Publications by authors named "Ching-Hua Kuo"

101 Publications

Measurement of Dabigatran Concentration Using Finger Prick Dried Blood Spot Sample Collection.

Front Pharmacol 2021 26;12:679431. Epub 2021 May 26.

Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.

Real-world laboratory monitoring of dabigatran activity is challenging. The purpose of the present study was to demonstrate the feasibility and accuracy of finger prick sampling with dried blood spot (fpDBS) cards in measuring the dabigatran concentration. Patients >20 years of age with atrial fibrillation and receiving dabigatran therapy for more than 7 days were included in the study. Peak and trough dabigatran concentrations were collected by simultaneous finger prick and venous puncture. The dabigatran concentration was measured by ultra-high performance liquid chromatography with tandem mass spectrometry. Our previously developed post-column infused internal standard (PCI-IS) method was applied to estimate the blood spot volume on fpDBS and to calibrate the drug concentration. Deming regression was used to analyze the correlation between dabigatran concentration on fpDBS cards and in plasma samples, followed by Bland-Altman analysis to compare the bias between two sampling techniques. A total of 33 patients were enrolled and contributed 66 plasma and 55 fpDBS dabigatran samples. The average patient age was 74.6 ± 7.9 years, mean creatinine clearance 58.1 ± 18.3 mL/min, and CHADS-VASc score 3.5 ± 1.6 points. The dabigatran concentration ranged from 41.8-1421.7 ng/mL. The plasma and DBS dabigatran concentrations correlated well ( = 0.98), and the conversion factor for fpDBS to plasma dabigatran concentration was 1.28. The Bland-Altman analysis showed that 94.5% of the fpDBS-predicted concentration fell within 20% of bias. The study showed that fpDBS measurement of dabigatran concentration is reliable and can be applied in clinical scenarios.
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http://dx.doi.org/10.3389/fphar.2021.679431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187780PMC
May 2021

Lipidomics of children and adolescents exposed to multiple industrial pollutants.

Environ Res 2021 Jun 10:111448. Epub 2021 Jun 10.

Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University. No. 17, Xu-Zhou Road, Taipei, 10055, Taiwan. Electronic address:

Background: There are limited studies on the lipidomics of children and adolescents exposed to multiple industrial pollutants.

Objectives: In this study, we aimed to investigate lipid profile perturbations in 99 children and adolescents (aged 9-15) who lived in a polluted area surrounding the largest petrochemical complex in Taiwan. Previous studies have reported increased risks of acute and chronic diseases including liver dysfunctions and chronic kidney disease (CKD) in residents living in this area.

Methods: We measured urinary concentrations of 11 metals and metalloids and polycyclic aromatic hydrocarbons (PAHs) metabolite 1-hydroxypyrene (1-OHP) as exposure biomarkers, and urinary oxidative stress biomarkers and serum acylcarnitines as early health effect biomarkers. The association between individual exposure biomarkers and early health effect biomarkers were analyzed using linear regression, while association of combined exposure biomarkers with four oxidative stress biomarkers and acylcarnitines were analyzed using weighted quantile sum (WQS) regression. Lipid profiles were analyzed using an untargeted liquid chromatography mass spectrometry-based technique. "Meet-in-the-middle" approach was applied to identify potential lipid features that linked multiple industrial pollutants exposure with early health effects.

Results: We identified 15 potential lipid features that linked elevated multiple industrial pollutants exposure with three increased oxidative stress biomarkers and eight deregulated serum acylcarnitines, including one lysophosphatidylcholines (LPCs), four phosphatidylcholines (PCs), and two sphingomyelins (SMs) that were up-regulated in high exposure group compared to low exposure group, and two LPCs, four PCs, and two phosphatidylinositols (PIs) down-regulated in high exposure group compared to low exposure group.

Conclusion: Our findings could provide information for understanding the health effects, including early indicators and biological mechanism identification, of children and adolescents exposed to multiple industrial pollutants during critical stages of development.
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http://dx.doi.org/10.1016/j.envres.2021.111448DOI Listing
June 2021

Development of an Efficient and Sensitive Chemical Derivatization-Based LC-MS/MS Method for Quantifying Gut Microbiota-Derived Metabolites in Human Plasma and Its Application in Studying Cardiovascular Disease.

J Proteome Res 2021 May 31. Epub 2021 May 31.

School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

Recently, the gut microbiota has been found to be associated with many diseases, such as inflammatory bowel disease, depression, Parkinson's disease, cancer, metabolic syndrome, and cardiovascular disease (CVD). Among various gut microbiota-derived metabolites (GMs), short-chain fatty acids (SCFAs), bile acids (BAs), and tryptophan (TRP) metabolites are the most frequently discussed metabolites. LC-MS/MS shows advantages in quantifying the levels of metabolites with good sensitivity and selectivity; however, the poor ionization efficiency and polar characteristics of SCFAs make their analysis challenging, especially when analyzing plasma samples with low SCFA concentrations. Moreover, without characteristic fragment ions for unconjugated BAs and different detection ion modes for TRP metabolites and BAs, GM analysis is complex and time-consuming. To overcome these problems, we developed a derivatization method combined with LC-MS/MS to enhance the sensitivity and LC retention of GMs. Through derivatization with 3-nitrophenylhydrazine (3-NPH), 7 SCFAs, 9 bile acids, and 6 tryptophan metabolites can be simultaneously analyzed via separation within 14 min on a reversed-phase C18 column. For accurate quantification, C-3NPH-labeled standards were used as one-to-one internal standards. This derivatization approach was optimized and then validated. We further applied this method to investigate the targeted GM profile in patients with CVD. The results showed a significant reduction in plasma butyrate levels in CVD patients compared with healthy controls, suggesting its potentially protective role in CVD. In summary, this work provides a sensitive and effective LC-MS/MS method for simultaneously quantifying gut microbiota-related metabolites in human plasma, which could benefit various future gut microbiota-related studies.
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http://dx.doi.org/10.1021/acs.jproteome.1c00147DOI Listing
May 2021

Maternal Plasma Lipids During Pregnancy, Insulin-like Growth Factor-1 and Excess Foetal Growth.

J Clin Endocrinol Metab 2021 May 22. Epub 2021 May 22.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background: Maternal lipids during pregnancy and placental growth factors are associated with excess foetal growth. However, how these factors interact to increase the risk of delivering large-for-gestational-age (LGA) neonates remains unclear. In this study, we investigated the relationship between maternal plasma triglyceride (TG) and free fatty acids (FAs) during pregnancy, cord blood insulin-like growth factors (IGF) and LGA. In a cell model, we studied the effect of different FAs on placental IGF-1 secretion.

Methods: This cohort study included pregnant women with term pregnancy and without diabetes or hypertensive disorders in pregnancy. Maternal fasting plasma TG and FFAs were measured in the second trimester. Cord blood IGF-1, IGF-2 and IGF binding protein-1 and protein-3 were measured at the time of delivery. A human trophoblast cell line, 3A-sub-E, was used to evaluate the effect of different FAs on placental IGF-1 secretion.

Results: We recruited 598 pregnant women-neonate pairs. Maternal plasma TG (180 (152.5-185.5) vs. 166 (133-206) mg/dL, p=0.04) and cord blood IGF-1 concentrations (72.7 ± 23.0 vs. 54.1 ± 22.8 ng/mL, p=0.0001) were higher in the LGA group and were significantly associated with birth weight z-score. Maternal plasma free palmitic acid (PA) and stearic acid (SA), but not oleic acid (OA) or linoleic acid (LA), were significantly associated with cord blood IGF-1 concentrations. In 3A-sub-E cells, treatment with PA, SA, and LA, but not OA, induced IGF-1 expression and secretion.

Conclusions: Certain FAs can induce placental IGF-1 secretion, which suggest a potential pathophysiology linking maternal plasma lipids and LGA.
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http://dx.doi.org/10.1210/clinem/dgab364DOI Listing
May 2021

Reply to letter to the editor: Plasma ceramides are associated with outcomes in acute ischemic stroke patients.

J Formos Med Assoc 2021 Apr 12. Epub 2021 Apr 12.

Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.jfma.2021.03.025DOI Listing
April 2021

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress.

Cell Rep 2021 Apr;35(2):108972

Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address:

Disruption of sphingolipid homeostasis is known to cause neurological disorders, but the mechanisms by which specific sphingolipid species modulate pathogenesis remain unclear. The last step of de novo sphingolipid synthesis is the conversion of dihydroceramide to ceramide by dihydroceramide desaturase (human DEGS1; Drosophila Ifc). Loss of ifc leads to dihydroceramide accumulation, oxidative stress, and photoreceptor degeneration, whereas human DEGS1 variants are associated with leukodystrophy and neuropathy. In this work, we demonstrate that DEGS1/ifc regulates Rac1 compartmentalization in neuronal cells and that dihydroceramide alters the association of active Rac1 with organelle-mimicking membranes. We further identify the Rac1-NADPH oxidase (NOX) complex as the major cause of reactive oxygen species (ROS) accumulation in ifc-knockout (ifc-KO) photoreceptors and in SH-SY5Y cells with the leukodystrophy-associated DEGS1 variant. Suppression of Rac1-NOX activity rescues degeneration of ifc-KO photoreceptors and ameliorates oxidative stress in DEGS1-carrying cells. Therefore, we conclude that DEGS1/ifc deficiency causes dihydroceramide accumulation, resulting in Rac1 mislocalization and NOX-dependent neurodegeneration.
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http://dx.doi.org/10.1016/j.celrep.2021.108972DOI Listing
April 2021

Cell metabolomics analyses revealed a role of altered fatty acid oxidation in neurotoxicity pattern difference between nab-paclitaxel and solvent-based paclitaxel.

PLoS One 2021 19;16(3):e0248942. Epub 2021 Mar 19.

School of Pharmacy, College of Medicine, National Taiwan University, Taipei City, Zhongzheng Dist., Taiwan.

Peripheral neuropathy (PN) is a dose-limiting, painful adverse reaction associated with the use of paclitaxel. This common side effect was often partially attributed to the solvent used for solubilization of the highly hydrophobic drug substance. Therefore, the development of alternative formulations thrived, which included that of Abraxane® containing nanoparticle albumin-bound paclitaxel (nab-paclitaxel). However, studies demonstrated inconsistent conclusions regarding the mitigation of PN in comparison with the traditional formulation. The mass spectrometry-based cell metabolomics approach was used in the present study to explore the potentially associated mechanisms. Although no significant difference in the effects on cell viability was observed, fold changes in carnitine, several acylcarnitines and long-chain fatty acid(s) were significantly different between treatment groups in differentiated and undifferentiated SH-SY5Y cells. The most prominent difference observed was the significant increase of octanoylcarnitine in cells treated with solvent-based paclitaxel, which was found to be associated with significant decrease of medium-chain acyl-CoA dehydrogenase (MCAD). The findings suggested the potential role of altered fatty acid oxidation in the different neurotoxicity patterns observed, which may be a possible target for therapeutic interventions worth further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248942PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978375PMC
March 2021

Differences in Fatty Acid Oxidation between -Paclitaxel- and Solvent-Based Paclitaxel-Treated A549 Cells Based on Metabolomics.

ACS Omega 2021 Mar 15;6(8):5138-5145. Epub 2021 Feb 15.

School of Pharmacy, College of Medicine, National Taiwan University, 33 Linsen S. Road, Zhongzheng District, Taipei City 10050, Taiwan.

The pharmacokinetics, safety, and anticancer efficacy profiles of nanoparticle albumin-bound ()-paclitaxel formulations are superior to those of solvent-based paclitaxel formulations. The aims of the present study were to study the effects of -paclitaxel and solvent-based paclitaxel formulations on the metabolic profiles of the model cell line (A549) and attempt to elucidate the associated metabolic pathways. A mass spectrometry-based cell metabolomics approach and viability evaluation were used to explore the potential difference. Western blotting was utilized to measure the levels of relevant proteins, and carnitine palmitoyltransferase 1 (CPT1) activities were quantified. Fold changes normalized to controls in levels of carnitine and several acylcarnitines were significantly different ( < 0.05) between A549 cells treated with -paclitaxel and those treated with solvent-based paclitaxel. Relative to the controls, there were also significant fold change differences in palmitic and linoleic acid levels in the cell lysates, mitochondrial CPT1 activities, and mitochondrial medium-chain acyl-CoA dehydrogenase (MCAD) protein levels in the A549 cells subjected to the -paclitaxel and solvent-based paclitaxel formulations. Results suggested that the two formulations differentially modulated fatty acid oxidation in the A549 cells. While cell viability results did not reveal significant differences, the findings implied that a mass spectrometry-based cell metabolomics approach could be a sensitive tool to explore the differences caused by formulation changes without using animals. Since uncertainties of products containing nanomaterials warrant holistic screening to address safety concerns, the aforementioned approach may be of regulatory importance and is worth further investigation.
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http://dx.doi.org/10.1021/acsomega.0c04385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931197PMC
March 2021

Failure of pre-exposure prophylaxis with on-demand tenofovir disoproxil fumarate/emtricitabine resulting in emergence of antiretroviral resistance.

J Microbiol Immunol Infect 2021 Feb 6. Epub 2021 Feb 6.

Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Tropical Medicine and Parasitology, National Taiwan University Hospital, Taipei, Taiwan.

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http://dx.doi.org/10.1016/j.jmii.2021.01.011DOI Listing
February 2021

Using matrix-induced ion suppression combined with LC-MS/MS for quantification of trimethylamine-N-oxide, choline, carnitine and acetylcarnitine in dried blood spot samples.

Anal Chim Acta 2021 Mar 12;1149:338214. Epub 2021 Jan 12.

School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; The Metabolomics Core Laboratory, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Recently, there has been significant interest in the influences of the human gut microbiota on many diseases, such as cardiovascular disease (CVD) and metabolic disorders. Trimethylamine N-oxide (TMAO) is one of the most frequently discussed gut-derived metabolites. Dried blood spot (DBS) sampling has been regarded as an attractive alternative sampling strategy for clinical studies and offers many advantages. For DBS sample processing, whole-spot analysis could minimize hematocrit-related bias, but it requires blood volume calibration. This study developed a method combining matrix-induced ion suppression (MIIS) with liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) to estimate blood volume and quantify TMAO and its precursors and derivatives, including choline, carnitine and acetylcarnitine, in DBSs. The MIIS method used an ion suppression indicator (ISI) to measure the extent of ion suppression caused by the blood matrix, which was related to the blood volume. The results showed that the volume estimation accuracy of the MIIS method was within 91.7-109.7%. The combined MIIS and LC-MS/MS method for quantifying TMAO, choline, carnitine and acetylcarnitine was validated in terms of linearity, precision and accuracy. The quantification accuracy was within 91.2-113.2% (with LLOQ <119%), and the imprecision was below 8.0% for all analytes. A stability study showed that the analytes in DBSs were stable at all evaluated temperatures for at least 30 days. The validated method was applied to quantify DBS samples (n = 56). Successful application of the new method demonstrated the potential of this method for real-world DBS samples and to facilitate our understanding of the gut microbiota in human health.
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http://dx.doi.org/10.1016/j.aca.2021.338214DOI Listing
March 2021

Plasma ceramides are associated with outcomes in acute ischemic stroke patients.

J Formos Med Assoc 2021 Jan 24. Epub 2021 Jan 24.

Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.

Background/purpose: Sphingolipids are major constituents of eukaryotic cell membranes and play key roles in cellular regulatory processes. Our recent results in an experimental stroke animal model demonstrated changes in sphingolipids in response to acute ischemic brain injury. This study aimed to investigate the plasma levels of sphingosine-1-phosphate (S1P) and ceramides in acute ischemic stroke (AIS) patients and their associations with functional outcomes.

Methods: Plasma samples were collected from patients with AIS at <48 and 48-72 h post stroke and from nonstroke controls. The levels of S1P and ceramides with different fatty acyl chain lengths were measured by the ultra-high-pressure liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). A poor functional outcome was defined as a modified Rankin Scale (mRS) score ≥2 at 3 months after AIS.

Results: The results showed that S1P and very-long-chain ceramides were significantly decreased in AIS patients (n = 87; poor outcome, 56.3%) compared to nonstroke controls (n = 30). In contrast, long-chain ceramides were significantly increased in AIS patients. More importantly, higher levels of Cer(d18:1/18:0), Cer(d18:1/20:0), and Cer(d18:1/22:0) at 48-72 h were significantly associated with poor functional outcomes after adjusting for potential clinical confounders, including age, sex, hypertension, and National Institutes of Health Stroke Scale score at admission.

Conclusion: Our study supported the dynamic metabolism of sphingolipids after the occurrence of AIS. Ceramides could be potential prognostic markers for patients with AIS.
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http://dx.doi.org/10.1016/j.jfma.2021.01.006DOI Listing
January 2021

Abnormally low prolactin levels in schizophrenia patients after switching to aripiprazole in a randomized trial: a biomarker for rebound in psychotic symptoms?

BMC Psychiatry 2020 11 23;20(1):552. Epub 2020 Nov 23.

Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.

Background: Switching to aripiprazole from other antipsychotics can avoid antipsychotic-induced hyperprolactinemia but may result in an abnormally low prolactin level. This study aimed to assess whether the aripiprazole-induced abnormally low prolactin level was a biomarker for subsequent rebound of positive symptoms in schizophrenia patients.

Methods: Participants were 63 patients in an 8-week trial of switching to aripiprazole, in which preswitching antipsychotics were maintained for the first 2 weeks and aripiprazole was fixed at 15 mg orally throughout the trial. A prolactin level of < 3.7 ng/ml was defined as abnormally low, and an increase of two or more points in the positive subscore of the Positive and Negative Syndrome Scale at two adjacent ratings was defined as a psychotic rebound.

Results: Among 63 patients, 25 (39.7%) had an abnormally low prolactin level and 21 (33.3%) had a psychotic rebound after switching to aripiprazole. In patients with abnormally low prolactin levels, 48.0% of them had a rebound in psychotic symptoms, whereas in those without abnormally low prolactin levels 23.7% did so. Multivariable logistic regression analysis with adjustment for sex, early age at onset, and preswitching medications revealed that abnormally low prolactin levels were associated with psychotic rebound (adjusted odds ratio = 3.55, 95% confidence interval = 1.02, 12.5). Furthermore, there was concurrency between the trend of the cumulative proportion of patients having an abnormally low prolactin level and that of the cumulative proportion of patients having a rebound in psychotic symptoms.

Conclusions: An abnormally low prolactin level after switching to aripiprazole in schizophrenia patients was a potential warning sign of a psychotic rebound. Hence, monitoring of prolactin levels after switching to aripiprazole may help avoid such rebound in schizophrenia.

Trial Registration: NCT00545467 ; Date of registration: 17/10/2007.
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http://dx.doi.org/10.1186/s12888-020-02957-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686669PMC
November 2020

Characterization of TMAO productivity from carnitine challenge facilitates personalized nutrition and microbiome signatures discovery.

Microbiome 2020 11 19;8(1):162. Epub 2020 Nov 19.

Department of Internal Medicine, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan.

The capability of gut microbiota in degrading foods and drugs administered orally can result in diversified efficacies and toxicity interpersonally and cause significant impact on human health. Production of atherogenic trimethylamine N-oxide (TMAO) from carnitine is a gut microbiota-directed pathway and varies widely among individuals. Here, we demonstrated a personalized TMAO formation and carnitine bioavailability from carnitine supplements by differentiating individual TMAO productivities with a recently developed oral carnitine challenge test (OCCT). By exploring gut microbiome in subjects characterized by TMAO producer phenotypes, we identified 39 operational taxonomy units that were highly correlated to TMAO productivity, including Emergencia timonensis, which has been recently discovered to convert γ-butyrobetaine to TMA in vitro. A microbiome-based random forest classifier was therefore constructed to predict the TMAO producer phenotype (AUROC = 0.81) which was then validated with an external cohort (AUROC = 0.80). A novel bacterium called Ihubacter massiliensis was also discovered to be a key microbe for TMA/TMAO production by using an OCCT-based humanized gnotobiotic mice model. Simply combining the presence of E. timonensis and I. massiliensis could account for 43% of high TMAO producers with 97% specificity. Collectively, this human gut microbiota phenotype-directed approach offers potential for developing precision medicine and provides insights into translational research. Video Abstract.
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http://dx.doi.org/10.1186/s40168-020-00912-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676756PMC
November 2020

The Gut Metabolite Trimethylamine N-oxide Is Associated With Parkinson's Disease Severity and Progression.

Mov Disord 2020 11 2;35(11):2115-2116. Epub 2020 Sep 2.

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

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http://dx.doi.org/10.1002/mds.28246DOI Listing
November 2020

Investigating the Association of the Biogenic Amine Profile in Urine with Therapeutic Response to Neoadjuvant Chemotherapy in Breast Cancer Patients.

J Proteome Res 2020 10 3;19(10):4061-4070. Epub 2020 Sep 3.

School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan.

Neoadjuvant treatment (NAT) can downstage breast cancer and can be utilized for different clinical applications. However, the response to NAT varies among individuals. Having effective biomarkers is important to optimize the treatment of breast cancer. Concentrations of biogenic amines have been found to show an association with cancer cell proliferation, but their clinical utility remains unclear. This study developed a postcolumn-infused internal standard (PCI-IS)-assisted liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) method for profiling biogenic amines in human urine. Putrescine- was selected as the PCI-IS to calibrate the errors caused by matrix effects in the urine sample. The optimized method was applied to investigate the association between changes in 14 amines and the therapeutic response to NAT in breast cancer patients. Urine samples were collected before initiation of chemotherapy ( = 60). Our results indicated that the levels of -acetylspermine, spermidine, norepinephrine, and dopamine were significantly higher in the responder group than the nonresponder group. These metabolites were incorporated with clinical factors to identify NAT responders, and the prediction model showed an area under the curve value of 0.949. These observations provide remarkable insights for future studies in elucidating the roles of biogenic amines in breast cancer. Additionally, the PCI-IS-assisted amine profiling method can facilitate these studies.
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http://dx.doi.org/10.1021/acs.jproteome.0c00362DOI Listing
October 2020

Metabolomics analysis of plasma reveals voriconazole-induced hepatotoxicity is associated with oxidative stress.

Toxicol Appl Pharmacol 2020 09 25;403:115157. Epub 2020 Jul 25.

School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan; Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Voriconazole is one of the most frequently used antifungal drugs for the initial treatment of invasive aspergillosis, but liver-related adverse events occur frequently and usually lead to drug discontinuation. Moreover, the mechanism of voriconazole-induced hepatotoxicity remains unsettled. A holistic understanding of its mechanism is critical to prevent liver-related adverse events. Metabolomics has been demonstrated to be a helpful strategy for investigating drug-induced toxicity. This study aimed to utilize human plasma samples to investigate the mechanism of voriconazole-induced hepatotoxicity through a metabolomics approach. Patients that were administered voriconazole were classified into a voriconazole-induced hepatotoxicity group and control group (n = 65, 18% hepatotoxicity). Plasma samples were analyzed by targeted metabolomics using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry. The obtained peak areas for each metabolite were utilized for correlation analysis, fold change evaluation, and univariate statistical tests to identify metabolites associated with voriconazole-induced hepatotoxicity. This study showed a significantly lower glutamine-to-glutamate ratio (p = .04) and a higher β-N-acetylglucosamine (p = .003) in the voriconazole-induced hepatotoxicity group, implying the presence of oxidative stress. Other significant metabolites also indicated several adaptive responses to oxidative stress in patients with voriconazole-induced toxicity, including cell repair, energy production, and alteration to bile acid hemostasis. Furthermore, a metabolite panel consisting of α-ketoglutarate, glycocholate, and β-N-acetylglucosamine demonstrated better performance for detecting voriconazole-induced hepatotoxicity than conventional liver function tests. These metabolomics findings reveal that voriconazole-induced hepatotoxicity is associated with oxidative stress.
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http://dx.doi.org/10.1016/j.taap.2020.115157DOI Listing
September 2020

A Pilot Study of Metabolomic Pathways Associated With Fatigue in Survivors of Colorectal Cancer.

Biol Res Nurs 2021 Jan 22;23(1):42-49. Epub 2020 Jul 22.

School of Nursing, 38005College of Medicine, National Taiwan University, Taipei.

Background: Over 30% of cancer survivors experience chronic fatigue. An alteration in energy metabolism is one of the hypothesized mechanisms for cancer-related fatigue (CRF). No studies have evaluated for changes in metabolic profiles in cancer survivors with CRF. The purpose of this pilot study was to evaluate for differences in metabolic profiles between fatigued and non-fatigued survivors of colorectal cancer (CRC).

Methods: Survivors were recruited from the surgical outpatient department and the oncology clinic of a medical center in northern Taiwan. Fatigue was assessed using the Fatigue Symptom Inventory. Fasting blood samples were collected on the day the fatigue questionnaire was completed. Metabolomic profile analysis was performed using non-targeted, liquid chromatography/time-of-flight mass spectrometry. Fold change analyses, t-tests, and pathway analyses were performed to identify differences in metabolomic profiles between the fatigued and non-fatigued survivors.

Results: Of the 56 CRC survivors in this study, 28.6% (n = 16) were in the fatigue group. Statistically significant differences in carnitine, L-norleucine, pyroglutamic acid, pyrrolidonecarboxylic acid, spermine, hydroxyoctanoic acid, and paraxanthine were found between the two fatigue groups. In addition, two pathways were enriched for these metabolites (i.e., glutathione metabolism, D-glutamine and D-glutamate metabolism).

Conclusions: Findings from this pilot study provide preliminary evidence that two pathways that are involved with the regulation of ATP production and cellular energy (i.e., glutathione metabolism, D-glutamine and D-glutamate metabolism) are associated with fatigue in CRC survivors. If these findings are confirmed, they may provide new therapeutic targets to decrease fatigue in cancer survivors.
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http://dx.doi.org/10.1177/1099800420942586DOI Listing
January 2021

Aspirin Modifies Inflammatory Mediators and Metabolomic Profiles and Contributes to the Suppression of Obesity-Associated Breast Cancer Cell Growth.

Int J Mol Sci 2020 Jun 30;21(13). Epub 2020 Jun 30.

School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

Breast cancer is the most common cancer among women. Adiposity generally accompanies immune cell infiltration and cytokine secretion, which is ideal for tumor development. Aspirin is a chemopreventive agent against several types of cancer. The aim of this study was to investigate whether aspirin inhibits the growth of 4T1 breast cancer cells by inhibiting the inflammatory response and regulating the metabolomic profile of 3T3-L1 adipocytes. 3T3-L1 adipocyte-conditioned medium (Ad-CM) was used to mimic the obese adipose tissue microenvironment in 4T1 cells. The results revealed that aspirin inhibited macrophage chemoattractant protein (MCP-1), interleukin (IL-6), IL-1β, and plasminogen activator inhibitor (PAI-1) production in 3T3-L1 adipocytes stimulated by tumor necrosis factor-alpha (TNF-α) and lipopolysaccharide (LPS). In the obesity-associated model, Ad-CM significantly promoted 4T1 cell growth and migration, which were attenuated after aspirin treatment. The results of metabolic analyses using Ad-CM showed that amino acid metabolites and oxidative stress were increased in mature 3T3-L1 adipocytes compared to those in fibroblasts. Aspirin treatment modified metabolites involved in suppressing lipogenesis, oxidative stress, and neoplastic formation. In the relative fatty acid quantitation analysis of Ad-CM, aspirin diminished fatty acid contents of C16:1, C18:1, C18:2, C20:4, and C24:1. This study is the first to show that aspirin modifies the metabolomics and fatty acid composition of 3T3-L1 adipocytes and inhibits obesity-associated inflammation that contributes to obesity-related breast cancer cell growth and migration.
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http://dx.doi.org/10.3390/ijms21134652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369784PMC
June 2020

Impact of high plasma concentrations of linezolid in Taiwanese adult patients- therapeutic drug monitoring in improving adverse drug reactions.

J Formos Med Assoc 2021 Jan 26;120(1 Pt 2):466-475. Epub 2020 Jun 26.

Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan; School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Background: Previous studies have shown that the development of thrombocytopenia was associated with the elevated plasma concentration of linezolid, but little is known about the relationship between other uncommon adverse drug reactions (ADRs) and plasma concentration. The appropriate dosing adjustment has remained controversial. This prospective observational study was conducted to investigate the association between the plasma concentration of linezolid, ADRs, and clinical outcomes.

Methods: Adult patients on linezolid treatment undergoing at least one therapeutic drug monitoring (TDM) were enrolled. The association between linezolid concentrations and ADRs was examined by multivariate Cox regression model. Predictors of linezolid concentrations was determined by linear regression model. The cut-off point of linezolid concentration and the effect of dosing adjustments based on TDM was also explored.

Results: Of 50 patients enrolled in the study, plasma concentrations were 1.5-3 times higher than what was described in the prescribing information. The median minimum concentration (C) was significantly higher in patients with thrombocytopenia compared to patients without thrombocytopenia (13.0 vs. 7.2 μg/mL, P = 0.0273), and a higher median maximum concentration was also observed in patients with lactic acidosis (33.0 vs. 27.5 μg/mL, P = 0.0420). The C was elevated in patients with advanced age and severely impaired renal function. Dosing adjustment tailored by early TDM with the upper limit of C 9 μg/mL may improve platelet counts.

Conclusion: Elevated linezolid concentrations were associated with thrombocytopenia and lactic acidosis. TDM-guided dosing adjustment could be considered as a pragmatic way to mitigate thrombocytopenia.
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http://dx.doi.org/10.1016/j.jfma.2020.06.011DOI Listing
January 2021

A case-control study of perfluoroalkyl substances and the risk of breast cancer in Taiwanese women.

Environ Int 2020 09 21;142:105850. Epub 2020 Jun 21.

Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei 100, Taiwan; Department of Public Health, National Taiwan University College of Public Health, Taipei 100, Taiwan; Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan; Office of Occupational Safety and Health, National Taiwan University College of Medicine and Hospital, Taipei 100, Taiwan; Innovation and Policy Center for Population Health and Sustainable Environment, National Taiwan University College of Public Health, Taipei 100, Taiwan. Electronic address:

Breast cancer (BC) is a common cancer in women worldwide; however, the incidence of BC is increasing in younger women, possibly associated with the environment. Perfluoroalkyl substances (PFAS) are one of endocrine disruptors that accumulate in environment and impact human health. This study aimed to investigate whether the PFAS and BC are associated. We enrolled 120 BCE patients and 119 controls at National Taiwan University Hospital (NTUH) and also collected bio-specimen and questionnaire from 2013 to 2015. All subjects' plasma PFAS levels were analyzed by ultra-performance liquid chromatography tandem mass spectrometry method with electrospray ionization (UHPLC-ESI-MS/MS). A logistic regression model was used to estimate the association between PFAS and BC. In the ≤50 years age group, the adjusted odds ratio (OR) was 2.34 (95% CI = 1.02, 5.38) for perfluorooctane sulfonate (PFOS) exposure per natural log unit increase. After stratifying the estrogen receptor (ER) status and age group, we obtained a positive association for PFHxS and PFOS concentrations with respect to the risk of ER positive tumors for ≤50 years age group. In conclusion, we found that PFAS were associated with the BC risk of ER positive tumors in young Taiwanese women. Further studies are needed to follow and explore whether these associations are causal.
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http://dx.doi.org/10.1016/j.envint.2020.105850DOI Listing
September 2020

Human Breathomics Database.

Database (Oxford) 2020 01;2020

Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan.

Breathomics is a special branch of metabolomics that quantifies volatile organic compounds (VOCs) from collected exhaled breath samples. Understanding how breath molecules are related to diseases, mechanisms and pathways identified from experimental analytical measurements is challenging due to the lack of an organized resource describing breath molecules, related references and biomedical information embedded in the literature. To provide breath VOCs, related references and biomedical information, we aim to organize a database composed of manually curated information and automatically extracted biomedical information. First, VOCs-related disease information was manually organized from 207 literature linked to 99 VOCs and known Medical Subject Headings (MeSH) terms. Then an automated text mining algorithm was used to extract biomedical information from this literature. In the end, the manually curated information and auto-extracted biomedical information was combined to form a breath molecule database-the Human Breathomics Database (HBDB). We first manually curated and organized disease information including MeSH term from 207 literatures associated with 99 VOCs. Then, an automatic pipeline of text mining approach was used to collect 2766 literatures and extract biomedical information from breath researches. We combined curated information with automatically extracted biomedical information to assemble a breath molecule database, the HBDB. The HBDB is a database that includes references, VOCs and diseases associated with human breathomics. Most of these VOCs were detected in human breath samples or exhaled breath condensate samples. So far, the database contains a total of 913 VOCs in relation to human exhaled breath researches reported in 2766 publications. The HBDB is the most comprehensive HBDB of VOCs in human exhaled breath to date. It is a useful and organized resource for researchers and clinicians to identify and further investigate potential biomarkers from the breath of patients. Database URL: https://hbdb.cmdm.tw.
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http://dx.doi.org/10.1093/database/baz139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978997PMC
January 2020

Using the PCI-IS Method to Simultaneously Estimate Blood Volume and Quantify Nonvitamin K Antagonist Oral Anticoagulant Concentrations in Dried Blood Spots.

Anal Chem 2020 02 22;92(3):2511-2518. Epub 2020 Jan 22.

Stroke Center and Department of Neurology , National Taiwan University Hospital , Taipei 10617 , Taiwan.

Nonvitamin K antagonist oral anticoagulants (NOACs) have emerged as the preferred choice for the treatment of atrial fibrillation (AF). The establishment of a therapeutic range to minimize bleeding and thrombosis is important for personalized treatment of NOACs. The importance of dried blood spots (DBSs) has increased in medical care. An efficient and effective DBS analytical method could facilitate the concentration management of NOACs. The postcolumn infused internal standard (PCI-IS) method was applied to estimate spot volume and quantify dabigatran, rivaroxaban, and apixaban concentrations on DBS cards. The extraction solvent contented 0.1% formic acid and 70% ACN with a successive extraction procedure. Paired DBS and plasma samples from patients undergoing NOAC therapy ( = 269) were used to calculate conversion factors. [C]-Rivaroxaban was selected as the PCI-IS. The quantification accuracy for the three NOACs was within 88.9-104.3%. The RSDs of the repeatability and intermediate precision were below 10%. The obtained conversion factors of DBS to plasma concentrations of dabigatran, apixaban, and rivaroxaban were 1.81, 1.59, and 1.31, respectively. Bland-Altman analysis showed that the % differences between predicted and measured plasma concentrations were within a bias of ±20%. The result showed that PCI-IS was an accurate and efficient LC-MS/MS method to simultaneously estimate blood volume and NOAC concentrations on DBS cards. The stability results revealed that the DBS sampling strategy could improve compound stability. The developed method offers a new strategy for the therapeutic drug monitoring of NOACs and may improve the safe use of these drugs.
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http://dx.doi.org/10.1021/acs.analchem.9b04063DOI Listing
February 2020

Gas chromatography-mass spectrometry-based analytical strategies for fatty acid analysis in biological samples.

J Food Drug Anal 2020 01 27;28(1):60-73. Epub 2019 Nov 27.

School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; The Metabolomics Core Laboratory, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan; Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Fatty acids play critical roles in biological systems. Imbalances in fatty acids are related to a variety of diseases, which makes the measurement of fatty acids in biological samples important. Many analytical strategies have been developed to investigate fatty acids in various biological samples. Due to the structural diversity of fatty acids, many factors need to be considered when developing analytical methods including extraction methods, derivatization methods, column selections, and internal standard selections. This review focused on gas chromatography-mass spectrometry (GC-MS)-based methods. We reviewed several commonly used fatty acid extraction approaches, including liquid-liquid extraction and solid-phase microextraction. Moreover, both acid and base derivatization methods and other specially designed methods were comprehensively reviewed, and their strengths and limitations were discussed. Having good separation efficiency is essential to building an accurate and reliable GC-MS platform for fatty acid analysis. We reviewed the separation performance of different columns and discussed the application of multidimensional GC for improving separations. The selection of internal standards was also discussed. In the final section, we introduced several biomedical studies that measured fatty acid levels in different sample matrices and provided hints on the relationships between fatty acid imbalances and diseases.
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http://dx.doi.org/10.1016/j.jfda.2019.10.003DOI Listing
January 2020

Post-column infused internal standard assisted lipidomics profiling strategy and its application on phosphatidylcholine research.

J Pharm Biomed Anal 2020 Jan 30;178:112956. Epub 2019 Oct 30.

Graduate Institute of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

Various lipidomics studies have revealed the potential of using phospholipids as disease biomarkers for conditions such as Alzheimer's disease, cancer, and sepsis. Establishing accurate quantification methods for targeted phospholipid analysis is important for making these potential markers more clinically relevant. Although a stable isotope labelled-internal standard method can provide good quantification accuracy for endogenous metabolite quantification, there are limited isotope labelled phosphatidylcholines (PCs) commercially available. For this reason, this study proposed a postcolumn infused-internal standard (PCI-IS) method for the accurate quantification of PCs. To demonstrate the quantification accuracy of the PCI-IS method combined with the matrix normalization factor (MNF), 2 LPCs and 6 PCs have been quantified in the human plasma specimens, and the results showed that the PCI-IS combined with MNF method can provide quantification results as accurate as those of the standard addition method (SAM) but without the need for the labor-intensive SAM procedure. We additionally applied the PCI-IS method for improving the PC profiling accuracy, and the results indicated that the biased estimation of the PC composition caused by the MEs can be resolved by PCI-IS correction. Finally, the method was applied to investigate drug resistance in lung cancer cells. Decreased levels of PCs in drug resistant cells disclose the potential role of PCs in drug resistance. We anticipate that the PCI-IS strategy could help quantitative lipidomics move forward and further contribute to various clinical and biomedical studies.
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http://dx.doi.org/10.1016/j.jpba.2019.112956DOI Listing
January 2020

Using post-column infused internal standard assisted quantitative metabolomics for establishing prediction models for breast cancer detection.

Rapid Commun Mass Spectrom 2020 Apr 5;34 Suppl 1:e8581. Epub 2020 Feb 5.

School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.

Rationale: Breast cancer is one of the most common cancers among women and its associated mortality is on the rise. Metabolomics is a potential strategy for breast cancer detection. The post-column infused internal standard (PCI-IS)-assisted liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been demonstrated as an effective strategy for quantitative metabolomics. In this study, we evaluated the performance of targeted metabolomics with the PCI-IS quantification method to identify women with breast cancer.

Methods: We used metabolite profiling to identify 17 dysregulated metabolites in breast cancer patients. Two LC/MS/MS methods in combination with the PCI-IS strategy were developed to quantify these metabolites in plasma samples. Detection models were built through the analysis of plasma samples from 176 subjects consisting of healthy volunteers and breast cancer patients.

Results: Three isotope standards were selected as the PCI-ISs for the metabolites. The accuracy was within 82.8-114.16%, except for citric acid and lactic acid at high concentration levels. The repeatability and intermediate precision were all lower than 15% relative standard deviation. We have identified several metabolites that indicate the presence of breast cancer. The area under the receiver operating characteristics (AUROC) curve, sensitivity and specificity of the linear combinations of metabolite concentrations and age with the highest AUROC were 0.940 (0.889-0.992), 88.4% and 94.2% for pre-menopausal woman, respectively, and 0.828 (0.734-0.922), 73.5% and 85.1% for post-menopausal women, respectively.

Conclusions: The targeted metabolomics with PCI-IS quantification method successfully established prediction models for breast cancer detection. Further study is essential to validate these proposed markers.
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http://dx.doi.org/10.1002/rcm.8581DOI Listing
April 2020

Therapeutic drug monitoring of the teicoplanin trough level after the loading doses in patients receiving venoarterial extracorporeal membrane oxygenation.

J Formos Med Assoc 2020 Jun 28;119(6):1086-1092. Epub 2019 Oct 28.

Section of Infectious Diseases, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Background: The optimal loading dose of teicoplanin in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) has never been determined by therapeutic drug monitoring. This study investigated the appropriateness of proposed loading dose regimens of teicoplanin when administered to patients receiving VA-ECMO by using a previously proposed loading dosage and measuring the teicoplanin trough concentration (C).

Methods: Patients who initiated teicoplanin therapy while receiving VA-ECMO were enrolled. Every included patient received four loading doses of teicoplanin at a dose of 12 mg/kg. The first three doses were administered 12 h apart, and the fourth dose was administered 24 h after the third dose. Blood samples were collected before administering the maintenance dose (i.e., the fifth dose), and the teicoplanin C was measured. Serum teicoplanin levels were determined using an Agilent 1290 ultra-high performance liquid chromatography system.

Results: The teicoplanin C was successfully tested in 11 patients. Their median age was 68.2 years, and 81.8% of them were men. The median of each loading dose was 11.6 (range, 10.7-12.8) mg/kg. The median teicoplanin C was 22.01 (range, 14.85-44.84) mg/L. All patients had a C of more than 10 mg/L, whereas 90.9% (10/11) of the patients achieved a C of more than 15 mg/L.

Conclusion: The loading dosage consisting of four doses of teicoplanin administered within the first 72 h at a dose of 12 mg/kg/dose could achieve an adequate therapeutic C of teicoplanin in patients receiving VA-ECMO.
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http://dx.doi.org/10.1016/j.jfma.2019.10.005DOI Listing
June 2020

Augmented renal clearance is associated with inadequate antibiotic pharmacokinetic/pharmacodynamic target in Asian ICU population: a prospective observational study.

Infect Drug Resist 2019 16;12:2531-2541. Epub 2019 Aug 16.

Division of Chest Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background: Augmented renal clearance (ARC) is common in critically ill patients and could result in subtherapeutic antibiotic concentration. However, data in the Asian population are still lacking. The aim of this study was to explore the incidence and risk factors of ARC and its effect on β-lactam pharmacokinetics/pharmacodynamics (PK/PD) in Asian populations admitted to a medical ICU. In addition, we evaluated the appropriateness of using three estimated glomerular filtration (eGFR) formulas [Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] as screening tools.

Methods: We measured 2-, 8-, and 24-hr creatinine clearance (CL) and calculated eGFR by using three formulas for each. ARC was defined as CL >130 mL/min/1.73 m. Concentrations at the mid-dosing interval and prior to the next dose were collected if patients received the β-lactam antibiotic of piperacillin/tazobactam, cefepime, and meropenem, to determine the PK/PD index of fT > MIC. Multiple logistic regression analysis was conducted to identify the risk factors for ARC. Pearson correlation coefficient and the Bland and Altman method were applied to assess the accuracy of CL, CL, and eGFR for predicting ARC.

Results: Of 100 patients, 46 (46%) manifested ARC. Younger age (<50 years) and lower Sequential Organ Failure Assessment score increased the likelihood of ARC. ARC resulted in a low chance of achieving 50% fT >4MIC (33% vs 75%, <0.01), 100% fT > MIC (23% vs 69%, <0.01), and 100% fT >4MIC (3% vs 25%, <0.02). CL wielded the best correlation and agreement with CL. eGFR was the most appropriate screening tool, and the optimal cutoff value for detecting ARC was 130.5 mL/min/1.73 m.

Conclusion: ARC is associated with inadequate β-lactam PK/PD target in Asian ICU.
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http://dx.doi.org/10.2147/IDR.S213183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701640PMC
August 2019

Specific diacylglycerols generated by hepatic lipogenesis stimulate the oncogenic androgen receptor activity in male hepatocytes.

Int J Obes (Lond) 2019 12 27;43(12):2469-2479. Epub 2019 Aug 27.

Department of Microbiology, National Taiwan University College of Medicine, Taipei, 100, Taiwan.

Background: Obesity-induced hepatocellular carcinoma (HCC) is more prevalent in males than in females, but the underlying mechanism remains unclear. The influence of hepatic androgen receptor (AR) pathway on the gender difference of HCC has been well documented. Here we investigated the role of hepatic lipogenesis, which is elevated in the livers of obese and nonalcoholic fatty liver disease (NAFLD) patients, in stimulating the AR pathway for the male preference of obesity induced HCC.

Methods: Male C57BL/6J mice were fed a fructose-rich high carbohydrate diet (HCD) to induce hepatic lipogenesis. The effect of hepatic lipogenesis on AR was examined by the expression of hydrodynamically injected AR reporter and the endogenous AR target gene; the mechanism was delineated in hepatoma cell lines and validated in male mice.

Results: The hepatic lipogenesis induced by a fructose-rich HCD enhanced the transcriptional activity of hepatic AR in male mice, which did not happen when fed a high fat diet. This AR activation was blocked by sh-RNAs or inhibitors targeting key enzymes in lipogenesis, either acetyl-CoA carboxylase subunit alpha (ACCα), or fatty acid synthase (FASN), in vivo and in vitro. Further mechanistic study identified that specific unsaturated fatty acid, the oleic acid (C18:1 n-9), incorporated DAGs produced by hepatic lipogenesis are the key molecules to enhance the AR activity, through activation of Akt kinase, and this novel mechanism is targeted by metformin.

Conclusions: Our study elucidates a novel mechanism underlying the higher risk of HCC in obese/NAFLD males, through specific DAGs enriched by hepatic lipogenesis to increase the transcriptional activity of hepatic AR, a confirmed risk factor for male HCC.
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http://dx.doi.org/10.1038/s41366-019-0431-zDOI Listing
December 2019

ASIC3-dependent metabolomics profiling of serum and urine in a mouse model of fibromyalgia.

Sci Rep 2019 08 20;9(1):12123. Epub 2019 Aug 20.

Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, 40402, Taiwan.

Fibromyalgia (FM) is characterized by chronic widespread pain. The pathogenesis of FM remains unclear. No specific biomarkers are available. Animal models of FM may provide an opportunity to explore potential biomarkers in a relative homogenous disease condition. Here, we probed the metabolomics profiles of serum and urine in a mouse model of FM induced by intermittent cold stress (ICS). We focused on the role of acid-sensing ion channel 3 (ASIC3) in the metabolomics profiling because ICS treatment induced chronic widespread muscle pain lasting for 1 month in wild-type (Asic3) but not Asic3-knockout (Asic3) mice. Serum and urine samples were collected from both genotypes at different ICS stages, including before ICS (basal level) and post-ICS at days 10 (middle phase, P10) and 40 (recovery phase, P40). Control naïve mice and ICS-induced FM mice differed in H-NMR- and LC-MS-based metabolomics profiling. On pathway analysis, the leading regulated pathways in Asic3 mice were taurine and hypotaurine, cysteine and methionine, glycerophospholipid, and ascorbate and aldarate metabolisms, and the major pathways in Asic3 mice involved amino acid-related metabolism. Finally, we developed an algorithm for the impactful metabolites in the FM model including cis-aconitate, kynurenate, taurine, pyroglutamic acid, pyrrolidonecarboxylic acid, and 4-methoxyphenylacetic acid in urine as well as carnitine, deoxycholic acid, lysoPC(16:0), lysoPC(20:3), oleoyl-L-carnitine, and trimethylamine N-oxide in serum. Asic3 mice were impaired in only muscle allodynia development but not other pain symptoms in the ICS model, so the ASIC3-dependent metabolomics changes could be useful for developing diagnostic biomarkers specific to chronic widespread muscle pain, the core symptom of FM. Further pharmacological validations are needed to validate these metabolomics changes as potential biomarkers for FM diagnosis and/or treatment responses.
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http://dx.doi.org/10.1038/s41598-019-48315-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702159PMC
August 2019

Metabolomics Investigation of Voriconazole-Induced Hepatotoxicity in Mice.

Chem Res Toxicol 2019 09 28;32(9):1840-1849. Epub 2019 Aug 28.

School of Pharmacy, College of Medicine , National Taiwan University , No. 33, Linsen S. Road , Taipei City 100 , Taiwan.

Voriconazole (VCZ) is a widely used triazole drug for the treatment of serious incidence of invasive fungal infections (IFIs), and its most commonly reported clinical side effect is hepatotoxicity. The mechanism of VCZ-induced hepatotoxicity is unclear, and no specific marker can be used for prediction and diagnosis. This study aims to apply the targeted metabolomics approach to identify specific VCZ-induced metabolites related to hepatotoxicity via liquid chromatography-triple quadrupole mass spectrometry (LC-QqQ-MS) in a C57BL/6 mouse model. Mice treated with three repeated doses of 40 mg/kg VCZ by tail vein injection to induce hepatotoxicity (VCZ-induced hepatotoxicity group, = 8) were compared with mice without treatment (control group, = 10). Both liver tissue and plasma were collected and analyzed to propose underlying mechanisms associated with VCZ-induced hepatotoxicity. The results indicated that the metabolites associated with oxidative stress were altered, and alterations in the metabolites involved in glutathione biosynthesis were noticed. The ratio of glutamine to glutamate showed a significant reduction in the VCZ-induced hepatotoxicity group compared to the control group, suggesting that glutamine might be transformed into glutamate for glutathione biosynthesis. Accordingly, we proposed that VCZ-induced hepatotoxicity is associated with oxidative stress to cause cell dysfunction, leading to alterations in energy metabolism, the urea cycle, and nucleoside metabolism. To the best of our knowledge, this is the first study to apply metabolomics for investigating the mechanism of VCZ-induced hepatotoxicity.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00176DOI Listing
September 2019