Publications by authors named "Chung-Ching Chio"

105 Publications

The Fibronectin Expression Determines the Distinct Progressions of Malignant Gliomas via Transforming Growth Factor-Beta Pathway.

Int J Mol Sci 2021 Apr 6;22(7). Epub 2021 Apr 6.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Due to the increasing incidence of malignant gliomas, particularly glioblastoma multiforme (GBM), a simple and reliable GBM diagnosis is needed to screen early the death-threaten patients. This study aimed to identify a protein that can be used to discriminate GBM from low-grade astrocytoma and elucidate further that it has a functional role during malignant glioma progressions. To identify proteins that display low or no expression in low-grade astrocytoma but elevated levels in GBM, glycoprotein fibronectin (FN) was particularly examined according to the mining of the Human Protein Atlas. Web-based open megadata minings revealed that FN was mainly mutated in the cBio Cancer Genomic Portal but dominantly overexpressed in the ONCOMINE (a cancer microarray database and integrated data-mining platform) in distinct tumor types. Furthermore, numerous different cancer patients with high FN indeed exhibited a poor prognosis in the PrognoScan mining, indicating that FN involves in tumor malignancy. To investigate further the significance of FN expression in glioma progression, tumor specimens from five malignant gliomas with recurrences that received at least two surgeries were enrolled and examined. The immunohistochemical staining showed that FN expression indeed determined the distinct progressions of malignant gliomas. Furthermore, the expression of vimentin (VIM), a mesenchymal protein that is strongly expressed in malignant cancers, was similar to the FN pattern. Moreover, the level of epithelial-mesenchymal transition (EMT) inducer transforming growth factor-beta (TGF-β) was almost recapitulated with the FN expression. Together, this study identifies a protein FN that can be used to diagnose GBM from low-grade astrocytoma; moreover, its expression functionally determines the malignant glioma progressions via TGF-β-induced EMT pathway.
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http://dx.doi.org/10.3390/ijms22073782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038731PMC
April 2021

Mesenchymal stem cell-conditioned medium attenuates the retinal pathology in amyloid-β-induced rat model of Alzheimer's disease: Underlying mechanisms.

Aging Cell 2021 05 30;20(5):e13340. Epub 2021 Mar 30.

Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.

Amyloid-beta (Aβ) oligomer is known to contribute to the pathophysiology of age-related macular degeneration. Herein, we aimed to elucidate the in vivo and in vitro effects of Aβ application on retinal morphology in rats. Our in vivo studies revealed that intracerebroventricular administration of Aβ oligomer caused dysmorphological changes in both retinal ganglion cells and retinal pigment epithelium. In addition, in vitro studies revealed that ARPE-19 cells following Aβ oligomer application had decreased viability along with apoptosis and decreased expression of the tight junction proteins, increased expression of both phosphor-AKT and phosphor-GSK3β and decreased expression of both SIRT1 and β-catenin. Application of conditioned medium (CM) obtained from mesenchymal stem cells (MSC) protected against Aβ oligomer-induced retinal pathology in both rats and ARPE-19 cells. In order to explore the potential role of peptides secreted from the MSCs, we applied mass spectrometry to compare the peptidomics profiles of the MSC-CM. Gene ontology enrichment analysis and String analysis were performed to explore the differentially expressed peptides by predicting the functions of their precursor proteins. Bioinformatics analysis showed that 3-8 out of 155-163 proteins in the MSC-CM maybe associated with SIRT1/pAKT/pGSK3β/β-catenin, tight junction proteins, and apoptosis pathway. In particular, the secretomes information on the MSC-CM may be helpful for the prevention and treatment of retinal pathology in age-related macular degeneration.
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http://dx.doi.org/10.1111/acel.13340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135003PMC
May 2021

Ischemia/reperfusion injured intestinal epithelial cells cause cortical neuron death by releasing exosomal microRNAs associated with apoptosis, necroptosis, and pyroptosis.

Sci Rep 2020 09 1;10(1):14409. Epub 2020 Sep 1.

Division of Neurosurgery, Department of Surgery, Chi Mei Medical Center, No. 901, Zhonghua Road, Yongkang District, Tainan City, 710, Taiwan.

To date, there is no good evidence that intestine epithelial cells (IEC) affected by ischemia/reperfusion (I/R) injury are able to cause cortical neuron injury directly. Additionally, it remains unclear whether the neuronal damage caused by I/R injured IEC can be affected by therapeutic hypothermia (TH, 32 °C). To address these questions, we performed an oxygen-glucose deprivation (OGD) affected IEC-6-primary cortical neuron coculture system under normothermia (37 °C) or TH (32 °C) conditions. It was found that OGD caused hyperpermeability in IEC-6 cell monolayers. OGD-preconditioned IEC-6 cells caused cortical neuronal death (e.g., decreased cell viability), synaptotoxicity, and neuronal apoptosis (evidenced by increased caspase-3 expression and the number of TUNEL-positive cells), necroptosis (evidenced by increased receptor-interacting serine/threonine-protein kinase-1 [RIPK1], RIPK3 and mixed lineage kinase domain-like pseudokinase [MLKL] expression), and pyroptosis (evidenced by an increase in caspase-1, gasdermin D [GSDMD], IL-1β, IL-18, the apoptosis-associated speck-like protein containing a caspase recruitment domain [ASC], and nucleotide oligomerization domain [NOD]-like receptor [NLRP]-1 expression). TH did not affect the intestinal epithelial hyperpermeability but did attenuate OGD-induced neuronal death and synaptotoxicity. We also performed quantitative real-time PCR to quantify the genes encoding 84 exosomal microRNAs in the medium of the control-IEC-6, the control-neuron, the OGD-IEC-6 at 37 °C, the OGD-IEC-6 at 32 °C, the neuron cocultured with OGD-IEC-6 at 37 °C, and the neurons cocultured with OGD-IEC-6 at 32 °C. We found that the control IEC-6 cell s or cortical neurons are able to secrete a basal level of exosomal miRNAs in their medium. OGD significantly up-regulated the basal level of each parameter for IEC-6 cells. As compared to those of the OGD-IEC-6 cells or the control neurons, the OGD-IEC-6 cocultured neurons had significantly higher levels of 19 exosomal miRNAs related to apoptosis, necroptosis, and/or pyroptosis events. Our results identify that I/R injured intestinal epithelium cells can induce cortical neuron death via releasing paracrine mediators such as exosomal miRNAs associated with apoptosis, necroptosis, and/or pyroptosis, which can be counteracted by TH.
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http://dx.doi.org/10.1038/s41598-020-71310-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462997PMC
September 2020

Triglyceride is a Good Biomarker of Increased Injury Severity on a High Fat Diet Rat After Traumatic Brain Injury.

Neurochem Res 2020 Jul 28;45(7):1536-1550. Epub 2020 Mar 28.

Department of Neurosurgery, Chi-Mei Medical Center, Liouying, Tainan, Taiwan.

Injury severity is correlated with poor prognosis after traumatic brain injury (TBI). It is not known whether triglycerides (TGs) or total cholesterol (TC) is good biomarker of increased injury of neuroinflammation and apoptosis in a high fat diet (HFD)-treated rat after TBI episodes. Five-week-old male Sprague-Dawley (SD) rats were fed a HFD for 8 weeks. The anesthetized male SD rats were divided into three sub-groups: sham-operated and TBI with 1.6 atm or with 2.4 atm fluid percussion injury (FPI). Cell infarction volume (triphenyltetrazolium chloride stain), tumor necrosis factor-alpha (TNF-α) expression in the microglia (OX42 marker) and astrocytes (Glial fibrillary acidic protein marker), TNF-α receptor expression in the neurons (TNFR1 and TNFR2 markers), and the extent of neuronal apoptosis (TUNEL marker) were evaluated by immunofluorescence, and the functional outcome was assessed by an inclined plane test. These tests were performed 72 h after TBI. Serum triglyceride and cholesterol levels were measured at 24, 48 and 72 h after TBI. The FPI with 2.4 atm significantly increased body weight loss, infarction volume, neuronal apoptosis and TNF-α expression in the microglia and astrocytes, and it decreased the maximum grasp degree and TNFR1 and TNFR2 expression in neurons at the 3rd day following TBI. The serum TG level was positively correlated with FPI force, infarction volume, Neu-N-TUNEL, GFAP-TNFα, and OX42-TNFα Simultaneously; the serum TG level was negatively correlated with Neu-N-TNFR1 and Neu-N-TNFR2. TG is a good biomarker of increased injury for neuroinflammation and apoptosis at the 3rd day after TBI in HFD rats.
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http://dx.doi.org/10.1007/s11064-020-03018-xDOI Listing
July 2020

Renal insufficiency plays a crucial association factor in severe knee osteoarthritis-induced pain in patients with total knee replacement: A retrospective study.

Medicine (Baltimore) 2020 Feb;99(6):e19125

Cell Physiology and Molecular Image Research Center, Wan Fang Hospital.

Pain, the main symptom of osteoarthritis (OA), can lead to functional disability in patients with knee OA. Understanding the association factors related to knee pain is important since preventing OA-induced disabilities can be achieved by modifying these pain-associated issues. Therefore, this study was aimed to investigate the association factors for OA-induced knee pain in Taiwanese patients who received total knee replacements (TKR).In this retrospective study, 357 subjects who had undergone TKR at the Taipei Municipal Wan-Fang Hospital were recruited. The distribution of pain severity among patients with knee OA was evaluated. Demographic data and clinical parameters were analyzed to determine relationships between these variables and the severity of knee OA pain.Of the 357 patients studied, 54% and 33% had moderate and severe knee pain, respectively. Furthermore, a multivariate logistic regression analysis revealed that serum creatinine (>1.5 mg/dL) and an estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m) were significantly associated with severe knee pain in OA patients. A significant correlation between severe knee pain and serum creatinine or eGFR was demonstrated by Pearson correlations.Taken together, the renal insufficiency defined by an elevated serum creatinine or a low eGFR in OA patients who required TKR was associated with severe knee pain. These variables must be considered while treating knee OA pain, especially in those patients with severe pain.
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http://dx.doi.org/10.1097/MD.0000000000019125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015635PMC
February 2020

The Short-Term Effects of Isolated Traumatic Brain Injury on the Heart in Experimental Healthy Rats.

Neurocrit Care 2020 10;33(2):438-448

Department of Neurosurgery, Chi-Mei Medical Center, #901 Chung Hwa Road, Yung Kang City, Tainan, Taiwan.

Background: To date, cardiac dysfunction after traumatic brain injury (TBI) has not been consistent. In this study, we hypothesized that TBI may play a role in the development of new-onset cardiac dysfunction in healthy experimental rats.

Materials And Methods: Anesthetized healthy male Sprague-Dawley rats were divided into two groups: a sham-operated control group and a TBI group. The brain was injured with 2.4 atm percussion via a fluid percussion injury model. During the 120 min after TBI, we continuously measured brain parameters, including intracranial pressure (ICP) and cerebral perfusion pressure (CPP), and cardiac parameters, such as heart rate (HR), inter-ventricular septum dimension (IVSD), left ventricular internal dimension diastole (LVIDd), end-diastolic volume (EDV), ejection fraction (EF), fractional shortening (FS), and LV mass diastole (LVd mass) by cardiac echo. On days 1, 3, 7, and 14 after TBI, the brain damage volume was evaluated with triphenyltetrazolium chloride; the physiological parameters of the heart, including HR, IVSd, LVIDd, EDV, EF, FS, and LVd mass, were evaluated with cardiac echo; the morphology of cardiomyocytes was examined by hematoxylin and eosin (HE) and Masson trichrome staining; and the biomarkers of cardiac injury troponin I and B-type natriuretic peptide (BNP) were also examined.

Results: Compared to sham-operated controls, the TBI groups had higher ICP, lower CPP, and higher brain neuronal apoptosis and infarction contusion volume. The impact of TBI on heart function showed hyperdynamic response trends in IVSd, LVIDd, EDV, EF, FS, and LVd mass within 30 min after TBI; however, EF and FS exhibited eventual decreasing trends. Simultaneously, the values of the biomarkers troponin I and BNP were within normal limits, and HE and Mass trichrome staining revealed no significant differences between the sham-operated control group and the TBI group.

Conclusions: Our results suggest that TBI due to 2.4 atm fluid percussion injury in healthy experimental rats may cause significant damage to the brain and affect the heart function as investigated by cardiac echo but not as investigated by HE and Masson trichrome stainings or troponin I and BNP evaluation.
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http://dx.doi.org/10.1007/s12028-019-00902-5DOI Listing
October 2020

Effects of a High-Fat Diet on Neuroinflammation and Apoptosis in Acute Stage After Moderate Traumatic Brain Injury in Rats.

Neurocrit Care 2020 08;33(1):230-240

Department of Neurosurgery, Chi-Mei Medical Center, Chiali, Tainan, Taiwan.

Background: A high-fat diet (HFD) is correlated with a higher risk of metabolic syndrome. The effect of HFD on neuroinflammation and apoptosis in acute stage after traumatic brain injury (TBI) in rats is not well known.

Materials And Methods: Five-week-old male Sprague-Dawley (SD) rats were fed a HFD or normal diet (ND) for 8 weeks. Anesthetized male SD rats were divided into two subgroups: sham-operated and TBI. Motor function was measured using an inclined plane. The numbers of apoptotic neurons (markers Neu-N, TUNEL, caspase-3), activated astrocytes (marker GFAP) and microglia (marker OX42), and TNF-α expression in microglia and astrocytes in the ischemic cortex were investigated using an immunofluorescence assay. All of the parameters were measured on the 3rd day after TBI.

Results: Rats fed a HFD for 8 weeks had higher body weight, serum cholesterol, and triglycerides. TBI-induced motor deficits, neuronal decrease, neuronal apoptosis, astrocyte and microglia activation, and TNF-α expression in microglia and astrocytes in the ischemia cortex were significantly increased in ND and HFD rats compared to sham rats. However, these parameters were not significantly different between the ND and HFD TBI groups, except motor deficit.

Conclusions: HFD has no significant effects on neuronal apoptosis or neuroinflammation in acute stage compared with ND for 8 weeks after moderate TBI in experimental rats.
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http://dx.doi.org/10.1007/s12028-019-00891-5DOI Listing
August 2020

The Neuroprotective Effects of Simvastatin on High Cholesterol Following Traumatic Brain Injury in Rats.

World Neurosurg 2019 Dec 10;132:e99-e108. Epub 2019 Sep 10.

Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan; Department of Medical Research Chi-Mei Medical Center, Tainan, Taiwan.

Background: High cholesterol has been correlated with a greater risk of cerebrovascular diseases. Whether pre-existing high cholesterol exacerbates traumatic brain injury (TBI), and whether treatment with the cholesterol-lowering agent simvastatin has neuroprotective effects, especially anti-neuroinflammatory effects, after TBI are not well investigated.

Methods: Five-week-old male Sprague-Dawley rats were fed a high-fat diet for 8 weeks to induce hypercholesterolemia. Anesthetized male Sprague-Dawley rats were divided into 5 groups, including the sham-operated control, TBI control, and TBI with simvastatin treatment (4 mg/kg, 10 mg/kg, or 20 mg/kg) groups. Simvastatin was intraperitoneally injected at 0, 24, and 48 hours after TBI. Motor function was measured using an inclined plane. Neuronal apoptosis (maker Neu-N, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling), tumor necrosis factor-α expression in microglia (marker OX42) and astrocytes (marker glial fibrillary acidic protein), and Tumor necrosis factor-alpha receptor (TNFR) 1 and TNFR2 expression in neurons in the ischemic cortex were investigated using an immunofluorescence assay. All of the parameters were measured on the third day after TBI.

Results: TBI significantly increased the serum levels of cholesterol. The TBI-induced motor deficit was significantly attenuated by 4, 10, and 20 mg/kg simvastatin therapy on the third day after TBI. TBI-induced neuronal TNFR1 activation and apoptosis, as well as tumor necrosis factor-α expression in astrocytes in the ischemic cortex, were significantly attenuated by simvastatin, particularly when 20 mg/kg was administered. Simultaneously, the serum cholesterol remained high despite simvastatin treatment.

Conclusions: The neuroprotection effects of simvastatin on the pre-existing hypercholesterolemia during TBI in rats may be related to its anti-neuroinflammatory effects but not to its cholesterol-lowing effects.
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http://dx.doi.org/10.1016/j.wneu.2019.08.250DOI Listing
December 2019

In-Hospital Mortality After Spinal Surgery in Hemodialysis Patients: An 11-Year Population-Based Study.

World Neurosurg 2019 02 26;122:e667-e675. Epub 2018 Oct 26.

Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Center for General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan.

Background: Patients with end-stage renal disease (ESRD) are at an increased risk of surgical mortality. We aimed to investigate the factors associated with in-hospital mortality in patients with ESRD who underwent spinal surgery, which remains to be determined.

Material And Methods: An age- and sex-matched cohort study was conducted using the Taiwan Longitudinal Health Insurance Database between January 2000 and December 2012. Kaplan-Meier curves were plotted with log-rank test to compare the differences between these 2 groups. The Cox proportional hazard model was used to estimate the hazard ratio of in-hospital mortality adjusted with potential confounding.

Results: In total, 4109 participants with pre-existing ESRD and 8218 patients without ESRD were included. The in-hospital mortality in ESRD (10.17%) was greater than without ESRD (1.39%). Spinal surgery patients with pre-existing ESRD had a 6.78-fold increase in-hospital mortality risk compared with those without ESRD. Spinal surgery patients with ESRD of any age, male or female, and comorbidities experienced a greater incidence of hospital mortality. In patients with ESRD, operations on spinal cords and spinal canal structures had the greatest hospital mortality (14.87%) compared with spinal fusion (3.46%) or excision or destruction of intervertebral disc (3.01%). Kaplan-Meier survival curves showed that patients with ESRD experienced greater hospital mortality than patients without ESRD in all 3 spinal surgery methods (log rank P < 0.0001).

Conclusions: Spinal surgery patients with ESRD have greater in-hospital mortality than patients without ESRD. Age, sex, history of comorbidities, and types of surgical methods were associated with greater in-hospital mortality among patients with ESRD.
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http://dx.doi.org/10.1016/j.wneu.2018.10.119DOI Listing
February 2019

Traumatic Brain Injury Increases the Risk of Major Adverse Cardiovascular and Cerebrovascular Events: A 13-Year, Population-Based Study.

World Neurosurg 2019 Feb 1;122:e740-e753. Epub 2018 Nov 1.

Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Center for General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan.

Background: Previous studies have indicated traumatic brain injury (TBI) as a risk factor for stroke and myocardial injury. Whether TBI increases new onset of major adverse cardiovascular and cerebrovascular events (MACCE) is not well established.

Methods: Patients with a diagnosis of TBI from 2000 to 2012 were 1:2 age-, sex-, and age-adjusted comorbidities matched with normal population cohorts. The MACCE, which included coronary artery disease, heart failure and arrhythmia, ischemic and hemorrhagic stroke, and death, was defined as one inpatient admission with MACCE diagnosis. The maximum follow-up duration to MACCE after the initial TBI diagnosis was 5 years. The baseline comorbidities before TBI, including hypertension, diabetes mellitus, renal disease, and liver disease, also were considered to estimate the risk of MACCE.

Results: In total, 16,211 patients with TBI and 32,422 people from the control group were enrolled in the current study. Our results showed that patients with TBI had a 2.77-fold risk of MACCE, 1.72-fold risk of cardiovascular disease, 2.10-fold risk of ischemic stroke, 6.02-fold risk of hemorrhagic stroke, and 3.13-fold risk of mortality compared with the control group (all P < 0.0001) after adjusting the confounding factors. In addition, the trend of cumulated incidence risk among MACCE, cardiovascular disease, ischemic and hemorrhagic stroke, and mortality presented the greatest incidence within the first year after diagnosis and persisted during the 5 years of follow-up.

Conclusions: Our results showed that patients with TBI have a significantly greater risk of MACCE than the control group. We hope this information will remind critical-care physicians and neurosurgeons to keep in mind the long-term effects of TBI on MACCE.
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http://dx.doi.org/10.1016/j.wneu.2018.10.130DOI Listing
February 2019

Probability of New-Onset Cancer Between Patients with Traumatic Brain Injury and a Comparison General Population Cohort.

World Neurosurg 2019 Jan 9;121:e817-e826. Epub 2018 Oct 9.

Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. Electronic address:

Background: Traumatic brain injury (TBI) has been reported as a risk factor for the development of brain tumors. However, whether TBI affects systemic cancer remains to be determined. We investigated the incidence and factors associated with cancer development in patients with TBI.

Methods: A propensity score (age, gender, and comorbidity)-matched longitudinal cohort study of 34,556 patients with pre-existing TBI and 69,112 patients without TBI from January 2000 to December 2015 was presented using the Taiwan's National Health Insurance Research Database. The Cox proportional hazard regression model was used to estimate the hazard ratio of developing cancer adjusted by the potential confounding factors. The stratified analysis of age, gender, and comorbidities for each cancer type was evaluated using forest plot analysis.

Results: The cancer incidence rate in the patients with TBI (4.38%) was greater than that in patients without TBI (3.88%). The interval to cancer development in those with TBI (5.65 ± 3.58 years) was shorter than that in those without TBI (6.02 ± 3.65 years). The cancer risk in those with TBI was increased 1.27-fold compared with that in the general population. Of the patients with TBI, age <55 years and male gender indicated a greater incidence of cancer than that of the general population. The patients with TBI had greater cancer frequencies in the head and neck structures compared with those in the general population.

Conclusions: TBI is a risk factor for cancer development, especially in males and those aged <55 years. We hope this information will remind physicians to consider the long-term effects of TBI on cancer development.
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http://dx.doi.org/10.1016/j.wneu.2018.09.229DOI Listing
January 2019

Honokiol enhances temozolomide-induced apoptotic insults to malignant glioma cells via an intrinsic mitochondrion-dependent pathway.

Phytomedicine 2018 Oct 8;49:41-51. Epub 2018 Aug 8.

Graduate Institute of Medical Sciences, College of Medicine, Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Brain Disease Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address:

Background: Temozolomide (TMZ) is a first-line chemotherapeutic drug for malignant gliomas. Nonetheless, TMZ-induced side effects and drug resistance remain challenges. Our previous study showed the suppressive effects of honokiol on growth of gliomas.

Purpose: This study was further aimed to evaluate if honokiol could enhance TMZ-induced insults toward malignant glioma cells and its possible mechanisms.

Methods: Human U87 MG glioma cells were exposed to TMZ, honokiol, and a combination of TMZ and honokiol. Cell survival, apoptosis, necrosis, and proliferation were successively assayed. Fluorometric substrate assays were conducted to determine activities of caspase-3, -6, -8, and -9. Levels of Fas ligand, Bax, and cytochrome c were immunodetected. Translocation of Bax to mitochondria were examined using confocal microscopy. Mitochondrial function was evaluated by assaying the mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and complex I enzyme activity. Caspase-6 activity was suppressed using specific peptide inhibitors. The honokiol-induced effects were further confirmed using human U373 MG and murine GL261 cells.

Results: Exposure of human U87 MG glioma cells to honokiol significantly increased TMZ-induced DNA fragmentation and cell apoptosis. Interestingly, honokiol enhanced intrinsic caspase-9 activity without affecting extrinsic Fas ligand levels and caspase-8 activity. Sequentially, TMZ-induced changes in Bax translocation, the MMP, mitochondrial complex I enzyme activity, intracellular ROS levels, and cytochrome c release were enhanced by honokiol. Consequently, honokiol amplified TMZ-induced activation of caspases-3 and -6 in human U87 MG cells. Fascinatingly, suppressing caspase-6 activity concurrently decreased honokiol-induced DNA fragmentation and cell apoptosis. The honokiol-involved improvement in TMZ-induced intrinsic apoptosis was also confirmed in human U373 MG and murine GL261 glioma cells.

Conclusions: This study showed that honokiol can enhance TMZ-induced apoptotic insults to glioma cells via an intrinsic mitochondrion-dependent mechanism. Our results suggest the therapeutic potential of honokiol to attenuate TMZ-induced side effects.
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http://dx.doi.org/10.1016/j.phymed.2018.06.012DOI Listing
October 2018

Improved effects of honokiol on temozolomide-induced autophagy and apoptosis of drug-sensitive and -tolerant glioma cells.

BMC Cancer 2018 04 3;18(1):379. Epub 2018 Apr 3.

Graduate Institute of Medical Sciences, College of Medicine and Comprehensive Cancer Center, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan.

Background: Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and -resistant glioma cells and the possible mechanisms.

Methods: TMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ.

Results: Exposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G phase but did not affect cell necrosis. The improved effects of honokiol on TMZ-induced cell insults were further verified in mouse GL261 glioma cells. Moreover, exposure of drug-tolerant human U87-MG-R9 cells to honokiol induced autophagy and consequent apoptosis. Pretreatments with 3-MA and CLQ caused significant attenuations in honokiol- and TMZ-induced cell autophagy and apoptosis in human TMZ-sensitive and -tolerant glioma cells.

Conclusions: Taken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas.
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http://dx.doi.org/10.1186/s12885-018-4267-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883267PMC
April 2018

Exercise Rehabilitation Attenuates Cognitive Deficits in Rats with Traumatic Brain Injury by Stimulating the Cerebral HSP20/BDNF/TrkB Signalling Axis.

Mol Neurobiol 2018 Nov 25;55(11):8602-8611. Epub 2018 Mar 25.

Division of Neurosurgery, Department of Surgery, Chi Mei Medical Center, Tainan, 710, Taiwan.

Physical exercise (PE) is an effective method for improving cognitive function among patients with traumatic brain injury (TBI). We previously demonstrated that PE with an infrared-sensing running wheel (ISRW) system provides strong neuroprotection in an experimental animal model of stroke. In this study, we used fluid percussion injury in rats to simulate mild TBI. For rats, we used both passive avoidance learning and the Y-maze tests to evaluate cognitive function. We investigated whether PE rehabilitation attenuated cognitive deficits in rats with TBI and determined the contribution of hippocampal and cortical expression of heat shock protein 20 (HSP20) to PE-mediated cognitive recovery. In addition to increasing hippocampal and cortical expression of HSP20, brain-derived neurotrophic factor (BDNF), and the tropomyosin receptor kinase B (TrkB) ratio, PE rehabilitation significantly attenuated brain contusion and improved cognitive deficits in the rat model. Furthermore, reducing hippocampal and cortical expression of HSP20 with an intracerebral injection of pSUPER hsp20 small interfering RNA significantly diminished the PE-induced overexpression of hippocampal and cortical BDNF and the TrkB ratio and also reversed the beneficial effect of PE in reducing neurotrauma and the cognitive deficits. A positive Pearson correlation was found between HSP20 and BDNF, as well as between HSP20 and TrkB, in the hippocampal and cortical tissues. We thus conclude that post-ischaemic ISRW exercise rehabilitation attenuates cognitive deficits, as well as brain contusions, in TBI rats by stimulating the cerebral HSP20/BDNF/TrkB signalling axis.
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http://dx.doi.org/10.1007/s12035-018-1011-2DOI Listing
November 2018

The Risk of Traumatic Brain Injury Occurring Among Patients with Parkinson Disease: A 14-Year Population-Based Study.

World Neurosurg 2018 May 13;113:e328-e335. Epub 2018 Feb 13.

Department of Neurosurgery, Chi Mei Medical Center, Tainan, Taiwan; Center for General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan. Electronic address:

Background: Previous studies have implicated traumatic brain injury (TBI) as a risk factor for Parkinson disease (PD). However, the incidence risk of new-onset TBI among patients with PD is not well established. This study investigated the contribution of PD to new-onset TBI associations.

Methods: The study selected 6076 patients with PD and using 1:2 propensity score matching 12,152 general population cohorts in a longitudinal population database in Taiwan. The Cox proportional hazard regression model was used to estimate the hazard ratio of TBI adjusted with the potential confounding factors.

Results: The incidence of TBI in patients with PD (2.57%) and compared cohorts (1.81%) was significantly different (P = 0.0007). Patients with PD had a higher risk of TBI (hazard ratio, 1.63; 95% confidence interval, 1.32-2.01) compared with the general population. Patients with PD with TBI incidence had a higher Charlson Comorbidity Index than did the general population with TBI (P < 0.0001). Fall is the major cause of TBI in patients with PD.

Conclusions: This study shows that patients with PD have a high risk of TBI, and the major cause of TBI in patients with PD is fall.
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http://dx.doi.org/10.1016/j.wneu.2018.02.027DOI Listing
May 2018

The Effects of Memantine on Glutamic Receptor-Associated Nitrosative Stress in a Traumatic Brain Injury Rat Model.

World Neurosurg 2018 Apr 31;112:e719-e731. Epub 2018 Jan 31.

Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. Electronic address:

Background: The main aim of this study is to elucidate whether the neuroprotective effect of memantine, a noncompetitive N-methyl-d-aspartate receptor 2B (NR2B) antagonist, affects neuronal nitrosative stress, apoptosis, and NR2B expression and improves functional outcomes.

Methods: Immediately after the onset of fluid percussion traumatic brain injury (TBI), anesthetized male Sprague-Dawley rats were divided into sham-operated, TBI + vehicle, and TBI + memantine groups. TBI rats were treated with a memantine intraperitoneal injection dose of 20 mg/kg intraperitoneally and then 1 mg/kg every 12 hours intraperitoneally for 6 doses. The motor function, proprioception, infarction volume, and neuronal apoptosis were then measured. Immunofluorescence was used to evaluate astrogliosis, microgliosis, nitrosative stress, and NR2A and NR2B expression in cortical cells. All the parameters were assessed 72 hours after TBI.

Results: Compared with the sham-operated controls, the TBI-induced motor and proprioception deficits, and increased infraction volume after TBI were significantly attenuated by memantine therapy. The TBI-induced neuronal apoptosis, astrogliosis, and microgliosis, the numbers of neuronal NO synthase and 3-nitro-l-tyrosine expression in neurons, and inducible NO synthase expression in microglia and astrocyte cells in the ischemic cortex after TBI were significantly improved by memantine therapy. Simultaneously, without affecting the NR2A expression in neuronal cells, the NR2B expression significantly decreased after memantine therapy, as evaluated by an immunofluorescence stain.

Conclusions: Intraperitoneal injection of memantine in the acute stage may ameliorate TBI in rats by affecting NR2B expression and decreasing neuronal apoptosis and nitrosative stress in the injured cortex. These effects might represent 1 mechanism by which functional recovery occurred.
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http://dx.doi.org/10.1016/j.wneu.2018.01.140DOI Listing
April 2018

Estrogen Receptor-α is Involved in Tamoxifen Neuroprotective Effects in a Traumatic Brain Injury Male Rat Model.

World Neurosurg 2018 Apr 31;112:e278-e287. Epub 2018 Jan 31.

Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. Electronic address:

Objective: To determine the neuroprotective mechanisms of tamoxifen (TMX) during traumatic brain injury (TBI), especially the effects on estrogen receptor-α (ERα) expression, as well as neuroinflammatory associations.

Materials And Methods: Anesthetized male Sprague-Dawley rats were divided into 4 groups: sham-operated controls, sham-operated controls given TMX (1 mg/kg/per day) for 3 days, those given a vehicle solution immediately after TBI, and those given TMX (1 mg/kg/per day) for 3 days. The functional outcome was evaluated by assessments of body weight and proprioception. The total ERα expression in the cortex also was investigated by Western blotting, and ERα expression in neurons, microglia, and astroglia were each detected via immunofluorescence staining. Neuronal apoptosis (marker caspase-3), activated microglia (marker OX42), astroglia (marker glial fibrillary acidic protein), and tumor necrosis factor-alpha expression in microglia and astroglia in the cortex were evaluated by immunofluorescence staining methods.

Results: Compared with sham-operated controls, the TBI-induced proprioception inhibition was significantly attenuated by TMX therapy on day 3 after TBI. Using immunofluorescence staining, we found that the TBI-induced neuronal loss, apoptosis, activated microglia, and astrocyte expression and tumor necrosis factor-alpha and ERα in the cortex were significantly reduced by TMX therapy.

Conclusions: Our results suggest that the intraperitoneal injection of TMX (1 mg/kg/per day) for 3 days may affect ERα expression in neurons and glia, which is accompanied by neuroinflammation and neuronal apoptosis, and it might represent one mechanism by which functional recovery occurs. We consider TMX administration to be a promising strategy for TBI.
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http://dx.doi.org/10.1016/j.wneu.2018.01.036DOI Listing
April 2018

Impact of grouping complications on mortality in traumatic brain injury: A nationwide population-based study.

PLoS One 2018 11;13(1):e0190683. Epub 2018 Jan 11.

Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan.

Traumatic brain injury (TBI) is an important health issue with high mortality. Various complications of physiological and cognitive impairment may result in disability or death after TBI. Grouping of these complications could be treated as integrated post-TBI syndromes. To improve risk estimation, grouping TBI complications should be investigated, to better predict TBI mortality. This study aimed to estimate mortality risk based on grouping of complications among TBI patients. Taiwan's National Health Insurance Research Database was used in this study. TBI was defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes: 801-804 and 850-854. The association rule data mining method was used to analyze coexisting complications after TBI. The mortality risk of post-TBI complication sets with the potential risk factors was estimated using Cox regression. A total 139,254 TBI patients were enrolled in this study. Intracerebral hemorrhage was the most common complication among TBI patients. After frequent item set mining, the most common post-TBI grouping of complications comprised pneumonia caused by acute respiratory failure (ARF) and urinary tract infection, with mortality risk 1.55 (95% C.I.: 1.51-1.60), compared with those without the selected combinations. TBI patients with the combined combinations have high mortality risk, especially those aged <20 years with septicemia, pneumonia, and ARF (HR: 4.95, 95% C.I.: 3.55-6.88). We used post-TBI complication sets to estimate mortality risk among TBI patients. According to the combinations determined by mining, especially the combination of septicemia with pneumonia and ARF, TBI patients have a 1.73-fold increased mortality risk, after controlling for potential demographic and clinical confounders. TBI patients aged<20 years with each combination of complications also have increased mortality risk. These results could provide physicians and caregivers with important information to increase their awareness about sequences of clinical syndromes among TBI patients, to prevent possible deaths among these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764255PMC
February 2018

Increased risk of brain cancer incidence in stroke patients: a clinical case series, population-based and longitudinal follow-up study.

Oncotarget 2017 Dec 15;8(65):108989-108999. Epub 2017 Nov 15.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Stroke and brain cancer are two distinct diseases. However, the relationship between both diseases has rarely been examined. This study investigated the longitudinal risk for developing brain cancer in stroke patients. To study this, we first reviewed the malignant gliomas previously with or without stroke using brain magnetic resonance imaging (MRI) images and the past histories. Two ischemic stroke patients before the malignant glioma were identified and belonged to the glioblastoma mutiforme (GBM). Particularly, both GBM specimens displayed strong hypoxia-inducible factor 1α (HIF-1α) expression in immunohistochemical (IHC) staining. To elucidate the significance of this relationship, we then used a nationwide population-based cohort in Taiwan to investigate the risk for the incidence of brain cancer in patients previously with or without stroke. The incidence of all tumors in the stroke group was lower than that in the control group with an adjusted hazard ratio (HR) of 0.79 (95% confidence interval [CI]: 0.74-0.84) in both gender and age older than 60 years. But the stroke patients had higher risk of developing only brain cancer with an adjusted HR of 3.09 (95% CI: 1.80-5.30), and otherwise had lower risk of developing head and neck, digestive, respiratory, bone and skin, as well as other tumors, all with p<0.05. After stratification by gender and age, the female and aged 40-60 year old stroke patients had higher risk of developing brain cancer with an adjusted HR of 7.41 (95% CI: 3.30-16.64) and 16.34 (95% CI: 4.45-62.13), respectively, both with p<0.05. Patients with stroke, in particular female and age 40-60 years old, have an increased risk for developing brain cancer.
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http://dx.doi.org/10.18632/oncotarget.22480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752498PMC
December 2017

Gamma-Secretase Inhibitors Attenuate Neurotrauma and Neurogenic Acute Lung Injury in Rats by Rescuing the Accumulation of Hypertrophic Microglia.

Cell Physiol Biochem 2017 6;44(5):1726-1740. Epub 2017 Dec 6.

Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.

Background/aims: In response to traumatic brain injury (TBI), activated microglia exhibit changes in their morphology from the resting ramified phenotype toward the activated hypertrophic or amoeboid phenotype. Here, we provide the first description of the mechanism underlying the neuroprotective effects of γ-secretase inhibitors on TBI outcomes in rats.

Methods: The neuroprotective effects of γ-secretase inhibitors such as LY411575 or CHF5074 on TBI-induced neurotoxicity were analysed using a neurological motor function evaluation, cerebral contusion assay, immunohistochemical staining for microglia phenotypes, lung injury score and Evans Blue dye extravasation assay of brain and lung oedema.

Results: Hypertrophic or amoeboid microglia accumulated in the injured cortex, the blood-brain-barrier was disrupted and neurological deficits and acute lung injury were observed 4 days after TBI in adult rats. However, a subcutaneous injection of LY411575 (5 mg/kg) or CHF5074 (30 mg/kg) immediately after TBI and once daily for 3 consecutive days post-TBI significantly attenutaed the accumulation of hypertrophic microglia in the injured brain, neurological injury, and neurogenic acute lung injury.

Conclusion: Gamma-secretase inhibitors attenuated neurotrauma and neurogenic acute lung injury in rats by reducing the accumulation of hypertrophic microglia in the vicinity of the lesion.
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http://dx.doi.org/10.1159/000485778DOI Listing
March 2018

Combined Hemorrhagic Shock and Unilateral Common Carotid Occlusion Induces Neurological Injury in Adult Male Rats.

Int J Med Sci 2017 15;14(13):1327-1334. Epub 2017 Oct 15.

Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan.

Clinical assessment reveals that patients after surgery of cardiopulmonary bypass or coronary bypass experience postoperative cognitive dysfunction. This study aimed to investigate whether resuscitation after a hemorrhagic shock (HS) and/or mild cerebral ischemia caused by a unilateral common carotid artery occlusion (UCCAO) can cause brain injury and concomitant neurological dysfunction, and explore the potential mechanisms. Blood withdrawal (6 mL/100 g body weight) for 60 min through the right jugular vein catheter-induced an HS. Immediately after the termination of HS, we reinfused the initially shed blood volumes to restore and maintain the mean arterial blood pressure (MABP) to the original value during the 30-min resuscitation. A cooling water blanket used to induce whole body cooling for 30 min after the end of resuscitation. An UCCAO caused a slight cerebral ischemia (cerebral blood flow [CBF] 70%) without hypotension (MABP 85 mmHg), systemic inflammation, multiple organs injuries, or neurological injury. An HS caused a moderate cerebral ischemia (52% of the original CBF levels), a moderate hypotension (MABP downed to 22 mmHg), systemic inflammation, and peripheral organs injuries. However, combined an UCCAO and an HS caused a severe cerebral ischemia (18% of the original CBF levels), a moderate hypotension (MABP downed to 17 mmHg), systemic inflammation, peripheral organs damage, and neurological injury, which can be attenuated by whole body cooling. When combined with an HS, an UCCAO is associated with ischemic neuronal injury in the ipsilateral hemisphere of adult rat brain, which can be attenuated by therapeutic hypothermia. A resuscitation from an HS regards as a reperfusion insult which may induce neurological injury in patients with an UCCAO disease.
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http://dx.doi.org/10.7150/ijms.21022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707749PMC
July 2018

The increased risk of stroke in early insomnia following traumatic brain injury: a population-based cohort study.

Sleep Med 2017 Sep 7;37:187-192. Epub 2017 Mar 7.

Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. Electronic address:

Objective: Insomnia, a common symptom after traumatic brain injury (TBI), may be a pre-symptom for developing stroke. This study aims to investigate whether insomnia is a potential risk factor for stroke after TBI, especially early insomnia.

Methods: Taiwan's Longitudinal Health Insurance Database 2000 from 1999 to 2013 was used in this cohort study. TBI patients with insomnia were selected based on the ICD-9-CM code (TBI: 801-804 and 850-854; insomnia: 307.4, 327, and 780.5). The outcome we were interested in was stroke (ICD-9-CM: 430-438). The incidence rate ratio of stroke between TBI with insomnia and the general population with insomnia was calculated by Poisson regression. The relative risk adjusted for potential confounding variables was estimated by Cox regression.

Results: For 1174 TBI patients with insomnia and 5870 general patients with insomnia, TBI patients have 209.85 incidence risk of new-onset stroke if they have insomnia. TBI patients have 2.28-fold (95% CI: 1.70-3.06) risk of new-onset stroke compared with the general population, even when controlling for age, gender, socioeconomic status, and comorbidities. The hazard ratio of new-onset stroke among different phases of new-onset insomnia after TBI surgery is 1.95-fold (95% CI: 1.05-3.62), 2.75-fold (95% CI: 1.73-4.37), and 2.66-fold (95% CI: 1.68-4.21) at ≤3, 3-12, and 12-24 months, compared with the general population with insomnia, respectively.

Conclusion: TBI patients with insomnia have a higher risk of stroke compared with the general population with insomnia. Early new-onset insomnias after TBI will have higher risk of stroke. Therefore, we consider that insomnia could be a signal of the development of new-onset stroke in TBI patients.
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http://dx.doi.org/10.1016/j.sleep.2017.02.010DOI Listing
September 2017

Increased Risk of Anxiety or Depression After Traumatic Spinal Cord Injury in Patients with Preexisting Hyperlipidemia: A Population-Based Study.

World Neurosurg 2017 Oct 12;106:402-408. Epub 2017 Jul 12.

Department of Neurosurgery, Chi-Mei Medical Center, Chiali, Tainan, Taiwan; Department of Medical Research, Chi-Mei Medical Center, Chiali, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. Electronic address:

Objective: Anxiety or depression (AD) is a common complication after traumatic spinal cord injury (tSCI). This study sought to investigate the role of preexisting hyperlipidemia in new-onset AD after tSCI using a longitudinal population database.

Methods: This retrospective cohort study used Longitudinal Health Insurance Database data from January 1997 to December 2011. The case and comparison groups were individuals who experienced tSCI and who did and did not have preexisting hyperlipidemia, respectively. Kaplan-Meier curves were plotted, and log-rank test was used to compare the differences between these 2 groups. A Cox regression model was used to estimate the relative risk of AD.

Results: A total of 26,892 adult patients were enrolled in this study. After 1:3 matching with age and gender, it showed 1) tSCI patients with preexisting hyperlipidemia have a 1.32-fold adjusted hazard ratio (HR) compared with those without hyperlipidemia (P < 0.05); 2) The Kaplan-Meier plot in tSCI patients with hyperlipidemia were more likely to develop the new-onset AD than those without hyperlipidemia during the follow-up period (P = 0.0003); and 3) the stratified analysis showed the risk of AD among patients with tSCI aged 18-34 years (HR, 3.2; 95% confidence interval (CI) 1.2-8.9), male patients (HR, 1.3; 95% CI 1.1-1.6), and higher Charlson's comorbidity index (CCI) score (CCI > 2; HR, 1.9; 95% CI 1.2-2.9), and those with a history of stroke (HR, 1.7; 95% CI 1.0-2.7).

Conclusions: Preexisting hyperlipidemia is an independent predictor of new-onset AD in patients with tSCI, especially in those who are younger, male, have a higher CCI score, and have stroke.
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http://dx.doi.org/10.1016/j.wneu.2017.06.182DOI Listing
October 2017

Exercise attenuates neurological deficits by stimulating a critical HSP70/NF-κB/IL-6/synapsin I axis in traumatic brain injury rats.

J Neuroinflammation 2017 04 24;14(1):90. Epub 2017 Apr 24.

Department of Emergency Medicine, Chi Mei Medical Center, Tainan, 710, Taiwan.

Background: Despite previous evidence for a potent inflammatory response after a traumatic brain injury (TBI), it is unknown whether exercise preconditioning (EP) improves outcomes after a TBI by modulating inflammatory responses.

Methods: We performed quantitative real-time PCR (qPCR) to quantify the genes encoding 84 cytokines and chemokines in the peripheral blood and used ELISA to determine both the cerebral and blood levels of interleukin-6 (IL-6). We also performed the chromatin immunoprecipitation (ChIP) assay to evaluate the extent of nuclear factor kappa-B (NF-κB) binding to the DNA elements in the IL-6 promoter regions. Also, we adopted the Western blotting assay to measure the cerebral levels of heat shock protein (HSP) 70, synapsin I, and β-actin. Finally, we performed both histoimmunological and behavioral assessment to measure brain injury and neurological deficits, respectively.

Results: We first demonstrated that TBI upregulated nine pro-inflammatory and/or neurodegenerative messenger RNAs (mRNAs) in the peripheral blood such as CXCL10, IL-18, IL-16, Cd-70, Mif, Ppbp, Ltd, Tnfrsf 11b, and Faslg. In addition to causing neurological injuries, TBI also upregulated the following 14 anti-inflammatory and/or neuroregenerative mRNAs in the peripheral blood such as Ccl19, Ccl3, Cxcl19, IL-10, IL-22, IL-6, Bmp6, Ccl22, IL-7, Bmp7, Ccl2, Ccl17, IL-1rn, and Gpi. Second, we observed that EP inhibited both neurological injuries and six pro-inflammatory and/or neurodegenerative genes (Cxcl10, IL-18, IL-16, Cd70, Mif, and Faslg) but potentiated four anti-inflammatory and/or neuroregenerative genes (Bmp6, IL-10, IL-22, and IL-6). Prior depletion of cerebral HSP70 with gene silence significantly reversed the beneficial effects of EP in reducing neurological injuries and altered gene profiles after a TBI. A positive Pearson correlation exists between IL-6 and HSP70 in the peripheral blood or in the cerebral levels. In addition, gene silence of cerebral HSP70 significantly reduced the overexpression of NF-κB, IL-6, and synapsin I in the ipsilateral brain regions after an EP in rats.

Conclusions: TBI causes neurological deficits associated with stimulating several pro-inflammatory gene profiles but inhibiting several anti-inflammatory gene profiles of cytokines and chemokines. Exercise protects against neurological injuries via stimulating an anti-inflammatory HSP70/NF-κB/IL-6/synapsin I axis in the injured brains.
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http://dx.doi.org/10.1186/s12974-017-0867-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404305PMC
April 2017

The Association Between Ventriculo-Peritoneal Shunt and Acute Appendicitis in Patients with Traumatic Brain Injury: A 14-Year, Population-Based Study.

World Neurosurg 2017 Jul 2;103:106-113. Epub 2017 Apr 2.

Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. Electronic address:

Objective: The association between preexisting ventriculoperitoneal (VP) shunt and the risk of new-onset acute appendicitis in patients with traumatic brain injury (TBI) is not well established. The aim of the present study was to determine the relationships between VP shunt and acute appendicitis in patients with TBI.

Methods: A longitudinal cohort study matched by a propensity score in patients with TBI with (4781 patients) or without (9562 patients) VP shunt was conducted using the National Health Insurance Research Database in Taiwan between January 1993 and December 2013.

Results: The main outcome studied was diagnosis of acute appendicitis. The cumulative probability of acute appendicitis was not different between these 2 groups (P = 0.6244). A Cox model showed central nervous system (CNS) infection to be an independent predictor of acute appendicitis with an adjusted hazard ratio of 2.98. Patients with TBI with both a VP shunt and a CNS infection had a greater risk of developing new-onset acute appendicitis (hazard ratio 4.25; 95% confidence interval 1.84-9.81) compared patients with TBI without a VP shunt or CNS infection.

Conclusions: We concluded that VP shunt is not a risk factor in the development of appendicitis in patients with TBI. Patients with TBI with a shunt and a CNS infection may have a greater risk of developing acute appendicitis. Therefore, care in avoiding CNS infection is a key for the prevention acute appendicitis in this patient population.
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http://dx.doi.org/10.1016/j.wneu.2017.03.122DOI Listing
July 2017

Cobalt chloride treatment induces autophagic apoptosis in human glioma cells via a p53-dependent pathway.

Int J Oncol 2017 Mar 25;50(3):964-974. Epub 2017 Jan 25.

Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan, R.O.C.

Malignant glioma is the most aggressive brain tumor. Hypoxic condition has been explored for killing cancer stem cells or drug-resistant tumor cells. This study investigated the effects of hypoxia on autophagic death and the possible mechanisms. Exposure of human malignant glioma U87-MG cells to cobalt chloride (CoCl2) increased cellular hypoxia-inducible factor-1α levels and concurrently decreased cell viability concentration- and time-dependently. In parallel, treatment with CoCl2 suppressed proliferation of human U87-MG cells. Autophagic cells and levels of LC3-II were concentration- and time-dependently induced in human U87-MG cells after exposure to CoCl2. However, pretreatment with 3-mehyladenine (3-MA) and chloroquine, inhibitors of cell autophagy, caused significant alleviations in CoCl2-induced cell autophagy. In contrast, exposure to rapamycin, an inducer of cell autophagy, synergistically induced hypoxia-induced autophagy of U87-MG cells. Administration of human U87-MG cells with CoCl2 triggered caspase-3 activation and cell apoptosis. Interestingly, pretreatment with 3-MA and chloroquine remarkably suppressed CoCl2-induced caspase-3 activation and cell apoptosis. Application of p53 small interference (si)RNA into human U87-MG cells downregulated levels of this protein and simultaneously lowered hypoxia- and 3-MA-induced alterations in cell autophagy, apoptosis, and death. The hypoxia-induced autophagy and apoptosis of DBTRG-05MG cells were significantly lowered by 3-MA pretreatment and p53 knockdown. Therefore, the present study shows that CoCl2 treatment can induce autophagy of human glioma cells and subsequent autophagic apoptosis via a p53-dependent pathway. Hypoxia-induced autophagic apoptosis may be applied as a therapeutic strategy for treatment of glioma patients.
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http://dx.doi.org/10.3892/ijo.2017.3861DOI Listing
March 2017

Hyperbaric Oxygen Effects on Depression-Like Behavior and Neuroinflammation in Traumatic Brain Injury Rats.

World Neurosurg 2017 Apr 6;100:128-137. Epub 2017 Jan 6.

Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. Electronic address:

Objective: The aim of this study was to determine whether hyperbaric oxygen (HBO) therapy causes attenuation of traumatic brain injury (TBI)-induced depression-like behavior and its associated anti-neuroinflammatory effects after fluid percussion injury.

Methods: Anesthetized male Sprague-Dawley rats were divided into 3 groups: sham operation plus normobaric air (NBA) (21% oxygen at 1 absolute atmosphere [ATA]), TBI plus NBA, and TBI plus HBO (100% oxygen at 2.0 ATA). HBO was applied immediately for 60 min/d after TBI for 3 days. Depression-like behavior was tested by a forced swimming test, motor function was tested by an inclined plane test, and infarction volume was tested by triphenyltetrazolium chloride (TTC) staining on days 4, 8, and 15. Neuronal apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling assay), microglial (marker OX42) activation, and tumor necrosis factor (TNF)-α expression in microglia in the hippocampus CA3 were measured by immunofluorescence methods.

Results: Compared with the TBI controls, without significant changes in TTC staining or in the motor function test, TBI-induced depression-like behavior was significantly attenuated by HBO therapy by day 15 after TBI. Simultaneously, TBI-induced neuronal apoptosis, microglial (marker OX42) activation, and TNF-α expression in the microglia in the hippocampus CA3 were significantly reduced by HBO.

Conclusions: Our results suggest that HBO treatment may ameliorate TBI-induced depression-like behavior in rats by attenuating neuroinflammation, representing one possible mechanism by which depression-like behavior recovery might occur. We also recommend HBO as a potential treatment for TBI-induced depression-like behavior if early intervention is possible.
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http://dx.doi.org/10.1016/j.wneu.2016.12.118DOI Listing
April 2017

Early electroacupuncture treatment ameliorates neuroinflammation in rats with traumatic brain injury.

BMC Complement Altern Med 2016 Nov 16;16(1):470. Epub 2016 Nov 16.

Department of Medical research, Chi-Mei Medical Center, Tainan, Taiwan.

Background: Neuroinflammation is the leading cause of neurological sequelae after traumatic brain injury (TBI). The aim of the present study was to investigate whether the neuroprotective effects of electroacupuncture (EA) are mediated by anti-neuroinflammatory effects in a rat model of TBI.

Methods: Male Sprague-Dawley rats were randomly divided into three groups: sham-operated, TBI control, and EA-treated. The animals in the sham-operated group underwent a sham operation, those in the TBI control group were subjected to TBI, but not EA, and those in the EA group were treated with EA for 60 min immediately after TBI, daily for 3 consecutive days. EA was applied at the acupuncture points GV20, GV26, LI4, and KI1, using a dense-dispersed wave, at frequencies of 0.2 and 1 Hz, and an amplitude of 1 mA. Cell infarction volume (TTC stain), neuronal apoptosis (markers: TUNEL and Caspase-3), activation of microglia (marker: Iba1) and astrocytes (marker: GFAP), and tumor necrosis factor (TNF)-α expression in the microglia and astrocytes were evaluated by immunofluorescence. Functional outcomes were assessed using the inclined plane test. All tests were performed 72 h after TBI.

Results: We found that TBI-induced loss of grasp strength, infarction volume, neuronal apoptosis, microglial and astrocyte activation, and TNF-α expression in activated microglia and astrocytes were significantly attenuated by EA treatment.

Conclusions: Treatment of TBI in the acute stage with EA for 60 min daily for 3 days could ameliorate neuroinflammation. This may thus represent a mechanism by which functional recovery can occur after TBI.
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http://dx.doi.org/10.1186/s12906-016-1457-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112630PMC
November 2016

A positive correlation exists between neurotrauma and TGF-β1-containing microglia in rats.

Eur J Clin Invest 2016 Dec 10;46(12):1063-1069. Epub 2016 Nov 10.

Department of Emergency Medicine, Chi Mei Medical Center, Tainan, Taiwan.

Background: Transforming growth factor-beta 1 (TGF-β1) regulates many processes after traumatic brain injury (TBI). Both Neuro AiD™ (MLC601) and astragaloside (AST) attenuate microglia activation in rats with TBI. The purpose of this study was to investigate whether MLC601 or AST improves output of TBI by affecting microglial expression of TGF-β1.

Materials And Methods: Adult male Sprague-Dawley rats (120 in number) were used to investigate the contribution of TGF-β1-containing microglia in the MLC601-mediated or the AST-mediated neuroprotection in the brain trauma condition using lateral fluid percussion injury.

Results: Pearson correlation analysis revealed that there was a positive correlation between brain injury (evidenced by both brain contused volume and neurological severity score) and the cortical numbers of TGF-β1-containing microglia for the rats (n = 12) 4 days post-TBI. MLC601 or AST significantly (P < 0·05) attenuated TBI-induced brain contused volume (119 ± 14 mm or 108 ± 11 mm vs. 160 ± 21 mm ), neurological severity score (7·8 ± 0·3 or 8·1 ± 0·4 vs. 10·2 ± 0·5) and numbers of TGF-β1-containing microglia (6% ± 2% or 11% ± 3% vs. 79% ± 7%) for the rats 4 days post-TBI.

Conclusions: There was a positive correlation between TBI and cortical numbers of TGF-β1-containing microglia which could be significantly attenuated by astragaloside or NeuroAiD™ (MLC601) in rats.
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http://dx.doi.org/10.1111/eci.12693DOI Listing
December 2016

Simvastatin Therapy in the Acute Stage of Traumatic Brain Injury Attenuates Brain Trauma-Induced Depression-Like Behavior in Rats by Reducing Neuroinflammation in the Hippocampus.

Neurocrit Care 2017 02;26(1):122-132

Departments of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan.

Background: The antidepressant-like effects of simvastatin on traumatic brain injury (TBI) remain unclear. The present study aimed to investigate the neuroprotective effects of simvastatin and determine whether simvastatin attenuates TBI-induced depression-like behavior and, more specifically, acts as an antineuroinflammatory.

Methods: Anesthetized male Sprague-Dawley rats were divided into five groups: sham-operated controls, TBI controls, and TBI treatment with simvastatin 4, 10, or 20 mg/kg. Simvastatin was intraperitoneally injected 0, 24, and 48 h after TBI. The motor function was measured using an inclined plane, and depression-like behavior was evaluated using forced swimming tests. Neuronal apoptosis (markers: NeuN, TUNEL, caspase-3), microglia (marker: OX42) and astrocyte (marker: GFAP) activation, and TNF-α expression in the microglia and astrocytes of the hippocampal CA3 area were investigated using immunofluorescence assay. All parameters were measured on the 4th, 8th, and 15th day, or only on the 15th day after TBI.

Results: TBI-induced depression-like behavior, which increased duration of immobility, was significantly attenuated by 20 mg simvastatin therapy on day 15 after TBI. TBI-induced neuronal apoptosis, microglia and astrocyte activation, and TNF-α expression in the microglia and astrocytes of the CA3 area of the hippocampus were significantly reduced by simvastatin treatment, particularly when 20 mg/kg was administered for 3 days.

Conclusions: Intraperitoneal injection of simvastatin attenuated TBI in rats during the acute stage by reducing neuronal apoptosis, microglia, and TNF-α expression, thereby resulting in a reduction of depressive-like behavior. Our results suggest that simvastatin may be a promising treatment for TBI-induced depression-like behavior.
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http://dx.doi.org/10.1007/s12028-016-0290-6DOI Listing
February 2017