Publications by authors named "Shu-Chuan Wu"

39 Publications

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

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

4'-O-β-D-Glucosyl-5-O-Methylvisamminol, A Natural Histone H3 Phosphorylation Epigenetic Suppressor, Exerts a Neuroprotective Effect Through PI3K/Akt Signaling Pathway on Focal Cerebral Ischemia in Rats.

World Neurosurg 2016 May 8;89:474-88. Epub 2016 Feb 8.

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

Background: A bursting inflammation has been observed that compromises neurologic function in patients who experience stroke. We sought to examine the neuroprotective efficacy of 4'-O-β-D-glucosyl-5-O-methylvisamminol (OGOMV), a novel histone H3 phosphorylation epigenetic suppressor) in a transient middle cerebral artery occlusion (tMCAO).

Methods: A rodent tMCAO model was used. Administration with 400 μg/kg/day OGOMV was initiated 12 hours before (prevention) and 1 hour after animals were subjected to tMCAO (reversal). The cerebral cortex was harvested to examine protein kinase B (PI3D/Akt), 5-bromo-2'-deoxyuridine (Western blot), and caspases (reverse-transcription polymerase chain reaction). In addition, cerebrospinal fluid samples were collected to examine interleukin 1-β, interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α (reverse-transcription polymerase chain reaction).

Results: Cortical 5-bromo-2'-deoxyuridine and phospho-PI3D/Akt were reduced in tMCAO animals, compared with the healthy controls but increased in the OGOMV treatment and prevention groups. Activated cortical caspase-3,-6, and -9a as well as increased IL-1β and TNF-α levels were observed in the tMCAO animals (P < 0.05). Both prevention and treatment with OGOMV significantly reduced cleaved caspase-3 and -9a groups, but no significant change in caspase-6 was noted. Perifosine, an Akt inhibitor, was added to reduce the bioexpression of phospho-P13D/Akt, and Bcl-2 level and increased cleaved caspase-9a level in both OGOMV prevention and treatment tMCAO groups (P > 0.05).

Conclusion: Our study suggests that OGOMV could exert a neuroprotective effect by inhibiting the P13D/Akt protein, attenuating inflammation, and cleaved caspase-3- and -9a-related apoptosis. This study also lends credence to support the notion that the prevention of OGOMV could attenuate proinflammatory cytokine mRNA and late-onset caspases in tMCAO and merits further study.
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http://dx.doi.org/10.1016/j.wneu.2016.01.061DOI Listing
May 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

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

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

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

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

Glycyrrhizin Attenuates Proinflammatory Cytokines through a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism and Experimental Vasospasm in a Rat Model.

J Vasc Res 2015 16;52(1):12-21. Epub 2015 Apr 16.

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

The peroxisome proliferator-activated receptor (PPAR) is downregulated in the cortex of experimental subarachnoid hemorrhage (SAH) animals. This study is to examine the effect of glycyrrhizin on the alternation of PPARs and proinflammatory cytokines in a rodent SAH model. CSF cytokines were evaluated by RT-PCR. Basilar arteries (BAs) were harvested to examine PPARs (RT-PCR and Western blot), and a morphological examination was conducted. Deformed endothelium and tortuous elastic lamina were observed in the BAs of the SAH groups, but they were absent in the glycyrrhizin groups or the healthy controls. The PPAR-γ and -δ protein levels were reduced in the SAH groups (p < 0.01). Glycyrrhizin significantly increased the expressed PPAR-γ protein and mRNA (preconditioning) and PPAR-δ mRNA (both treatment and preconditioning), which corresponded to the reduced IL-1β and TNF-α levels. The administration of a PPAR-γ inhibitor, BADGE, halted the reduction of IL-1β and TNF-α in the glycyrrhizin groups. Conclusively, glycyrrhizin exerts anti-inflammatory effects on SAH-induced vasospasm and attenuates the expression of PPARs, especially PPAR-γ, which corresponds to the severity of SAH-related inflammation. These findings also offer credit to the antivasospastic effect of glycyrrhizin and its vasculoprotective effect in animals subjected to SAH.
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http://dx.doi.org/10.1159/000381099DOI Listing
July 2015

Preconditioning with pitavastatin, an HMG-CoA reductase inhibitor, attenuates C-Jun N-terminal kinase activation in experimental subarachnoid hemorrhage-induced apoptosis.

Acta Neurochir (Wien) 2015 Jun 19;157(6):1031-41; discussion 1041. Epub 2015 Apr 19.

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

Background: Accumulating results have disclosed that early brain injury (EBI) may play a major role in the determination of the outcome of aneurysmal subarachnoid hemorrhage (SAH) patients. This study is of interest to examine the efficacy of pitavastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) inhibitor, on SAH-induced apoptosis.

Methods: A rodent double SAH model was employed. Pitavastatin was administered orally. CSF IL-1β, IL-6, IL-8 and TNF-α were measured (rt-PCR). Basilar arteries were harvested for C-Jun N-terminal kinase p46/p55 (cJNK (p46/p55)), matrix metallopeptidase-9 (MMP-9) (Western blot), caspase and Bcl-2 (rt-PCR) evaluation.

Results: Pitavastatin reduced the bioexpression of cJNK p55 compared with the SAH groups. Cleaved caspase-9a was significantly reduced in the pitavastatin-preconditioned group compared with the SAH group (p > 0.05). IL-1β and TNF-α levels were reduced in the pitavastatin-preconditioned group. Pretreatment with pitavastatin significantly reduced activated MMP-9, capsase-9a and B-cell lymphoma 2(Bcl) mRNA.

Conclusion: Preconditioning with pitavastatin exerts its neuroprotective effect through the dual action of inhibiting cJNK(p46/p55) activation and reducing cleaved caspase-9a expression. Besides, the bioinhibition of MMP-9 may partially contribute to the neuroprotective effect. This study lends credence to the theory that statins, especially in the preconditioning status, may attenuate SAH-induced neuron apoptosis.
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http://dx.doi.org/10.1007/s00701-015-2399-3DOI Listing
June 2015

Curcumin, encapsulated in nano-sized PLGA, down-regulates nuclear factor κB (p65) and subarachnoid hemorrhage induced early brain injury in a rat model.

Brain Res 2015 May 5;1608:215-24. Epub 2015 Mar 5.

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.

Background: More and more evidence revealed early brain injury (EBI) may determine the final outcome in aneurismal subarachnoid hemorrhage (SAH) patients. This study is of interest to examine the efficacy of nano-particle curcumin (nanocurcumin), a diarylheptanoid, on a SAH-induced EBI model.

Methods: A rodent double hemorrhage model was employed. Nanocurcumin (75/150/300μg/kg/day) was administered via osmotic mini-pump post-SAH. CSF samples were collected to examine IL-1β, IL-6, IL-8 and TNF-α (rt-PCR). Cerebral cortex was harvested for NF-κB (p50/p65) (western blot), caspases (rt-PCR) measurement.

Results: Nanocurcumin significantly reduced the bio-expression of NF-κB (p65), when compared with the SAH groups. The levels of IL-1β and IL-6 were increased in animals subjected to SAH, compared with the healthy controls, but absent in the high dose nanocurcumin+SAH group. Moreover, the levels of TNF-α in the SAH groups were significantly elevated. Treatment with nanocurcumin (300μg/kg) reduced the level to the healthy control. The cleaved caspase-3 and -9a was significantly reduced in 300μg/kg nanocurcumin treatment groups (P<0.05).

Conclusion: Treatment with nanocurcumin exerts its neuroprotective effect through the upward regulation of NF-κB (p65) and also reduced mitochondrion related caspase-9a expression. Besides, nanocurcumin decreased CSF levels of TNF-α and IL-1β, which may contribute to the extrinsic antiapoptotic effect. This study shows promise to support curcuminin, in a nano-particle, could attenuate SAH induced EBI.
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http://dx.doi.org/10.1016/j.brainres.2015.02.039DOI Listing
May 2015

Purpurogallin, a natural phenol, attenuates high-mobility group box 1 in subarachnoid hemorrhage induced vasospasm in a rat model.

Int J Vasc Med 2014 17;2014:254270. Epub 2014 Nov 17.

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

High-mobility group box 1 (HMGB1) was shown to be an important extracellular mediator involved in vascular inflammation of animals following subarachnoid hemorrhage (SAH). This study is of interest to examine the efficacy of purpurogallin, a natural phenol, on the alternation of cytokines and HMGB1 in a SAH model. A rodent double hemorrhage SAH model was employed. Basilar arteries (BAs) were harvested to examine HMGB1 mRNA and protein expression (Western blot). CSF samples were to examine IL-1β, IL-6, IL-8, and TNF-α (rt-PCR). Deformed endothelial wall, tortuous elastic lamina, and necrotic smooth muscle were observed in the vessels of SAH groups but were absent in the purpurogallin group. IL-1β, IL-6, and TNF-α in the SAH only and SAH plus vehicle groups were significantly elevated (P < 0.01). Purpurgallin dose-dependently reduced HMGB1 protein expression. Likewise, high dose purpurogallin reduced TNF-α and HMGB1 mRNA levels. In conclusion, purpurogallin exerts its neuroinflammation effect through the dual effect of inhibiting IL-6 and TNF-α mRNA expression and reducing HMGB1 protein and mRNA expression. This study supports purpurogallin could attenuate both proinflammatory cytokines and late-onset inflammasome in SAH induced vasospasm.
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http://dx.doi.org/10.1155/2014/254270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251792PMC
December 2014

Glycyrrhizin attenuates Toll like receptor-2, -4 and experimental vasospasm in a rat model.

J Immunol Res 2014 23;2014:740549. Epub 2014 Jul 23.

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.

Upregulated TLRs are observed in the serum of animals following experimental subarachnoid hemorrhage. This study was to examine glycyrrhizin's effect on proinflammatory cytokines and TLRs in SAH rats. Administration with glycyrrhizin was initiated 24 hr before and 1 hr later using osmotic minipump. Basilar arteries were harvested to examine TLRs mRNA and protein (rt-PCR and western blot) and CSF cytokines (rt-PCR). Morphologically, deformed endothelium, tortuous elastic lamina, and smooth muscle necrosis were observed in the SAH rats, but were absent in the glycyrrhizin pretreatment group. The TLR-3 protein level was not increased in SAH animals, compared with the controls, while that of TLR-2 and -4 in the SAH only and SAH plus vehicle groups was significantly elevated (P < 0.01). Pretreatment and treatment with glycyrrhizin reduced TLR-2 and -4 by 28 ± 8% and 33.4 ± 9.2%, respectively. Likewise, glycyrrhizin was able to reduce the IL-1β and MCP-1 mRNA levels. This study shows glycyrrhizin exerts anti-inflammatory effects on SAH induced vasospasm and attenuates the ultrashort time expression of TLRs, like TLR-2 and -4. It corresponds to SAH induced early brain injury. These findings offer credit to the antivasospastic effect of glycyrrhizin and its effect on SAH induced early brain injury.
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http://dx.doi.org/10.1155/2014/740549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134788PMC
May 2015

Alteration of basilar artery rho-kinase and soluble guanylyl cyclase protein expression in a rat model of cerebral vasospasm following subarachnoid hemorrhage.

Biomed Res Int 2014 1;2014:531508. Epub 2014 Jun 1.

Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan ; Department of Neurosurgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan ; Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.

Background And Purpose: The vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). Previous results showed that CGS 26303, an endothelin converting enzyme (ECE) inhibitor, effectively prevented and reversed arterial narrowing in animal models of SAH. In the present study, we assessed the effect of CGS 26303 on neurological deficits in SAH rats. The involvement of vasoactive pathways downstream of ET-1 signaling in SAH was also investigated.

Methods: Sprague-Dawley rats were divided into five groups (n = 6/group): (1) normal control, (2) SAH, (3) SAH+vehicle, (4) SAH+CGS 26303 (prevention), and (5) SAH+CGS 26303 (reversal). SAH was induced by injecting autologous blood into cisterna magna. CGS 26303 (10 mg/kg) was injected intravenously at 1 and 24 hr after the initiation of SAH in the prevention and reversal protocols, respectively. Behavioral changes were assessed at 48 hr after SAH. Protein expression was analyzed by Western blots.

Results: Deficits in motor function were obvious in the SAH rats, and CGS 26303 significantly improved the rate of paraplegia. Expressions of rho-kinase-II and membrane-bound protein kinase C- δ and rhoA were significantly increased, while those of soluble guanylyl cyclase α 1 and β 1 as well as protein kinase G were significantly decreased in the basilar artery of SAH rats. Treatment with CGS 26303 nearly normalized these effects.

Conclusions: These results demonstrate that the rhoA/rho-kinase and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. It also shows that ECE inhibition is an effective strategy for the treatment of this disease.
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http://dx.doi.org/10.1155/2014/531508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058103PMC
February 2015

Magnesium lithospermate B, an active extract of Salvia miltiorrhiza, mediates sGC/cGMP/PKG translocation in experimental vasospasm.

Biomed Res Int 2014 2;2014:272101. Epub 2014 Apr 2.

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.

Background: Soluble guanylyl cyclases (sGCs) and Ras homolog gene family, member A (rhoA)/Ras homolog gene family kinase(rho-kinase) plays a role in vascular smooth muscle relaxation in subarachnoid hemorrhage (SAH). It is of interest to examine the effect of MLB on rhoA/ROCK and sGC/cGMP/PKG expression.

Methods: A rodent SAH model was employed. Tissue samples were for sGC α 1, sGC β 1, PKG, rhoA, ROCK (Western blot), and cGMP (ELISA) measurement.

Results: MLB morphologically improved convolution of the internal elastic lamina, distortion of endothelial wall, and necrosis of the smooth muscle in the SAH rats. Expressed cGMP, sGC α 1, sGC β 1, and PKG in the SAH groups were reduced (P < 0.01), and MLB precondition significantly induced cGMP, sGCα1, sGCβ1, and PKG. L-NAME reversed the vasodilation effect of MLB, reduced the bioexpression of PKG and cGMP (P < 0.01), and tends to reduce sGCα1 level and induce rhoA, ROCK level in MLB precondition + SAH groups.

Conclusion: These results demonstrate that sGC/cGMP/PKG and NO/ET pathways play pivotal roles in SAH-induced vasospasm. Through activating sGC/cGMP/PKG pathway and partially by inactivating rho-kinase in a NO-dependent mechanism, MLB shows promise to be an effective strategy for the treatment of this disease entity.
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http://dx.doi.org/10.1155/2014/272101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996929PMC
February 2015

Restrictive dermopathy: report of two siblings.

Pediatr Neonatol 2013 Jun 10;54(3):198-201. Epub 2013 Jan 10.

Department of Pediatrics, Saint Mary's Hospital Luodong, Luodong, Yilan County, Taiwan.

Restrictive dermopathy (RD) is a rare and lethal autosomal recessive syndrome characterized by very tight, thin, and easily eroded skin and contracture of joints. We present two siblings in a family. Case 1, a female neonate, showed mild characteristic presentations of RD and survived for 16 days, and Case 2, a male neonate, was stillborn with typical severe features of RD. His skin biopsy showed typical histological findings, and genetic study revealed a homozygous nonsense mutation on the exon 6 of zinc metalloproteinase STE24 (ZMPSTE24). The exact pathogenic mechanism of RD remains poorly understood. The most recent studies on mutations in lamin A and/or ZMPSTE24 have shed some light on the pathophysiology of RD and may help direct the development of future therapeutic approaches.
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http://dx.doi.org/10.1016/j.pedneo.2012.11.012DOI Listing
June 2013

Attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage by the bronchodilator KMUP-3.

Acta Neurochir Suppl 2013 ;115:239-46

Poznan University of Medical Sciences, Poznan, Poland.

Delayed cerebral vasospasm is a main cause of morbidity and mortality as well as poor outcome in patients following aneurysmal subarachnoid hemorrhage (SAH). In this study, the effect of the bronchodilator KMUP-3 (7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) on basilar artery narrowing, neurological outcome, and expression of rhoA/rho kinase II (ROCKII), rhoA, and protein kinase C (PKC) γ proteins were evaluated in a rat model of SAH. SAH was induced by double injection of autologous blood into the cistern magna on days 0 and 3. KMUP-3 was administered (0.3 mg/kg/day) by osmotic minipumps implanted subcutaneously (beginning day -3 in pretreatment group and at 1 h after the initiation of the first autologous blood injection in the treatment group). Neurological outcome was assessed by ambulation and placing/stepping reflex responses at 48 h after the second injection of autologous blood. Tissue morphology and protein expression were conducted on day 7 post-day 0 injection. Both KMUP-3 treatment regimens significantly improved neurological outcome and completely attenuated basilar artery narrowing as well as reduced the enhancement of ROCKII, rhoA, and PKCγ protein expression in rats subjected to SAH, compared with normal and untreated SAH rats. These results suggest that KMUP-3 may be a novel agent for the treatment of cerebral vasospasm following SAH.
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http://dx.doi.org/10.1007/978-3-7091-1192-5_43DOI Listing
December 2012

Purine anti-metabolite attenuates nuclear factor κB and related pro-inflammatory cytokines in experimental vasospasm.

Acta Neurochir (Wien) 2012 Oct 4;154(10):1877-85. Epub 2012 Aug 4.

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

Background: Increased nuclear factor κB (NF-κB) bioexpression, as well as TNF-α, IL-1β and IL-6 levels, were observed after aneurysmal subarachnoid hemorrhage (SAH). It is of interest to investigate the effect of 6-mercaptopurine (6-mp) on cytokines/NF-κB in this SAH model.

Materials And Methods: A rodent double-hemorrhage SAH model was employed. Serum and cerebrospinal fluid (CSF) samples were collected to examine IL-1, IL-6 and TNF-α levels. NF-κB subunit p65 and its inhibitor of nuclear factor κB (IκB) were examined (by Western blot). TNF-α was used to induce the phosphorylation of IκB in the presence or absence of 6-mp.

Results: Nuclear NF-κB subunit p65/IκB kinase in the basilar artery was over-expressed, and cytokines was notably increased in the SAH groups, compared with the controls (P < 0.01). In the 6-mp SAH group, obvious reduction was observed in NF-κB subunit p65 (nuclei) (P < 0.01). Treatment with 6-mp significantly reduced IL-1β and TNF-α levels to those of the healthy control. 6-Mercaptopurine also significantly increased the level of IκB in the TNF-α-stimulated SAH rats.

Conclusions: Through inhibiting IκB bioexpression, 6-mp decreases NF-κB-related IL-1β, IL-6, and TNF-α in the presence of SAH. The study suggests 6-mp exerts vascular anti-inflammatory properties through inhibiting IκB kinase and subsequently blocks bio-activation of NF-κB and related cytokines, which may contribute to its antivasospastic effect in animals subjected to SAH.
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http://dx.doi.org/10.1007/s00701-012-1452-8DOI Listing
October 2012

Assisted peripheral nerve recovery by KMUP-1, an activator of large-conductance Ca(2+)-activated potassium channel, in a rat model of sciatic nerve crush injury.

Acta Neurochir (Wien) 2012 Oct 8;154(10):1773-9. Epub 2012 Jul 8.

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

Background: Axonal regeneration in peripheral nerves after injury is a complicated process. Numerous cytokines, growth factors, channels, kinases, and receptors are involved, and matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis subsequent to nerve injury. In this study, the effect of KMUP-1, an activator of large-conductance Ca(2+)-activated potassium channel, on functional recovery, myelinated axon growth, and immunoreactivity of MMP-9 was evaluated in rats subjected to sciatic nerve crush injury.

Method: A total of 144 male Sprague-Dawley rats were divided into the following six groups (n = 24/group): group 1, sham-operated; group 2, sciatic nerve injury without treatment; group 3, injured and vehicle-treated; group 4, injured and treated with 1 mM KMUP-1 by topical application; group 5, injured and treated with 10 mM KMUP-1; group 6, injured and treated with 50 mM KMUP-1. Functional recovery was evaluated using walking track analysis at 1, 2, 3, and 4 weeks (n = 6/group at each time point) after injury. In addition, the number of myelinated axons and MMP-9 in the nerve was also examined.

Findings: Animals subjected to sciatic nerve crush injury had decreased motor function, a reduced number of myelinated axons, and increased MMP-9 in the nerve. Treatment with KMUP-1 concentration-dependently improved functional recovery, increased the number of myelinated axons, and decreased MMP-9.

Conclusions: These results suggest that KMUP-1 may be a novel agent for assisting peripheral nerve recovery after injury. The beneficial effect is probably due to known ability of the compound in activating the nitric oxide/cGMP/protein kinase G pathway.
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http://dx.doi.org/10.1007/s00701-012-1433-yDOI Listing
October 2012

A pediatric clinic-based approach to early literacy promotion--experience in a well-baby clinic in Taiwan.

J Formos Med Assoc 2012 May 28;111(5):258-64. Epub 2012 Apr 28.

Department of Pediatrics, Saint Mary's Hospital Luodong, 160 Jhongjheng South Road, Luodong Town, Yilan, Taiwan, ROC.

Background/purpose: Reach Out and Read (ROR) is an evidence-based intervention situated in pediatric offices and can help pediatricians to promote parents' reading to their children. The objective of this study was to determine if the program could also achieve good results in different culture, such as in Taiwan.

Methods: The intervention group (n=205) was enrolled from a well-baby clinic participated in a program modified from ROR (receiving anticipatory guidance and an appropriate children's book at a well-baby clinic) at a mean age of 9 months. The control group (n=210) was recruited from a general pediatric outpatient service at the compatible age. Both groups were queried about the reading habits of primary caregivers and the frequency of book sharing with their child. When children were at aged 12 to 18 month, follow-up questionnaires were collected.

Results: At follow-up, ANCOVA analysis indicated that the intervention group exhibited significantly greater increase in child-centered literacy scores (frequency of shared reading, reading as one of their three favorite interaction activities and child interested in shared reading). Caregivers were willing to accept their pediatrician's advice to read to their infants.

Conclusion: In this study, the simple intervention, implemented at a well-baby clinic in Taiwan, changed Taiwanese parents' attitudes toward the importance of reading with their infants and toddlers. As primary health care providers, pediatricians are in a unique position to affect and encourage parental behaviors that foster early literacy development in children.
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http://dx.doi.org/10.1016/j.jfma.2011.05.008DOI Listing
May 2012

Magnesium lithospermate B alleviates the production of endothelin-1 through an NO-dependent mechanism and reduces experimental vasospasm in rats.

Acta Neurochir (Wien) 2011 Nov 11;153(11):2211-7. Epub 2011 Aug 11.

Department of Surgery, College of Medicine, Kaohsiung Medical University, Taiwan, Republic of China.

Objective: Magnesium lithospermate B (MLB), a working extract from Salvia miltiorrhiza, was effective against coronary artery disease, ischemic stroke, and chronic renal disease. This study examined the effect of MLB on endothelin-1/endothelial nitric oxide synthase (eNOS) in a subarachnoid hemorrhage (SAH) animal model.

Methods: A rodent double-hemorrhage model was employed. Animals were randomly assigned to five groups (sham, SAH only, vehicle, 10 mg/kg/day MLB treatment, and pretreatment groups). A radiolabeled NOS Assay Kit was used to detect eNOS. Serum and cerebrospinal fluid sampling for ET-1 (ELISA) was measured. The basilar arteries (BAs) were garnered and sliced, and their cross-sectional areas were determined. In addition, NOS inhibitor nitro-arginine methyl ester (L-NAME) was employed in the SAH+ MLB treatment groups.

Results: Significant vasoconstriction was perceived in the SAH group (lumen patency: 44.6%, p < 0.01), but not in the MLB group (lumen patency: 89.3%). The ET-1 level was reduced in the MLP plus SAH group (34%, p < 0.01) when compared with the SAH groups (SAH only and vehicle). MLB dose-dependently increased the level of eNOS when compared with the vehicle plus SAH group. However, the administration of L-NAME reversed the expression of eNOS and vasoconstriction (lumen patency: 56.2%) in the MLB group.

Conclusion: The enhanced expression of eNOS and decreased ET-1 levels in the MLB groups may reflect its anti-spastic effect. In the study of NOS, L-NAME reversed MLB's anti-vasospastic effect. This finding lends credence to the hypothesis that MLB modulates ET-1 levels through a NOS-dependent mechanism in the pathogenesis of cerebral vasospasm following SAH.
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http://dx.doi.org/10.1007/s00701-011-1082-6DOI Listing
November 2011

6-Mercaptopurine reverses experimental vasospasm and alleviates the production of endothelins in NO-independent mechanism-a laboratory study.

Acta Neurochir (Wien) 2011 Apr 19;153(4):939-49. Epub 2010 Dec 19.

Department of Surgery, College of Medicine, Kaohsiung Medical University, Taiwan, Republic of China.

Introduction: Increased endothelin-1 (ET-1) production and diminished nitric oxide synthase (NOS) bioavailability has been observed in aneurysmal subarachnoid hemorrhage (SAH). The authors previously found that 6-mercaptopurine (6-mp) is effective in preventing and reversing arterial narrowing in a rodent SAH model. This present study is of interest to examine the effect of 6-mp on ET-1/endothelial nitric oxide synthase (eNOS) in this animal model.

Methods: A rodent double hemorrhage SAH model was employed. Animals were randomly assigned to six groups (sham, SAH only, vehicle, 0.5, 1.0 and 2 mg kg(-1) day(-1) 6-mp treatment). Monoclonal CD45 immunostaining was utilized to evaluate monocytes and microglia. The level of pro-inflammatory cytokines, such as IL-1, IL-6 and TNF-α(RT-PCR), and ET-1 (ELISA) was measured. The basilar arteries (BAs) were harvested and sliced, and their cross-sectional areas were determined. Radiolabeled NOS assay kit was applied to detect eNOS.

Results: Morphologically, convolution of internal elastic lamina, endothelial cells distortion, and necrotic smooth muscle were prevalently present in the basilar artery of SAH groups, which was absent in the 1 and 2 mg kg(-1) day(-1) 6-mp plus SAH group or the healthy controls. Significant vasospasm was noted in the vehicle group (lumen patency, 54.6%, p ≤ 0.01 compared with the sham group), but it was less prominent in the 2 mg kg(-1) day(-1) 6-mp treatment group (lumen patency, 87.6%, p < 0.05). In addition, administration with 2 mg kg(-1) day(-1) 6-mp reduced cytokine levels by 11%, 47%, and 34% for IL-1, IL-6, and TNF-α, respectively, and increased ET-1 levels were found in all the animals subject to SAH (SAH only, SAH plus vehicle, SAH plus 0.5 and 1.0 mg kg(-1) day(-1) 6-mp) except in the 2 mg kg(-1) day(-1) 6-mp SAH group, when compared with the healthy controls (no SAH). Meanwhile, treatment with 6-mp did not induce the levels of expressed eNOS in BAs in the 6-mp groups (0.5, 1.0, and 2 mg kg(-1) day(-1) 6-mp plus SAH) when compared with that in the SAH groups (p > 0.1).

Conclusion: In summary, treatment with 6-mp decreased the release of pro-inflammatory cytokines and diminished experimental vasospasm. This study offered first evidence that 6-mp dose-dependently reduces the level of ET-1 in a NO-independent mechanism, which corresponds to its antivasospastic effect in the condition of chronic vasospasm.
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http://dx.doi.org/10.1007/s00701-010-0865-5DOI Listing
April 2011

Atorvastatin preconditioning attenuates the production of endothelin-1 and prevents experimental vasospasm in rats.

Acta Neurochir (Wien) 2010 Aug 4;152(8):1399-406; discussion 1405-6. Epub 2010 May 4.

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

Objective: Induced endothelin-1 (ET-1) production and decreased nitric oxide synthase (NOS) bioavailability have been found in aneurysmal subarachnoid hemorrhage (SAH). Atorvastatin is recognized to have pleiotropic effects including increasing NOS bioavailability as well as reducing inflammation and oxidative damage other than reducing dyslipidemia. This study is of interest to examine the effect of atorvastatin on ET-1/endothelial nitric oxide synthase (eNOS) in experimental SAH.

Methods: A rodent double-hemorrhage SAH model was employed. Animals were randomly assigned as sham-operated, SAH, vehicle plus SAH, 5 mg/day atorvastatin treatment plus SAH and 5 mg/day atorvastatin precondition plus SAH groups. Administration with atorvastatin (5 mg/day) was initiated 1 week before (precondition) and 24 hr later (treatment). Cerebrospinal fluid samples were collected at 72 hr after second SAH. ET-1 (ELISA) was measured. The basilar arteries (BAs) were harvested and sliced, and their cross-sectional areas were measured. Radiolabeled NOS assay kit was used to detect eNOS.

Results: Morphologically, convoluted internal elastic lamina, distorted endothelial cells and myonecrosis of the smooth muscle were predominantly observed in the BA of SAH and vehicle-treated SAH groups, which was not detected in the atorvastatin-preconditioned SAH group or the healthy controls. Significant vasospasm was noted in the vehicle group (lumen potency 64.5%, compared with the sham group, p
Conclusion: This study offers first evidence that atorvastatin in the preconditioning status reduces the level of ET-1, which corresponds to its antivasospastic effect in the condition of chronic vasospasm. Although there is increased expression of NOS in both atorvastatin precondition and reversal groups, BA's lumen potency is significantly increased in the atorvastatin precondition group when compared with the SAH group (p < 0.01).
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http://dx.doi.org/10.1007/s00701-010-0652-3DOI Listing
August 2010

Upregulation of estrogen receptor alpha and mediation of 17beta-estradiol vasoprotective effects via estrogen receptor alpha in basilar arteries in rats after experimental subarachnoid hemorrhage.

J Neurosurg 2008 Jul;109(1):92-9

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

Object: The authors previously demonstrated that 17beta-estradiol benzoate (E2) treatment prevents subarachnoid hemorrhage (SAH)-induced cerebral vasospasm and preserves endothelial nitric oxide synthase (eNOS) in male rats. Changes in the expression of estrogen receptor (ER) subtypes ERalpha and -beta and their roles in the E2-mediated preservation of eNOS in SAH remain unknown. In the present study the effects of SAH on the expression of ERalpha and -beta in the cerebral arteries were clarified, and the receptor roles in the E2-mediated preservation of eNOS expression in SAH were differentiated.

Methods: A 2-hemorrhage SAH model was induced by 2 autologous blood injections into the cisterna magna of adult male rats. The effect of SAH on ERalpha and -beta expression was evaluated. Other rats subcutaneously received implanted Silastic tubes containing corn oil with E2 and daily injections of various doses of an ERalpha- (methyl-piperidinopyrazole [MPP]) or ERbeta-selective antagonist (R,R-tetrahydrochrysene) after the first hemorrhage. The protein levels of ERalpha, ERbeta, eNOS, and inducible nitric oxide synthase (iNOS) from basilar arteries were examined using Western blot analysis, and their mRNAs were evaluated by reverse transcription-polymerase chain reaction.

Results: The ERalpha but not the ERbeta was upregulated in the basilar artery after SAH. Treatment with MPP eliminated E2-mediated effects in SAH, relieved cerebral vasospasm, preserved eNOS expression, and suppressed iNOS expression.

Conclusions: Estrogen receptor alpha is upregulated in the basilar artery after SAH. Note that E2 exerts its protective effects through ERalpha-dependent pathways to relieve cerebral vasospasm and preserve eNOS expression. A selective ERalpha agonist may be the drug of choice for the treatment of patients with SAH.
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http://dx.doi.org/10.3171/JNS/2008/109/7/0092DOI Listing
July 2008

Attenuation of experimental subarachnoid hemorrhage-induced increases in circulating intercellular adhesion molecule-1 and cerebral vasospasm by the endothelin-converting enzyme inhibitor CGS 26303.

J Neurosurg 2007 Mar;106(3):442-8

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

Object: Adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, are important mediators of inflammation, and their levels are elevated in the serum of patients following aneurysmal subarachnoid hemorrhage (SAH). The investigators previously found that CGS 26303 is effective in preventing and reversing arterial narrowing in a rabbit model of SAH. The purpose of the present study was to examine whether levels of adhesion molecules are altered after treatment with CGS 26303 in this animal model.

Methods: New Zealand White rabbits were each injected with 3 ml of autologous blood in the cisterna magna, and intravenous treatment with CGS 26303 (30 mg/kg) was initiated 1 hour later. The compound was subsequently administered at 12, 24, and 36 hours post-SAH. Blood samples were collected at 48 hours post-SAH to measure ICAM-1, VCAM-1, and E-selectin levels. After the rabbits had been killed by perfusion-fixation, the basilar arteries (BAs) were removed and sliced, and their cross-sectional areas were measured. Treatment with CGS 26303 attenuated arterial narrowing after SAH. Morphologically, corrugation of the internal elastic lamina of BAs was prominently observed in the SAH only and vehicle-treated SAH groups, but not in the CGS 26303-treated SAH group or in healthy controls. There were no significant differences in the levels of VCAM-1 among the four groups. The levels of E-selectin were increased in all animals subjected to SAH (those in the SAH only, SAH plus vehicle, and SAH plus CGS 26303 groups) compared with healthy controls (no SAH); however, the levels of ICAM-1 in the SAH only and SAH plus vehicle groups were significantly elevated (p < 0.001), and treatment with CGS 26303 reduced ICAM-1 to control levels following SAH.

Conclusions: These results show that ICAM-1 may play a role in mediating SAH-induced vasospasm and that a reduction of ICAM-1 levels after SAH may partly contribute to the antispastic effect of CGS 26303.
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http://dx.doi.org/10.3171/jns.2007.106.3.442DOI Listing
March 2007

[Effect of very early kangaroo care on extrauterine temperature adaptation in newborn infants with hypothermia problems].

Hu Li Za Zhi 2006 Aug;53(4):41-8

Department of Nursing, Tungs' Taichung MetroHarbor Hospital, Taiwan, ROC.

Increased morbidity and mortality has been associated with neonates admitted with body temperatures below 36 degrees C. We employed an experimental design in a randomized control trial to compare the effectiveness of using early kangaroo care (KC) for extrauterine temperature adaptation against that of using radiant warmers. Trial subjects included 78 consecutive cesarean newborn infants with hypothermia problems. The KC group received skin-to-skin contact with their mothers in the post-operative room, while infants in the control group received routine care under radiant warmers. The mean temperature of the KC group was slightly higher than that of the control group (36.29 degrees C vs. 36.22 degrees C, p = .044). After four hours, 97.43% of KC group infants had reached normal body temperatures, compared with 82.05% in the radiant warmer group. Results demonstrate the positive effects of KC for extrauterine temperature adaptation in hypothermia infants. In the course of evidence-based practice, KC could be incorporated into the standard care regimen in order to improve hypothermia care.
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August 2006

17beta-estradiol inhibits endothelin-1 production and attenuates cerebral vasospasm after experimental subarachnoid hemorrhage.

Exp Biol Med (Maywood) 2006 Jun;231(6):1054-7

Department of Neurosurgery, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung, Taiwan, Republic of China.

Though cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) has been recognized for over half a century, it remains a major complication in patients with SAH. Clinical studies have shown that elevated levels of endothelin-1 (ET-1) are present in the cerebrospinal fluid of patients with SAH, suggesting that ET-1-mediated vasoconstriction contributes to vascular constriction after SAH. Administration of estrogen promotes vasodilation in humans and in experimental animals, in part by decreasing the production of ET-1. This study evaluated the influence of 17beta-estradiol (E2) on the production of ET-1 and cerebrovasospasm in an experimental SAH 2-hemorrhage model in rat. A 30-mm Silastic tube filled with E2 in corn oil (0.3 mg/ml) was subcutaneously implanted in male rats just before SAH induction. The degree of vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Plasma samples collected before death were assayed for ET-1. The protective effect of E2 in attenuating vasospasm achieved statistical significance when compared with the SAH only or SAH plus vehicle groups (P < 0.01). Concentrations of ET-1 were higher in the SAH only and SAH plus vehicle groups than in controls (P < 0.001). Serum levels of ET-1 in the SAH plus E2 and E2 only groups were significantly lower than those in the SAH only and SAH plus vehicle groups (P < 0.001). There was no significant difference between ET-1 levels in the healthy control and SAH plus E2 groups. A significant correlation was found between the cross-sectional areas of basilar artery and ET-1 levels (P < 0.001). The beneficial effect of E2 in attenuating SAH-induced vasospasm may be due in part to decreasing ET-1 production after SAH. The role of E2 in the treatment of cerebral vasospasm after SAH is promising and is worthy of further investigation.
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June 2006

Early endocytosis pathways in SSN-1 cells infected by dragon grouper nervous necrosis virus.

J Gen Virol 2005 Sep;86(Pt 9):2553-2561

Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan.

Many fish undergo betanodavirus infection. To study the infection process of dragon grouper nervous necrosis virus (DGNNV), native virus and virus-like particles (VLPs) were used to analyse the binding and internalization in SSN-1 cells. The binding of DGNNV and VLPs to SSN-1 cells was demonstrated using Western blotting and immunofluorescence microscopy. As estimated by indirect ELISA, the DGNNV particles bound SSN-1 cells in a dose-dependent manner up to 8 x 10(4) particles per cell. The binding of VLPs was sensitive to neuraminidase and tunicamycin, suggesting that cell-surface sialic acid is involved in binding. The penetration of DGNNV into cells, which was monitored by electron microscopy, appeared to occur mainly via the spherical pit and membrane ruffling pathways. Occasionally, a spherical pit was engulfed by membrane ruffling so as to form a large figure-of-eight-shaped vesicle with an open connection. Our observations suggest that DGNNV utilizes both micro- and macropinocytosis pathways to enter SSN-1 cells.
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http://dx.doi.org/10.1099/vir.0.81021-0DOI Listing
September 2005