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1.  Compliance Index, a Marker of Peripheral Arterial Stiffness, may Predict Renal Function Decline in Patients with Chronic Kidney Disease 
Background: Compliance index derived from digital volume pulse (CI-DVP), measuring the relationship between volume and pressure changes in fingertip, is a surrogate marker of peripheral arterial stiffness. This study investigated if CI-DVP can predict renal function deterioration, cardiovascular events and mortality in patients with chronic kidney disease (CKD).
Methods: In this prospective observational study, 149 CKD patients were included for final analysis. CI-DVP and brachial-ankle pulse wave velocity (baPWV) were measured, decline in renal function was assessed by the estimated glomerular filtration rate (eGFR) slope. Composite renal and cardiovascular outcomes were evaluated, including ≥50% eGFR decline, start of renal replacement therapy, and major adverse events.
Results: Patients in CKD stages 3b to 5 had higher baPWV and lower CI-DVP values than those in patients with CKD stages 1 to 3a. Stepwise multivariate linear regression analysis showed that lower CI-DVP (p =0.0001) and greater proteinuria (p =0.0023) were independent determinants of higher eGFR decline rate. Multivariate Cox regression analysis revealed that CI-DVP (HR 0.68, 95% CI 0.46-1.00), baseline eGFR (HR 0.96, 95% CI 0.94-0.98) and serum albumin (HR 0.17, 95% CI 0.07-0.42) were independent predictors for composite renal and cardiovascular outcomes.
Conclusions: Compliance index, CI-DVP, was significantly associated with renal function decline in patients with CKD. A higher CI-DVP may have independent prognostic value in slower renal function decline and better composite renal and cardiovascular outcomes in CKD patients.
doi:10.7150/ijms.12164
PMCID: PMC4502056  PMID: 26180508
Arterial stiffness; Chronic kidney disease; Compliance index; Glomerular filtration rate; Major adverse event
2.  Biochemical and Functional Characterization of Charge-defined Subfractions of High-density Lipoprotein From Normal Adults 
Analytical chemistry  2013;85(23):11440-11448.
High-density lipoprotein (HDL) is regarded as atheroprotective because it provides antioxidant and anti-inflammatory benefits and plays an important role in reverse cholesterol transport. In this paper, we outline a novel methodology for studying the heterogeneity of HDL. Using anion-exchange chromatography, we separated HDL from 6 healthy individuals into 5 subfractions (H1 through H5) with increasing charge and evaluated the composition and biologic activities of each subfraction. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis showed that apolipoprotein (apo) AI and apoAII were present in all 5 subfractions; apoCI was present only in H1; and apoCIII and apoE were most abundantly present in H4 and H5. HDL-associated antioxidant enzymes such as lecithin-cholesterol acyltransferase, lipoprotein-associated phospholipase A2, and paraoxonase 1 were most abundant in H4 and H5. Lipoprotein isoforms were analyzed in each subfraction by using matrix-assisted laser desorption–time of flight mass spectrometry. To quantify other proteins in the HDL subfractions, we used the isobaric tags for relative and absolute quantitation approach followed by nanoflow liquid chromatography–tandem mass spectrometry analysis. Most antioxidant proteins detected were found in H4 and H5. The ability of each subfraction to induce cholesterol efflux from macrophages increased with increasing HDL electronegativity, with the exception of H5, which promoted the least efflux activity. In conclusion, anion-exchange chromatography is an attractive method for separating HDL into subfractions with distinct lipoprotein compositions and biologic activities. By comparing the properties of these subfractions, it may be possible to uncover HDL-specific proteins that play a role in disease.
doi:10.1021/ac402516u
PMCID: PMC3919464  PMID: 24171625
3.  A pediatric case of Bickerstaff's brainstem encephalitis 
Korean Journal of Pediatrics  2014;57(12):542-545.
Bickerstaff's brainstem encephalitis is characterized by ophthalmoplegia, ataxia, and disturbance of consciousness. It is similar to Miller Fisher syndrome, a variant of Guillain-Barre syndrome, in that they share features such as ophthalmoplegia and ataxia. The difference is that patients with Bickerstaff's brainstem encephalitis have impaired consciousness, whereas patients with Miller Fisher syndrome have alert consciousness and areflexia. Here, we report the case of a 3-year-old child who was diagnosed with Bickerstaff's brainstem encephalitis presenting typical clinical features and interesting radiological findings. The patient showed ophthalmoplegia, ataxia, and subsequent stuporous mentality. Brain magnetic resonance imaging revealed high signal intensity in the pons and cerebellum around the 4th ventricle on a T2-weighted image. He was successfully treated with intravenous immunoglobulin. Differentiation of Bickerstaff's brainstem encephalitis and Miller Fisher syndrome is often difficult because they possess many overlapping features. Brain magnetic resonance imaging may be helpful in diagnosing Bickerstaff's brainstem encephalitis, especially when lesions are definitely found.
doi:10.3345/kjp.2014.57.12.542
PMCID: PMC4316599  PMID: 25653689
Encephalitis; Miller Fisher syndrome; Ophthalmoplegia; Ataxia
4.  Inhibitory and combinatorial effect of diphyllin, a v-ATPase blocker, on influenza viruses 
Antiviral research  2013;99(3):371-382.
An influenza pandemic poses a serious threat to humans and animals. Conventional treatments against influenza include two classes of pathogen-targeting antivirals: M2 ion channel blockers (such as amantadine) and neuraminidase inhibitors (such as oseltamivir). Examination of the mechanism of influenza viral infection has shown that endosomal acidification plays a major role in facilitating the fusion between viral and endosomal membranes. This pathway has led to investigations on vacuolar ATPase (v-ATPase) activity, whose role as a regulating factor on influenza virus replication has been verified in extensive genome-wide screenings. Blocking v-ATPase activity thus presents the opportunity to interfere with influenza viral infection by preventing the pH-dependent membrane fusion between endosomes and virions. This study aims to apply diphyllin, a natural compound shown to be as a novel v-ATPase inhibitor, as a potential antiviral for various influenza virus strains using cell-based assays. The results show that diphyllin alters cellular susceptibility to influenza viruses through the inhibition of endosomal acidification, thus interfering with downstream virus replication, including that of known drug-resistant strains. In addition, combinatorial treatment of the host-targeting diphyllin with pathogen-targeting therapeutics (oseltamivir and amantadine) demonstrates enhanced antiviral effects and cell protection in vitro.
doi:10.1016/j.antiviral.2013.06.014
PMCID: PMC3787953  PMID: 23820269
Influenza virus; Vacuolar ATPase inhibitor; Diphyllin; Oseltamivir; Amantadine
5.  Trends in the Incidence and Management of Acute Myocardial Infarction From 1999 to 2008: Get With the Guidelines Performance Measures in Taiwan 
Background
The American Heart Association Get With the Guidelines (GWTG) program has improved care quality of acute myocardial infarction (AMI) with important implications for other countries in the world. This study evaluated the incidence and care of AMI in Taiwan and assessed the compliance of GWTG in Taiwan.
Methods and Results
We used the Taiwan National Health Insurance Research Database (1999–2008) to identify hospitalized patients ≥18 years of age presenting with AMI. The temporal trends of annual incidence and care quality of AMI were evaluated. The age‐adjusted incidence of AMI (/100 000 person‐years) increased from 28.0 in 1999 to 44.4 in 2008 (P<0.001). The use of guideline‐based medications for AMI was evaluated. The use of dual antiplatelet therapy (DAPT) increased from 65% in 2004 to 83.9% in 2008 (P<0.001). Angiotensin‐converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) was used in 72.6% in 2004 and 71.7% in 2008 (P=NS) and β‐blocker was used in 60% in 2004 and 59.7% in 2008 (P=NS). Statin use increased from 32.1% to 50.1% from 2004 to 2008 (P<0.001). The in‐hospital mortality decreased from 15.9% in 1999 to 12.3% in 2008 (P<0.0001). Multivariable analysis showed that DAPT, ACE inhibitor/ARB, β‐blocker, and statin use during hospitalization were all associated with reduced in‐hospital mortality in our AMI patients.
Conclusions
AMI incidence was increasing, but the guideline‐based medications for AMI were underutilized in Taiwan. Quality improvement programs, such as GWTG, should be promoted to improve AMI care and outcomes in Taiwan.
doi:10.1161/JAHA.114.001066
PMCID: PMC4310397  PMID: 25112555
epidemiology; incidence; myocardial infarction; population
6.  Fecal calprotectin concentration in neonatal necrotizing enterocolitis 
Korean Journal of Pediatrics  2014;57(8):351-356.
Purpose
Among the many factors associated with acute intestinal mucosal infection, numerous studies have proposed the usefulness of fecal calprotectin. The aim of this study was to evaluate the usefulness of fecal calprotectin in the diagnosis of necrotizing enterocolitis (NEC).
Methods
We collected 154 stool samples from 16 very low birth weight and premature newborns at the Konyang University Hospital neonatal intensive care unit or neonatal nursery. The stool samples were collected using the Calprest device, and the fecal calprotectin level was measured with the BÜHLMANN Calprotectin enzyme-linked immunosorbent assay kit.
Results
Fecal calprotectin levels were significantly higher in the NEC group than in the non-NEC group (P=0.02). There was a significant positive linear relationship between the fecal calprotectin level and number of days after birth (P=0.00) in the gestational age <26 weeks group. There was a significant negative linear relationship between the calprotectin level and number of days after birth (P=0.03) in the gestational age ≥26 weeks and <30 weeks group. There was no difference in the calprotectin levels according to the type and method of feeding between the NEC and non-NEC groups.
Conclusion
Fecal calprotectin levels were significantly increased in premature infants with NEC. The fecal calprotectin test is a noninvasive, easy, and useful tool for the diagnosis of NEC.
doi:10.3345/kjp.2014.57.8.351
PMCID: PMC4155179  PMID: 25210522
Necrotizing enterocolitis; Premature infant; Calprotectin; Fecal calprotectin
7.  Fumarate Analogs Act as Allosteric Inhibitors of the Human Mitochondrial NAD(P)+-Dependent Malic Enzyme 
PLoS ONE  2014;9(6):e98385.
Human mitochondrial NAD(P)+-dependent malic enzyme (m-NAD(P)-ME) is allosterically activated by the four-carbon trans dicarboxylic acid, fumarate. Previous studies have suggested that the dicarboxylic acid in a trans conformation around the carbon-carbon double bond is required for the allosteric activation of the enzyme. In this paper, the allosteric effects of fumarate analogs on m-NAD(P)-ME are investigated. Two fumarate-insensitive mutants, m-NAD(P)-ME_R67A/R91A and m-NAD(P)-ME_K57S/E59N/K73E/D102S, as well as c-NADP-ME, were used as the negative controls. Among these analogs, mesaconate, trans-aconitate, monomethyl fumarate and monoethyl fumarate were allosteric activators of the enzyme, while oxaloacetate, diethyl oxalacetate, and dimethyl fumarate were found to be allosteric inhibitors of human m-NAD(P)-ME. The IC50 value for diethyl oxalacetate was approximately 2.5 mM. This paper suggests that the allosteric inhibitors may impede the conformational change from open form to closed form and therefore inhibit m-NAD(P)-ME enzyme activity.
doi:10.1371/journal.pone.0098385
PMCID: PMC4049574  PMID: 24911153
8.  Effect of Chinese Medical Herbs-Huiru Yizeng Yihao on Hyperprolactinemia and Hyperplasia of Mammary Gland in Mice 
The study investigated the pharmacodynamism and mechanism of Chinese medicinal formula-Huiru Yizeng Yihao (NO.1 HRYZ) on the model rats of hyperpro-lactinemia and the model rats of hyperplasia of mammary gland (HMG), and studied the internal connection between hyperprolactinemia and HMG.. The hyperprolactinemia rat models were established by injecting metoclopramide dihydrochloride in the back of rats. The model rat of HMG was prepared by injecting estradiol in the thigh muscle of the rats and progesterone consecutively, while the tails of rats were clipped with tongs. Rats were treated with either NO.1 HRYZ or positive control drugs for four weeks. The concentrations of sex hormone in rat serum were examined using ELISA kits, and the morphology of mammary gland tissue in all group rats was observed with microscope. NO.1 HRYZ significantly decreased prolactin (PRL) and increased estradiol (E2), progesterone (P), follicle stimulating hormone (FSH), luteinizing hormone (LH) concentrations of hyperprolactinemia rats. It decreased E2, PRL, FSH, gonadotropin-releasing hormone (GnRH), 5-hydroxytryptamine (5-HT) and increased P concentrations of HMG rat. It also eliminated hyperplasia of lobules and gland alveolus compared with the model group. Treatment with NO.1 HRYZ could significantly regulate the sex hormone disorder of hyperprolactinemia and HMG rat models, and could eliminate the formation of HMG. Hyperprolactinemia was closely correlated with HMG, and hyperprolactinemia promoted the formation of HMG.
PMCID: PMC3794387  PMID: 24146497
NO.1 HRYZ; hyperprolactinemia; HMG; sex hormone; morphology of mammary gland
9.  Pitavastatin and Atorvastatin Double-Blind Randomized ComPArative Study among HiGh-Risk Patients, Including ThOse with Type 2 Diabetes Mellitus, in Taiwan (PAPAGO-T Study) 
PLoS ONE  2013;8(10):e76298.
Background
Evidence about the efficacy and safety of statin treatment in high-risk patients with hypercholesterolemia is available for some populations, but not for ethnic Chinese. To test the hypothesis that treatment with pitavastatin (2 mg/day) is not inferior to treatment with atorvastatin (10 mg/day) for reducing low-density lipoprotein cholesterol (LDL-C), a 12-week multicenter collaborative randomized parallel-group comparative study of high-risk ethnic Chinese patients with hypercholesterolemia was conducted in Taiwan. In addition, the effects on other lipid parameters, inflammatory markers, insulin-resistance-associated biomarkers and safety were evaluated.
Methods and Results
Between July 2011 and April 2012, 251 patients were screened, 225 (mean age: 58.7 ± 8.6; women 38.2% [86/225]) were randomized and treated with pitavastatin (n = 112) or atorvastatin (n = 113) for 12 weeks. Baseline characteristics in both groups were similar, but after 12 weeks of treatment, LDL-C levels were significantly lower: pitavastatin group = −35.0 ± 14.1% and atorvastatin group = −38.4 ± 12.8% (both: p < 0.001). For the subgroup with diabetes mellitus (DM) (n = 125), LDL-C levels (−37.1 ± 12.9% vs. −38.0 ± 13.1%, p = 0.62) were similarly lowered after either pitavastatin (n = 63) or atorvastatin (n = 62) treatment. Triglycerides, non-high density lipoprotein cholesterol, and apoprotein B were similarly and significantly lower in both treatment groups. In non-lipid profiles, HOMA-IR and insulin levels were higher to a similar degree in both statin groups. Hemoglobin A1C was significantly (p = 0.001) higher in the atorvastatin group but not in the pitavastatin group. Both statins were well tolerated, and both groups had a similar low incidence of treatment-emergent adverse events.
Conclusion
Both pitavastatin (2 mg/day) and atorvastatin (10 mg/day) were well tolerated, lowered LDL-C, and improved the lipid profile to a comparable degree in high-risk Taiwanese patients with hypercholesterolemia.
Trial Registration
ClinicalTrials.gov NCT01386853 http://clinicaltrials.gov/ct2/show/NCT01386853?term=NCT01386853&rank=1
doi:10.1371/journal.pone.0076298
PMCID: PMC3788128  PMID: 24098467
10.  Decellularized porcine pulmonary arteries cross-linked by carbodiimide 
The physical properties of the tissues are weakened after decellularization, and the exposed collagen fibers are prone to thrombogenesis. Several studies have proven that the use of carbodiimide (EDC) as a cross-linking agent can improve the properties of decellularized xenogeneic scaffold materials. We adopted EDC for the treatment of porcine pulmonary arteries in an effort to improve the physical properties of these arteries following decellularization. Twenty porcine pulmonary arteries were randomly divided into 3 groups. The control group (group A) consisted of fresh porcine pulmonary arteries with no further processing; group B was treated with trypsin and the detergent Triton X-100 to remove cells; and group C was cross-linked with EDC after trypsin and Triton X-100 treatment, as in group B. The pulmonary arteries were assessed based on water content, thickness, tensile strength, and thermal shrinkage temperature, to evaluate the physical properties of all of the samples. The scaffolds were then subcutaneously embedded in rabbits. These constructs were removed after 4 weeks and checked. The cells and matrix components of the arterial walls were removed and the fibrous scaffolds were retained. In group B, the moisture content of the pulmonary arterial walls was increased; and the thickness of the walls and the tensile strength of the pulmonary arteries were decreased in comparison with group A. In subcutaneous embedding of the group B samples in rabbits, after 4 weeks, fibroblasts had grown into the scaffolds and regenerated the tissue. The water content was decreased in the pulmonary arterial walls, there was an increase in the tensile strength and the thermal shrinkage temperature in group C compared with group B. The EDC-based cross-linking procedure can enhance the tensile strength of decellularized pulmonary arteries and decrease scaffold rejection and degradation and promote tissue regeneration in vivo.
PMCID: PMC3731183  PMID: 23936590
EDC cross-linking; decellularization; pulmonary arteries
11.  Increase in Aminotransferase Levels during Urinary Tract Infections in Children 
Purpose
The aim of this study was to evaluate the prevalence of increased aminotransferase levels and to identify associated factors in children admitted to hospital with urinary tract infections (UTIs).
Methods
The study included children with a diagnosis of UTI who were admitted to the Konyang University Hospital from January 2007 to May 2011. The total number of patients was 249 and the mean age was 15.88±28.21 months. UTI was defined as a positive urine culture (>105/colony forming unit [CFU]) with pyrexia. Patients were treated by intravenous antibiotics, such as ampicillin/sulbactam, aminoglycoside, cephalosporins or vancomycin. Patients with neonatal jaundice or other liver disease were excluded. We investigated the relationship of aminotransferase levels with the type of antibiotic, degree of vesicoureteral reflux (VUR), and causative organisms.
Results
Children with increased aminotransferase levels were younger than those with normal levels (p=0.001), but white blood cell count, platelet count, causative organisms, type of antibiotics and presence of VUR were not associated with aminotransferase levels. Aminotransferase levels became normal within 1 month after discharge without special measures, except in 1 case.
Conclusion
We found that many children with UTI have abnormal aminotransferase levels. In most cases, this change is mild and self-limiting. We conclude that increased aminotransferase level increase during UTI do not require unnecessary tests and excessive treatment.
doi:10.5223/pghn.2013.16.2.89
PMCID: PMC3760695  PMID: 24010112
Urinary tract infections; Aminotransferase abnormality; Liver function tests; Sepsis
12.  Patterns and predictors of antihypertensive medication used 1 year after ischemic stroke or TIA in urban China 
Background
Antihypertensive treatment is recommended for secondary prevention in patients with ischemic stroke or transient ischemic attack. Prescription of and persistence with antihypertensives for secondary prevention is high in developed countries; whether this is true in China is unclear. The aim of this study was to describe the patterns of antihypertensive medication use, and factors associated with its use, 1 year after stroke in China.
Methods
A total of 7880 hypertensive patients diagnosed with ischemic stroke or transient ischemic attack in the China National Stroke Registry were analyzed. Multivariate logistic regression was used to identify factors associated with antihypertensive medication use at discharge and 12 months.
Results
Antihypertensive medication was used by 4458 (56.6%) participants at discharge and 2927 (37.1%) at 12 months. Calcium channel blockers were the most common among five classes of antihypertensive medication prescribed at discharge, and participants prescribed this class had the highest 1-year persistence. In-hospital health education was the strongest predictor of antihypertensive medication use at discharge; age and stroke severity were the strongest negative predictors of use at 12 months.
Conclusion
Use of antihypertensive medication 1 year after stroke is extremely low in China. Intervention is needed to improve adherence to antihypertensive medication, especially for the elderly and severe stroke patients.
doi:10.2147/PPA.S39800
PMCID: PMC3553336  PMID: 23378743
antihypertensive agents; secondary stroke prevention; stroke
13.  Rationale and design of a double-blind, placebo-controlled, randomized trial to evaluate the safety and efficacy of nimodipine in preventing cognitive impairment in ischemic cerebrovascular events (NICE) 
BMC Neurology  2012;12:88.
Background
Stroke is the second most common cause of mortality and the leading cause of neurological disability, cognitive impairment and dementia worldwide. Nimodipine is a dihydropyridinic calcium antagonist with a role in neuroprotection, making it a promising therapy for vascular cognitive impairment and dementia.
Methods/design
The NICE study is a multicenter, randomized, double-blind, placebo-controlled study being carried out in 23 centers in China. The study population includes patients aged 30–80 who have suffered an ischemic stroke (≤7 days). Participants are randomly allocated to nimodipine (90 mg/d) or placebo (90 mg/d). The primary efficacy is to evaluate the level of mild cognitive impairment following treatment of an ischemic stroke with nimodipine or placebo for 6 months. Safety is being assessed by observing side effects of nimodipine. Assuming a relative risk reduction of 22%, at least 656 patients are required in this study to obtain statistical power of 90%. The first patient was recruited in November 2010.
Discussion
Previous studies suggested that nimodipine could improve cognitive function in vascular dementia and Alzheimer’s disease dementia. It is unclear that at which time-point intervention with nimodipine should occur. Therefore, the NICE study is designed to evaluate the benefits and safety of nimodipine, which was adminstered within seven days, in preventing/treating mild cognitive impairment following ischemic stroke.
doi:10.1186/1471-2377-12-88
PMCID: PMC3488311  PMID: 22950711
14.  Oil Production from Yarrowia lipolytica Po1g Using Rice Bran Hydrolysate 
The purpose of this study was to produce microbial oil from Yarrowia lipolytica Po1g grown in defatted rice bran hydrolysate. After removing oil from rice bran by Soxhlet extraction, the bran is subjected to acid hydrolysis with various sulfuric acid concentrations (1–4% v/v), reaction times (1–8 h), and reaction temperatures (60–120°C). The optimal conditions for maximum total sugar production from the hydrolysate were found to be 3% sulfuric acid at 90°C for 6 h. Glucose was the predominant sugar (43.20 ± 0.28 g/L) followed by xylose (4.93 ± 0.03 g/L) and arabinose (2.09 ± 0.01 g/L). The hydrolysate was subsequently detoxified by neutralization to reduce the amount of inhibitors such as 5-hydroxymethylfurfural (HMF) and furfural to increase its potential as a medium for culturing Y. lipolytica Po1g. Dry cell mass and lipid content of Y. lipolytica Po1g grown in detoxified defatted rice bran hydrolysate (DRBH) under optimum conditions were 10.75 g/L and 48.02%, respectively.
doi:10.1155/2012/378384
PMCID: PMC3303617  PMID: 22496604
15.  Determinants of Nucleotide-Binding Selectivity of Malic Enzyme 
PLoS ONE  2011;6(9):e25312.
Malic enzymes have high cofactor selectivity. An isoform-specific distribution of residues 314, 346, 347 and 362 implies that they may play key roles in determining the cofactor specificity. Currently, Glu314, Ser346, Lys347 and Lys362 in human c-NADP-ME were changed to the corresponding residues of human m-NAD(P)-ME (Glu, Lys, Tyr and Gln, respectively) or Ascaris suum m-NAD-ME (Ala, Ile, Asp and His, respectively). Kinetic data demonstrated that the S346K/K347Y/K362Q c-NADP-ME was transformed into a debilitated NAD+-utilizing enzyme, as shown by a severe decrease in catalytic efficiency using NADP+ as the cofactor without a significant increase in catalysis using NAD+ as the cofactor. However, the S346K/K347Y/K362H enzyme displayed an enhanced value for kcat,NAD, suggesting that His at residue 362 may be more beneficial than Gln for NAD+ binding. Furthermore, the S346I/K347D/K362H mutant had a very large Km,NADP value compared to other mutants, suggesting that this mutant exclusively utilizes NAD+ as its cofactor. Since the S346K/K347Y/K362Q, S346K/K347Y/K362H and S346I/K347D/K362H c-NADP-ME mutants did not show significant reductions in their Km,NAD values, the E314A mutation was then introduced into these triple mutants. Comparison of the kinetic parameters of each triple-quadruple mutant pair (for example, S346K/K347Y/K362Q versus E314A/S346K/K347Y/K362Q) revealed that all of the Km values for NAD+ and NADP+ of the quadruple mutants were significantly decreased, while either kcat,NAD or kcat,NADP was substantially increased. By adding the E314A mutation to these triple mutant enzymes, the E314A/S346K/K347Y/K362Q, E314A/S346K/K347Y/K362H and E314A/S346I/K347D/K362H c-NADP-ME variants are no longer debilitated but become mainly NAD+-utilizing enzymes by a considerable increase in catalysis using NAD+ as the cofactor. These results suggest that abolishing the repulsive effect of Glu314 in these quadruple mutants increases the binding affinity of NAD+. Here, we demonstrate that a series of E314A-containing c-NADP-ME quadruple mutants have been changed to NAD+-utilizing enzymes by abrogating NADP+ binding and increasing NAD+ binding.
doi:10.1371/journal.pone.0025312
PMCID: PMC3183043  PMID: 21980421
16.  Minimal Antizyme Peptide Fully Functioning in the Binding and Inhibition of Ornithine Decarboxylase and Antizyme Inhibitor 
PLoS ONE  2011;6(9):e24366.
Antizyme (AZ) is a protein with 228 amino acid residues that regulates ornithine decarboxylase (ODC) by binding to ODC and dissociating its homodimer, thus inhibiting its enzyme activity. Antizyme inhibitor (AZI) is homologous to ODC, but has a higher affinity than ODC for AZ. In this study, we quantified the biomolecular interactions between AZ and ODC as well as AZ and AZI to identify functional AZ peptides that could bind to ODC and AZI and inhibit their function as efficiently as the full-length AZ protein. For these AZ peptides, the inhibitory ability of AZ_95-228 was similar to that of AZ_WT. Furthermore, AZ_95-176 displayed an inhibition (IC50: 0.20 µM) similar to that of AZ-95-228 (IC50: 0.16 µM), even though a large segment spanning residues 177–228 was deleted. However, further deletion of AZ_95-176 from either the N-terminus or the C-terminus decreased its ability to inhibit ODC. The AZ_100-176 and AZ_95-169 peptides displayed a noteworthy decrease in ability to inhibit ODC, with IC50 values of 0.43 and 0.37 µM, respectively. The AZ_95-228, AZ_100-228 and AZ_95-176 peptides had IC50 values comparable to that of AZ_WT and formed AZ-ODC complexes with Kd,AZ-ODC values of 1.5, 5.3 and 5.6 µM, respectively. Importantly, our data also indicate that AZI can rescue AZ peptide-inhibited ODC enzyme activity and that it can bind to AZ peptides with a higher affinity than ODC. Together, these data suggest that these truncated AZ proteins retain their AZI-binding ability. Thus, we suggest that AZ_95-176 is the minimal AZ peptide that is fully functioning in the binding of ODC and AZI and inhibition of their function.
doi:10.1371/journal.pone.0024366
PMCID: PMC3170320  PMID: 21931692
17.  Biphasic Effect of Curcumin on Morphine Tolerance: A Preliminary Evidence from Cytokine/Chemokine Protein Array Analysis 
The aim of this study was to evaluate the effect of curcumin on morphine tolerance and the corresponding cytokine/chemokine changes. Male ICR mice were made tolerant to morphine by daily subcutaneous injection for 7 days. Intraperitoneal injections of vehicle, low-dose or high-dose curcumin were administered 15 min after morphine injection, either acutely or chronically for 7 days to test the effect of curcumin on morphine-induced antinociception and development of morphine tolerance. On day 8, cumulative dose-response curves were generated and the 50% of maximal analgesic dose values were calculated and compared among groups. Corresponding set of mice were used for analyzing the cytokine responses by antibody-based cytokine protein array. Acute, high-dose curcumin enhanced morphine-induced antinociception. While morphine tolerance was attenuated by administration of low-dose curcumin following morphine injections for 7 days, it was aggravated by chronic high-dose curcumin following morphine injection, suggesting a biphasic effect of curcumin on morphine-induced tolerance. Of the 96 cytokine/chemokines analyzed by mouse cytokine protein array, 14 cytokines exhibited significant changes after the different 7-day treatments. Mechanisms for the modulatory effects of low-dose and high-dose curcumin on morphine tolerance were discussed. Even though curcumin itself is a neuroprotectant and low doses of the compound serve to attenuate morphine tolerance, high-doses of curcumin might cause neurotoxicity and aggravate morphine tolerance by inhibiting the expression of antiapoptotic cytokines and neuroprotective factors. Our results indicate that the effect of curcumin on morphine tolerance may be biphasic, and therefore curcumin should be used cautiously.
doi:10.1093/ecam/neq018
PMCID: PMC3150782  PMID: 21826185
18.  Atypical presentation of "takotsubo cardiomyopathy" without ST segment elevation: a case report 
Cases Journal  2008;1:309.
Introduction
"Takotsubo cardiomyopathy" is characterized by transient LV dysfunction and mimicking acute myocardial infarction.
Case presentation
We reported a case with atypical presentation of "takotsubo cardiomyopathy" without ST segment elevation, but with severe transient left ventricular dysfunction.
Conclusion
Diagnosis of "takotsubo cardiomyopathy" should be based on typical left ventricular dysfunction without coronary artery disease.
doi:10.1186/1757-1626-1-309
PMCID: PMC2613892  PMID: 19014564

Results 1-18 (18)