Doctor of Philosophy, National Taiwan University (2015)
Michael Snyder, Postdoctoral Faculty Sponsor
Statins Are Associated With Increased Insulin Resistance and Secretion.
Arteriosclerosis, thrombosis, and vascular biology
OBJECTIVE: Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. Approach and Results: We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISRAUC) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m2). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P<0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% (P=0.01) and insulin secretion (ISRAUC) by a median of 9% (P<0.001). There were small increases in oral glucose tolerance test glucoseAUC (median increase, 0.05%; P=0.03) and fasting insulin (median increase, 7%; P=0.01).CONCLUSIONS: In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02437084.
View details for DOI 10.1161/ATVBAHA.121.316159
View details for PubMedID 34433298
Prevention of Severe Intestinal Barrier Dysfunction Through a Single-Species Probiotics Is Associated With the Activation of Microbiome-Mediated Glutamate-Glutamine Biosynthesis.
Shock (Augusta, Ga.)
INTRODUCTION: Intra-abdominal hypertension (IAH), the leading complication in the intensive care unit, significantly disturbs the gut microbial composition by decreasing the relative abundance of Lactobacillus and increasing the relative abundance of opportunistic infectious bacteria.METHODS: To evaluate the preventative effect of Lactobacillus-based probiotics on IAH-induced intestinal barrier damages, a single-species probiotics (L92) and a multi-species probiotics (VSL#3) were introduced orally to Sprague-Dawley rats for 7 days before inducing IAH. The intestinal histology and permeability to macromolecules (fluoresceine isothiocyanate, FITC-dextran, N = 8 for each group), the parameters of immunomodulatory and oxidative responses [Monocyte chemotactic protein 1(MCP-1), interleukin-1beta (IL-1beta), interleukin-4 (IL-4), interleukin-10 (IL-10), malonaldehyde (MDA), glutathione peroxidase (GSH- Px), catalase (CAT), and superoxide dismutase (SOD); N = 4 for each group], and the microbiome profiling (N = 4 for each group) were analyzed.RESULTS: 7-day pretreatments of L92 significantly alleviated the IAH-induced increase in intestinal permeability to FITC-dextran and histological damage(P < 0.0001), accompanied with the suppression of inflammatory and oxidative activation. The increase of MCP-1 and IL-1beta were significantly inhibited (P < 0.05); the anti-inflammatory cytokines, IL-4 and IL-10 were maintained at high levels; and the suppression of CAT (P < 0.05) were significantly reversed when pretreated with L92. On the contrary, no significant protective effects were observed in the VSL#3-pretreated group. Among the 84 identified species, 260 MetaCyc pathways, and 217 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, the protective effects of L92 were correlated with an increased relative abundance of Bacteroides finegoldii, Odoribacter splanchnicus, and the global activation of amino acid biosynthesis pathways, especially the glutamate-glutamine biosynthesis pathway.CONCLUSIONS: 7-day pretreatment with a single-species probiotics can prevent IAH induced severe intestinal barrier dysfunction, potentially through microbial modulation.
View details for DOI 10.1097/SHK.0000000000001593
View details for PubMedID 32694391
Molecular Choreography of Acute Exercise.
2020; 181 (5): 1112–30.e16
Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.
View details for DOI 10.1016/j.cell.2020.04.043
View details for PubMedID 32470399
Multi-Omics Profiling, Microscopic Cervical Remodeling, and Parturition: Insights from the Smart Diaphragm Study.
SAGE PUBLICATIONS INC. 2019: 216A
View details for Web of Science ID 000459610400452
- Smart Diaphragm Study: Multi-omics profiling and cervical device measurements during pregnancy MOSBY-ELSEVIER. 2019: S649
Traversal of the Blood-Brain Barrier by Cleavable L-Lysine Conjugates of Apigenin
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
2018; 66 (30): 8124–31
Apigenin, a flavone abundant in parsley and celery, is known to act on several CNS receptors, but its very poor water solubility (<0.001 mg/mL) impedes its absorption in vivo and prevents clinical use. Herein, apigenin was directly conjugated with glycine, l-phenylalanine, and l-lysine to give the corresponding carbamate derivatives, all of which were much more soluble than apigenin itself (0.017, 0.018, and 0.13 mg/mL, respectively). The Lys-apigenin carbamate 10 had a temporary sedative effect on the mice within 5 min of intraperitoneal administration (single dose of 0.4 mg/g) and could be detected in the mice brain tissues at a concentration of 0.82 μg/g of intact Lys-apigenin carbamate 10 and 0.42 ug/g of apigenin at 1.5 h. This study accomplished the delivery of apigenin across the BBB in a manner that might be applicable to other congeners, which should inform the future development of BBB-crossing flavonoids.
View details for DOI 10.1021/acs.jafc.8b01187
View details for Web of Science ID 000440876900031
View details for PubMedID 29923397
Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome.
2016; 9: 257-277
Dravet syndrome is a devastating genetic brain disorder caused by heterozygous loss-of-function mutation in the voltage-gated sodium channel gene SCN1A. There are currently no treatments, but the upregulation of SCN1A healthy allele represents an appealing therapeutic strategy. In this study we identified a novel, evolutionary conserved mechanism controlling the expression of SCN1A that is mediated by an antisense non-coding RNA (SCN1ANAT). Using oligonucleotide-based compounds (AntagoNATs) targeting SCN1ANAT we were able to induce specific upregulation of SCN1A both in vitro and in vivo, in the brain of Dravet knock-in mouse model and a non-human primate. AntagoNAT-mediated upregulation of Scn1a in postnatal Dravet mice led to significant improvements in seizure phenotype and excitability of hippocampal interneurons. These results further elucidate the pathophysiology of Dravet syndrome and outline a possible new approach for the treatment of this and other genetic disorders with similar etiology.
View details for DOI 10.1016/j.ebiom.2016.05.011
View details for PubMedID 27333023
View details for PubMedCentralID PMC4972487
Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant Dravet Syndrome model during development
NEUROBIOLOGY OF DISEASE
2015; 77: 35-48
Dravet syndrome (DS) is characterized by severe infant-onset myoclonic epilepsy along with delayed psychomotor development and heightened premature mortality. A primary monogenic cause is mutation of the SCN1A gene, which encodes the voltage-gated sodium channel subunit Nav1.1. The nature and timing of changes caused by SCN1A mutation in the hippocampal dentate gyrus (DG) network, a core area for gating major excitatory input to hippocampus and a classic epileptogenic zone, are not well known. In particularly, it is still not clear whether the developmental deficit of this epileptogenic neural network temporally matches with the progress of seizure development. Here, we investigated the emerging functional and structural deficits of the DG network in a novel mouse model (Scn1a(E1099X/+)) that mimics the genetic deficit of human DS. Scn1a(E1099X/+) (Het) mice, similarly to human DS patients, exhibited early spontaneous seizures and were more susceptible to hyperthermia-induced seizures starting at postnatal week (PW) 3, with seizures peaking at PW4. During the same period, the Het DG exhibited a greater reduction of Nav1.1-expressing GABAergic neurons compared to other hippocampal areas. Het DG GABAergic neurons showed altered action potential kinetics, reduced excitability, and generated fewer spontaneous inhibitory inputs into DG granule cells. The effect of reduced inhibitory input to DG granule cells was exacerbated by heightened spontaneous excitatory transmission and elevated excitatory release probability in these cells. In addition to electrophysiological deficit, we observed emerging morphological abnormalities of DG granule cells. Het granule cells exhibited progressively reduced dendritic arborization and excessive spines, which coincided with imbalanced network activity and the developmental onset of spontaneous seizures. Taken together, our results establish the existence of significant structural and functional developmental deficits of the DG network and the temporal correlation between emergence of these deficits and the onset of seizures in Het animals. Most importantly, our results uncover the developmental deficits of neural connectivity in Het mice. Such structural abnormalities likely further exacerbate network instability and compromise higher-order cognitive processing later in development, and thus highlight the multifaceted impacts of Scn1a deficiency on neural development.
View details for DOI 10.1016/j.nbd.2015.02.010
View details for Web of Science ID 000353612200004
View details for PubMedID 25725421
Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation
HUMAN MOLECULAR GENETICS
2012; 21 (19): 4270-4285
Mutation in CUL4B, which encodes a scaffold protein of the E3 ubiquitin ligase complex, has been found in patients with X-linked mental retardation (XLMR). However, early deletion of Cul4b in mice causes prenatal lethality, which has frustrated attempts to characterize the phenotypes in vivo. In this report, we successfully rescued Cul4b mutant mice by crossing female mice in which exons 4-5 of Cul4b were flanked by loxP sequences with Sox2-Cre male mice. In Cul4b-deficient (Cul4b(Δ)/Y) mice, no CUL4B protein was detected in any of the major organs, including the brain. In the hippocampus, the levels of CUL4A, CUL4B substrates (TOP1, β-catenin, cyclin E and WDR5) and neuronal markers (MAP2, tau-1, GAP-43, PSD95 and syn-1) were not sensitive to Cul4b deletion, whereas the number of parvalbumin (PV)-positive GABAergic interneurons was decreased in Cul4b(Δ)/Y mice, especially in the dentate gyrus (DG). Some dendritic features, including the complexity, diameter and spine density in the CA1 and DG hippocampal neurons, were also affected by Cul4b deletion. Together, the decrease in the number of PV-positive neurons and altered dendritic properties in Cul4b(Δ)/Y mice imply a reduction in inhibitory regulation and dendritic integration in the hippocampal neural circuit, which lead to increased epileptic susceptibility and spatial learning deficits. Our results identify Cul4b(Δ)/Y mice as a potential model for the non-syndromic model of XLMR that replicates the CUL4B-associated MR and is valuable for the development of a therapeutic strategy for treating MR.
View details for DOI 10.1093/hmg/dds261
View details for Web of Science ID 000308888100011
View details for PubMedID 22763239
R26R-GR: A Cre-Activable Dual Fluorescent Protein Reporter Mouse
2012; 7 (9)
Green fluorescent protein (GFP) and its derivatives are the most widely used molecular reporters for live cell imagining. The development of organelle-specific fusion fluorescent proteins improves the labeling resolution to a higher level. Here we generate a R26 dual fluorescent protein reporter mouse, activated by Cre-mediated DNA recombination, labeling target cells with a chromatin-specific enhanced green fluorescence protein (EGFP) and a plasma membrane-anchored monomeric cherry fluorescent protein (mCherry). This dual labeling allows the visualization of mitotic events, cell shapes and intracellular vesicle behaviors. We expect this reporter mouse to have a wide application in developmental biology studies, transplantation experiments as well as cancer/stem cell lineage tracing.
View details for DOI 10.1371/journal.pone.0046171
View details for Web of Science ID 000309556100146
View details for PubMedID 23049968
View details for PubMedCentralID PMC3458011
Statistical identification of gene association by CID in application of constructing ER regulatory network
A variety of high-throughput techniques are now available for constructing comprehensive gene regulatory networks in systems biology. In this study, we report a new statistical approach for facilitating in silico inference of regulatory network structure. The new measure of association, coefficient of intrinsic dependence (CID), is model-free and can be applied to both continuous and categorical distributions. When given two variables X and Y, CID answers whether Y is dependent on X by examining the conditional distribution of Y given X. In this paper, we apply CID to analyze the regulatory relationships between transcription factors (TFs) (X) and their downstream genes (Y) based on clinical data. More specifically, we use estrogen receptor alpha (ERalpha) as the variable X, and the analyses are based on 48 clinical breast cancer gene expression arrays (48A).The analytical utility of CID was evaluated in comparison with four commonly used statistical methods, Galton-Pearson's correlation coefficient (GPCC), Student's t-test (STT), coefficient of determination (CoD), and mutual information (MI). When being compared to GPCC, CoD, and MI, CID reveals its preferential ability to discover the regulatory association where distribution of the mRNA expression levels on X and Y does not fit linear models. On the other hand, when CID is used to measure the association of a continuous variable (Y) against a discrete variable (X), it shows similar performance as compared to STT, and appears to outperform CoD and MI. In addition, this study established a two-layer transcriptional regulatory network to exemplify the usage of CID, in combination with GPCC, in deciphering gene networks based on gene expression profiles from patient arrays.CID is shown to provide useful information for identifying associations between genes and transcription factors of interest in patient arrays. When coupled with the relationships detected by GPCC, the association predicted by CID are applicable to the construction of transcriptional regulatory networks. This study shows how information from different data sources and learning algorithms can be integrated to investigate whether relevant regulatory mechanisms identified in cell models can also be partially re-identified in clinical samples of breast cancers.the implementation of CID in R codes can be freely downloaded from (http://homepage.ntu.edu.tw/~lyliu/BC/).
View details for DOI 10.1186/1471-2105-10-85
View details for Web of Science ID 000266602700001
View details for PubMedID 19292896
View details for PubMedCentralID PMC2679734