• The Korean Journal of Pharmacology
• /
• v.24 no.1
• /
• pp.83-92
• /
• 1988

Although the release of lysosomal enzymes from activated PMN leukocyte can be regulated by intracellular cyclic nucleotide levels, other responses of PMN leukocyte according to the binding of neurotransmitters to either ${\beta}$-adrenergic or muscarinic receptors are still not clarified. In addition, the function of PMN leukocyte mediated by ${\alpha}$-adrenergic receptors is uncertain. Atropine, phentolamine and propranolol inhibited calcium uptake, superoxide generation, NADPH oxidase activity and phagocytic activity in activated PMN leukocyte, whereas carbachol and isoproterenol slightly further stimulated the responses of activated cells. Either carbachol or isoproterenol stimulated superoxide generation was inhibited by their antagonists, atropine and propranolol, respectively. The response of activated PMN leukocyte was inhibited by chlorpromazine, verapamil and dantrolene but slightly stimulated by lithium. On the other hand, chlorpromazine and dibucaine did not affect NADPH oxidase activity. Atropine, phentolamine and propranolol suppressed the calcium dependent phagocytic activity. Thus, the results suggest that atropine, phentolamine and propranolol may inhibit superoxide generation in activated PMN leukocyte by the inhibition of calcium influx and by their direct action on the NADPH oxidase system which is associated with autonomic receptors.

• Asian-Australasian Journal of Animal Sciences
• /
• v.32 no.11
• /
• pp.1776-1788
• /
• 2019

Objective: The demands for measures to improve disease resistance and productivity of livestock are increasing, as most countries prohibit the addition of antibiotics to feed. This study therefore aimed to uncover functional feed additives to help enhance livestock immunity and disease resistance, using Acanthopanax sessiliflorus fruit extract (ASF). Methods: ASF was extracted with 70% EtOH, and total polyphenolic and catechin contents were measured by the Folin-Ciocalteu and vanillin assay, respectively. The 3D4/31 porcine macrophage cells ($M{\Phi}$) were activated by phorbol 12-myristate 13-acetate (PMA), and cell survival and growth rate were measured with or without ASF treatment. Flow-cytometric analysis determined the lysosomal activity, reactive oxygen species levels (ROS), and cell cycle distribution. Nuclear factor kappa B ($NF-{\kappa}B$) and superoxide dismutase (SOD) protein expression levels were quantified by western blotting and densitometry analysis. Quantitative polymerase chain reaction was applied to measure the lipid metabolism-related genes expression level. Lastly, the antibacterial activity of 3D4/31 $M{\Phi}$ cells was evaluated by the colony forming unit assay. Results: ASF upregulated the cell viability and growth rate of 3D4/31 $M{\Phi}$, with or without PMA activation. Moreover, lysosomal activity and intracellular ROS levels were increased after ASF exposure. In addition, the antioxidant enzyme SOD2 expression levels were proportionately increased with ROS levels. Both ASF and PMA treatment resulted in upregulation of $NF-{\kappa}B$ protein, tumor necrosis factor $(TNF){\alpha}$ mRNA expression levels, lipid synthesis, and fatty acid oxidation metabolism. Interestingly, co-treatment of ASF with PMA resulted in recovery of $NF-{\kappa}B$, $TNF{\alpha}$, and lipid metabolism levels. Finally, ASF pretreatment enhanced the in vitro bactericidal activity of 3D4/31 $M{\Phi}$ against Escherichia coli. Conclusion: This study provides a novel insight into the regulation of $NF-{\kappa}B$ activity and lipid metabolism in $M{\Phi}$, and we anticipate that ASF has the potential to be effective as a feed additive to enhance livestock immunity.

• BMB Reports
• /
• v.40 no.5
• /
• pp.636-643
• /
• 2007

This study was designed to identify and characterize the mechanism of macrophage activation by AAP, an acidic polysaccharide fraction isolated from the roots of Angelica sinensis (Oliv.) Diels. As a result, AAP significantly enhanced nitric oxide (NO) production and cellular lysosomal enzyme activity in murine peritoneal macrophages in vitro and in vivo. Furthermore, L-NAME, a specific inhibitor of inducible nitric oxide synthase (iNOS), effectively suppressed AAP-induced NO generation in macrophages, indicating that AAP stimulated macrophages to produce NO through the induction of iNOS gene expression and the result was further confirmed by the experiment of the increase of AAP-induced iNOS transcription in a dose-dependent manner. To further investigate, AAP was shown to strongly augment toll-like receptor 4 (TLR4) mRNA expression and the pretreatment of macrophages with anti-TLR4 antibody significantly blocked AAP-induced NO release and the increase of iNOS activity, and tumor necrosis factor-$\alpha$ (TNF-$\alpha$) secretion.

• Journal of Genetic Medicine
• /
• v.13 no.2
• /
• pp.59-64
• /
• 2016

Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by deficiency of acid ${\beta}$-glucosidase. The diminished enzyme activity leads to the accumulation of substrates and results in multi-systemic manifestations including hepatosplenomegaly, anemia, thrombocytopenia, and bone diseases. Enzyme replacement therapy (ERT) by infusion of recombinant protein has been the standard treatment for over 20 years. Despite the successful long-term treatment with ERT, several unmet needs remain in the treatment of GD1 such as severe pulmonary and skeletal manifestations. Substrate reduction therapy (SRT) reduces the accumulation of substrates by inhibiting their biosynthesis. Eliglustat, a new oral SRT, was approved in United States and Europe as a first-line therapy for treating adult patients with GD1 who have compatible CYP2D6 metabolism phenotypes. Although eliglustat is not yet available in Korea, introduction and summary of this new treatment modality are provided in this paper by review of literatures. Despite the fact that there are only limited studies to draw resolute conclusions, the current data demonstrated that eliglustat is not inferior to ERT in terms of its clinical efficacy. The approval of eligustat enables eligible adult GD1 patients to have the option of oral therapy although it still needs further studies on long-term outcomes. The individual patient should be assessed carefully for the choice of treatment modality when eliglustat becomes available in Korea. Furthermore, the clinical guidelines for Korean patients with GD1 regarding the use of eliglustat needs to be developed in near future.

• Childhood Kidney Diseases
• /
• v.20 no.2
• /
• pp.79-82
• /
• 2016

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme ${\alpha}-galactosidase$ A, resulting in the accumulation of glycosphingolipids within the lysosomes of various cell types. It has a wide spectrum of clinical phenotypes, and renal failure is a serious complication. Fabry disease is confirmed either by measurement of ${\alpha}-galactosidase$ A activity or by genetic testing for GLA mutations. Renal biopsy findings on light microscopy, specifically enlarged podocytes with foamy cytoplasm, and osmiophilic inclusion bodies in the cytoplasm in all types of renal cells on electron microscopy, are characteristic of this disease. The predominant differential diagnosis is iatrogenic phospholipidosis in association with certain drugs that can cause cellular injuries indistinguishable from Fabry disease. Here, we report the case of a 10-year-old boy with microscopic hematuria who underwent a renal biopsy that showed morphological findings consistent with Fabry disease, although the patient had neither a GLA mutation nor a history of drug consumption. Six years later, spontaneous regression of this renal pathology was observed in a second renal biopsy examination.

• Journal of Genetic Medicine
• /
• v.13 no.2
• /
• pp.72-77
• /
• 2016

Purpose: Gaucher disease (GD) is the most common lysosomal storage disease caused by beta-glucocerebrosidase (GBA) deficiency. Oral substrate reduction therapy with miglustat ($Zavesca^{(R)}$) was approved for the treatment of adults with GD type 1, for whom enzyme replacement therapy (ERT) is unsuitable or not a therapeutic option. In this study, we report the effect of miglustat ($Zavesca^{(R)}$) in three Korean GD patients. Materials and Methods: Clinical findings comprising age at diagnosis, presenting signs, laboratory findings at diagnosis, GBA activity and mutations, and clinical courses of the three patients were reviewed. Results: Miglustat was administered to three patients who reported allergic reactions during intravenous imiglucerase infusions. One patient withdrew after 15 months of miglustat administration owing to continuous elevation of disease biomarker levels (chitotriosidase, acid phosphatase, and angiotensin-converting enzyme). Poor adherence to medication was suspected but was denied by the patient. In the other two patients, platelet count and levels of hemoglobin and other biomarkers remained stable during miglustat administration. However, they suffered from severe diarrhea and weight loss, which led to miglustat discontinuation after 1 and 12 months of administration. Conclusion: Our study shows that although miglustat is suggested to GD patients as an alternative treatment to ERT, significant adverse reactions may lead to discontinuation of miglustat. In addition, it is difficult to monitor the drug adherence.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.17 no.2
• /
• pp.63-68
• /
• 2017

Gaucher disease (GD) is caused by the deficiency of glucocerebrosidase. In pediatric patients with GD, especially Type I GD, enzyme replacement therapy (ERT) can reduce the hepatosplenomegaly and improve the hematologic finding and growth velocity. Herein, we report a 2-year-old girl with Type I GD presented with hepatosplenomegaly, bone pain and growth retardation. A 2 year-old-girl was referred to our hospital due to severe hepatosplenomegaly and growth retardation. She suffered from both leg pain and chronic fatigue. Simple x-ray showed widened distal long bones like that of an 'Erlenmeyer flask' which is associated with GD. The laboratory test showed anemia and thrombocytopenia. The enzyme activity was markedly reduced and the direct sequencing of the GBA gene showed the compound heterozygous mutations, p.G46E and p.L444P. As the G46E have been considered as the protective gene against neuronopathic genotype, we could assess the Type I GD in this patient. After one year of ERT, the growth velocity became 11 cm per year. Bone pain and fatigue disappeared. The volume of liver and spleen was reduced from $683cm^3$ and $703cm^3$ to $590cm^3$ and $235cm^3$, respectively. Although GD is an extremely rare disease in Korea, growth retardation and bone pain in children are the important signs which lead to early detection of GD and a simple radiologic finding is helpful to assess the GD at outpatient clinic. We highlight that the early diagnosis and early ERT is important for good growth and outcome for pediatric patients with GD.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.13 no.1
• /
• pp.37-42
• /
• 2013

Gaucher disease is a lysosomal storage disease caused by deficiency of glucocerebrosidase (GBA). This condition is characterized by accumulation of glucocerebrosidase in liver, spleen, lung, skeletal system, and central nervous system. Gaucher disease is the prototype of disease in which efficacy of enzyme replacement therapy has been established. However, because recombinant enzyme is not able to enter the central nervous system, its efficacy is limited to the non-neurological manifestations of Gaucher disease. Importantly, approximately a half of Korean patients with Gaucher disease suffer from neurological manifestations. In addition, Korean Gaucher disease patients exhibit distinct mutation spectrum from those in other populations. Common mutations in Korean patients with Gaucher disease are also associated with neurological phenotype. Therefore, therapeutic strategies tailored to Korean patients were necessary. Interestingly, a chemical chaperone, ambroxol, has been known to increase residual enzymatic activities of the select mutant GBAs encoded by mutations prevalent in Korean patients. One promising aspect of this drug is that it can cross blood-brain barrier, and enhance the enzyme activity in the brain. In vitro study suggested this chemical chaperone as one of new therapeutic agents in Gaucher disease, and a well-designed human trial is required to confirm its efficacy.

• Journal of mucopolysaccharidosis and rare diseases
• /
• v.3 no.1
• /
• pp.20-27
• /
• 2017

Purpose: Mucopolysaccharidosis IV (MPS IV) is a disease characterized by deficient activity of N-acetylgalactosamine-6-sulfatase (GALNS) causing excessive lysosomal storage of keratan sulfate (KS). The identification of the relevant disaccharide units of KS after keratanase II digestion followed by liquid chromatography/tandem mass spectrometry detection (LC-MS/MS) is validated and applicable for the preliminary diagnosis of MPS IV. Methods: A total of 67 urine samples were collected and analyzed from 11 MPS IV patients comprising 10 MPS IVA and one MPS IVB patients, and 56 normal controls. Urinary glycosaminoglycan was first precipitated by the Alcian blue method followed by a digestion of keratanase II. The protonated species of the digested disaccharide products were detected by using multiple reaction monitoring experiment. Results: One particular disaccharide of KS was selected. The transition mass-to-charge (m/z) of the parent ion and its daughter ion after collision was $462.0{\rightarrow}97.0$, whereas the chondrosine used as an internal standard in this assay was m/z $353.9{\rightarrow}73.0$. The results corresponded well with the two-dimensional electrophoresis method. The quantities of urinary KS were significantly raised in confirmed MPS IV patients when comparing with those of normal controls ($170.2{\pm}81.1$ vs. $4.06{\pm}1.92{\mu}g/mL$). Conclusion: The LC-MS/MS method for MPS IVA determination is specific, sensitive, validated, and applicable for urinary KS quantification. This method can be used not only as a first-line biochemistry examination of MPS IVA, but also as an outcome survey after enzyme replacement therapy.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.24 no.1
• /
• pp.17-25
• /
• 2024

Fabry disease (FD) is an X-linked lysosomal storage disorder. It is caused by mutations in the α-galactosidase A gene, which results in deficient or absent activity of α-galactosidase A (α-Gal A). This leads to a progressive accumulation of globotriaosylceramide (Gb3) in various tissues. Manifestations of Fabry disease include serious and progressive impairment of renal and cardiac function. In addition, patients experience pain, gastrointestinal disturbance, transient ischaemic attacks, and strokes. Additional effects on the skin, eyes, ears, lungs, and bones are often seen. Reduced life expectancy and deadly consequences are being caused by cardiac involvement. Chaperone therapy or enzyme replacement therapy (ERT) are two disease-specific treatments for FD. Thus, early detection of FD is critical for decreasing morbidity and mortality. Globotriaosysphingosine (lyso-Gb3) for identifying atypical FD variants and highly sensitive troponin T (hsTNT) for detecting cardiac involvement are both significant diagnostic indicators. This review aimed to offer a basic resource for the early diagnosis and update on the diagnosis of having FD. We will also provide a general diagnostic algorithm and information on ERT and its accompanying treatments.