Publications by authors named "An-Kuo Chou"

45 Publications

Pulsed Ultrasound Remedies Post-thoracotomy Hypersensitivity and Increases Spinal Anti-inflammatory Cytokine in Rats.

Ultrasound Med Biol 2020 12 3;46(12):3296-3304. Epub 2020 Sep 3.

Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

The purpose of the experiment was to study the effect of pulsed ultrasound (PUS) on post-thoracotomy pain and local tissue temperature and to correlate the findings with the alteration in spinal anti-inflammatory and pro-inflammatory cytokines. Mechanical sensitivity, subcutaneous temperature and spinal interleukin-10 (IL-10), IL-6 or tumor necrosis factor-alpha (TNF-α) expression were examined in a rat model of experimental post-thoracotomy pain. Group 1 received a sham surgery where thoracotomy was performed except for rib retraction. Group 2 underwent thoracotomy with rib retraction (TRR). Group 3 received the TRR procedure followed by PUS. Group 4 underwent the TRR procedure followed by only the massage with the ultrasound turned off. Compared with group 1 (sham), groups 2-4 showed a decrease in mechanical withdrawal thresholds on postoperative days (PODs) 10 and 11. On PODs 16, 23 and 30, group 3 (TRR+PUS-1) displayed an increase in mechanical withdrawal thresholds compared with groups 2 and 4. Subcutaneous and body temperatures in group 3 were not prominently different from group 1, group 2 (TRR only) or group 4 (TRR+PUS-0). Compared with group 2, group 3 had an increase in spinal IL-10 level on POD 30 and a decrease in spinal IL-6 or TNF-α expression on PODs 16 and 30. We concluded that mechanical hypersensitivity after TRR is postponed by PUS, and its effect continues for 3 wk. A PUS dose not increase local tissue temperature. The beneficial effect of PUS appears related to upregulation of spinal anti-inflammatory cytokine and downregulation of spinal pro-inflammatory cytokines.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.08.002DOI Listing
December 2020

Association between Maternal Pre-pregnancy Body Mass Index and Breastfeeding Duration in Taiwan: A Population-Based Cohort Study.

Nutrients 2020 Aug 7;12(8). Epub 2020 Aug 7.

Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu 30059, Taiwan.

An association between high pre-pregnancy body mass index (BMI) and early breastfeeding cessation has been previously observed, but studies examining the effect of underweight are still scant and remain inconclusive. This study analyzed data from a nationally representative cohort of 18,312 women (mean age 28.3 years; underweight 20.1%; overweight 8.2%; obesity 1.9%) who delivered singleton live births in 2005 in Taiwan. Comprehensive face-to-face interviews and surveys were completed at 6 and 18 months postpartum. BMI status and breastfeeding duration were calculated from the self-reported data in the questionnaires. In the adjusted ordinal logistic regression model, maternal obesity and underweight had a higher odds of shorter breastfeeding duration compared with normal-weight women. The risk of breastfeeding cessation was significantly higher in underweight women than in normal-weight women after adjustments in the logistic regression model (2 m: aOR = 1.11, 95% CI = 1.03-1.2; 4 m: aOR = 1.32, 95% CI = 1.21-1.43; 6 m: aOR = 1.3, 95% CI = 1.18-1.42). Our findings indicated that maternal underweight and obesity are associated with earlier breastfeeding cessation in Taiwan. Optimizing maternal BMI during the pre-conception period is essential, and future interventions to promote and support breastfeeding in underweight mothers are necessary to improve maternal and child health.
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http://dx.doi.org/10.3390/nu12082361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468738PMC
August 2020

Association of Genotypes With Colorectal Cancer Susceptibility in Taiwan.

Anticancer Res 2020 Mar;40(3):1297-1306

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

Aim: To investigate the association between adiponectin (ADIPOQ) genotypes and colorectal cancer (CRC) risk among Taiwanese.

Materials And Methods: Polymerase chain reaction-restriction fragment length polymorphism was adopted to identify ADIPOQ rs266729, rs2241766 and rs1501299 genotypes among 362 CRC patients and 362 healthy controls.

Results: ADIPOQ rs266729 GG genotype (p=0.0075) and G allele (p=0.0061) are associated with a significantly increased CRC risk. There is no differential distribution of rs2241766 and rs1501299 genotypes. As for the gene-lifestyle interaction, there are obvious joint effects of rs266729 genotype on the CRC risk among non-smoker, non-alcohol drinker, while not on smoker or non-drinker subgroups. No significant correlation was observed between rs266729 genotypic distributions and age, gender, tumor size, location or metastasis status. Interestingly, a correlation of rs266729 genotype and larger BMI on CRC risk was found.

Conclusion: G allele at ADIPOQ rs266729 may serve as a determiner for CRC risk, especially for those with BMI ≥24.
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http://dx.doi.org/10.21873/anticanres.14071DOI Listing
March 2020

The functional interplay of lncRNA EGOT and HuR regulates hypoxia-induced autophagy in renal tubular cells.

J Cell Biochem 2020 11 7;121(11):4522-4534. Epub 2020 Feb 7.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.

Autophagy, an important cellular homeostatic mechanism regulates cell survival under stress and protects against acute kidney injury. However, the role of long noncoding RNA (lncRNA) in autophagy regulation in renal tubular cells (HK-2) is unclear. The study was aimed to understand the importance of lncRNA in hypoxia-induced autophagy in HK-2 cells. LncRNA eosinophil granule ontogeny transcript (EGOT) was identified as autophagy-associated lncRNA under hypoxia. The lncRNA EGOT expression was significantly downregulated in renal tubular cells during hypoxia-induced autophagy. Gain- and loss-of-EGOT functional studies revealed that EGOT overexpression reduced autophagy by downregulation of ATG7, ATG16L1, LC3II expressions and LC 3 puncta while EGOT knockdown reversed the suppression of autophagy. Importantly, RNA-binding protein, (ELAVL1)/Hu antigen R (HuR) binds and stabilizes the EGOT expression under normoxia and ATG7/16L1 expressions under hypoxia. Furthermore, HuR mediated stabilization of ATG7/16L1 expressions under hypoxia causes a decline in EGOT levels and thereby promotes autophagy. Altogether, the study first reveals the functional interplay of lncRNA EGOT and HuR on the posttranscriptional regulation of the ATG7/16L1 expressions. Thus, the HuR/EGOT/ATG7/16L1 axis is crucial for hypoxia-induced autophagy in renal tubular cells.
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http://dx.doi.org/10.1002/jcb.29669DOI Listing
November 2020

Socioeconomic status and deaths due to unintentional injury among children: A socio-spatial analysis in Taiwan.

Geospat Health 2019 05 13;14(1). Epub 2019 May 13.

Department of Pediatrics, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu; Institute of Health Policy and Management, College of Public Health, National Taiwan University.

In Taiwan, unintentional injury is the leading cause of death among children <10 years old. Low socioeconomic status is a risk factor associated with a high prevalence of injuries and our study aimed to explore the geographic distribution of mortality due to unintentional injury in this age group assessing the association between this type of injury on the one hand and socioeconomic disadvantages and family structure on the other using cluster and spatial regression analyses. Using exploratory factor analysis, we assembled nine socioeconomic variables into four composite factors including area-level poverty, family burden, family fragility and unemployment. We found significant spatial clusters of childhood deaths due to unintentional injury and identified three major causes of death involved, i.e. traffic accidents, drowning and suffocation. Significant associations were found between death due to unintentional injury and area-level social disadvantages including poverty, family fragility, family economic burden and unemployment, while controlling for spatial autocorrelation. Our conclusion is that socioeconomic disadvantages need to be addressed to reduce the number of deaths due to childhood unintentional injury.
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http://dx.doi.org/10.4081/gh.2019.736DOI Listing
May 2019

Phentolamine Reverses Epinephrine-Enhanced Skin Antinociception of Dibucaine in Rats.

Anesth Analg 2019 06;128(6):1336-1343

Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.

Background: The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction between dibucaine and epinephrine, phentolamine, a nonselective α-adrenergic antagonist, was added to the mixture.

Methods: We assessed sensory blockade with these drugs by injecting 0.6 mL of drug-in-saline in the dorsal thoracolumbar area of rats; pinprick of the "wheal" formed by the injectate was the area targeted for stimulation to elicit a cutaneous trunci muscle reflex. The sensory block of dibucaine was compared with that of bupivacaine or epinephrine. Drug-drug interactions were analyzed by isobologram. Phentolamine was added to investigate the antinociceptive effect of dibucaine coinjected with epinephrine.

Results: We demonstrated that dibucaine, epinephrine, and bupivacaine produced dose-dependent skin antinociception. On the median effective dose (ED50) basis, the potency was higher for epinephrine (mean, 0.011 [95% confidence interval {CI}, 0.007-0.015] μmol) than for dibucaine (mean, 0.493 [95% CI, 0.435-0.560] μmol) (P < .01), while there were no significant differences between dibucaine and bupivacaine (mean, 0.450 [95% CI, 0.400-0.505] μmol). On the equipotent basis (75% effective dose, median effective dose, and 25% effective dose), sensory block duration provoked by epinephrine was greater (P < .01) than that provoked by dibucaine or bupivacaine. Coadministration of dibucaine with epinephrine produced a synergistic nociceptive block, whereas phentolamine blocked that synergistic block.

Conclusions: The preclinical data indicated that there is no statistically significant difference between the potency and duration of dibucaine and bupivacaine in this model. Epinephrine synergistically enhances the effects of dibucaine, while phentolamine partially blocked those effects. α-Adrenergic receptors play an important role in controlling synergistic analgesic effect of dibucaine combined with epinephrine.
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http://dx.doi.org/10.1213/ANE.0000000000003421DOI Listing
June 2019

Reference levels for glucose-6-phosphate dehydrogenase enzyme activity in infants 7-90 days old in Taiwan.

J Formos Med Assoc 2020 Jan 10;119(1 Pt 1):69-74. Epub 2019 Apr 10.

Department of Pediatrics, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan. Electronic address:

Background: Nationwide newborn screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency has been implemented in Taiwan since 1987 and the G6PD enzyme activity levels were applied for diagnosis confirmation. As the reference value of G6PD enzyme activity was not available for infants aged 7-90 days, this study was performed to determine the enzyme level in different genotypes.

Methods: Between January 1, 2016 and June 30, 2017, 410 term infants aged 7-90 days old visiting National Taiwan University Hospital Hsinchu branch were enrolled. The comparisons of G6PD enzyme activities among genotype groups were performed.

Results: G6PD enzyme activity was negatively correlated with age (R = -0.212, p = 0.01). For infants under 30 days of age, the G6PD enzyme activity levels were 1.4 ± 0.9 U/g Hb in hemizygotes (n = 76), 6.5 ± 2.0 U/g Hb in heterozygotes (n = 47), and 13.6 ± 3.7 U/g Hb in those without G6PD mutations (n = 70). Among infants more than 30 days old, G6PD enzyme activity levels were 0.9 ± 0.5 U/g Hb in hemizygotes (n = 46), 6.0 ± 2.7 U/g Hb in heterozygotes (n = 23), and 11.7 ± 3.4 U/g Hb in those without G6PD mutations (n = 148). G6PD levels differed significantly among the groups defined by genotypes.

Conclusion: We determined G6PD enzyme activity levels in infants aged between 7 and 90 days in Taiwan. Completing the reference data and determining the cutoff values for different G6PD deficiency disease statuses will help pediatricians to make accurate diagnoses.
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http://dx.doi.org/10.1016/j.jfma.2019.03.010DOI Listing
January 2020

Risk of subsequent health disorders among living kidney donors.

Medicine (Baltimore) 2019 Feb;98(7):e14494

Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University.

Few studies have investigated the risk of physiological sequelae in living kidney donors (KDs). We conducted a population-based cohort study using the National Health Insurance Research Database of Taiwan, which covers more than 99% of citizens.We comprehensively investigated the risk of medical disorders after kidney donation in living KDs using a maximum follow-up of 13 years. From January 1997 to December 2010, 1081 living KDs and 1082 age- and sex-matched non-KDs were eligible. Primary outcomes comprised end-stage renal disease, chronic kidney disease, stroke, cancer, acute myocardial infarction, acute renal failure (ARF), and diabetes.The adjusted hazard ratios (HRs) for developing ARF, diabetes, hyperlipidemia, hypertension, cancer, end-stage renal disease, acute myocardial infarction, and stroke were similar between the KD and non-KD cohorts (P > .05). Although differences in the adjusted HRs of ARF were nonsignificant, the cumulative incidence rate of ARF 13 years after donation was 7.48 per 1000 person-years in the KD cohort compared with 3.46 in the matched non-KD cohort. The incidence rate ratio for ARF between donors and nondonors significantly increased to 2.16 (95% confidence interval, 1.61-2.71).Living KDs experienced no significant health disorders following kidney donation but should be alert to the higher incidence rate of ARF.
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http://dx.doi.org/10.1097/MD.0000000000014494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408042PMC
February 2019

Serotonin enhances oxybuprocaine- and proxymetacaine-induced cutaneous analgesia in rats.

Eur J Pharmacol 2019 Mar 11;846:73-78. Epub 2019 Jan 11.

Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

The aim of the study was to investigate the analgesic effects of adding serotonin to oxybuprocaine or proxymetacaine preparations. We employed a rat model of the cutaneous trunci muscle reflex (CTMR) to conduct the dose-response curves and duration of drugs (oxybuprocaine, proxymetacaine, or serotonin) as an infiltrative anesthetic. The use of isobolographic methods to analyze the drug-drug interactions. We showed that oxybuprocaine and proxymetacaine, as well as serotonin produced dose-dependent skin antinociception. On the basis of 50% effective dose (ED), the rank order of drug potency was serotonin [7.22 (6.45-8.09) μmol/kg] < oxybuprocaine [1.03 (0.93-1.15) μmol/kg] < proxymetacaine [0.59 (0.53-0.66) μmol/kg] (P < 0.01 for each comparison). The sensory block duration of serotonin was longer (P < 0.01) than that of oxybuprocaine or proxymetacaine at the equipotent doses (ED, ED, and ED). The mixture of serotonin with oxybuprocaine or proxymetacaine produced a better analgesic effect than the drug itself. We have concluded that oxybuprocaine, proxymetacaine, or serotonin displays dose-related cutaneous analgesia. Oxybuprocaine or proxymetacaine is more potent and has a shorter duration of cutaneous analgesia than serotonin. Serotonin produces a synergistic antinociceptive interaction with oxybuprocaine or proxymetacaine.
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http://dx.doi.org/10.1016/j.ejphar.2019.01.009DOI Listing
March 2019

Skin nociceptive block with pramoxine delivery by subcutaneous injection in rats.

Pharmacol Rep 2018 Dec 10;70(6):1180-1184. Epub 2018 Sep 10.

Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Pramoxine has been shown to produce spinal anesthesia, while cutaneous analgesia (peripheral) of pramoxine is not established. The experimental goal was to examine cutaneous antinociception produced by a local anesthetic (LA) pramoxine and compare this result with that of another well-known LA lidocaine.

Methods: Cutaneous antinociception was evaluated by blockade of pinprick- induced cutaneous trunci muscle reflex (CTMR) on the skin of rat's back. After the dose-related curves were constructed, the quality and duration of drug's (lidocaine and pramoxine) cutaneous antinociception were compared.

Results: We showed that pramoxine, as well as lidocaine produced skin antinociception in a dose-related fashion. The relative potency (ED [50% effective dose] basis) was lidocaine (5.44 [4.67-6.35] μmol) greater than pramoxine (42.1 [38.8-45.7] μmol) (p < 0.01). On the basis of equianalgesic doses (ED, ED, and ED), pramoxine caused equivalent duration of cutaneous antinociception to lidocaine.

Conclusions: These preclinical data indicated that pramoxine elicits skin antinociception dose-relatedly. Pramoxine exhibits a potency less than that of lidocaine while they have a comparable duration of skin antinociceptive action.
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http://dx.doi.org/10.1016/j.pharep.2018.09.001DOI Listing
December 2018

Development of a Prediction Model for Colorectal Cancer among Patients with Type 2 Diabetes Mellitus Using a Deep Neural Network.

J Clin Med 2018 Sep 12;7(9). Epub 2018 Sep 12.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.

Objectives: Observational studies suggested that patients with type 2 diabetes mellitus (T2DM) presented a higher risk of developing colorectal cancer (CRC). The current study aims to create a deep neural network (DNN) to predict the onset of CRC for patients with T2DM.

Methods: We employed the national health insurance database of Taiwan to create predictive models for detecting an increased risk of subsequent CRC development in T2DM patients in Taiwan. We identified a total of 1,349,640 patients between 2000 and 2012 with newly diagnosed T2DM. All the available possible risk factors for CRC were also included in the analyses. The data were split into training and test sets with 97.5% of the patients in the training set and 2.5% of the patients in the test set. The deep neural network (DNN) model was optimized using Adam with Nesterov's accelerated gradient descent. The recall, precision, F₁ values, and the area under the receiver operating characteristic (ROC) curve were used to evaluate predictor performance.

Results: The F₁, precision, and recall values of the DNN model across all data were 0.931, 0.982, and 0.889, respectively. The area under the ROC curve of the DNN model across all data was 0.738, compared to the ideal value of 1. The metrics indicate that the DNN model appropriately predicted CRC. In contrast, a single variable predictor using adapted the Diabetes Complication Severity Index showed poorer performance compared to the DNN model.

Conclusions: Our results indicated that the DNN model is an appropriate tool to predict CRC risk in patients with T2DM in Taiwan.
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http://dx.doi.org/10.3390/jcm7090277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162847PMC
September 2018

The origin of GSKIP, a multifaceted regulatory factor in the mammalian Wnt pathway.

Biochim Biophys Acta Mol Cell Res 2018 08 23;1865(8):1046-1059. Epub 2018 Apr 23.

Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Electronic address:

GSK3β interacting protein (GSKIP) is a naturally occurring negative regulator of GSK3β and retains both the Protein Kinase A Regulatory subunit binding (PKA-RII) domain and GSK3β interacting domain. Of these two domains, we found that PKA-RII is required for forming a working complex comprising PKA/GSKIP/GSK3β/Drp1 to influence phosphorylation of Drp1 Ser637. In this study, bioinformatics and experimental explorations re-analyzing GSKIP's biofunctions suggest that the evolutionarily conserved Domain of Unknown Function (DUF727) is an ancestral prototype of GSKIP in prokaryotes, and acquired the C-terminal GSK3β binding site (tail) in invertebrates except for Saccharomyces spp., after which the N-terminal PKA-RII binding region (head) evolved in vertebrates. These two regions mutually influence each other and modulate GSKIP binding to GSK3β in yeast two-hybrid assays and co-immunoprecipitation. Molecular modeling showed that mammalian GSKIP could form a dimer through the L130 residue (GSK3β binding site) rather than V41/L45 residues. In contrast, V41/L45P mutant facilitated a gain-of-function effect on GSKIP dimerization, further influencing binding behavior to GSK3β compared to GSKIP wild-type (wt). The V41/L45 residues are not only responsible for PKA RII binding that controls GSK3β activity, but also affect dimerization of GSKIP monomer, with net results of gain-of-function in GSKIP-GSK3β interaction. In addition to its reported role in modulating Drp1, Ser637 phosphorylation caused mitochondrial elongation; we postulated that GSKIP might be involved in the Wnt signaling pathway as a scavenger to recruit GSK3β away from the β-catenin destruction complex and as a competitor to compete for GSK3β binding, resulting in accumulation of S675 phosphorylated β-catenin.
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http://dx.doi.org/10.1016/j.bbamcr.2018.04.008DOI Listing
August 2018

Intrathecal pramoxine causes long-lasting spinal sensory and motor block in rats.

J Pharm Pharmacol 2018 Apr 13;70(4):543-549. Epub 2018 Feb 13.

Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Objectives: The objective of this experiment was to investigate spinal anaesthetic effects of pramoxine and its comparison with bupivacaine, a long-lasting local anaesthetic.

Methods: After intrathecal injection, three neurobehavioural assessments, which consisted of nociceptive, proprioceptive and motor block, were constructed in rats. The effects of bupivacaine and pramoxine (four doses of each drug) in a dose-related manner were conducted to obtain the ED (50% effective dose). Pramoxine potency and duration at provoking spinal nociceptive, proprioceptive and motor block were compared with those of bupivacaine.

Key Findings: We manifested that pramoxine provoked dose-relatedly spinal blockades of nociception, proprioception and motor function. Based on the ED , the rank potency at producing spinal nociceptive, proprioceptive and motor block was bupivacaine (0.90 (0.82-1.02), 1.00 (0.92-1.08) and 1.16 (1.02-1.34) μmol/kg) greater (P < 0.01 for the differences) than pramoxine (15.47 (14.04-17.05), 16.46 (15.06-17.99), and 17.77 (16.48-19.15) μmol/kg). The spinal block duration created by bupivacaine was not predominantly different (P > 0.05 for the differences) from that created by pramoxine at the equipotent doses (ED , ED and ED ).

Conclusions: Our preclinical experiment indicated that pramoxine elicited a dose-related spinal block, was less potent than bupivacaine and had a similar duration of spinal block compared with bupivacaine.
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http://dx.doi.org/10.1111/jphp.12894DOI Listing
April 2018

The Association of MMP-8 Genotypes with Pterygium.

In Vivo 2018 Jan-Feb;32(1):41-46

Department of Physiology, China Medical University, Taichung, Taiwan, R.O.C.

Background/aim: Pterygium is composed of proliferating fibrovascular tissue, and its formation and progression are closely related to the homeostasis of the extracellular microenvironment. However, few studies have examined the contribution of matrix metalloproteinases (MMP) to either diagnostic or prognostic potential in pterygium. In this study, we investigated the contribution of a polymorphism in the promoter region of MMP-8 (-799C/T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to pterygium.

Materials And Methods: In this study, 134 patients with pterygium and 268 non-cancer controls patients were collected and the MMP-8 -799C/T, Val436Ala and Lys460Thr polymorphic genotypes of each subject were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results: The results showed that the three polymorphisms investigated were not significantly associated with risk of pterygium. In addition, the stratified analysis showed that there was no interaction between MMP-8 genotype with age or gender on pterygium risk determination.

Conclusion: Polymorphisms at MMP-8 -799C/T, Val436Ala and Lys460Thr may not mainly contribute to determining personal susceptibility to pterygium in the Taiwanese examined.
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http://dx.doi.org/10.21873/invivo.11202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892621PMC
August 2018

Contribution of Matrix Metalloproteinase-7 Genotypes to the Risk of Non-solid Tumor, Childhood Leukemia.

Anticancer Res 2017 12;37(12):6679-6684

Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan, R.O.C.

Background/aim: The matrix metalloproteinases (MMPs) are important in inflammation and carcinogenesis, and the genotypic role of MMP7 has never been examined in leukemia to date. Therefore, in this study we aimed to evaluate the contribution of the genotypic variants in the promoter region of MMP7 (A-181G and C-153T) to childhood acute lymphoblastic leukemia (ALL) risk in Taiwan.

Materials And Methods: In this case-control study, 266 patients with childhood ALL and 266 non-cancer controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism methodology.

Results: The distribution of AA, AG and GG for MMP7 promoter A-181G genotype was 83.5, 12.0 and 4.5% in the childhood ALL group and 89.8%, 9.4 and 0.8% in the non-cancer control group, respectively (p for trend=0.0134), significantly differentially distributed between childhood ALL and control groups. The comparisons in allelic frequency distribution also support the findings that G appears to be the risky allele in childhood ALL. In genotype and gender interaction analysis, it was found that boys carrying the MMP7 A-181G GG and AG+GG genotypes had 9.05- and 2.45-fold odds ratios (ORs) (p=0.0135 and 0.0142, respectively) for childhood ALL compared to those carrying wild-type AA genotype. But these differences were not found in girls. Analysis of genotype interaction with age of onset age showed those aged less than 3.5 years at onset carrying the GG or AG+GG genotypes also had elevated ORs of 8.79- and 2.04-fold (p=0.0150 and 0.0413, respectively) for childhood ALL, but there was no such difference for those having an age at onset of 3.5 years or more.

Conclusion: Our results indicate that the MMP7 A-181G genotype interacts with age and gender and may serve as an early and predictive biomarker for childhood ALL.
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http://dx.doi.org/10.21873/anticanres.12126DOI Listing
December 2017

The Association of Flap Endonuclease 1 Genotypes with the Susceptibility of Endometriosis.

Cancer Genomics Proteomics 2017 Nov-Dec;14(6):455-460

Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.

Background/aim: Flap endonuclease 1 (FEN1), a protein with multiple functions in genome stability maintenance, is important in cancer prevention. The two functional germline variants of FEN1, rs174538 and rs4246215, regarding cancer susceptibility have been reported in lung, breast, liver, esophageal, gastric, colorectal cancer, glioma and leukemia, but not endometriosis. In this study, we firstly aimed at evaluating the contribution of FEN1 genotypes to endometriosis risk in a representative Taiwan population.

Materials And Methods: In total, 153 patients with endometriosis and 636 non-cancer healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology.

Results: The genotypes of FEN1 rs174538, but not those of rs4246215, were differently distributed between the endometriosis and control groups. In detail, the AA of FEN1 rs174538 genotypes were significantly less frequently found among endometriosis patients than among controls (odds ratio [OR]=0.43, 95% confidence interval [CI]=0.24-0.78, p=0.0125). The A allele at FEN1 rs174538 was also significantly less frequent among cases than controls (OR=0.65, 95%CI=0.50-0.86, p=0.0021). As for age of first menarche, those with first menarche at the age >12.8 carrying the FEN1 rs174538 AA genotype conferred lower OR of 0.29 (95%CI=0.11-0.78, p=0.0381) for endometriosis. Regarding the full pregnancy status, those without having had a full-term pregnancy carrying the FEN1 rs174538 AA genotype were of lower risk (ORs=0.12, 95%CI=0.03-0.53, p=0.0050).

Conclusion: The FEN1 rs174538 A allele is a novel protective biomarker for endometriosis and this genotype may have interactions with age- and hormone-related factors on the development of endometriosis.
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http://dx.doi.org/10.21873/cgp.20055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070328PMC
July 2018

The Contribution of Matrix Metalloproteinase-7 Promoter Genotypes in Breast Cancer in Taiwan.

Anticancer Res 2017 09;37(9):4973-4977

Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan, R.O.C.

Background/aim: The matrix metalloproteinase (MMP) family of enzymes are in charge of degradation of various components of the extracellular matrix and their functional genetic polymorphisms may be associated with cancer susceptibility. The functional polymorphisms in the promoter region of MMP7 (A-181G and C-153T) have been reported to influence the binding capacity of nuclear proteins and may contribute to genetic susceptibility to cancer. In this study, we focused on investigating the contribution of the genotypes of MMP7 (A-181G and C-153T) to breast cancer in Taiwan.

Materials And Methods: These two polymorphisms were genotyped in 1,232 patients with breast cancer and 1,232 controls by polymerase chain reaction-restriction fragment length polymorphism methodology.

Results: The odds ratios (ORs) after adjusting for age, family history of cancer, smoking and alcohol drinking status for those carrying AG and GG genotypes at MMP7 promoter A-181G were 1.22 (95%CI=0.91-1.63, p=0.2235) and 2.84 (95%CI=1.64-7.48, p=0.0007) respectively, compared to those carrying the wild-type AA genotype. Supporting this finding, the adjusted OR for those carrying the G allele at MMP7 promoter A-181G was 1.57 (95%CI=1.29-1.93, p=0.0008), compared to those carrying the wild-type A allele. There was no polymorphic genotype at MMP7 C-153T found among any of the investigated individuals.

Conclusion: Our findings suggest that the MMP7 A-181G polymorphisms may play a role in determining personal cancer susceptibility and GG genotype at MMP7 A-181G may serve as a biomarker for early detection and prediction of breast cancer in Taiwanese.
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http://dx.doi.org/10.21873/anticanres.11908DOI Listing
September 2017

The Contribution of Excision Repair Cross-complementing Group 1 Genotypes to Colorectal Cancer Susceptibility in Taiwan.

Anticancer Res 2017 05;37(5):2307-2313

Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.

Aim: To evaluate the contribution of ERCC1 rs11615 and rs3212986 genotypes regarding the risk of colorectal cancer (CRC) in Taiwan.

Materials And Methods: In this case-control study, ERCC1 rs11615 and rs3212986 genotypes and their interaction with consumption of cigarettes and alcohol in determining CRC risk were investigated among 362 CRC patients and 362 age- and gender-matched healthy controls.

Results: The percentages of CC, CT and TT for ERCC1 rs11615 genotype were 44.2%, 36.2% and 19.6% in the CRC group and 49.7%, 38.4% and 11.9% in the control group, respectively (p for trend=0.0158). The allelic frequency distribution analysis showed that the variant T allele of ERCC1 rs11615 conferred increased CRC susceptibility to the wild-type C allele (odds ratio (OR)=1.34, 95% confidence interval (CI)=1.08-1.67, p=0.0079). As for the gene-lifestyle interaction, there were obvious joint effects of ERCC1 rs11615 genotype on the risk of CRC among ever smokers and alcohol drinkers, but not non-smokers or non-drinkers. There is a positive correlation of ERCC1 rs11615 genotype with lymph node metastasis, but not other CRC prognosis, including tumor size and location.

Conclusion: ERCC1 rs11615 T allele serves as a predictive marker for CRC risk and future studies with larger samples and functional evaluation are warranted to validate these findings.
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http://dx.doi.org/10.21873/anticanres.11568DOI Listing
May 2017

Infectious complications in children with acute lymphoblastic leukemia treated with the Taiwan Pediatric Oncology Group protocol: A 16-year tertiary single-institution experience.

Pediatr Blood Cancer 2017 Oct 1;64(10). Epub 2017 Apr 1.

Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.

Background: Infection is a major complication in pediatric patients with acute lymphoblastic leukemia during chemotherapy. In this study, the infection characteristics were determined and risk factors analyzed based on the Taiwan Pediatric Oncology Group (TPOG) acute lymphoblastic leukemia (ALL) protocol.

Procedure: We retrospectively reviewed fever events during chemotherapy in 252 patients treated during two consecutive clinical trials at a single institution between 1997 and 2012. Patients were classified as standard, high, and very high risk by treatment regimen according to the TPOG definitions. We analyzed the characteristics and risk factors for infection.

Results: Fever occurred in 219 patients (86.9%) with a mean of 2.74 episodes per person. The fever events comprised 64% febrile neutropenia, 39% clinically documented infections, and 44% microbiologically documented infections. The microbiologically documented infections were mostly noted during the induction phase and increased in very high risk patients (89 vs. 24% and 46% in standard-risk and high-risk patients, respectively). Younger age and higher risk (high-risk and very high risk groups) were risk factors for fever and microbiologic and bloodstream infections. Female gender and obesity were additive risk factors for urinary tract infection (odds ratios = 3.52 and 3.24, P < 0.001 and P = 0.004, respectively).

Conclusions: Infections developed primarily during the induction phase, for which younger age and higher risk by treatment regimen were risk factors. Female gender and obesity were additive risk factors for urinary tract infection.
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http://dx.doi.org/10.1002/pbc.26535DOI Listing
October 2017

The Impacts of Cord Blood Cotinine and Glutathione-S-Transferase Gene Polymorphisms on Birth Outcome.

Pediatr Neonatol 2017 08 17;58(4):362-369. Epub 2017 Jan 17.

Department of Pediatrics, National Taiwan University Children's Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan; Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan. Electronic address:

Background: This study aimed to investigate the association between cord blood cotinine levels and birth outcome, and to determine whether fetal metabolic gene polymorphisms of glutathione-S-transferase (GST) modulate the effect of environmental tobacco smoke exposure during pregnancy.

Methods: This study included 328 maternal and neonatal pairs. Maternal and cord blood cotinine levels were measured using high performance liquid chromatography. The GST T1 (GSTT1) and GST M1 (GSTM1) polymorphisms were examined using the polymerase chain reaction method. The birth outcomes included birth weight, length, and head circumference, and the risks of having low birth weight and being small for gestational age (SGA).

Results: Cord cotinine level had a dose-dependent impact on the reduction of birth weight, length, and head circumference in newborns. Elevation of cord blood cotinine concentration increased the rate of SGA and low birth weight. The neonates who had GSTT1 or GSTM1 polymorphism were associated with an increased risk of being SGA. A combination of the GSTT1 and GSTM1 null genotype exacerbated the effect of maternal environmental tobacco smoke exposure on SGA more than the presence of either genotype alone (odds ratio=8.90, 95% confidence interval=1.00-79.5).

Conclusion: Cord blood cotinine adversely affects birth outcomes. GSTT1 and GSTM1 null genotype may modify the effect of cord blood cotinine on birth outcomes.
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http://dx.doi.org/10.1016/j.pedneo.2016.08.006DOI Listing
August 2017

The Development of Diabetes after Subtotal Gastrectomy with Billroth II Anastomosis for Peptic Ulcer Disease.

PLoS One 2016 28;11(11):e0167321. Epub 2016 Nov 28.

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

Purpose: A duodenal bypass after a Roux-en-Y gastric bypass operation for obesity can ameliorate the development of diabetes mellitus (DM). We attempted to determine the subsequent risk of developing DM after subtotal gastrectomy with Billroth II anastomosis (SGBIIA) for peptic ulcer disease (PUD).

Methods: We identified 662 patients undergoing SGBIIA for PUD between 2000 and 2011 from the Longitudinal Health Insurance Database as the study cohort, and we randomly selected 2647 controls from the peptic ulcer population not undergoing SGBIIA and were frequency-matched by age, sex, and index year for the control cohort. All patient cases in both cohorts were followed until the end of 2011 to measure the incidence of DM. We analyzed DM risk by using a Cox proportional hazards regression model.

Results: The patients who underwent SGBIIA demonstrated a lower cumulative incidence of DM compared with the control cohort (log-rank test, P < .001 and 6.73 vs 12.6 per 1000 person-y). The difference in the DM risk between patients with and without SGBIIA increased gradually with the follow-up duration. Age and sex did not affect the subsequent risk of developing DM, according to the multivariable Cox regression model. Nevertheless, the SGBIIA cohort exhibited a lower DM risk after we adjusted for the comorbidities of hypertension, hyperlipidemia, and coronary artery disease (adjusted hazard ratio (aHR): 0.56, 95% confidence interval (CI): 0.40-0.78). The incidence rate ratio (IRR) of DM in the SGBIIA cohort was lower than that in the control cohort for all age groups (age ≤ 49 y, IRR: 0.40, 95% CI: 0.16-0.99; age 50-64 y, IRR: 0.54, 95% CI: 0.31-0.96; age ≧ 65 y, IRR: 0.57, 95% CI: 0.36-0.91). Moreover, the IRR of DM was significantly lower in the SGBIIA cohort with comorbidities (IRR: 0.50, 95% CI: 0.31-0.78) compared with those without a comorbidity (IRR: 0.65, 95% CI: 0.40-1.04).

Conclusion: The findings of this population-based cohort study revealed that SGBIIA was associated with a reduced risk of DM development, and the inverse association was greater in the presence of a comorbidity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125684PMC
August 2017

Matrix Metalloproteinase-1 Genotype Contributes to the Risk of Non-solid Tumor in Childhood Leukemia.

Anticancer Res 2016 10;36(10):5127-5132

Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan, R.O.C.

Aim: Up-regulation of metalloproteinase (MMPs) proteins have been shown in various types of solid cancers and the genotype of MMP1 has been associated with the risk of solid cancers. However, the contribution of MMP1 genotype to leukemia has never been investigated to our knowledge. Therefore, in this study we aimed to evaluate the contribution of the genotypic variants in the promoter region of MMP1 to childhood acute lymphoblastic leukemia (ALL) risk in Taiwan.

Materials And Methods: In this case-control study, 266 patients with childhood ALL and 266 non-cancer controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism methodology.

Results: The distribution of 2G/2G, 1G/2G and 1G/1G for MMP1 promoter rs1799750 genotype was 49.2%, 39.5% and 11.3% in the childhood ALL group and 36.8%, 43.6% and 19.5% in the non-cancer control group, respectively (p for trend=0.0046), significantly differentially distributed between childhood ALL and control groups. The carrier comparisons in dominant and recessive models also support the findings that 1G appears to be the protective allele in childhood ALL. In genotype and gender interaction analysis, it was found that boys carrying the MMP1 rs1799750 1G/2G or 1G/1G genotypes had lower odds ratios(ORs) of 0.68 and 0.43 [95% confidence intervals (CI)=0.47-0.98 and 0.26-0.73, p=0.0395 and 0.0013, respectively] for childhood ALL than those carrying the 2G/2G genotype. Analysis of genotype inaction with age of onset age showed those aged less than 3.5 years at onset carrying the 1G/2G or 1G/1G genotypes had lower ORs (0.0183 and 0.0004, respectively) for childhood ALL, but there was no such difference for those having an age at onset of 3.5 years or more.

Conclusion: Our results indicate that the MMP1 rs1799750 1G allele is a protective biomarker for childhood ALL.
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http://dx.doi.org/10.21873/anticanres.11082DOI Listing
October 2016

Quality Improvement of Nasal Continuous Positive Airway Pressure Therapy in Neonatal Intensive Care Unit.

Pediatr Neonatol 2017 06 26;58(3):229-235. Epub 2016 Jul 26.

Department of Pediatrics, National Taiwan University Children Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan. Electronic address:

Background: Nasal continuous positive airway pressure (NCPAP) therapy is widely used in neonates, but the clinical practice varies. However, nursing practice differs among individuals, and an inappropriate application method may delay the respiratory therapy, influence the beneficial effect of NCPAP, and increase complications. We introduced a quality improvement project to expedite the application of NCPAP therapy and decrease the incidence of nasal trauma.

Methods: A new strategy of mobile NCPAP cart with prepacked fixation kits and a written protocol was implemented from April 2006. All medical staff answered a questionnaire to assess their basic knowledge before and after intensive training. The records of the patients who were treated with NCPAP from October 2005 to November 2006 were reviewed.

Results: Fifty-nine medical staff were involved in the project, and their mean score for the questionnaire improved from 69.2 points to 98.3 points after training. From October 2005 to November 2006, 113 infants were recruited in total and 82 of them were admitted after the protocol was implemented. The NCPAP cart dramatically shortened the preparation time (from 520 seconds to 72 seconds) and the application time (from 468 seconds to 200 seconds). The use of the nursing protocol significantly decreased the incidence of nasal trauma in the study population (45.2% vs. 19.6%, p = 0.006), but not in infants with a birth weight of < 1000 g. Risk factors for nasal skin trauma included lower gestational age and birth weight, longer duration of NCPAP use, and lack of standardized nursing care.

Conclusion: The mobile NCPAP cart with prepacked fixation kits is a practical way of expediting the initiation of NCPAP therapy. The written nursing protocol decreased the incidence of nasal trauma in infants, except for those with an extremely low birth weight.
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http://dx.doi.org/10.1016/j.pedneo.2016.04.005DOI Listing
June 2017

Two-Dimensional Differential Gel Electrophoresis to Identify Protein Biomarkers in Amniotic Fluid of Edwards Syndrome (Trisomy 18) Pregnancies.

PLoS One 2016 11;11(1):e0145908. Epub 2016 Jan 11.

Genomic Medicine Research Core Laboratory, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

Background: Edwards syndrome (ES) is a severe chromosomal abnormality with a prevalence of about 0.8 in 10,000 infants born alive. The aims of this study were to identify candidate proteins associated with ES pregnancies from amniotic fluid supernatant (AFS) using proteomics, and to explore the role of biological networks in the pathophysiology of ES.

Methods: AFS from six second trimester pregnancies with ES fetuses and six normal cases were included in this study. Fluorescence-based two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) were used for comparative proteomic analysis. The identified proteins were further validated by Western blotting and the role of biological networks was analyzed.

Results: Twelve protein spots were differentially expressed by more than 1.5-fold in the AFS of the ES pregnancies. MALDI-TOF/MS identified one up-regulated protein: apolipoprotein A1 (ApoA1), and four under-regulated proteins: vitamin D binding protein (VDBP), alpha-1-antitrypsin (A1AT), insulin-like growth factor-binding protein 1 (IGFBP-1), and transthyretin (TTR). Western blot and densitometric analysis of ApoA1, A1AT, IGFBP-1, and TTR confirmed the alteration of these proteins in the amniotic fluid samples. Biological network analysis revealed that the proteins of the ES AFS were involved mainly in lipid and hormone metabolism, immune response, and cardiovascular disease.

Conclusions: These five proteins may be involved in the pathogenesis of ES. Further studies are needed to explore.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713428PMC
June 2016

Proteomic profiling reveals α1-antitrypsin, α1-microglobulin, and clusterin as preeclampsia-related serum proteins in pregnant women.

Taiwan J Obstet Gynecol 2015 Oct;54(5):499-504

Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan. Electronic address:

Objective: Preeclampsia is a major cause of mortality in pregnant women but the underlying mechanism remains unclear to date. In this study, we attempted to identify candidate proteins that might be associated with preeclampsia in pregnant women by means of proteomics tools.

Materials And Methods: Differentially expressed proteins in serum samples obtained from pregnant women with severe preeclampsia (n = 8) and control participants (n = 8) were identified using two-dimensional gel electrophoresis (2-DE) followed by peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS). Additional serum samples from 50 normal and 41 pregnant women with severe preeclampsia were analyzed by immunoassay for validation.

Results: Ten protein spots were found to be upregulated significantly in women with severe preeclampsia. These protein spots had the peptide mass fingerprints matched to α1-antitrypsin, α1-microglobulin, clusterin, and haptoglobin. Immunoassays in an independent series of serum samples showed that serum α1-antitrypsin, α1-microglobulin, and clusterin levels of severe preeclampsia patients (n = 41) were significantly higher than those in the normal participants (n = 50; α1-antitrypsin 295.95 ± 50.94 mg/dL vs. 259.31 ± 33.90 mg/dL, p = 0.02; α1-microglobulin 0.029 ± 0.004 mg/mL vs. 0.020 ± 0.004 mg/mL, p < 0.0001; clusterin 77.6 ± 16.15 μg/dL vs. 67.6 ± 15.87 μg/dL, p < 0.05).

Conclusion: Identification of these proteins by proteomics analysis enables further understanding of the pathophysiology of preeclampsia. Further studies are warranted to investigate the role of these biomarkers in prediction of this disease.
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http://dx.doi.org/10.1016/j.tjog.2014.01.007DOI Listing
October 2015

AIBp regulates mitotic entry and mitotic spindle assembly by controlling activation of both Aurora-A and Plk1.

Cell Cycle 2015 26;14(17):2764-76. Epub 2015 Jun 26.

a Department of Biochemistry ; Faculty of Medicine; College of Medicine; Kaohsiung Medical University ; Kaohsiung , Taiwan.

We previously reported that Aurora-A and the hNinein binding protein AIBp facilitate centrosomal structure maintenance and contribute to spindle formation. Here, we report that AIBp also interacts with Plk1, raising the possibility of functional similarity to Bora, which subsequently promotes Aurora-A-mediated Plk1 activation at Thr210 as well as Aurora-A activation at Thr288. In kinase assays, AIBp acts not only as a substrate but also as a positive regulator of both Aurora-A and Plk1. However, AIBp functions as a negative regulator to block phosphorylation of hNinein mediated by Aurora-A and Plk1. These findings suggest a novel AIBp-dependent regulatory machinery that controls mitotic entry. Additionally, knockdown of hNinein caused failure of AIBp to target the centrosome, whereas depletion of AIBp did not affect the localization of hNinein and microtubule nucleation. Notably, knockdown of AIBp in HeLa cells impaired both Aurora-A and Plk1 kinase, resulting in phenotypes with multiple spindle pole formation and chromosome misalignment. Our data show that depletion of AIBp results in the mis-localization of TACC3 and ch-TOG, but not CEP192 and CEP215, suggesting that loss of AIBp dominantly affects the Aurora-A substrate to cause mitotic aberrations. Collectively, our data demonstrate that AIBp contributes to mitotic entry and bipolar spindle assembly and may partially control localization, phosphorylation, and activation of both Aurora-A and Plk1 via hNinein during mitotic progression.
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http://dx.doi.org/10.1080/15384101.2015.1066536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614063PMC
June 2016

GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis signaling in the regulation of mitochondrial elongation.

Biochim Biophys Acta 2015 Aug 25;1853(8):1796-807. Epub 2015 Apr 25.

Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

GSK3β binding of GSKIP affects neurite outgrowth, but the physiological significance of PKA binding to GSKIP remains to be determined. We hypothesized that GSKIP and GSK3β mediate cAMP/PKA/Drp1 axis signaling and modulate mitochondrial morphology by forming a working complex comprising PKA/GSKIP/GSK3β/Drp1. We demonstrated that GSKIP wild-type overexpression increased phosphorylation of Drp1 S637 by 7-8-fold compared to PKA kinase-inactive mutants (V41/L45) and a GSK3β binding-defective mutant (L130) under H2O2 and forskolin challenge in HEK293 cells, indicating that not only V41/L45, but also L130 may be involved in Drp1-associated protection of GSKIP. Interestingly, silencing either GSKIP or GSK3β but not GSK3α resulted in a dramatic decrease in Drp1 S637 phosphorylation, revealing that both GSKIP and GSK3β are required in this novel PKA/GSKIP/GSK3β/Drp1 complex. Moreover, overexpressed kinase-dead GSK3β-K85R, which retains the capacity to bind GSKIP, but not K85M which shows total loss of GSKIP-binding, has a higher Drp1 S637 phosphorylation similar to the GSKIP wt overexpression group, indicating that GSK3β recruits Drp1 by anchoring rather than in a kinase role. With further overexpression of either V41/L45P or the L130P GSKIP mutant, the elongated mitochondrial phenotype was lost; however, ectopically expressed Drp1 S637D, a phosphomimetic mutant, but not S637A, a non-phosphorylated mutant, restored the elongated mitochondrial morphology, indicating that Drp1 is a downstream effector of direct PKA signaling and possibly has an indirect GSKIP function involved in the cAMP/PKA/Drp1 signaling axis. Collectively, our data revealed that both GSKIP and GSK3β function as anchoring proteins in the cAMP/PKA/Drp1 signaling axis modulating Drp1 phosphorylation.
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http://dx.doi.org/10.1016/j.bbamcr.2015.04.013DOI Listing
August 2015

Bcl2L12 with a BH3-like domain in regulating apoptosis and TMZ-induced autophagy: a prospective combination of ABT-737 and TMZ for treating glioma.

Int J Oncol 2015 Mar 13;46(3):1304-16. Epub 2015 Jan 13.

Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C.

Bcl2L12 as a new member of the Bcl2 family, which contains a BH2 domain and shares a lower amino acid similarity with other Bcl2 family proteins. Bcl2L12 is reported to be involved in apoptosis regulation, but this role remains controversial in different cancer type. Temozolomide (TMZ) is currently used to intervene glioma multiforme (GBM), but an acquired chemotherapeutic resistance maybe occurred due to undesired autophagy. Previous studies uncovered that Bcl2L12 may interact with Bcl-xL and may harbor a BH3-like domain. Therefore, we investigated whether this BH3-like domain is responsible for the Bcl2L12 anti-apoptotic property. Moreover, we tested whether ABT-737, a BH3 mimetic agent, can be combined with TMZ to treat GBM. We aligned Bcl2L12 with Bcl2 family members, compared interacting pattern of BH3 domain and their protein 3D structure. We identified that Bcl2L12 interacts with Bcl-xL and Bcl2 in yeast two-hybrid system. Bcl2L12192-220 was a minimal region for Bcl2L12-Bcl-xL interaction. Five-point mutations with respect to hydrophobic and charge residues were generated to test whether they are the key residue of BH3-like domain. Our data showed that both h1 (L213) and h2 residue (L217) are essential for Bcl2L12 interacting with Bcl2 family proteins. Ectopically expressed h1 or h2 mutant in U87MG cell line resulted in reactivation of cleaved-PARP, caspase-3 and cytochrome c releasing compared to Bcl2L12 wt group. Implementing ABT-737 combined with TMZ provided a superior effect on apoptosis induction in Bcl2L12 wt group, which effectively reactivated apoptotic markers. Altogether, our findings indicated that Bcl2L12 retains a BH3-like domain, which is important for the Bcl2L12 anti-apoptotic property and TMZ-induced autophagy. Our results basically support the idea of using ABT-737 to counteract the anti-apoptotic role of Bcl2L12 and sensitize drug response of the GBM cells to TMZ.
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http://dx.doi.org/10.3892/ijo.2015.2838DOI Listing
March 2015

Adenoviral-mediated glial cell line-derived neurotrophic factor gene transfer has a protective effect on sciatic nerve following constriction-induced spinal cord injury.

PLoS One 2014 18;9(3):e92264. Epub 2014 Mar 18.

Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan, R.O.C.; Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.

Neuropathic pain due to peripheral nerve injury may be associated with abnormal central nerve activity. Glial cell-line-derived neurotrophic factor (GDNF) can help attenuate neuropathic pain in different animal models of nerve injury. However, whether GDNF can ameliorate neuropathic pain in the spinal cord dorsal horn (SCDH) in constriction-induced peripheral nerve injury remains unknown. We investigated the therapeutic effects of adenoviral-mediated GDNF on neuropathic pain behaviors, microglial activation, pro-inflammatory cytokine expression and programmed cell death in a chronic constriction injury (CCI) nerve injury animal model. In this study, neuropathic pain was produced by CCI on the ipsilateral SCDH. Mechanical allodynia was examined with von Frey filaments and thermal sensitivity was tested using a plantar test apparatus post-operatively. Target proteins GDNF-1, GDNFRa-1, MMP2, MMP9, p38, phospho-p38, ED1, IL6, IL1β, AIF, caspase-9, cleaved caspase-9, caspase-3, cleaved caspase-3, PARP, cleaved PARP, SPECTRIN, cleaved SPECTRIN, Beclin-1, PKCσ, PKCγ, iNOS, eNOS and nNOS were detected. Microglial activity was measured by observing changes in immunoreactivity with OX-42. NeuN and TUNEL staining were used to reveal whether apoptosis was attenuated by GDNF. Results showed that administrating GDNF began to attenuate both allodynia and thermal hyperalgesia at day 7. CCI-rats were found to have lower GDNF and GDNFRa-1 expression compared to controls, and GDNF re-activated their expression. Also, GDNF significantly down-regulated CCI-induced protein expression except for MMP2, eNOS and nNOS, indicating that the protective action of GDNF might be associated with anti-inflammation and prohibition of microglia activation. Immunocytochemistry staining showed that GDNF reduced CCI-induced neuronal apoptosis. In sum, GDNF enhanced the neurotrophic effect by inhibiting microglia activation and cytokine production via p38 and PKC signaling. GDNF could be a good therapeutic tool to attenuate programmed cell death, including apoptosis and autophagy, consequent to CCI-induced peripheral nerve injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092264PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958488PMC
November 2014

Target-controlled infusion vs. manually controlled infusion of propofol with alfentanil for bidirectional endoscopy: a randomized controlled trial.

Endoscopy 2013 Nov 28;45(11):907-14. Epub 2013 Oct 28.

Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Background And Study Aims: The best anesthesia methods for analgesia and sedation during gastrointestinal endoscopy are still debated. The aim of this study was to compare the recovery time, clinical presentations, and satisfaction between target-controlled infusion (TCI) and manually controlled infusion (MCI) in same-day bidirectional endoscopy (esophagogastroduodenoscopy followed by colonoscopy).

Patients And Methods: A total of 220 patients with American Society of Anesthesiology physical status 1 or 2 were enrolled and randomized into the TCI or MCI groups. The clinical presentations, vasoactive drug demand, propofol consumption, and adverse events were recorded for both groups peri-procedurally. The concentrations of propofol in the plasma (Cp) and at the site of drug effect (Ce) by computerized simulation were also monitored in both groups. Finally, the satisfaction of patients, endoscopists, and nurse anesthetists was assessed by questionnaire after the examinations.

Results: Compared with the MCI group, the TCI group had a faster recovery time (17.91 ± 7.72 minutes vs. 14.58 ± 8.55 minutes; P = 0.002), less moderate hypotension (7.37 ± 15.46 % vs. 1.82 ± 5.15 %; P < 0.001), and shorter period of bradypnea (13.81 ± 15.92 % vs. 9.18 ± 12.00 %; P = 0.013). In addition, the TCI group reduced the relative risk of moderate desaturation by 50 % compared with the MCI group (30.9 % vs. 15.5 %; 95 % confidence interval 1.191-3.360; P = 0.007).

Conclusions: The study demonstrated that TCI of propofol combined with alfentanil was associated with a faster recovery time, and better hemodynamic and respiratory stability than MCI in same-day bidirectional endoscopy.

Clinical Trial Registration: CGMH IRB Identifier 97-0969B.
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http://dx.doi.org/10.1055/s-0033-1344645DOI Listing
November 2013