Fabry disease is a progressive X-linked disorder of glycosphingolipid metabolism caused by a deficiency of the alpha-galactosidase lysosomal enzyme. The partial or complete deficiency of the lysosomal enzyme leads to an accumulation of neutral glycosphingolipids in the vascular endothelium and visceral tissues throughout the body. In the heart, glycosphingolipids deposition causes progressive left ventricular hypertrophy (LVH). We report a case of Fabry disease which was suspected based upon two-dimensional echocardiographic finding of LVH. A 44-year-old man was admitted to evaluation of aggravated exertional dyspnea of two weeks duration. He had been diagnosed with end-stage renal disease of unknown etiology at age 41 followed by renal transplantation that year. He had been treated with oral immunosuppressive agents. On hospital day two, transthoracic echocardiography revealed concentric LVH. Left ventricular systolic function was preserved but diastolic dysfunction was present. Fabry disease was confirmed by demonstration of a low plasma alpha-galactosidase A (alpha-Gal A) activity. Analysis of genomic DNA showed alpha-Gal A gene mutation. The patient was diagnosed with Fabry disease.
alpha-Galactosidase ; Cardiomyopathies ; DNA ; Dyspnea ; Echocardiography ; Endothelium, Vascular ; Fabry Disease ; Genes, vif ; Glycosphingolipids ; Heart ; Humans ; Hypertrophy, Left Ventricular ; Immunosuppressive Agents ; Kidney Failure, Chronic ; Kidney Transplantation ; Neutral Glycosphingolipids ; Plasma

Fabry's disease is a rare, inborn error, sex-linked disorder of glycosphingolipid metabolism with death occurring from myocardial or renal involvement at 4th or 5th decades. The primary metabolic defect lies in the deficient tissue activity of the enzyme alpha-galactosidase A which results in progressive accumulation of the specific neutral glycosphingolipids, cerebroside dihexoside(CDH) and cerebroside triihexoside(CTH), within the lysosomes of endothelial, perithelial and smooth muscle cells of the cardiovascular and renal systems predominantly. Clinical manifestations are sequelae of the anatomic and physiologic alterations produced by the progressive deposition of glycosphingolipid in the tissues. We report the first case of successful renal transplantation in a patient with Fabry's disease in Korea. The patient was a 33-year-old male. Fabry's disease was confirmed by measurement of serum alpha- galactosidase level and renal biopsy. Biopsy finding showed lamellar inclusion bodies on electron microscopy. Galactosidase activity was also markedly decreased. He has been well for 49 months.
Adult ; alpha-Galactosidase ; Biopsy ; Fabry Disease* ; Galactosidases ; Humans ; Inclusion Bodies ; Kidney Transplantation* ; Korea ; Lysosomes ; Male ; Metabolism ; Microscopy, Electron ; Myocytes, Smooth Muscle ; Neutral Glycosphingolipids ; Transplantation

Fabry's disease is a rare, inborn error, sex-linked disorder of glycosphingolipid metabolism with death occurring from myocardial or renal involvement at 4th or 5th decades. The primary metabolic defect lies in the deficient tissue activity of the enzyme alpha-galactosidase A which results in progressive accumulation of the specific neutral glycosphingolipids, cerebroside dihexoside(CDH) and cerebroside triihexoside(CTH), within the lysosomes of endothelial, perithelial and smooth muscle cells of the cardiovascular and renal systems predominantly. Clinical manifestations are sequelae of the anatomic and physiologic alterations produced by the progressive deposition of glycosphingolipid in the tissues. We report the first case of successful renal transplantation in a patient with Fabry's disease in Korea. The patient was a 33-year-old male. Fabry's disease was confirmed by measurement of serum alpha- galactosidase level and renal biopsy. Biopsy finding showed lamellar inclusion bodies on electron microscopy. Galactosidase activity was also markedly decreased. He has been well for 49 months.
Adult ; alpha-Galactosidase ; Biopsy ; Fabry Disease* ; Galactosidases ; Humans ; Inclusion Bodies ; Kidney Transplantation* ; Korea ; Lysosomes ; Male ; Metabolism ; Microscopy, Electron ; Myocytes, Smooth Muscle ; Neutral Glycosphingolipids ; Transplantation

Fabry disease, angiokeratoma corporis diffusum, is a rare X-linked inborn error of glycosphingolipid metabolism due to the lack of the lysosomal enzyme, alpha-galactosidase A, resulting in a progressive deposition of specific neutral glycosphingolipids within the lysosomes of endothelial and smooth muscle cells of the cardiovascular and renal systems predominantly. We reported a case of Fabry disease, following renal biopsy for the investigation of proteinuria(Creatinine clearance 87.28 mL/min/1.73, serum creatinine 1.1 mg/dL, 24-hour urine protein 1,125 mg, 24-hour urine creatinine 1,382 mg). The patient was 46 year old male. He had experienced anterior chest pain regarded as angina pectoris for a few years. A 12- lead electrocardiogram was abnormal(T-wave inversion in II, III, AVF, and V3-V6), but echocardiography and coronary angiography revealed no abnormal. Kidney biopsy findings showed lamella inclusion bodies on electron microscopy, which are typical finding of Fabry disease. The patient is followed at O.P.D without any significant complaints for 18 months after diagnosis of Fabry disease.
alpha-Galactosidase ; Angina Pectoris ; Biopsy* ; Chest Pain ; Coronary Angiography ; Creatinine ; Diagnosis ; Echocardiography ; Electrocardiography ; Fabry Disease* ; Humans ; Inclusion Bodies ; Kidney ; Lysosomes ; Male ; Metabolism ; Microscopy, Electron ; Middle Aged ; Myocytes, Smooth Muscle ; Neutral Glycosphingolipids ; Proteinuria*

Fabry's disease, angiokeratoma corporis diffusum, is a rare X-linked inborn error of glycosphingolipid metabolism due to the lack of the lysosomal enzyme, alpha-galactosidase A, resulting in a progressive intracellular deposition of neutral glycosphingolipids in various tissues, including the dorsal root ganglia, autonomic nervous system, vascular endothelial, and smooth muscle cells. Clinical manifestations of Fabry's disease result predominantly from the progressive deposition of globotriaocylceramide in the nervous system or vascular endothelium, and are characterized by acro-paresthesia, angiokeratoma, corneal opacity, TIA or stroke, ischemic heart disease, and renal failure. We report a case of a 19-year-old man presenting with a 12-year history of severe distal pain, acroparesthesia, short stature, and delayed puberty. An enzymatic assay disclosed substantially diminished alpha-galactosidase A activity and an electron microscopy of the peripheral nerve showed lipid inclusions which were composed of concentrically laminated, ovoid osmiophilic bodies in the perineural fibroblast and endothelial cells. These findings are typical of Fabry's disease and additional genetic study revealed deletion mutation(TTAG) at the 6th exon of the alpha-galactosidase A gene, which is a novel mutation that had never been reported in literatures. Symptomatic treatment with carbamazepine and clonazepam was tried with a good response.
alpha-Galactosidase ; Angiokeratoma ; Autonomic Nervous System ; Carbamazepine ; Clonazepam ; Corneal Opacity ; Endothelial Cells ; Endothelium, Vascular ; Enzyme Assays ; Exons* ; Fabry Disease* ; Fibroblasts ; Ganglia, Spinal ; Humans ; Metabolism ; Microscopy, Electron ; Myocardial Ischemia ; Myocytes, Smooth Muscle ; Nervous System ; Neutral Glycosphingolipids ; Peripheral Nerves ; Puberty, Delayed ; Renal Insufficiency ; Stroke ; Young Adult

Apoptosis ; Ceramides ; biosynthesis ; Sphingomyelins ; metabolism

Oral administration of royal jelly (RJ) promotes wound healing in diabetic mice. Concerns have arisen regarding the efficacy of RJ on the wound healing process of normal skin cells. In this study, a wound was created by scratching normal human dermal fibroblasts, one of the major cells involved in the wound healing process. The area was promptly treated with RJ at varying concentrations of 0.1, 1.0, or 5 mg/ml for up to 48 hrs and migration was analyzed by evaluating closure of the wound margins. Furthermore, altered levels of lipids, which were recently reported to participate in the wound healing process, were analyzed by HPTLC and HPLC. Migration of fibroblasts peaked at 24 hrs after wounding. RJ treatment significantly accelerated the migration of fibroblasts in a dose-dependent manner at 8 hrs. Although RJ also accelerated the migration of fibroblasts at both 20 hrs and 24 hrs after wounding, the efficacy was less potent than at 8 hrs. Among various lipid classes within fibroblasts, the level of cholesterol was significantly decreased at 8 hrs following administration of both 0.1 ug/ml and 5 mg/ml RJ. Despite a dose-dependent increase in sphinganines, the levels of sphingosines, ceramides, and glucosylceramides were not altered with any concentration of RJ. We demonstrated that RJ enhances the migration of fibroblasts and alters the levels of various lipids involved in the wound healing process.
Administration, Oral ; Animals ; Ceramides ; Cholesterol ; Chromatography, High Pressure Liquid ; Fatty Acids ; Fibroblasts ; Glucosylceramides ; Humans ; Mice ; Skin ; Sphingosine ; Wound Healing

AIMTo study the bioactive components from Helicia nilagirica.

METHODSCompounds were separated with a combination of multi-chromatography. Their chemical structures were determined on the basis of spectral analysis and chemical evidence.

RESULTSTwo compounds were isolated from the leaves of Helicia nilagirica. Compound 1 was elucidated as 1-O-3-D-glucopyranosyl-(2S,3S,4R,8Z)-2-[(2'R)-2'-hyd roxylignocenoyl-amino]-8-octadecene-1, 3, 4-triol. Compound 2 was an analogue of 1.

CONCLUSIONThe two compounds are new cerebrosides.

Cerebrosides ; chemistry ; isolation & purification ; Glucosylceramides ; chemistry ; isolation & purification ; Molecular Conformation ; Molecular Structure ; Plant Leaves ; chemistry ; Plants, Medicinal ; chemistry ; Proteaceae ; chemistry

Animals ; Antioxidants ; pharmacology ; Apoptosis ; drug effects ; Atherosclerosis ; prevention & control ; Ceramides ; analysis ; Dietary Fats ; administration & dosage ; Emodin ; pharmacology ; Lipids ; blood ; Male ; Rabbits ; Signal Transduction ; Sphingomyelin Phosphodiesterase ; metabolism ; Sphingomyelins ; metabolism

Because nerve growth factor (NGF) is elevated during inflammation, plays a causal role in the initiation of hyperalgesia, and is known to activate the sphingomyelin signalling pathway, we examined whether NGF and its putative second messenger, ceramide, could modulate the excitability of capsaicin-sensitive adult sensory neurons. Using the whole-cell patch-clamp recording technique, exposure of isolated sensory neurons to either 100 ng/mL NGF or 1 mmol/L N-acetyl sphingosine (C2-ceramide) produced a 3-4 fold increase in the number of action potentials (APs) evoked by a ramp of depolarizing current in a time-dependent manner. Intracellular perfusion with bacterial sphingomyelinase (SMase) also increased the number of APs suggesting that the release of native ceramide enhanced neuronal excitability. Glutathione, an inhibitor of neutral SMase, completely blocked the NGF-induced augmentation of AP firing, whereas dithiothreitol, an inhibitor of acidic SMase, was without effect. In the presence of glutathione and NGF, exogenous ceramide still enhanced the number of evoked APs, indicating that the sensitizing action of ceramide was downstream of NGF. To investigate the mechanisms of actions for NGF and ceramide, isolated membrane currents were examined. Both NGF and ceramide facilitated the peak amplitude of the TTX-resistant sodium current (TTX-R I(Na)) by approximately 1.5-fold and shifted the activation to more hyperpolarized voltages. In addition, NGF and ceramide suppressed an outward potassium current (I(K)) by ~35%. The inflammatory prostaglandin, PGE2, produced an additional suppression of I(K) after exposure to ceramide (~35%), suggesting that these agents might act on different targets. Based on the existing literature, it is not clear whether this NGF-induced sensitization is mediated by the high-affinity TrkA receptor or the low-affinity p75 neurotrophin receptor. Pretreatment with the p75 blocking antibody completely prevents the NGF-induced increase in the number of APs evoked by the current ramp. Although the sensitization by NGF was blocked, the antibody had no effect on the capacity of ceramide, a putative downstream signalling molecule, to enhance the excitability. Ceramide can be metabolized by ceramidase to sphingosine (Sph) and Sph to sphingosine 1-phosphate (S1P) by sphingosine kinase. It is well established that each of these products of sphingomyelin metabolism can act as intracellular signalling molecules. This raises the question as to whether the enhanced excitability produced by NGF was mediated directly by ceramide or required additional metabolism to Sph and/or S1P. Sph applied externally did not affect the neuronal excitability whereas internally perfused Sph augmented the number of APs evoked by the depolarizing ramp. Furthermore, internally perfused S1P enhanced the number of evoked APs. This sensitizing action of NGF, ceramide, and internally perfused Sph, were abolished by dimethylsphingosine (DMS), an inhibitor of sphingosine kinase. In contrast, internally perfused S1P enhanced the number of evoked APs in the presence of DMS. These observations support the idea that the metabolism of ceramide/Sph to S1P is critical for the sphingolipid-induced modulation of excitability. Thus, our findings indicate that the pro-inflammatory agent, NGF, can rapidly enhance the excitability of sensory neurons. This NGF-induced sensitization is mediated by activation of the sphingomyelin signalling pathway wherein intracellular S1P derived from ceramide, acts as an internal second messenger to regulate membrane excitability, however, the effector system whereby S1P modulates excitability remains undetermined.
Action Potentials ; Animals ; Cells, Cultured ; Ceramides ; pharmacology ; Lysophospholipids ; metabolism ; Nerve Growth Factor ; physiology ; Patch-Clamp Techniques ; Phosphotransferases (Alcohol Group Acceptor) ; metabolism ; Sensory Receptor Cells ; cytology ; Signal Transduction ; Sphingomyelins ; physiology ; Sphingosine ; analogs & derivatives ; metabolism