• Clinical and Experimental Pediatrics
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• v.54 no.6
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• pp.241-245
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• 2011

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that results from mutations in the TSC1 or TSC2 genes, and is associated with hamartomas in several organs, including subependymal giant cell tumors. The neurological manifestations of TSC are particularly challenging and include infantile spasms, intractable epilepsy, cognitive disabilities, and autism. The TSC1- and TSC2-encoded proteins modulate cell function via the mammalian target of rapamycin (mTOR) signaling cascade, and are key factors in the regulation of cell growth and proliferation. The mTOR pathway provides an intersection for an intricate network of protein cascades that respond to cellular nutrition, energy levels, and growth factor stimulation. In the brain, TSC1 and TSC2 have been implicated in cell body size, dendritic arborization, axonal outgrowth and targeting, neuronal migration, cortical lamination, and spine formation. The mTOR pathway represents a logical candidate for drug targeting, because mTOR regulates multiple cellular functions that may contribute to epileptogenesis, including protein synthesis, cell growth and proliferation, and synaptic plasticity. Antagonism of the mTOR pathway with rapamycin and related compounds may provide new therapeutic options for TSC patients.

• The Journal of Korean Medicine
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• v.36 no.2
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• pp.50-55
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• 2015

Infants with tuberous sclerosis complex (TSC) have a higher chance of experiencing seizures before the age of 1 year; in particular, they commonly accompany infantile spasms. In cases where infantile spasms resulting from TSC are drug-resistant, more severe neuro-developmental and cognitive impairments occur. This particular case dealt with an infant with TSC who continued to experience partial seizures and infantile spasms despite using two different kinds of antiepileptic drugs (AEDs). His spasms ceased on the seventh day of taking modified Yukmijihwang-tang (YMJ), at which point he stopped the use of all AEDs. He became seizure-free after a month of the treatment and modified hypsarrythmia was found to have been resolved in the electroencephalogram test. Until now, the infant has been taking YMJ for 16 months and is maintaining the seizure-free state without side effects. Moreover, his developmental status is continually improving, with a significant progress in language and cognitive-adaptive abilities. Such results suggest that YMJ can serve as an alternative treatment option for refractory epilepsy.

• Journal of Genetic Medicine
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• v.13 no.1
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• pp.36-40
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• 2016

Tuberous sclerosis complex (TSC, MIM#191100) is an autosomal dominant neurocutaneous syndrome caused by mutation or deletion of TSC1 encoding hamartin or TSC2 encoding tuberin and characterized by seizure, mental retardation, and multiple hamartomas or benign tumors in the skin, brain, retina, heart, kidney, and lungs. The TSC2 gene on chromosome 16p13.3 lies adjacent to the PKD1 gene which is responsible for autosomal dominant polycystic kidney disease (MIM#173900). The TSC2/PKD1 contiguous gene syndrome (TSC2/PKD1 CGDS, MIM#600273) is caused by deletion of both TSC2 and PKD1 gene. We recently experienced a 15 month-old boy and a 26 month-old girl with TSC2/PKD1 CGDS confirmed by multiplex ligation-dependent probe amplification (MLPA) analysis. They showed not only typical neurologic manifestations of TSC such as epilepsy, subependymal nodules, and subcortical tubers, but also polycystic kidney disease. The contiguous gene syndrome involving PKD1 and TSC2 should be suspected in children with enlarged polycystic kidneys and TSC. MLPA analysis is a useful method for the genetic confirmation of TSC2/PKD1 CGDS.

• Childhood Kidney Diseases
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• v.18 no.2
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• pp.132-136
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• 2014

Tuberous sclerosis complex (TSC) is a genetic disorder that affects multiple organ systems and causes tumors. It is important that physicians are aware of the manifestations of TSC, and that they follow the recommendations for screening and evaluation. Several types of renal abnormalities may develop in individuals with TSC. Individuals with TSC may require ongoing treatment that can be adapted for each arising manifestation of renal disease. Herein, we report 4 patients with TSC who presented with a range of different renal manifestations, including angiomyolipoma, renal cell carcinoma, renal infarction, renal cyst, and nephrolithiasis.

• Journal of Korean Neurosurgical Society
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• v.41 no.6
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• pp.397-402
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• 2007

Objective : Balloon cells and dysplastic neurons are histopathological hallmarks of the cortical tubers of tuberous sclerosis complex [TSC] and focal cortical dysplasia [FCD] of the Taylor type. They are believed to be the epileptogenic substrate and cause therapeutic drug resistant epilepsy in man. P-glycoprotein [P-gp] is the product of multidrug resistance gene [MDR1], and it maintains intracellular drug concentration at a relatively low level. The authors investigated expression of P-gp in balloon cells and dysplastic neurons of cortical tubers in patients with TSC. Methods : An immunohistochemical study using the primary antibody for P-gp, as an indicative of drug resistance, was performed in the cortical tuber tissues in two patients of surgical resection for epilepsy and six autopsy cases. Results : Balloon cells of each lesion showed different intensity and number in P-gp immunopositivity. P-gp immunopositivity in balloon cells were 28.2%, and dysplastic neurons were 22.7%. These immunoreactivities were more prominent in balloon cells distributed in the subpial region than deeper region of the cortical tubers. Capillary endothelial cells within the cortical tubers also showed P-gp immunopositivity. Conclusion : In this study, the drug resistance protein P-glycoprotein in balloon cells and dysplastic neurons might explain medically refractory epilepsy in TSC.

• Journal of the Korean Child Neurology Society
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• v.26 no.4
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• pp.284-287
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• 2018

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutation of one of two genes, TSC1 (encoding hamartin, 9q34) and TSC2 (encoding tuberin, 16p13). It invades the central nervous system and various parts of the body, causing various symptoms. Crohn's disease (CD) is a chronic immune-mediated disease that has not been clearly elucidated. It is thought to be caused by an excessive immune response of the body to bacteria that normally exist in the digestive tract with genetic factors. No cases have been reported in which both of the above-mentioned diseases occurred simultaneously. We report a case of CD in a patient with TSC. A 12-year-old boy was brought to our hospital because of abdominal pain. Skin lesions were observed in the TSC. Fundus examination revealed a hamartoma in the right retina. Brain magnetic resonance imaging revealed a subendothelial giant cell astrocytoma (SEGA). On the basis of these findings, he was diagnosed as having TSC. Blood test results showed increased levels of inflammatory markers. On abdominal ultrasonography, his colon walls were observed to be thickened with increased vascularity of the proximal ascending colon, ileocecal valve, and terminal ileum. Colonoscopy revealed discontinuous ulcerations and inflammations of the ileum, IC valve, and cecum, similar to those found in CD. Everolimus was administered orally for the SEGA but was discontinued frequently owing to the exacerbation of CD. The possibility of CD should be kept in mind in patients with TSC considering to undergo treatment for SEGA.

• Clinical and Experimental Pediatrics
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• v.50 no.2
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• pp.178-181
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• 2007

Purpose : The renal manifestations of tuberous sclerosis complex (TSC) are remarkably diverse, including polycystic kidney disease, simple renal cysts, renal cell carcinomas, and angiomyolipomas. All of these occur in children as well as adults in TSC. Angiomyolipomas, which can cause spontaneous life-threatening hemorrhages, are by far the most prevalent and the greatest source of morbidity. Here, we will address our experience, adding to the literature on pediatric patients with TSC requiring evaluation and treatment for renal manifestations. Methods : A retrospective analysis was made on 19 patients in whom TSC was diagnosed between May 2001 and Oct. 2005 at Severance Hospital. All patients had clinical diagnoses of TSC as defined by the 1998 tuberous sclerosis complex consensus conference. Results : The patients consisted of 13 boys and 6 girls with a mean age of 7.3 years (range 1 to 22). The renal disease associated with TSC included angiomyolipoma in nine patients (47.4 percent), renal simple cyst in one (5.3 percent), hydronephrosis in one (5.3 percent) patient. Eight patients (42.1 percent) presented with normal kidney contours at abdominal ultrasonography. One patient underwent renal replacement therapy due to chronic renal insufficiency after nephrectomy. Hemorrhage from angiomyolipoma was not detected. Conclusion : In our review of 19 cases of TSC, renal manifestations are reported in 57.9 percent of patients. Asymptomatic angiomyolipoma associated with TSC grow gradually, although severe hemorrhages are rare. So patients with TSC should be followed up with serial computerized tomography or abdominal ultrasonography. And also, renal function should be monitored conservatively.

• BMB Reports
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• v.55 no.5
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• pp.244-249
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• 2022

Characterized by abnormal proliferation and migration of vascular smooth muscle cells (VSMCs), neointima hyperplasia is a hallmark of vascular restenosis after percutaneous vascular interventions. Vaccinia-related kinase 1 (VRK1) is a stress adaption-associated ser/thr protein kinase that can induce the proliferation of various types of cells. However, the role of VRK1 in the proliferation and migration of VSMCs and neointima hyperplasia after vascular injury remains unknown. We observed increased expression of VRK1 in VSMCs subjected to platelet-derived growth factor (PDGF)-BB by western blotting. Silencing VRK1 by shVrk1 reduced the number of Ki-67-positive VSMCs and attenuated the migration of VSMCs. Mechanistically, we found that relative expression levels of β-catenin and effectors of mTOR complex 1 (mTORC1) such as phospho (p)-mammalian target of rapamycin (mTOR), p-S6, and p-4EBP1 were decreased after silencing VRK1. Restoration of β-catenin expression by SKL2001 and re-activation of mTORC1 by Tuberous sclerosis 1 siRNA (siTsc1) both abolished shVrk1-mediated inhibitory effect on VSMC proliferation and migration. siTsc1 also rescued the reduced expression of β-catenin caused by VRK1 inhibition. Furthermore, mTORC1 re-activation failed to recover the attenuated proliferation and migration of VSMC resulting from shVrk1 after silencing β-catenin. We also found that the vascular expression of VRK1 was increased after injury. VRK1 inactivation in vivo inhibited vascular injury-induced neointima hyperplasia in a β-catenin-dependent manner. These results demonstrate that inhibition of VRK1 can suppress the proliferation and migration of VSMC and neointima hyperplasia after vascular injury via mTORC1/β-catenin pathway.

• Biomolecules & Therapeutics
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• v.29 no.5
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• pp.506-518
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• 2021

The imprinted tumour suppressor NOEY2 is downregulated in various cancer types, including ovarian cancers. Recent data suggest that NOEY2 plays an essential role in regulating the cell cycle, angiogenesis and autophagy in tumorigenesis. However, its detailed molecular function and mechanisms in ovarian tumours remain unclear. In this report, we initially demonstrated the inhibitory effect of NOEY2 on tumour growth by utilising a xenograft tumour model. NOEY2 attenuated the cell growth approximately fourfold and significantly reduced tumour vascularity. NOEY2 inhibited the phosphorylation of the signalling components downstream of phosphatidylinositol-3'-kinase (PI3K), including phosphoinositide-dependent protein kinase 1 (PDK-1), tuberous sclerosis complex 2 (TSC-2) and p70 ribosomal protein S6 kinase (p70S6K), during ovarian tumour progression via direct binding to vascular endothelial growth factor receptor-2 (VEGFR-2). Particularly, the N-terminal domain of NOEY2 (NOEY2-N) had a potent anti-angiogenic activity and dramatically downregulated VEGF and hypoxia-inducible factor-1α (HIF-1α), key regulators of angiogenesis. Since no X-ray or nuclear magnetic resonance structures is available for NOEY2, we constructed the three-dimensional structure of this protein via molecular modelling methods, such as homology modelling and molecular dynamic simulations. Thereby, Lys15 and Arg16 appeared as key residues in the N-terminal domain. We also found that NOEY2-N acts as a potent inhibitor of tumorigenesis and angiogenesis. These findings provide convincing evidence that NOEY2-N regulates endothelial cell function and angiogenesis by interrupting the VEGFR-2/PDK-1/GSK-3β signal transduction and thus strongly suggest that NOEY2-N might serve as a novel anti-tumour and anti-angiogenic agent against many diseases, including ovarian cancer.

• Journal of the Korean Society of Food Science and Nutrition
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• v.45 no.9
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• pp.1257-1264
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• 2016

Extracts from Artemisia annua $Linn\acute{e}$ (AAE) have various functions (anti-malaria, anti-virus, and anti-oxidant). However, the mechanism of the effects of AAE is not well known. Thus, we determined the apoptotic effects of AAE in AGS human gastric carcinoma cells. In this study, we suggested that AAE may exert cancer cell apoptosis through the Akt/mammalian target of rapamycin (mTOR)/glycogen synthase kinase (GSK)-$3{\beta}$ signal pathway and mitochondria-mediated apoptotic proteins. Activation by Akt phosphorylation resulted in cell proliferation through phosphorylation of tuberous sclerosis complex 2 (TSC2), mTOR, and GSK-$3{\beta}$. Thus, de-phosphorylation of Akt inhibited cell proliferation and induced apoptosis through inhibition of Akt, mTOR, phosphorylation of GSK-$3{\beta}$ at serine9, and control of Bcl-2 family members. Inhibition of GSK-$3{\beta}$ attenuated loss of mitochondrial membrane potential and release of cytochrome C. Bax and pro-apoptotic proteins were activated by their translocation into mitochondria from the cytosol. Translocation of Bax induced outer membrane transmission and generated apoptosis through cytochrome C release and caspase activity. We also measured 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, lactate dehydrogenase assay, Hoechst 33342 staining, Annexin V-PI staining, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide staining, and Western blotting. Accordingly, our study showed that AAE treatment to AGS cells resulted in inhibition of Akt, TSC2, GSK-$3{\beta}$-phosphorylated, Bim, Bcl-2, and pro-caspase 3 as well as activation of Bax and Bak expression. These results indicate that AAE induced apoptosis via a mitochondrial event through regulation of the Akt/mTOR/GSK-$3{\beta}$ signaling pathways.