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4 results on '"Cystatin B (CSTB)"'

1. CSTB Downregulation Promotes Cell Proliferation and Migration and Suppresses Apoptosis in Gastric Cancer SGC-7901 Cell Line

Author

XiaoGuang Zou, Jian Zhang, JinXing Huang, and ZhenFeng Shi

Subjects
0301 basic medicine, Cancer Research, Cell Survival, Proliferation, Down-Regulation, Apoptosis, Transfection, Article, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, Cell Movement, Stomach Neoplasms, Cell Line, Tumor, Humans, Cystatin B, Viability assay, RNA, Small Interfering, Protein kinase B, Migration, PI3K/AKT/mTOR pathway, Cell Proliferation, Cell growth, Chemistry, TOR Serine-Threonine Kinases, General Medicine, Cystatin B (CSTB), PI3K/Akt/mTOR pathway, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, Lipofectamine, Cancer research, Gastric cancer, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

This study aimed to investigate the pivotal role of cystatin B (CSTB) in the development of gastric cancer and to explore its possible regulatory mechanism. Human gastric cancer SGC-7901 cells as a model in vitro were transfected with plasmid PCDNA3.1-CSTB and siRNA-CSTB using Lipofectamine 2000. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to determine the relative expression of CSTB and PI3K/Akt/mTOR pathway-related protein. Moreover, MTT assay, Transwell assay, and flow cytometry were used to assess cell proliferation, migration, and apoptosis, respectively. The results showed that CSTB was significantly downregulated in SGC-7901 cells compared with gastric epithelial cells. CSTB was successfully overexpressed and suppressed after cells were transfected with pc-CSTB and si-CSTB, respectively. Moreover, cell viability and migration were significantly decreased after being transfected with pc-CSTB when compared with the control group, while being obviously increased after transfection with si-CSTB. However, cell apoptosis was significantly induced after being transfected with pc-CSTB, while being obviously suppressed after transfection with si-CSTB. Besides, the expression levels of p-PI3K, p-Akt, and p-mTOR proteins were all significantly decreased in the pc-CSTB transfection group when compared with the control group, while being increased in the si-CSTB transfection group. Our findings suggest that CSTB downregulation may promote the development of gastric cancer by affecting cell proliferation and migration, and the PI3K/Akt/mTOR signaling pathway was activated in this process. CSTB may serve as a potential therapeutic target for gastric cancer.

Published
2016
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2. A pathogenetic hypothesis of Unverricht-Lundborg disease onset and progression

Author

Giuliano Avanzini, Giulio Sancini, Maia Chikhladze, Carolina Frassoni, Andrea Buzzi, Giuseppina Magnaghi, Silvia Zucchini, Silvana Franceschetti, Beatrice Paradiso, Michele Simonato, Franceschetti, S, Sancini, G, Buzzi, A, Zucchini, S, Paradiso, B, Magnaghi, G, Frassoni, C, Chikhladze, M, Avanzini, G, and Simonato, M

Subjects
medicine.medical_specialty, Pathology, Population, Unverricht-Lundborg disease (EPM1), Hippocampus, Kainate receptor, Epilepsies, Myoclonic, Progressive myoclonus epilepsy, EPM1, Biology, lcsh:RC321-571, Epilepsy, Mice, Organ Culture Techniques, Unverricht-Lundborg Syndrome, BIO/09 - FISIOLOGIA, Internal medicine, medicine, Excitatory Amino Acid Agonists, Animals, Genetic Predisposition to Disease, Cystatin B, Neurodegeneration, Excitotoxicity, education, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Cell damage, Mice, Knockout, Neurons, education.field_of_study, Kainic Acid, medicine.disease, Cystatins, Unverricht–Lundborg disease, Electrophysiology, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Neurology, Nerve Degeneration, cystatin B (CSTB), Disease Progression, Microglia
Abstract

Unverricht-Lundborg disease (EPM1), the most common progressive myoclonic epilepsy, is associated with a defect of cystatin B (CSTB), a protease inhibitor. We used CSTB knockout mice to test the hypothesis that EPM1 onset is related to a latent hyperexcitability and that progression depends on higher susceptibility to seizure-induced cell damage. Hippocampal slices prepared from CSTB-deficient mice were hyperexcitable, as they responded to afferent stimuli in CA1 with multiple population spikes and kainate perfusion provoked the appearance of epileptic-like activity earlier than in WT mice. This hyperexcitability may depend on loss of inhibition, because the density of GABA-immunoreactive cells was reduced in the hippocampus of CSTB knockouts. In vivo, CSTB-deficient mice treated with kainate displayed increased susceptibility to seizures, with shorter latency to seizure onset and increased seizure severity compared with WT littermates. Furthermore, a greater degree of neuronal damage was observed in CSTB-deficient than in WT mice after seizures of identical grade, indicating increased susceptibility to seizure-induced cell death.

Published
2006

3. A pathogenetic hypothesis of Unverricht-Lundborg disease onset and progression

Author

Franceschetti, S, Sancini, G, Buzzi, A, Zucchini, S, Paradiso, B, Magnaghi, G, Frassoni, C, Chikhladze, M, Avanzini, G, Simonato, M, Simonato, M., SANCINI, GIULIO ALFREDO, Franceschetti, S, Sancini, G, Buzzi, A, Zucchini, S, Paradiso, B, Magnaghi, G, Frassoni, C, Chikhladze, M, Avanzini, G, Simonato, M, Simonato, M., and SANCINI, GIULIO ALFREDO

Abstract

Unverricht-Lundborg disease (EPM1), the most common progressive myoclonic epilepsy, is associated with a defect of cystatin B (CSTB), a protease inhibitor. We used CSTB knockout mice to test the hypothesis that EPM1 onset is related to a latent hyperexcitability and that progression depends on higher susceptibility to seizure-induced cell damage. Hippocampal slices prepared from CSTB-deficient mice were hyperexcitable, as they responded to afferent stimuli in CA1 with multiple population spikes and kainate perfusion provoked the appearance of epileptic-like activity earlier than in WT mice. This hyperexcitability may depend on loss of inhibition, because the density of GABA-immunoreactive cells was reduced in the hippocampus of CSTB knockouts. In vivo, CSTB-deficient mice treated with kainate displayed increased susceptibility to seizures, with shorter latency to seizure onset and increased seizure severity compared with WT littermates. Furthermore, a greater degree of neuronal damage was observed in CSTB-deficient than in WT mice after seizures of identical grade, indicating increased susceptibility to seizure-induced cell death.

Published
2007

4. Niemann-Pick Type C Disease: Protective Mechanisms from Neurodegeneration and Targets for Therapeutic Intervention.

Author

Chung, Chan

Subjects
Niemann-Pick type C (NPC), Cystatin B (CSTB), Heat shock protein beta-1 (HSPB1), Neurodegeneration in NPC disease, Cathepsins mislocalization
Abstract

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder that causes progressive neurodegeneration and early death, often in children. The two disease-causing proteins, NPC1 and NPC2, are involved in the movement of unesterified cholesterol out of late endosomes and lysosomes (LE/Lys). Loss-of-function mutations in the NPC1 or NPC2 genes lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/Lys. NPC disease is characterized by severe neurological symptoms including ataxia, cognitive decline, seizures, dystonia, and vertical gaze palsy. The mechanism underlying this neurodegeneration has not been identified, and there is no effective treatment for the disease. This dissertation aims to characterize a pathway leading to neuronal death and several modifier genes that promote neuronal survival in NPC disease. This work may provide a foundation for future studies that could lead to the development of novel therapies. Chapter 1 introduces the genetics and pathology of NPC disease, and reviews lysosomal proteases and heat shock protein beta-1 (HSPB1). After reviewing the known factors involved in NPC disease, chapter 2 presents studies demonstrating that cystatin B (CSTB), an endogenous inhibitor of cathepsins B, H, and L, protects Purkinje cells against cerebellar degeneration in a mouse model of NPC disease. Chapter 3 presents research that seeks to identify genes that may be neuroprotective or create vulnerability in the NPC brain, using the Allen Brain Atlas. One candidate gene, HSPB1, is confirmed to promote neuronal survival in cellular and mice models of NPC disease, and the mechanism by which HSPB1 protects cells from NPC deficiency is shown. Finally, chapter 4 summarizes these findings, discusses relevant questions that remain open, and suggests future directions for work in this area. The work described in this thesis will help us understand the pathways leading to neurodegeneration in NPC disease. It is my hope that this knowledge will enable the identification of targets for the future development of disease modifying therapies.

Published
2016

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