function leads to intra-lysosomal cystine accumulation in all body cells and organs. The kidneys are initially affected during the first year of life through proximal tubular damage followed by progressive glomerular damage and end stage renal failure during mid-childhood if not treated. Other affected organs include eyes, thyroid, pancreas, gonads, muscles and CNS. Leucocyte cystine assay is the cornerstone for both diagnosis and therapeutic monitoring of the disease. Several lines of treatment are available for cystinosis including the cystine depleting agent cysteamine, renal replacement therapy, hormonal therapy and others; however, no curative treatment is yet available. In the current review we will discuss the most important clinical features of the disease, advantages and disadvantages of the current diagnostic and therapeutic options and the main topics of future research in cystinosis

Ca(2+) signalling in human proximal tubular epithelial cells deficient for cystinosin

Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder caused by loss-of-function mutations in the CTNS gene coding for the lysosomal cystine transporter, cystinosin. Recent studies have demonstrated that, apart from cystine accumulation in the lysosomes, cystinosin-deficient cells, especially renal proximal tubular epithelial cells are characterized by abnormal vesicle trafficking and endocytosis, possible lysosomal dysfunction and perturbed intracellular signalling cascades. It is therefore possible that Ca(2+) signalling is disturbed in cystinosis, as it has been demonstrated for other disorders associated with lysosomal dysfunction, such as Gaucher, Niemann-Pick type C and Alzheimer's diseases. In this study we investigated ATP-induced, IP3-induced and lysosomal Ca(2+) release in human proximal tubular epithelial cells derived from control and cystinotic patients. No major dysregulation of intracellular Ca(2+) dynamics was found, although ATP-induced Ca(2+) release appeared slightly sensitized in cystinotic cells compared to control cells. Hence, these subtle changes in Ca(2+) signals elicited by agonists may contribute to the pathogenesis of the disease

Clinical utility of chitotriosidase enzyme activity in nephropathic cystinosis

Contains fulltext : 138675.pdf (publisher's version ) (Open Access)BackgroundNephropathic cystinosis is an inherited autosomal recessive lysosomal storage disorder characterized by the pathological accumulation and crystallization of cystine inside different cell types. WBC cystine determination forms the basis for the diagnosis and therapeutic monitoring with the cystine depleting drug (cysteamine). The chitotriosidase enzyme is a human chitinase, produced by activated macrophages. Its elevation is documented in several lysosomal storage disorders. Although, about 6% of Caucasians have enzyme deficiency due to homozygosity of 24-bp duplication mutation in the chitotriosidase gene, it is currently established as a screening marker and therapeutic monitor for Gaucher inverted question marks disease.MethodsPlasma chitotriosidase activity was measured in 45 cystinotic patients, and compared with 87 healthy controls and 54 renal disease patients with different degrees of renal failure (CKD1-5). Chitotriosidase levels were also correlated with WBC cystine in 32 treated patients. Furthermore, we incubated control human macrophages in-vitro with different concentrations of cystine crystals and monitored the response of tumor necrosis factor-alpha (TNF- inverted question mark) and chitotriosidase activity. We also compared plasma chitotriosidase activity in cystinotic knocked-out (n inverted question mark= inverted question mark10) versus wild-type mice (n inverted question mark= inverted question mark10).ResultsPlasma chitotriosidase activity in cystinotic patients (0 inverted question mark3880, median 163 nmol/ml/h) was significantly elevated compared to healthy controls (0 inverted question mark90, median 18 nmol/ml/h) and to CKD patients (0 inverted question mark321, median 52 nmol/ml/h), P inverted question mark< inverted question mark0.001 for both groups. Controls with decreased renal function had mild to moderate chitotriosidase elevations; however, their levels were significantly lower than in cystinotic patients with comparable degree of renal insufficiency. Chitotriosidase activity positively correlated with WBC cystine content for patients on cysteamine therapy (r inverted question mark= inverted question mark0.8), P inverted question mark< inverted question mark0.001. In culture, human control macrophages engulfed cystine crystals and released TNF- inverted question mark into culture supernatant in a crystal concentration dependent manner. Chitotriosidase activity was also significantly increased in macrophage supernatant and cell-lysate. Furthermore, chitotriosidase activity was significantly higher in cystinotic knocked-out than in the wild-type mice, P inverted question mark= inverted question mark0.003.ConclusionsThis study indicates that cystine crystals are potent activators of human macrophages and that chitotriosidase activity is a useful marker for this activation and a promising clinical biomarker and therapeutic monitor for nephropathic cystinosis

Connective tissue growth factor (CTGF) from basics to clinics

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Altered mTOR signalling in nephropathic cystinosis

Lysosomes play a central role in regulating autophagy via activation of mammalian target of rapamycin complex 1 (mTORC1). We examined mTORC1 signalling in the lysosomal storage disease nephropathic cystinosis (MIM 219800), in which accumulation of autophagy markers has been previously demonstrated. Cystinosis is caused by mutations in the lysosomal cystine transporter cystinosin and initially affects kidney proximal tubules causing renal Fanconi syndrome, followed by a gradual development of end-stage renal disease and extrarenal complications. Using proximal tubular kidney cells obtained from healthy donors and from cystinotic patients, we demonstrate that cystinosin deficiency is associated with a perturbed mTORC1 signalling, delayed reactivation of mTORC1 after starvation and abnormal lysosomal retention of mTOR during starvation. These effects could not be reversed by treatment with cystine-depleting drug cysteamine. Altered mTORC1 signalling can contribute to the development of proximal tubular dysfunction in cystinosis and points to new possibilities in therapeutic intervention through modulation of mTORC-dependent signalling cascades