Publications by authors named "Aij-Lie Kwan"

115 Publications

The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis.

Biomolecules 2021 Mar 13;11(3). Epub 2021 Mar 13.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan.

Mitochondrial fission and fusion cycles are integrated with cell cycle progression. Here we first re-visited how mitochondrial ETC inhibition disturbed mitosis progression, resulting in multipolar spindles formation in HeLa cells. Inhibitors of ETC complex I (rotenone, ROT) and complex III (antimycin A, AA) decreased the phosphorylation of Plk1 T210 and Aurora A T288 in the mitotic phase (M-phase), especially ROT, affecting the dynamic phosphorylation status of fission protein dynamin-related protein 1 (Drp1) and the Ser637/Ser616 ratio. We then tested whether specific Drp1 inhibitors, Mdivi-1 or Dynasore, affected the dynamic phosphorylation status of Drp1. Similar to the effects of ROT and AA, our results showed that Mdivi-1 but not Dynasore influenced the dynamic phosphorylation status of Ser637 and Ser616 in Drp1, which converged with mitotic kinases (Cdk1, Plk1, Aurora A) and centrosome-associated proteins to significantly accelerate mitotic defects. Moreover, our data also indicated that evoking mito-Drp1-Ser637 by protein kinase A (PKA) rather than Drp1-Ser616 by Cdk1/Cyclin B resulted in mitochondrial fission via the PINK1/Parkin pathway to promote more efficient mitophagy and simultaneously caused multipolar spindles. Collectively, this study is the first to uncover that mito-Drp1-Ser637 by PKA, but not Drp1-Ser616, drives mitophagy to exert multipolar spindles formation during M-phase.
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http://dx.doi.org/10.3390/biom11030424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998912PMC
March 2021

High Expression of Sp1 is Associated with Recurrence of Meningioma.

World Neurosurg 2021 May 13;149:e1056-e1060. Epub 2021 Jan 13.

Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA. Electronic address:

Background: Meningioma has the second highest incidence among primary intracranial tumors. There is no effective treatment or targeted therapy for meningioma except excision and radiotherapy. Sp1 (specificity protein 1) is a transcription factor that regulates tumor growth, but the literature describing the relationship between Sp1 and meningioma is scarce. The purpose of this study was to investigate the relationship between Sp1 expression and the clinicopathological parameters in meningioma by immunohistochemical staining.

Methods: We collected samples from 74 patients from 2008-2012 in Kaohsiung Medical University Hospital, with staging and prognosis of the pathological section of the meningioma.

Results: Our results show that Sp1 expression was significantly associated with World Health Organization grade, malignancy, and recurrence in patients with meningioma.

Conclusions: High expression of Sp1 in patients with meningioma was linked to poor prognosis of recurrence-free time. Therefore Sp1 may be a candidate biomarker of prognosis and therapy target in meningioma.
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http://dx.doi.org/10.1016/j.wneu.2021.01.016DOI Listing
May 2021

Impact of hyperglycemia on neuronal apoptosis after subarachnoid hemorrhage in rodent brain: An experimental research.

Int J Surg 2020 Nov 30;83:246-252. Epub 2020 Jul 30.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Background: Hyperglycemia, a derangement after subarachnoid hemorrhage (SAH), is known to be associated with unfavorable outcomes. Whether the connection between hyperglycemia and poor prognosis results from severe neuronal apoptosis is unknown, and we aim at investigating their relationship.

Material And Methods: Streptozotocin (STZ) was administrated to trigger hyperglycemia before SAH induction in Sprague-Dawley rats that were assigned to one of four groups: control, SAH only, hyperglycemia only, and SAH with hyperglycemia. The severity of neuronal apoptosis was analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nickend labelling (TUNEL) staining of cerebral cortex.

Results: When subjected to SAH, hyperglycemic animals had worse neurobehavioral functions than normoglycemic ones. Hyperglycemia-exacerbated apoptosis was evident by greater increases in cleaved caspase-3 expression and TUNEL-positive cell density in the SAH with hyperglycemia group than those in the SAH only group, whereas there was no significant difference in cleaved caspase-9 expression and Bax/Bcl-2 ratio between the two groups. Furthermore, there was a remarkable decrease in the ratio of phosphorylated extracellular regulated kinase (ERK)/total ERK in the hyperglycemic rats after SAH.

Conclusion: Hyperglycemia aggravated neuronal apoptosis after SAH and was associated with impaired neurological outcomes. Activation of the extrinsic caspase cascade through the ERK signal pathway may contribute to hyperglycemia-mediated apoptosis.
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http://dx.doi.org/10.1016/j.ijsu.2020.07.009DOI Listing
November 2020

Increased Vascular Adhesion Protein 1 (VAP-1) Levels are Associated with Alternative M2 Macrophage Activation and Poor Prognosis for Human Gliomas.

Diagnostics (Basel) 2020 Apr 27;10(5). Epub 2020 Apr 27.

Department of Neurosurgery, Kaohsiung Medical University Chung Ho Memorial Hospital, Kaohsiung 80756, Taiwan.

Glioma is characterized by a high heterogeneity in the brain tumor. Abundant tumor-associated macrophages (TAMs) exist as neoplastic tissues, implicating tumor plasticity and thus leading to therapeutic challenges. Vascular adhesion protein (VAP-1) potentially serves as a mediator for TAM immunity in tumor milieu. We previously demonstrated that VAP-1 could contribute to tumor malignancy, but its characteristics in TAM immunity of glioma progression are still unclear. This study explored the association of VAP-1 expression with TAM distribution as well as the resulting clinical significance and prognostic value in human gliomas. An in-depth analysis of (VAP-1) gene expression was performed using 695 glioma samples derived from the cancer genome atlas (TCGA)-lower grade glioma and glioblastoma (GBMLGG) cohort. Bioinformatic analysis confirmed that VAP-1 expression is associated with poor prognosis of glioma patients ( = 0.0283). VAP-1 and TAM biomarkers (CD68, iNOS, and CD163) were evaluated by immunohistochemistry in 108 gliomas from Kaohsiung Medical University Hospital. VAP-1+ was expressed in 56 (51.85%) cases and this phenotype revealed a significant association with overall survival in Kaplan-Meier analysis ( < 0.0001). Immunohistochemical double staining showed that VAP-1 immunoreactivity was present around CD163+ M2 infiltration location, including aggressive lesions and neighboring neovasculature. We demonstrated that high VAP-1 expression levels positively correlated with CD163+ M2 activation and coexpression of these two proteins was associated with worse survival in gliomas ( < 0.0001). Multivariate analysis indicated that VAP-1 alone and co-expressed with CD163 were the significantly independent indicators (both < 0.0001). Furthermore, VAP-1/CD163 coexpression exhibited excellent diagnostic accuracy in gliomas (AUC = 0.8008). In conclusion, VAP-1 and TAM CD163 M2 coexpression was found in glioma tissues belonging to a highly malignant subgroup that was associated with poor prognosis. These results implied VAP-1 abundance is closely linked to alternative M2 activation during glioma progression. From the aforementioned data, a reasonable inference is that VAP-1 combined with targeting M2 immunity might be an effective therapeutic target for human gliomas.
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http://dx.doi.org/10.3390/diagnostics10050256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278017PMC
April 2020

Erythropoietin Alleviates Burn-induced Muscle Wasting.

Int J Med Sci 2020 1;17(1):33-44. Epub 2020 Jan 1.

Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Burn injury induces long-term skeletal muscle pathology. We hypothesized EPO could attenuate burn-induced muscle fiber atrophy. Rats were allocated into four groups: a sham burn group, an untreated burn group subjected to third degree hind paw burn, and two burn groups treated with weekly or daily EPO for four weeks. Gastrocnemius muscle was analyzed at four weeks post-burn. EPO attenuated the reduction of mean myofiber cross-sectional area post-burn and the level of the protective effect was no significant difference between two EPO-treated groups (p=0.784). Furthermore, EPO decreased the expression of atrophy-related ubiquitin ligase, atrogin-1, which was up-regulated in response to burn. Compared to untreated burn rats, those receiving weekly or daily EPO groups had less cell apoptosis by TUNEL assay. EPO decreased the expression of cleaved caspase 3 (key factor in the caspase-dependent pathway) and apoptosis-inducing factor (implicated in the caspase-independent pathway) after burn. Furthermore, EPO alleviated connective tissue overproduction following burn via transforming growth factor beta 1-Smad2/3 pathway. Daily EPO group caused significant erythrocytosis compared with untreated burn group but not weekly EPO group. EPO therapy attenuated skeletal muscle apoptosis and fibrosis at four weeks post-burn. Weekly EPO may be a safe and effective option in muscle wasting post-burn.
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http://dx.doi.org/10.7150/ijms.38590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945565PMC
October 2020

The Association between Mortality-to-Incidence Ratios and Health Expenditures in Brain and Nervous System Cancers.

Int J Environ Res Public Health 2019 07 31;16(15). Epub 2019 Jul 31.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

Mortality-to-incidence ratios (MIRs) are alternative parameters used to evaluate the prognosis of a disease. In addition, MIRs are associated with the ranking of health care systems and expenditures for certain types of cancer. However, a lack of association between MIRs and pancreatic cancer has been noted. Given the poor prognosis of brain and nervous system cancers, similar to pancreatic cancer, the relation of MIRs and health care disparities is worth investigating. We used the Spearman's rank correlation coefficient (CC) to analyze the correlation between the MIRs in brain and nervous system cancers and inter-country disparities, including expenditures on health and human development index. Interestingly, the MIRs in brain and nervous system cancers are associated with the human development index score (N = 157, CC = -0.394, < 0.001), current health expenditure (CHE) per capita (N = 157, CC = -0.438, < 0.001), and CHE as percentage of gross domestic product (N = 157, CC = -0.245, = 0.002). In conclusion, the MIRs in the brain and nervous system cancer are significantly associated with health expenditures and human development index. However, their role as an indicator of health disparity warrants further investigation.
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http://dx.doi.org/10.3390/ijerph16152739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696604PMC
July 2019

Predictive Factors of 2-Year Postoperative Outcomes in Patients with Spontaneous Cerebellar Hemorrhage.

J Clin Med 2019 Jun 8;8(6). Epub 2019 Jun 8.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

Spontaneous cerebellar hemorrhage (SCH) is associated with high patient mortality and morbidity, but the clinical and radiographic predictors of the postoperative outcome have not been widely addressed in the literature. The purpose of this study was to define the prognostic factors for the two-year postoperative outcome in patients with SCH. We conducted a retrospective study of 48 consecutive patients with SCH who underwent neurosurgical intervention. Correlation analysis was performed to examine the possible link between clinical and radiographic parameters, and the National Institutes of Health Stroke Scale (NIHSS) score at each patient's discharge and the two-year postoperative outcome as defined according to the Glasgow outcome scale (GOS). A total of 48 patients with SCH underwent neurological surgery, which included suboccipital craniectomy and/or external ventricular drainage (EVD). The mean patient age was 63 years. Nine patients underwent suboccipital craniectomy only; 38 underwent both suboccipital craniectomy and EVD. The overall mortality rate was 35.4%. Fourteen patients (29.2%) had good outcomes. A good outcome on the GOS at 2 years after surgical treatment of SCH was associated with the NIHSS score at discharge. An increase of one point in a patient's NIHSS score at discharge following neurological surgery will increase the probability of a poor two-year postoperative outcome by 28.5%.
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http://dx.doi.org/10.3390/jcm8060818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617345PMC
June 2019

Glycine receptors expression in rat spinal cord and dorsal root ganglion in prostaglandin E2 intrathecal injection models.

BMC Neurosci 2018 Nov 9;19(1):72. Epub 2018 Nov 9.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Glycine receptors (GlyRs) are involved in the development of spinal pain sensitization. The GlyRα3 subunit has recently emerged as a key factor in inflammatory pain pathways in the spinal cord dorsal horn (DH). Our study is to identify the extent of location and cell types expressing different GlyR subunits in spinal cord and dorsal root ganglion (DRGs). To tease out the possible actions of GlyRs on pain transmission, we investigate the effects produced by GlyRs on acute inflammatory pain by behavioral testing using prostaglandin E2 (PGE2) intrathecal injection models. Furthermore, we investigate the changes of GlyR expression in DRGs and spinal cord in rats after the induction of acute inflammatory pain.

Results: Compared to the vehicle administration, the PGE2 intrathecal injection model produced significantly higher hyperalgesia, which started 3 h after PGE2 injection and lasted more than 5 h. PGE2 intrathecal injection significantly decreased GlyRα1 and GlyRα3 protein expressions in the L5 DH at 1 h and lasted to 5 h, and similar results were observed in the L5 DRG at 5 h. Confocal microscopic images showed the co-existence of punctate gephyrin and GlyRα3 immunoreactivity (IR) throughout the gray matter of the spinal cord, mainly in DH laminae I-III neurons and in ventral horn neurons. It also showed the co-existence of punctate gephyrin and GlyRα3 IR in DRG neurons.

Conclusions: In this study, PGE2 intrathecal injection significantly decreased protein expression of gephyrin, GlyRα1 and GlyRα3 in spinal cord DH and DRG. The gephyrin and GlyRα3 were localized on neuron cells both in the DH and DRG.
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http://dx.doi.org/10.1186/s12868-018-0470-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230273PMC
November 2018

Vascular adhesion protein-1 as indicator of breast cancer tumor aggressiveness and invasiveness.

APMIS 2018 Sep;126(9):755-761

Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Recent studies suggest that vascular adhesion protein-1 (VAP-1), a 180-KDa homodimeric glycoprotein, may be associated with cancer-related events including tumor cell migration, motility, invasion, or metastasis. Therefore, this study applies VAP-1 immunohistochemical staining to demonstrate the invasiveness component of the breast cancer. The VAP-1 staining results were compared in 148 breast cancer cases to identify possible correlations with clinical status, including age, tumor size, tumor grade, TNM stage, lymphatic invasion, metastasis, recurrence, and survival rate. Immunohistochemical staining results showed VAP-1 negative or weak staining in normal ducts and ductal carcinoma in situ (DCIS), but these phenotypes were positively associated with a stiffened VAP-1 that presented at the invasive front of the lesion. Our data demonstrated that VAP-1 expression was positively associated with lymphatic invasion, distant metastasis, and patient survival in breast carcinoma. Notably, VAP-1 expression was found to be significantly correlated with the overall survival (p < 0.0001). Multivariate Cox analysis indicated that VAP-1 expression was a significant independent prognostic indicator of overall survival in breast carcinoma (p < 0.0001). In conclusion, this study suggests that VAP-1 is linked to progression of tumor invasion and metastasis in breast carcinoma. VAP-1 is shown to be a biomarker that can be predict invasive potential and clinical outcome in breast cancer.
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http://dx.doi.org/10.1111/apm.12885DOI Listing
September 2018

High-level Sp1 is Associated with Proliferation, Invasion, and Poor Prognosis in Astrocytoma.

Pathol Oncol Res 2019 Jul 9;25(3):1003-1013. Epub 2018 Jun 9.

Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Astrocytoma is the most common and the most lethal primary brain tumor in adults. Grade IV glioblastoma is usually refractory to currently available surgical, chemotherapeutic, and radiotherapeutic treatments. The Specificity protein 1 (Sp1) transcription factor is known to regulate tumorigenesis in many cancers. The aim of this study was to investigate the clinicopathologic role of Sp1 protein in the carcinogenesis of astrocytoma. This study analyzed 98 astrocytoma cases treated at Kaohsiung Medical University Hospital during 2002-2012. Clinicopathologic parameters associated with Sp1 were analyzed by chi-square test, Kaplan-Meier analysis, and Cox regression analyses. In vitro proliferation, invasion, and migration were compared between non-siRNA groups and Sp1 siRNA groups. In glioblastoma cells treated with Sp1 siRNA, Western blot was also used to detect expressions of Sp1, Ki-67, VEGF, cyclin D1, E-cadherin, cleaved caspase-3 and Bax proteins. Expression of Sp1 was significantly associated with WHO grade (p = 0.005) and with overall survival time (p < 0.001). Multivariate analysis further revealed that prognosis of astrocytoma was significantly associated with Sp1 expression (p = 0.036) and IDH-1 expression (p < 0.001). In vitro silencing of Sp1 downregulated Sp1, Ki-67, and cyclin D1 but upregulated E-cadherin, Bax, and cleaved caspase-3. These data suggest that Sp1 is a potential prognostic marker and therapeutic target in astrocytoma.
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http://dx.doi.org/10.1007/s12253-018-0422-8DOI Listing
July 2019

Erythropoietin attenuates motor neuron programmed cell death in a burn animal model.

PLoS One 2018 31;13(1):e0190039. Epub 2018 Jan 31.

Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Burn-induced neuromuscular dysfunction may contribute to long-term morbidity; therefore, it is imperative to develop novel treatments. The present study investigated whether erythropoietin (EPO) administration attenuates burn-induced motor neuron apoptosis and neuroinflammatory response. To validate our hypothesis, a third-degree hind paw burn rat model was developed by bringing the paw into contact with a metal surface at 75°C for 10 s. A total of 24 male Sprague-Dawley rats were randomly assigned to four groups: Group A, sham-control; Group B, burn-induced; Group C, burn + single EPO dose (5000 IU/kg i.p. at D0); and Group D, burn + daily EPO dosage (3000 IU/kg/day i.p. at D0-D6). Two treatment regimens were used to evaluate single versus multiple doses treatment effects. Before sacrifice, blood samples were collected for hematological parameter examination. The histological analyses of microglia activation, iNOS, and COX-2 in the spinal cord ventral horn were performed at week 1 post-burn. In addition, we examined autophagy changes by biomarkers of LC3B and ATG5. The expression of BCL-2, BAX, cleaved caspase-3, phospho-AKT, and mTOR was assessed simultaneously through Western blotting. EPO administration after burn injury attenuated neuroinflammation through various mechanisms, including the reduction of microglia activity as well as iNOS and COX-2 expression in the spinal cord ventral horn. In addition, the expression of phospho-AKT, mTOR and apoptotic indicators, such as BAX, BCL-2, and cleaved caspase-3, was modulated. Furthermore, the activity of burn-induced autophagy in the spinal cord ventral horn characterized by the expression of autophagic biomarkers, LC3B and ATG5, was reduced after EPO administration. The present results indicate that EPO inhibits the AKT-mTOR pathway to attenuate burn-induced motor neuron programmed cell death and microglia activation. EPO can modulate neuroinflammation and programmed cell death and may be a therapeutic candidate for neuroprotection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190039PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791978PMC
February 2018

Overexpression of Fli-1 in astrocytoma is associated with poor prognosis.

Oncotarget 2017 Apr;8(17):29174-29186

Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Background: Astrocytoma, a common and highly malignant type of brain tumor, is associated with poor overall survival despite advances in surgical treatment, radiotherapy, and chemotherapy. The nuclear transcription factor Fli-1 has been shown to increase cellular proliferation and tumorigenesis in many types of cancer; however, previous reports have not described a correlation between clinical outcomes and Fli-1 in astrocytoma patients. The present study aimed to elucidate the clinical role of Fli-1 in astrocytoma.

Results: High-level of Fli-1 protein expression was significantly association with World Health Organization (WHO) high grade and poor prognosis. A multivariate analysis revealed that the WHO grade and Fli-1 protein expression were independent factor of prognostic factors of patients with astrocytoma. In addition, Fli-1 silencing inhibited proliferation, migration, and invasion and led to the downregulation of Ki-67, VEGF, and cyclin D1 expression in the astrocytoma cells.

Materials And Methods: Fli-1 protein expression in astrocytoma tissue samples were detected via immunohistochemistry, and potential correlations between clinical parameters and Fli-1 expression were assessed in patients with astrocytoma. Additionally, proliferation, invasion, and migration assays of astrocytoma cell lines were conducted to evaluate the effects of short interfering RNA (siRNA) on these processes; in addition, these cells were subjected to western blotting to detect the expression levels of Fli-1, Ki-67, VEGF, and Cyclin D1.

Conclusion: Fli-1 shows promise as a potential prognostic biomarker and therapeutic molecular target for astrocytoma patients.
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http://dx.doi.org/10.18632/oncotarget.16303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438722PMC
April 2017

Combined Genetic Biomarkers and Betel Quid Chewing for Identifying High-Risk Group for Oral Cancer Occurrence.

Cancer Prev Res (Phila) 2017 Jun 11;10(6):355-362. Epub 2017 Apr 11.

Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.

We integrated genetic risk scores (GRS) and environmental factors for identifying high-risk subjects for oral squamous cell carcinoma (OSCC) occurrence by using case-control study. A total of 447 patients diagnosed with OSCC and 580 unrelated subjects were recruited from two medical centers in Taiwan. A multinomial logistic regression model was conducted to access interaction between GRS and betel quid (BQ) chewing. We employed ROC curve to compare the accuracy of OSCC occurrence. Four tag SNPs were found in , and genes that were significantly associated with OSCC occurrence. GRS was calculated by the four tag SNP risk alleles. The higher GRS (scores = 4) remained independently associated with risk of OSCC after adjustment for age, the use of alcohol, BQ, and cigarette: adjusted OR = 4.42 [95% confidence interval (95% CI), 1.34-14.55]. The GRS and BQ chewing interaction showed an increased risk for OSCC occurrence with adjusting for other substance use and age (OR = 70.77; 95% CI, 8.70-575.73). The synergy index was 16.58 (95% CI, 2.27-70.56), suggesting a positive additive interaction between GRS and BQ chewing. The areas under the ROC curves (AUROC) were 0.91 for combined GRS and BQ chewing with sensitivity of 88.6% and specificity of 86.7%. The AUROC of GRS and BQ chewing is above 90%, which may be valuable in identifying high-risk subjects. Early screening can allow the clinician to provide the appropriate intervention and to reduce the OSCC occurrence. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0259DOI Listing
June 2017

Hyperglycemia Aggravates Cerebral Vasospasm after Subarachnoid Hemorrhage in a Rat Model.

Neurosurgery 2017 May;80(5):809-815

Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Hyperglycemia is common and showed to be risky for poor prognosis in patients with subarachnoid hemorrhage (SAH). However, the causality and mechanism underlying this observation are not well established.

Objective: To investigate the relationship between hyperglycemia and cerebral vasospasm with its pathogenesis in a rat model of SAH.

Methods: One-shot SAH model was employed in male Sprague-Dawley rats. Hyperglycemia was triggered by intraperitoneal streptozotocin administration (50 mg/kg) 7 days before SAH induction. The severity of cerebral vasospasm was determined by the cross-sectional area of basilar artery (BA) in male rats randomly assigned to 1 of 4 groups: control, hyperglycemia only, SAH only, and SAH with hyperglycemia. The expression of endothelial nitric oxide synthase (eNOS) and induced nitric oxide synthase (iNOS) in the BA were analyzed by immunohistochemistry.

Results: The mean (standard deviation) blood glucose level was 433.0 (98.3) and 156.5 (31.7) mg/dL in streptozotocin -treated and untreated rats, respectively. Hyperglycemic rats exhibited poorer neurobehavioral performance than normoglycemic rats when subjected to SAH. Hyperglycemia-mediated exacerbation of vasospasm was evident by the greater decrease in the BA cross-sectional area in the hyperglycemic SAH group than in the SAH only group. Furthermore, there was more decreased expression of eNOS and increased expression of iNOS within the vessels of the hyperglycemic SAH rats.

Conclusion: Hyperglycemia exacerbated cerebral vasospasm and was associated with poorer neurological outcomes following SAH. Our findings also suggested the nitric oxide pathway as a potential underlying mechanism via the dysregulation of eNOS and iNOS.
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http://dx.doi.org/10.1093/neuros/nyx016DOI Listing
May 2017

Corrigendum to "Magnesium Lithospermate B, an Active Extract of , Mediates sGC/cGMP/PKG Translocation in Experimental Vasospasm".

Biomed Res Int 2016;2016:6240750. Epub 2016 May 10.

Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Neurosurgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung 80752, Taiwan.

[This corrects the article DOI: 10.1155/2014/272101.].
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http://dx.doi.org/10.1155/2016/6240750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877462PMC
May 2016

Intrathecal CGS-26303 Pretreatment Attenuates Spinal Nerve Ligation-Induced Neuropathic Pain in the Spinal Cord.

World Neurosurg 2016 Jul 4;91:532-541.e1. Epub 2016 Mar 4.

Department of Microbiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Background: Matrix metalloproteinase (MMPs) and endothelin-1 may prove to be important in the generation of pain induced by inflammation and nerve lesion. This study aimed to investigate the relationship between endothelin receptors and MMPs.

Methods: Male Sprague-Dawley rats (250-300 g) were divided into 5 groups: a normal (control) group; an L5 spinal nerve ligation (SNL) group; a CGS-26303 IT + L5 SNL group; a BQ-123 IT + L5 SNL group; and a BQ-788 IT + L5 SNL group. The expression of glial fibrillary acidic protein, endothelin-A receptor (ETAR), endothelin-B receptor, MMP-2, and MMP-9 in the ipsilateral L5 dorsal root ganglion (DRG) and the activation of microglia and astrocytes in the L5 spinal dorsal horn (SDH) were quantified by immunofluorescence and Western blotting.

Results: Intrathecal pretreatment with CGS-26303 significantly attenuated the hyperalgesic and mechanical responses induced by SNL for 4 days, whereas BQ-123 administration alleviated the hyperalgesia only for 3 hours and mechanical allodynia for only 1 hour. Pretreatment with CGS-26303 significantly down-regulated the glial fibrillary acidic protein, ET-A, MMP-2, and MMP-9 expressions in DRG and their effect lasted for 6 hours, 1 day, 7 days, and 1 day, respectively. By immunofluorescence and Western blotting, there was colocalization of ETAR and MMP-9 in the DRG neurons, whereas MMP-2 was expressed in DRG satellite cells. Furthermore, CGS-26303 treatment also reduced SNL-induced microglia and astrocyte activation on the SDH for 7 days.

Conclusions: In this study, CGS-26303 can attenuate SNL-induced neuropathic pain by down-regulating MMP-9, MMP-2, and ETAR expressions in the DRG and by glia cell activation in the SDH.
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http://dx.doi.org/10.1016/j.wneu.2016.02.093DOI Listing
July 2016

Overexpression of vascular adhesion protein-1 is associated with poor prognosis of astrocytomas.

APMIS 2016 Jun 2;124(6):462-8. Epub 2016 Mar 2.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Vascular adhesion protein-1 (VAP-1) is one of the endothelial adhesion molecules that is believed to play a role in tumor progression and metastasis, supporting cancer cell extravasation. Very few studies have been performed on analyzing the contribution of VAP-1 in brain tumor. Astrocytomas are the most common type of brain tumors, which are classified by World Health Organization (WHO) into four grades according to the degree of malignancy. This study was designed to investigate VAP-1 expression level in different astrocytoma grades and its correlation with clinicopathological features as well as prognosis of astrocytoma patients. Eighty-seven patients with different grades of astrocytoma (WHO Grade I-Grade IV) were enrolled in this study. The expression of VAP-1 was assayed by immunohistochemistry. The correlation between VAP-1 expression and clinicopathological features was evaluated by Chi-square test, and overall survival was analyzed by Kaplan-Meier method. Cox regression analysis was applied to analyze the independent influence of each parameter on overall survival. The expression level of VAP-1 was significantly higher in diffuse astrocytoma than those of pilocytic astrocytoma (p < 0.0001). In the subgroup analysis, upregulated VAP-1 expression was frequently found in older age patients (≥50 years). The VAP-1 expression was found to be significantly correlated with the overall survival (p = 0.0002). There was a statistical correlation between VAP-1(high) tumors in diffuse astrocytoma and VAP-1(low) tumors in pilocytic astrocytoma (p < 0.0001). Multivariate Cox analysis indicated VAP-1 was an independent predictive marker for poorer prognosis (p = 0.0036). Therefore, VAP-1 could be a promising prognostic biomarker in astrocytoma.
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http://dx.doi.org/10.1111/apm.12525DOI Listing
June 2016

Decreased expression of autophagy protein LC3 and stemness (CD44+/CD24-/low) indicate poor prognosis in triple-negative breast cancer.

Hum Pathol 2016 Feb 26;48:48-55. Epub 2015 Oct 26.

Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. Electronic address:

This study evaluated the prognostic value of expression of autophagy protein light chain 3 (LC3) and the prognostic value of coexpression of LC3 and stemness markers CD44+/CD24-/low in triple-negative breast cancer (TNBC). LC3 and LC3/CD44+/CD24-/low immunophenotypes in tumor tissues were evaluated by immunohistochemistry in 67 TNBC patients. LC3- was expressed in 30 (44.78%) cases. The LC3- phenotype revealed a significant negative association with overall survival in both univariate (P = .0006) and multivariate (P = .0153) analyses. LC3-/CD44+/CD24-/low phenotype was observed in 24 (35.82%) of 67 TNBC patients. According to Kaplan-Meier analysis, prognosis was significantly worse in tumors with LC3-/CD44+/CD24-/low phenotype (P = .0280). Multivariate analysis indicated that LC3-/CD44+/CD24-/low phenotype was a significant independent prognostic indicator of overall survival. These results suggest that LC3 suppresses TNBC in mature tumor cells and cancer stem cells (CSCs). In conclusion, this study suggests that CSCs are linked to progression of autophagy in TNBC. During the progression and development of TNBC, autophagy of CSCs/progenitor cells is low. LC3-/CD44+/CD24-/low immunophenotype indicates a highly aggressive TNBC subgroup associated with a poor prognosis. This study investigated that LC3 deficiency may restrain TNBC in mature tumor cells and CSCs. Therefore, a reasonable inference is that inducing autophagy may be an effective therapeutic strategy in TNBC.
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http://dx.doi.org/10.1016/j.humpath.2015.09.034DOI Listing
February 2016

Arctigenin, a Potent Ingredient of Arctium lappa L., Induces Endothelial Nitric Oxide Synthase and Attenuates Subarachnoid Hemorrhage-Induced Vasospasm through PI3K/Akt Pathway in a Rat Model.

Biomed Res Int 2015 11;2015:490209. Epub 2015 Oct 11.

Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan ; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.

Upregulation of protein kinase B (PKB, also known as Akt) is observed within the cerebral arteries of subarachnoid hemorrhage (SAH) animals. This study is of interest to examine Arctigenin, a potent antioxidant, on endothelial nitric oxide synthase (eNOS) and Akt pathways in a SAH in vitro study. Basilar arteries (BAs) were obtained to examine phosphatidylinositol-3-kinase (PI3K), phospho-PI3K, Akt, phospho-Akt (Western blot) and morphological examination. Endothelins (ETs) and eNOS evaluation (Western blot and immunostaining) were also determined. Arctigenin treatment significantly alleviates disrupted endothelial cells and tortured internal elastic layer observed in the SAH groups (p < 0.01). The reduced eNOS protein and phospho-Akt expression in the SAH groups were relieved by the treatment of Arctigenin (p < 0.01). This result confirmed that Arctigenin might exert dural effects in preventing SAH-induced vasospasm through upregulating eNOS expression via the PI3K/Akt signaling pathway and attenuate endothelins after SAH. Arctigenin shows therapeutic promise in the treatment of cerebral vasospasm following SAH.
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http://dx.doi.org/10.1155/2015/490209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619842PMC
August 2016

The Role of Serial Oxidative Stress Levels in Acute Traumatic Brain Injury and as Predictors of Outcome.

World Neurosurg 2016 Mar 23;87:463-70. Epub 2015 Oct 23.

Department of Biological Science, National Sun Yat-Sen University, Kaohsiung, Taiwan; Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Neurology, Xiamen Chang Gung Memorial Hospital, Xiamen, Fujian, Taiwan. Electronic address:

Background: Oxidative stress is thought to participate in the pathobiology of secondary brain injury after acute traumatic brain injury (TBI). This study posits that oxidative stress levels in acute TBI are predictive of outcome.

Methods: Two hundred and twenty-nine blood samples from 88 patients admitted within 24 hours after TBI were obtained on admission and on days 4 and 7. Serial plasma oxidative level and antioxidant were examined in 88 patients with acute TBI and 27 control individuals.

Results: Compared with controls, patients with TBI had significantly increased serum glutathione (GSH) levels on presentation and significantly decreased erythrocyte superoxide dismutase levels. Outcome was assessed on discharge using the Glasgow Outcome Scale. Serum GSH and erythrocyte superoxide dismutase levels were significantly higher in the good outcome group than in the poor outcome group on day 1 (P = 0.008 and P = 0.026, respectively). In the logistic regression analysis, only motor deficits and GSH levels on presentation were independently associated with outcome. A GSH cutoff value of 1.106 μmol/L on presentation was associated with good outcome in patients with acute TBI.

Conclusions: Quantifying biomarkers of oxidative stress and antioxidant status of serum correlate with trauma severity and may be used to predict outcomes after TBI. Higher serum GSH levels on admission are associated with better outcome.
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http://dx.doi.org/10.1016/j.wneu.2015.10.010DOI Listing
March 2016

4'-O-β-D-glucosyl-5-O-methylvisamminol, an active ingredient of Saposhnikovia divaricata, attenuates high-mobility group box 1 and subarachnoid hemorrhage-induced vasospasm in a rat model.

Behav Brain Funct 2015 Sep 22;11(1):28. Epub 2015 Sep 22.

Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: High-mobility group box 1 (HMGB1) was observed to be an important extracellular mediator involved in vascular inflammation associated with subarachnoid hemorrhage (SAH). This study is of interest to examine the efficacy of 4'-O-β-D-glucosyl-5-O-methylvisamminol (4OGOMV), C22H28O10, on the alternation of cytokines and HMGB1 in an animal model.

Methods: A rodent double hemorrhage SAH model was employed. Administration with 4OGOMV was initiated 1 h after animals were subjected to SAH. Basilar arteries (BAs) were harvested and cortexes examined for HMGB1 mRNA, protein expression (Western blot) and monocyte chemoattractant protein-1 (MCP-1) immunostaining. Cerebrospinal fluid samples were collected to examine IL-1β, IL-6, IL-8 and MCP-1 (rt-PCR).

Results: Morphological findings revealed endothelial cell deformity, intravascular elastic lamina torture, and smooth muscle necrosis in the vessels of SAH groups. Correspondently, IL-1β, IL-6 and MCP-1 in the SAH-only and SAH-plus vehicle groups was also elevated. 4OGOMV dose-dependently reduced HMGB1 protein expression when compared with the SAH groups.(p < 0.01) Likewise, 400 μg/kg 4OGOMV reduced IL-1β, MCP-1 and HMGB1 mRNA levels as well as MCP-1(+) monocytes when compared with the SAH groups..

Conclusion: 4OGOMV exerts its neuro-protective effect partly through the dual effect of inhibiting IL-6 and MCP-1 activation and also reduced HMGB1 protein, mRNA and MCP-1(+) leukocytes translocation. This study lends credence to validating 4OGOMV as able to attenuate pro-inflammatory cytokine mRNA, late-onset inflammasome, and cellular basis in SAH-induced vasospasm.
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http://dx.doi.org/10.1186/s12993-015-0074-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578329PMC
September 2015

Fat Grafting in Burn Scar Alleviates Neuropathic Pain via Anti-Inflammation Effect in Scar and Spinal Cord.

PLoS One 2015 14;10(9):e0137563. Epub 2015 Sep 14.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.

Burn-induced neuropathic pain is complex, and fat grafting has reportedly improved neuropathic pain. However, the mechanism of fat grafting in improving neuropathic pain is unclear. Previous investigations have found that neuroinflammation causes neuropathic pain, and anti-inflammatory targeting may provide potential therapeutic opportunities in neuropathic pain. We hypothesized that fat grafting in burn scars improves the neuropathic pain through anti-inflammation. Burn-induced scar pain was confirmed using a mechanical response test 4 weeks after burn injuries, and autologous fat grafting in the scar area was performed simultaneously. After 4 weeks, the animals were sacrificed, and specimens were collected for the inflammation test, including COX-2, iNOS, and nNOS in the injured skin and spinal cord dorsal horns through immunohistochemistry and Western assays. Furthermore, pro-inflammatory cytokines (IL-1 β and TNF-α) in the spinal cord were collected. Double immunofluorescent staining images for measuring p-IκB, p-NFκB, p-JNK, and TUNEL as well as Western blots of AKT, Bax/Bcl-2 for the inflammatory process, and apoptosis were analyzed. Fat grafting significantly reduced COX2, nNOS, and iNOS in the skin and spinal cord dorsal horns, as well as IL-1β and TNF-α, compared with the burn group. Moreover, regarding the anti-inflammatory effect, the apoptosis cells in the spinal cord significantly decreased after the fat grafting in the burn injury group. Fat grafting was effective in treating burn-induced neuropathic pain through the alleviation of neuroinflammation and ameliorated spinal neuronal apoptosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137563PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569053PMC
June 2016

Rhinacanthin-C, A Fat-Soluble Extract from Rhinacanthus nasutus, Modulates High-Mobility Group Box 1-Related Neuro-Inflammation and Subarachnoid Hemorrhage-Induced Brain Apoptosis in a Rat Model.

World Neurosurg 2016 Feb 7;86:349-60. Epub 2015 Sep 7.

Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Objective: High-mobility group box 1 (HMGB1) was shown to be a major extracellular mediator involved in relayed neuro-inflammation in animals after subarachnoid hemorrhage (SAH). It is of interest to examine the effect of rhinacanthin-C (RCT-C, C25H30O5) on pro-inflammatory cytokines/HMGB1 in an SAH-related early brain injury model.

Methods: A rodent double SAH model was used. RCT-C was administered orally at 100, 200, and 400 μmol/kg/day. Cerebral spinal fluid samples were obtained to assess interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor α using a real-time polymerase chain reaction. Basilar arteries were harvested and cerebral cortex was examined for HMGB1 mRNA and protein expression (western blot) and caspases (real-time polymerase chain reaction). An intrathecal injection of 1 ng of HMGB-1 recombinant protein was given in the 400 μmol/kg/day RCT-C plus SAH groups.

Results: The levels of IL-1β, IL-6, and tumor necrosis factor α mRNA were significantly increased in animals subject to SAH, compared with the healthy controls, but were absent in the RCT-C groups. Cleaved caspase-9a as well as HMGB-1 mRNA and protein were significantly reduced in the 400 μmol/kg/day RCT-C treatment groups. Similarly, administration of RCT-C reduced HMGB-1 mRNA and protein expression (P <0.01).

Conclusions: RCT-C exerts a neuroprotective effect by reducing cleaved caspase-3- and caspase-9a-related apoptosis. Decreased HMGB-1 mRNA and protein expression in the RCT-C groups corresponds to its anti-inflammatory effect. HMGB-1 recombinant protein administration impaired the neuroprotective and immunosuppressive effect of RCT-C. This finding lends credence that RCT-C modulates the HMGB-1-related pathway and attenuates brain apoptosis in the pathogenesis of SAH.
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http://dx.doi.org/10.1016/j.wneu.2015.08.071DOI Listing
February 2016

Osteoporosis Self-Assessment Tool for Asians Can Predict Neurologic Prognosis in Patients with Isolated Moderate Traumatic Brain Injury.

PLoS One 2015 17;10(7):e0132685. Epub 2015 Jul 17.

Division of Traumatology, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Emergency Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Objectives: Osteoporosis Self-Assessment Tool for Asians (OSTA) has been proved to be a simple and effective tool for recognizing osteoporosis risk. Our previous study has demonstrated that the preoperative OSTA index was a good prognostic predictor for stage II and III colon cancer patients after surgery. We aim to evaluate the value of OSTA index in prognostication of isolated traumatic brain injury with moderate severity (GCS 9-13).

Methods: We retrospectively reviewed all patients visiting Kaohsiung Medical University Hospital emergency department due to isolated moderate traumatic brain injury from Jan. 2010 to Dec. 2012. Background data (including the OSTA index), clinical presentations, management and outcomes (ICU admission days, total admission days, complications, Glasgow outcome score (GOS) at discharge, mortality) of the patients were recorded for further analysis. Our major outcome was good neurologic recovery defined as GOS of 5. Pearson chi-square test and the Mann-Whitney U test were used to compare demographic features. Multiple logistic regression was used to identify independent risk factors.

Results: 107 isolated moderate TBI patients were studied. 40 patients (37.4%) showed good recovery and 10 (9.3%) died at discharge. The univariate analysis revealed that younger age, higher OSTA index, lower ISS, lower AIS-H, and avoidance to neurosurgery were associated with better neurologic outcome for all moderate TBI patients. Multivariate analysis revealed that lower ISS, higher OSTA, and the avoidance of neurosurgery were independent risk factors predicting good neurologic recovery.

Conclusion: Higher ISS, lower OSTA index and exposure to neurosurgery were the independent risk factors for poorer recovery from isolated moderate TBI. In addition to labeling the cohort harboring osteoporotic risk, OSTA index could predict neurologic prognosis in patients with isolated moderate traumatic brain injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132685PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506087PMC
May 2016

A purine antimetabolite attenuates toll-like receptor-2, -4, and subarachnoid hemorrhage-induced brain apoptosis.

J Surg Res 2015 Dec 12;199(2):676-87. Epub 2015 Jun 12.

Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan, Republic of China; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan, Republic of China.

Background: Upregulation of high-level toll-like receptors (TLRs) is observed in the serum of animals following experimental subarachnoid hemorrhage (SAH) and is highly related to SAH-induced early brain injury (EBI). The present study was of interest to examine the effect of 6-mercaptopurine (6-MP) on alternation of TLR-2, -3, and -4 in this model.

Methods: A rodent SAH model was used. Administration with 6-MP (0.5/1/2 mg/kg/d) was initiated 1 h after the induction of SAH via an osmotic minipump. Cerebral cortex was harvested to measure TLRs messenger RNA and protein (reverse transcription polymerase chain reaction [rt-PCR] and Western blot). Cerebral cortex was harvested for activated caspases (rt-PCR) measurement.

Results: Cellular evaluation revealed increased neuronal nuclei(+) neurons with vacuolated nuclear and glial fibrillary acidic protein(+) astrocytes in the SAH group, but absent in the 6-MP treatment and healthy controls. The TLR-3 levels were not significantly increased in animals subject to SAH, compared with the controls (no SAH). The levels of TLR-2 and -4 in the SAH only and SAH plus vehicle groups were significantly elevated (P < 0.01), and treatment with 6-MP reduced TLR-2, -3 (at 2 mg/kg), and -4 (dose-dependently) protein expression following SAH. Likewise, the TLR-4 messenger RNA levels were also significantly reduced in the 6-MP (at 1 mg/kg and 2 mg/kg) groups. Cleaved caspase-3 and caspase-9a were reduced at 2-mg/kg 6-MP treatment group.

Conclusions: These results show that 6-MP attenuates the expression of TLR-2, -4, especially TLR-4, which play an antiapoptotic effect on SAH-induced EBI. This finding supported that through modulating TLRs, 6-MP can attenuate SAH-induced EBI. Those results offer credit to the neuroprotective effect of 6-MP.
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http://dx.doi.org/10.1016/j.jss.2015.06.011DOI Listing
December 2015

Autologous adipose-derived stem cells attenuate muscular atrophy and protect spinal cord ventral horn motor neurons in an animal model of burn injury.

Cytotherapy 2015 Aug;17(8):1066-75

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Background Aims: Burn injuries might increase muscle mass loss, but the mechanisms are still unclear. In this study, we demonstrated that burn injury induced spinal cord ventral horn motor neuron (VHMN) apoptosis and subsequently caused muscle atrophy and revealed the potential protection of autologous adipose-derived stem cells (ASCs) transplantation on spinal cord VHMNs and muscle against burn injury.

Methods: Third-degree hind-paw burns were established by contact with a 75°C metal surface for 10 seconds. Adipose tissues were harvested from the groin fat pad, expanded in culture and labeled with chloromethyl-benzamido/1,1'-dioctadecyl-3,3,3',3'- tetramethyl indocarbocyanine perchlorate. The ASCs were transplanted into the injured hind paw at 4 weeks after burn injury. The lumbar spinal cord, sciatic nerve, gastrocnemius muscle and hind-paw skin were processed for immunofluorescent staining at 4 weeks after transplantation, including terminal deoxynucleotidyl transferase (TUNEL) assay, caspase-3, caspase-9, CD 90 and S100, and the gastrocnemius muscle was evaluated through the use of hematoxylin and eosin staining.

Results: Caspase-3-positive, caspase-9-positive and TUNEL-positive cells were significantly increased in the corresponding dermatome spinal cord VHMNs after burn injury. Moreover, the decrease of Schwann cells in sciatic nerve and the increase of denervation atrophy in gastrocnemius muscle were observed. Furthermore, ASCs transplantation significantly attenuated apoptotic death of VHMNs and the area of muscle denervation atrophy in the gastrocnemius muscle fibers.

Conclusions: The animal model of third-degree burns in the hind paw showed significant apoptosis in the corresponding spinal cord VHMNs, which suggests that neuroprotection might be the potentially therapeutic target in burn-induced muscle atrophy. ASCs have potential neuroprotection against burn injuries through its anti-apoptotic effects.
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http://dx.doi.org/10.1016/j.jcyt.2015.03.687DOI Listing
August 2015

Magnesium Lithospermate B Implicates 3'-5'-Cyclic Adenosine Monophosphate/Protein Kinase A Pathway and N-Methyl-d-Aspartate Receptors in an Experimental Traumatic Brain Injury.

World Neurosurg 2015 Oct 18;84(4):954-63. Epub 2015 Jun 18.

Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Objective: Decreased 3'-5'-cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and increased N-methyl-d-aspartate (NMDA) related apoptosis were observed in traumatic brain injury (TBI). It is of interest to examine the effect of magnesium lithospermate B (MLB) on cAMP/PKA pathway and NMDAR in TBI.

Methods: A rodent weight-drop TBI model was used. Administration of MLB was initiated 1 week before (precondition) and 24 hours later (reversal). Cortical homogenates were harvested to measure cAMP (enzyme-linked immunosorbent assay), soluble guanylyl cyclases, PKA and NMDA receptor-2β (Western blot). In addition, cAMP kinase antagonist and H-89 dihydrochloride hydrate were used to test MLB's effect on the cytoplasm cAMP/PKA pathway after TBI.

Results: Morphologically, vacuolated neuron and activated microglia were observed in the TBI groups but absent in the MLB preconditioning and healthy controls. Induced cAMP, soluble guanylyl cyclase α1, and PKA were observed in the MLB groups, when compared with the TBI group (P < 0.01) Administration of H-89 dihydrochloride hydrate reversed the effect of MLB on cortical PKA and NMDA-2β expression after TBI.

Conclusions: This study showed that MLB exerted an antioxidant effect on the enhancement of cytoplasm cAMP and PKA. This compound also decreased NMDA-2β levels, which may correspond to its neuroprotective effects. This finding lends credence to the presumption that MLB modulates the NMDA-2β neurotoxicity through a cAMP-dependent mechanism in the pathogenesis of TBI.
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http://dx.doi.org/10.1016/j.wneu.2015.05.075DOI Listing
October 2015

Valproic acid attenuates intercellular adhesion molecule-1 and E-selectin through a chemokine ligand 5 dependent mechanism and subarachnoid hemorrhage induced vasospasm in a rat model.

J Inflamm (Lond) 2015 2;12:27. Epub 2015 Apr 2.

Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan ; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung, Taiwan.

Background: Up-regulation of regulated upon activation, normal T-cell expressed and secreted (RANTES/CCL5) and adhesion molecules is observed in the serum of animals following experimental subarachnoid hemorrhage (SAH). The present study was to examine the effect of valproic acid (VPA) on RANTES and alternation of adhesion molecules in this model.

Methods: A rodent SAH model was employed. Animals were randomly assigned into six groups. Basilar artery (BA) was harvested for intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin evaluation (western blotting) and RANTES (rt-PCR). 1 ng CCL5 recombinant protein intrathecal injection was performed in the VPA + SAH groups. (N = 5).

Results: Convoluted internal elastic lamina, distorted endothelial wall, and smooth muscle micro-necrosis was prominently observed in the SAH groups, which is absent in the VPA treatment and the healthy controls. Treatment with VPA dose-dependently reduced the ICAM-1, E-selectin and RANTES level, compared with the SAH group (p <0.01). The administration of CCL5 significantly increased CD45(+) glia and ICAM-1 level in the VPA treatment groups.

Conclusion: VPA exerts its anti-vasospastic effect through the dual effect of inhibiting RANTES expression and reduced adhesion molecules. Besides, VPA also decreased CD45(+) cells transmigrated to the vascular wall. The administration of CCL5 significantly reversed the inhibitory effect of this compound on CD45(+) monocytes, E-selectin, and ICAM-1 level. This study also lends credence to support this compound could attenuate SAH induced adhesion molecules and neuro-inflammation in a CCL5 dependent mechanism.
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http://dx.doi.org/10.1186/s12950-015-0074-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407545PMC
April 2015

Nucleophosmin overexpression is associated with poor survival in astrocytoma.

APMIS 2015 Jun 23;123(6):515-22. Epub 2015 Apr 23.

Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

The multiple functions of the protein nucleophosmin (NPM) include the regulation and balance of cell growth, proliferation, and apoptosis. Many cancers have suspected associations with overexpression of NPM or with mutation of the NPM gene. Although NPM and anaplastic lymphoma kinase fusion proteins are known to be related to the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) signaling pathway, the relationships of NPM, JAK2, and STAT5 to astrocytoma remain unclear. Therefore, this study performed histochemical analyses of expressions of NPM, p-JAK2, and STAT5B proteins in patients with astrocytoma. The results showed that high NPM expression was significantly associated with high tumor grade (p = 0.000), old age (p = 0.000), low Karnofsky Performance Scale (KPS) score (p = 0.000), and tumor recurrence (p = 0.045). High p-JAK2 expression was significantly associated with old age (p = 0.000), high tumor grade (p = 0.000), low KPS score (p = 0.000), and tumor recurrence (p = 0.036). Expression of STAT5B was significantly correlated with tumor grade (p = 0.018) and KPS score (p = 0.002). High expressions of NPM, p-JAK2, and STAT5B were associated with a short survival time (p = 0.035, 0.003 and 0.002, respectively). In multivariable analysis, STAT5B expression was a significant predictor of survival time (p = 0.003). In conclusion, NPM and p-JAK2/STAT5B may have important roles in tumor progression, and STAT5B is an independent prognostic marker of astrocytoma.
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http://dx.doi.org/10.1111/apm.12381DOI Listing
June 2015