Kai-Yun Chen - Academia.edu (original) (raw)

Papers by Kai-Yun Chen

Research paper thumbnail of The functional roles of IGF-1 variants in the susceptibility and clinical outcomes of mild traumatic brain injury

Journal of Biomedical Science, 2019

Background Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts n... more Background Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts neuroprotective and neuroreparative effects after a brain injury. However, the roles of IGF-1 variants in mild traumatic brain injury (mTBI) are not yet fully understood. This study attempted to elucidate the effects of IGF-1 variants on the risk and neuropsychiatric outcomes of mTBI. Methods Based on 176 recruited mTBI patients and 1517 control subjects from the Taiwan Biobank project, we first compared the genotypic distributions of IGF-1 variants between the two groups. Then, we analyzed associations of IGF-1 variants with neuropsychiatric symptoms after mTBI, including anxiety, depression, dizziness, and sleep disturbances. Functional annotation of IGF-1 variants was also performed through bioinformatics databases. Results The minor allele of rs7136446 was over-represented in mTBI patients compared to community-based control subjects. Patients carrying minor alleles of rs7136446 and r...

Research paper thumbnail of The role of tyrosine kinase Etk/Bmx in EGF-induced apoptosis of MDA-MB-468 breast cancer cells

Oncogene, Jan 11, 2004

Etk/Bmx, a member of the Tec family of tyrosine kinases, mediates various signaling pathways and ... more Etk/Bmx, a member of the Tec family of tyrosine kinases, mediates various signaling pathways and confers several cellular functions. In the present study, we have explored the functional role of Etk in mediating EGF-induced apoptosis, using MDA-MB-468 cell line as a model. We first demonstrated that EGF treatment induces Etk tyrosine phosphorylation in both HeLa and MDA-MB-468 cells. Overexpression of Etk by recombinant adenovirus in MDA-MB-468 cells potentiates the extent of EGF-induced cell apoptosis. The observed Etk-enhanced MDA-MB-468 cell apoptosis is associated with the Stat1 activation, as demonstrated by electrophoresis mobility shift assays and reporter gene assays. By contrast, a kinase domain deletion mutant EtkDeltaK, functioning as a dominant-negative mutant, ameliorates EGF-induced Stat1 activation and apoptosis in MDA-MB-468 cells. To explore whether the activated Etk alone is sufficient for inducing apoptosis, a conditionally activated Etk (DeltaEtk-ER), a chimeric ...

Research paper thumbnail of The Influence of BMX Gene Polymorphisms on Clinical Symptoms after Mild Traumatic Brain Injury

BioMed Research International, 2014

Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patient... more Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patients diagnosed with mTBI could fully recover, but 15% of patients suffer from persistent symptoms. In recent studies, genetic factors were found to be associated with recovery and clinical outcomes after TBI. In addition, results from our previous research have demonstrated that the bone marrow tyrosine kinase gene in chromosome X (BMX), a member of the Tec family of kinases, is highly expressed in rats with TBI. Therefore, our aim in this study was to identify the association between genetic polymorphisms of BMX and clinical symptoms following mTBI. Four tagging single nucleotide polymorphisms (tSNPs) of BMX with minimum allele frequency (MAF) >1% were selected from the HapMap Han Chinese database. Among these polymorphisms, rs16979956 was found to be associated with the Beck anxiety inventory (BAI) and dizziness handicap inventory (DHI) scores within the first week after head injury. Additionally, another SNP, rs35697037, showed a significant correlation with dizziness symptoms. These findings suggested that polymorphisms of the BMX gene could be a potential predictor of clinical symptoms following mTBI.

Research paper thumbnail of Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression

Biochemical and biophysical research communications, Jan 6, 2009

CD133-expressing glioma cells play a critical role in tumor recovery after treatment and are resi... more CD133-expressing glioma cells play a critical role in tumor recovery after treatment and are resistant to radiotherapy. Herein, we demonstrated that glioblastoma-derived CD133-positive cells (GBM-CD133(+)) are capable of self-renewal and express high levels of embryonic stem cell genes and SirT1 compared to GBM-CD133(-) cells. To evaluate the role of SirT1 in GBM-CD133(+), we used a lentiviral vector expressing shRNA to knock-down SirT1 expression (sh-SirT1) in GBM-CD133(+). Silencing of SirT1 significantly enhanced the sensitivity of GBM-CD133(+) to radiation and increased the level of radiation-mediated apoptosis. Importantly, knock-down of SirT1 increased the effectiveness of radiotherapy in the inhibition of tumor growth in nude mice transplanted with GBM-CD133(+). Kaplan-Meier survival analysis indicated that the mean survival rate of GBM-CD133(+) mice treated with radiotherapy was significantly improved by Sh-SirT1 as well. In sum, these results suggest that SirT1 is a potenti...

Research paper thumbnail of Post-Receptor Crosstalk between Growth Hormone and Insulin Signal in Rats Born Small for Gestational Age with Catch-Up Growth

PLoS ONE, 2014

Insulin resistance has been observed in individuals born small for gestational age (SGA) with cat... more Insulin resistance has been observed in individuals born small for gestational age (SGA) with catch-up growth (CUG), yet the mechanisms involved remain unclear. This study examined the role of GH and insulin signaling crosstalk in insulin resistance of SGA rats with CUG. SGA rats were developed by dietary restriction in pregnant rats. GH receptor inhibition was performed on four-week old CUG-SGA and AGA rats. Phosphorylation of IRS-1, AKT, and ERK, and expression of SOCS3 in the skeletal muscle were determined via immunoblot analysis at baseline and after insulin stimulation in CUG-SGA, NCUG-SGA and AGA groups. Compared to AGA controls, phosphorylation of IRS-1 and AKT in response to insulin stimulation in CUG-SGA rats was significantly blunted (P<0.05), and phosphorylation of ERK at baseline was dramatically activated (P<0.05). SOCS3 expression was significantly increased in CUG-SGA compared to AGA (P = 0.001) and NCUG-SGA (P = 0.006) rats, and was significantly suppressed following GHR inhibition (P<0.05). Furthermore, phosphorylation of IRS-1 and AKT in response to insulin stimulation increased after GHR inhibition (P<0.05). Insulin resistance in CUG-SGA rats is associated with impairment of IRS-1-PI3K-AKT signaling, which may result from GH signaling-induced up-regulation of SOCS3.

Research paper thumbnail of Different sham procedures for rats in traumatic brain injury experiments induce corresponding increases in levels of trauma markers

Journal of Surgical Research, 2013

Controlled cortical impact Marker a b s t r a c t Background: In traumatic brain injury animal mo... more Controlled cortical impact Marker a b s t r a c t Background: In traumatic brain injury animal models, sham or naïve control groups are often used for the analysis of injured animals; however, the existence and/or significance of differences in the control groups has yet to be studied. In addition, recent controversies regarding the decompressive craniectomy trial in which decompressive craniectomies in patients with severe traumatic brain injury and refractory increased intracranial pressure remains unsettled. Although the report demonstrated that the procedure may result in less favorable long-term outcomes despite the decrease in intracranial pressure and shorter length of intensive care unit stay, the study has been criticized, and the debate is still inconclusive partly because of a lack of mechanistic explanation. We have recently discovered epithelial and endothelial tyrosine kinase (Etk) to exhibit upregulation after traumatic neural injury and will compare the effects of craniectomy procedure with those of other procedures inducing different levels of severity.

Research paper thumbnail of Suppression of Etk/Bmx Protects Against Ischemic Brain Injury

Cell Transplantation, 2012

Etk/Bmx (epithelial and endothelial tyrosine kinase, also known as BMX), a member of the Tec (tyr... more Etk/Bmx (epithelial and endothelial tyrosine kinase, also known as BMX), a member of the Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of protein-tyrosine kinases, is an important regulator of signal transduction for the activation of cell growth, differentiation, and development. We have previously reported that activation of Etk leads to apoptosis in MDA-MB-468 cells. The purpose of this study was to examine the role of Etk in neuronal injury induced by H(2)O(2) or ischemia. Using Western blot analysis and immunohistochemistry, we found that treatment with H(2)O(2) significantly enhanced phosphorylation of Etk and its downstream signaling molecule Stat1 in primary cortical neurons. Inhibiting Etk activity by LFM-A13 or knocking down Etk expression by a specific shRNA increased the survival of primary cortical neurons. Similarly, at 1 day after a 60-min middle cerebral artery occlusion (MCAo) in adult rats, both phosphorylated Etk and Stat1 were coexpressed with apoptotic markers in neurons in the penumbra. Pretreatment with LFM-A13 or an adenoviral vector encoding the kinase deletion mutant Etkk attenuated caspase-3 activity and infarct volume in ischemic brain. All together, our data suggest that Etk is activated after neuronal injury. Suppressing Etk activity protects against neurodegeneration in ischemic brain.

Research paper thumbnail of Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury

Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting sympto... more Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting symptoms of mTBI and the characterization of those symptoms has been challenging. Biomarkers that correlate clinical symptoms to disease outcome are desired to improve understanding of the disease and optimize patient care. BMX, a member of the TEC family of nonreceptor tyrosine kinases, is upregulated after traumatic neural injury in a rat model of mTBI. The objective of this investigation was to determine if BMX serum concentrations can effectively be used to predict outcomes after mTBI in a clinical setting. A total of 63 patients with mTBI (Glasgow Coma Score [GCS] between13-15) were included. Blood samples taken at the time of hospital admission were analyzed for BMX. Data collected included demographic and clinical variables. Outcomes were assessed using the Dizziness Handicap Inventory (DHI) questionnaire at baseline and 6 weeks post-injury. The participant was asssigned to 'case gr...

Research paper thumbnail of The functional roles of IGF-1 variants in the susceptibility and clinical outcomes of mild traumatic brain injury

Journal of Biomedical Science, 2019

Background Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts n... more Background Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts neuroprotective and neuroreparative effects after a brain injury. However, the roles of IGF-1 variants in mild traumatic brain injury (mTBI) are not yet fully understood. This study attempted to elucidate the effects of IGF-1 variants on the risk and neuropsychiatric outcomes of mTBI. Methods Based on 176 recruited mTBI patients and 1517 control subjects from the Taiwan Biobank project, we first compared the genotypic distributions of IGF-1 variants between the two groups. Then, we analyzed associations of IGF-1 variants with neuropsychiatric symptoms after mTBI, including anxiety, depression, dizziness, and sleep disturbances. Functional annotation of IGF-1 variants was also performed through bioinformatics databases. Results The minor allele of rs7136446 was over-represented in mTBI patients compared to community-based control subjects. Patients carrying minor alleles of rs7136446 and r...

Research paper thumbnail of The role of tyrosine kinase Etk/Bmx in EGF-induced apoptosis of MDA-MB-468 breast cancer cells

Oncogene, Jan 11, 2004

Etk/Bmx, a member of the Tec family of tyrosine kinases, mediates various signaling pathways and ... more Etk/Bmx, a member of the Tec family of tyrosine kinases, mediates various signaling pathways and confers several cellular functions. In the present study, we have explored the functional role of Etk in mediating EGF-induced apoptosis, using MDA-MB-468 cell line as a model. We first demonstrated that EGF treatment induces Etk tyrosine phosphorylation in both HeLa and MDA-MB-468 cells. Overexpression of Etk by recombinant adenovirus in MDA-MB-468 cells potentiates the extent of EGF-induced cell apoptosis. The observed Etk-enhanced MDA-MB-468 cell apoptosis is associated with the Stat1 activation, as demonstrated by electrophoresis mobility shift assays and reporter gene assays. By contrast, a kinase domain deletion mutant EtkDeltaK, functioning as a dominant-negative mutant, ameliorates EGF-induced Stat1 activation and apoptosis in MDA-MB-468 cells. To explore whether the activated Etk alone is sufficient for inducing apoptosis, a conditionally activated Etk (DeltaEtk-ER), a chimeric ...

Research paper thumbnail of The Influence of BMX Gene Polymorphisms on Clinical Symptoms after Mild Traumatic Brain Injury

BioMed Research International, 2014

Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patient... more Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patients diagnosed with mTBI could fully recover, but 15% of patients suffer from persistent symptoms. In recent studies, genetic factors were found to be associated with recovery and clinical outcomes after TBI. In addition, results from our previous research have demonstrated that the bone marrow tyrosine kinase gene in chromosome X (BMX), a member of the Tec family of kinases, is highly expressed in rats with TBI. Therefore, our aim in this study was to identify the association between genetic polymorphisms of BMX and clinical symptoms following mTBI. Four tagging single nucleotide polymorphisms (tSNPs) of BMX with minimum allele frequency (MAF) >1% were selected from the HapMap Han Chinese database. Among these polymorphisms, rs16979956 was found to be associated with the Beck anxiety inventory (BAI) and dizziness handicap inventory (DHI) scores within the first week after head injury. Additionally, another SNP, rs35697037, showed a significant correlation with dizziness symptoms. These findings suggested that polymorphisms of the BMX gene could be a potential predictor of clinical symptoms following mTBI.

Research paper thumbnail of Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression

Biochemical and biophysical research communications, Jan 6, 2009

CD133-expressing glioma cells play a critical role in tumor recovery after treatment and are resi... more CD133-expressing glioma cells play a critical role in tumor recovery after treatment and are resistant to radiotherapy. Herein, we demonstrated that glioblastoma-derived CD133-positive cells (GBM-CD133(+)) are capable of self-renewal and express high levels of embryonic stem cell genes and SirT1 compared to GBM-CD133(-) cells. To evaluate the role of SirT1 in GBM-CD133(+), we used a lentiviral vector expressing shRNA to knock-down SirT1 expression (sh-SirT1) in GBM-CD133(+). Silencing of SirT1 significantly enhanced the sensitivity of GBM-CD133(+) to radiation and increased the level of radiation-mediated apoptosis. Importantly, knock-down of SirT1 increased the effectiveness of radiotherapy in the inhibition of tumor growth in nude mice transplanted with GBM-CD133(+). Kaplan-Meier survival analysis indicated that the mean survival rate of GBM-CD133(+) mice treated with radiotherapy was significantly improved by Sh-SirT1 as well. In sum, these results suggest that SirT1 is a potenti...

Research paper thumbnail of Post-Receptor Crosstalk between Growth Hormone and Insulin Signal in Rats Born Small for Gestational Age with Catch-Up Growth

PLoS ONE, 2014

Insulin resistance has been observed in individuals born small for gestational age (SGA) with cat... more Insulin resistance has been observed in individuals born small for gestational age (SGA) with catch-up growth (CUG), yet the mechanisms involved remain unclear. This study examined the role of GH and insulin signaling crosstalk in insulin resistance of SGA rats with CUG. SGA rats were developed by dietary restriction in pregnant rats. GH receptor inhibition was performed on four-week old CUG-SGA and AGA rats. Phosphorylation of IRS-1, AKT, and ERK, and expression of SOCS3 in the skeletal muscle were determined via immunoblot analysis at baseline and after insulin stimulation in CUG-SGA, NCUG-SGA and AGA groups. Compared to AGA controls, phosphorylation of IRS-1 and AKT in response to insulin stimulation in CUG-SGA rats was significantly blunted (P<0.05), and phosphorylation of ERK at baseline was dramatically activated (P<0.05). SOCS3 expression was significantly increased in CUG-SGA compared to AGA (P = 0.001) and NCUG-SGA (P = 0.006) rats, and was significantly suppressed following GHR inhibition (P<0.05). Furthermore, phosphorylation of IRS-1 and AKT in response to insulin stimulation increased after GHR inhibition (P<0.05). Insulin resistance in CUG-SGA rats is associated with impairment of IRS-1-PI3K-AKT signaling, which may result from GH signaling-induced up-regulation of SOCS3.

Research paper thumbnail of Different sham procedures for rats in traumatic brain injury experiments induce corresponding increases in levels of trauma markers

Journal of Surgical Research, 2013

Controlled cortical impact Marker a b s t r a c t Background: In traumatic brain injury animal mo... more Controlled cortical impact Marker a b s t r a c t Background: In traumatic brain injury animal models, sham or naïve control groups are often used for the analysis of injured animals; however, the existence and/or significance of differences in the control groups has yet to be studied. In addition, recent controversies regarding the decompressive craniectomy trial in which decompressive craniectomies in patients with severe traumatic brain injury and refractory increased intracranial pressure remains unsettled. Although the report demonstrated that the procedure may result in less favorable long-term outcomes despite the decrease in intracranial pressure and shorter length of intensive care unit stay, the study has been criticized, and the debate is still inconclusive partly because of a lack of mechanistic explanation. We have recently discovered epithelial and endothelial tyrosine kinase (Etk) to exhibit upregulation after traumatic neural injury and will compare the effects of craniectomy procedure with those of other procedures inducing different levels of severity.

Research paper thumbnail of Suppression of Etk/Bmx Protects Against Ischemic Brain Injury

Cell Transplantation, 2012

Etk/Bmx (epithelial and endothelial tyrosine kinase, also known as BMX), a member of the Tec (tyr... more Etk/Bmx (epithelial and endothelial tyrosine kinase, also known as BMX), a member of the Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of protein-tyrosine kinases, is an important regulator of signal transduction for the activation of cell growth, differentiation, and development. We have previously reported that activation of Etk leads to apoptosis in MDA-MB-468 cells. The purpose of this study was to examine the role of Etk in neuronal injury induced by H(2)O(2) or ischemia. Using Western blot analysis and immunohistochemistry, we found that treatment with H(2)O(2) significantly enhanced phosphorylation of Etk and its downstream signaling molecule Stat1 in primary cortical neurons. Inhibiting Etk activity by LFM-A13 or knocking down Etk expression by a specific shRNA increased the survival of primary cortical neurons. Similarly, at 1 day after a 60-min middle cerebral artery occlusion (MCAo) in adult rats, both phosphorylated Etk and Stat1 were coexpressed with apoptotic markers in neurons in the penumbra. Pretreatment with LFM-A13 or an adenoviral vector encoding the kinase deletion mutant Etkk attenuated caspase-3 activity and infarct volume in ischemic brain. All together, our data suggest that Etk is activated after neuronal injury. Suppressing Etk activity protects against neurodegeneration in ischemic brain.

Research paper thumbnail of Worsening of dizziness impairment is associated with BMX level in patients after mild traumatic brain injury

Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting sympto... more Over 2 million people suffer from mild traumatic brain injury (mTBI) each year. Predicting symptoms of mTBI and the characterization of those symptoms has been challenging. Biomarkers that correlate clinical symptoms to disease outcome are desired to improve understanding of the disease and optimize patient care. BMX, a member of the TEC family of nonreceptor tyrosine kinases, is upregulated after traumatic neural injury in a rat model of mTBI. The objective of this investigation was to determine if BMX serum concentrations can effectively be used to predict outcomes after mTBI in a clinical setting. A total of 63 patients with mTBI (Glasgow Coma Score [GCS] between13-15) were included. Blood samples taken at the time of hospital admission were analyzed for BMX. Data collected included demographic and clinical variables. Outcomes were assessed using the Dizziness Handicap Inventory (DHI) questionnaire at baseline and 6 weeks post-injury. The participant was asssigned to 'case gr...