Honors & Awards


  • Linda & Jack Gill Graduate Student Award, Gill Center for Bimolecular Science (2022)
  • Larry Kays Fellowship, Stark Neurosciences Research Institute (2022)
  • Trainee Professional Development Award, Society for Neuroscience (2021)
  • NIH Outstanding Scholars in Neuroscience Award Program, National Institutes of Health (2021)
  • Eli Lilly-Stark Research Fellowship in Neurodegeneration, Indiana Clinical and Translational Science Institute (2021)
  • Cagiantas Scholar, Indiana University School of Medicine (2020)
  • IUPUI Elite 50, Indiana University (2020)
  • Paul & Carole Stark Fellowship, Stark Neurosciences Research Institute (2018)

Professional Education


  • Doctor of Philosophy, Indiana University (2022)
  • Master of Science, Tzu Chi University (2014)
  • Bachelor of Science, Tzu Chi University (2013)

Stanford Advisors


All Publications


  • The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model. Alzheimer's & dementia : the journal of the Alzheimer's Association Claes, C., England, W. E., Danhash, E. P., Kiani Shabestari, S., Jairaman, A., Chadarevian, J. P., Hasselmann, J., Tsai, A. P., Coburn, M. A., Sanchez, J., Lim, T. E., Hidalgo, J. L., Tu, C., Cahalan, M. D., Lamb, B. T., Landreth, G. E., Spitale, R. C., Blurton-Jones, M., Davtyan, H. 2022; 18 (10): 1765-1778

    Abstract

    The P522R variant of PLCG2, expressed by microglia, is associated with reduced risk of Alzheimer's disease (AD). Yet, the impact of this protective mutation on microglial responses to AD pathology remains unknown. Chimeric AD and wild-type mice were generated by transplanting PLCG2-P522R or isogenic wild-type human induced pluripotent stem cell microglia. At 7 months of age, single-cell and bulk RNA sequencing, and histological analyses were performed. The PLCG2-P522R variant induced a significant increase in microglial human leukocyte antigen (HLA) expression and the induction of antigen presentation, chemokine signaling, and T cell proliferation pathways. Examination of immune-intact AD mice further demonstrated that the PLCG2-P522R variant promotes the recruitment of CD8+ T cells to the brain. These data provide the first evidence that the PLCG2-P522R variant increases the capacity of microglia to recruit T cells and present antigens, promoting a microglial transcriptional state that has recently been shown to be reduced in AD patient brains.

    View details for DOI 10.1002/alz.12577

    View details for PubMedID 35142046

    View details for PubMedCentralID PMC9360195

  • Age-dependent microstructure alterations in 5xFAD mice by high-resolution diffusion tensor imaging. Frontiers in neuroscience Maharjan, S., Tsai, A. P., Lin, P. B., Ingraham, C., Jewett, M. R., Landreth, G. E., Oblak, A. L., Wang, N. 2022; 16: 964654

    Abstract

    To evaluate the age-dependent microstructure changes in 5xFAD mice using high-resolution diffusion tensor imaging (DTI).The 5xFAD mice at 4, 7.5, and 12 months and the wild-type controls at 4 months were scanned at 9.4T using a 3D echo-planar imaging (EPI) pulse sequence with the isotropic spatial resolution of 100 μm. The b-value was 3000 s/mm2 for all the diffusion MRI scans. The samples were also acquired with a gradient echo pulse sequence at 50 μm isotropic resolution. The microstructure changes were quantified with DTI metrics, including fractional anisotropy (FA) and mean diffusivity (MD). The conventional histology was performed to validate with MRI findings.The FA values (p = 0.028) showed significant differences in the cortex between wild-type (WT) and 5xFAD mice at 4 months, while hippocampus, anterior commissure, corpus callosum, and fornix showed no significant differences for either FA and MD. FA values of 5xFAD mice gradually decreased in cortex (0.140 ± 0.007 at 4 months, 0.132 ± 0.008 at 7.5 months, 0.126 ± 0.013 at 12 months) and fornix (0.140 ± 0.007 at 4 months, 0.132 ± 0.008 at 7.5 months, 0.126 ± 0.013 at 12 months) with aging. Both FA (p = 0.029) and MD (p = 0.037) demonstrated significant differences in corpus callosum between 4 and 12 months age old. FA and MD were not significantly different in the hippocampus or anterior commissure. The age-dependent microstructure alterations were better captured by FA when compared to MD.FA showed higher sensitivity to monitor amyloid deposition in 5xFAD mice. DTI may be utilized as a sensitive biomarker to monitor beta-amyloid progression for preclinical studies.

    View details for DOI 10.3389/fnins.2022.964654

    View details for PubMedID 36061588

    View details for PubMedCentralID PMC9428354

  • Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer's Disease-Relevant Phenotypes in Mice. Frontiers in aging neuroscience Oblak, A. L., Kotredes, K. P., Pandey, R. S., Reagan, A. M., Ingraham, C., Perkins, B., Lloyd, C., Baker, D., Lin, P. B., Soni, D. M., Tsai, A. P., Persohn, S. A., Bedwell, A. A., Eldridge, K., Speedy, R., Meyer, J. A., Peters, J. S., Figueiredo, L. L., Sasner, M., Territo, P. R., Sukoff Rizzo, S. J., Carter, G. W., Lamb, B. T., Howell, G. R. 2022; 14: 886575

    Abstract

    Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model with APOE4 and a variant in triggering receptor expressed on myeloid cells 2 (Trem2R47H ). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (Plcg2M28L ) and the 677C > T variant in methylenetetrahydrofolate reductase (Mthfr 677C > T ) were engineered by CRISPR onto LOAD1 to generate LOAD1.Plcg2M28L and LOAD1.Mthfr 677C > T . At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1.Plcg2M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1.Mthfr 677C > T animals fed with HFD. Furthermore, LOAD1.Plcg2M28L but not LOAD1.Mthfr 677C > T or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD.

    View details for DOI 10.3389/fnagi.2022.886575

    View details for PubMedID 35813947

    View details for PubMedCentralID PMC9263289

  • The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer's disease. Science translational medicine Moutinho, M., Puntambekar, S. S., Tsai, A. P., Coronel, I., Lin, P. B., Casali, B. T., Martinez, P., Oblak, A. L., Lasagna-Reeves, C. A., Lamb, B. T., Landreth, G. E. 2022; 14 (637): eabl7634

    Abstract

    Increased dietary intake of niacin has been correlated with reduced risk of Alzheimer's disease (AD). Niacin serves as a high-affinity ligand for the receptor HCAR2 (GPR109A). In the brain, HCAR2 is expressed selectively by microglia and is robustly induced by amyloid pathology in AD. The genetic inactivation of Hcar2 in 5xFAD mice, a model of AD, results in impairment of the microglial response to amyloid deposition, including deficits in gene expression, proliferation, envelopment of amyloid plaques, and uptake of amyloid-β (Aβ), ultimately leading to exacerbation of amyloid burden, neuronal loss, and cognitive deficits. In contrast, activation of HCAR2 with an FDA-approved formulation of niacin (Niaspan) in 5xFAD mice leads to reduced plaque burden and neuronal dystrophy, attenuation of neuronal loss, and rescue of working memory deficits. These data provide direct evidence that HCAR2 is required for an efficient and neuroprotective response of microglia to amyloid pathology. Administration of Niaspan potentiates the HCAR2-mediated microglial protective response and consequently attenuates amyloid-induced pathology, suggesting that its use may be a promising therapeutic approach to AD that specifically targets the neuroimmune response.

    View details for DOI 10.1126/scitranslmed.abl7634

    View details for PubMedID 35320002

  • PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease. Genome medicine Tsai, A. P., Dong, C., Lin, P. B., Messenger, E. J., Casali, B. T., Moutinho, M., Liu, Y., Oblak, A. L., Lamb, B. T., Landreth, G. E., Bissel, S. J., Nho, K. 2022; 14 (1): 17

    Abstract

    Alzheimer's disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD (LOAD) pathophysiology. However, the role of PLCG2 in AD is still poorly understood.Using bulk RNA-Seq (N=1249) data from the Accelerating Medicines Partnership-Alzheimer's Disease Consortium (AMP-AD), we investigated whether PLCG2 expression increased in the brains of LOAD patients. We also evaluated the relationship between PLCG2 expression levels, amyloid plaque density, and expression levels of microglia specific markers (AIF1 and TMEM119). Finally, we investigated the longitudinal changes of PLCG2 expression in the 5xFAD mouse model of AD. To further understand the role of PLCG2 in different signaling pathways, differential gene expression and co-expression network analyses were performed using bulk RNA-Seq and microglial single-cell RNA-Seq data. To substantiate the human analyses, we performed differential gene expression analysis on wild-type (WT) and inactivated Plcg2 mice and used immunostaining to determine if the differentially expressed genes/pathways were altered by microglial cell coverage or morphology.We observed significant upregulation of PLCG2 expression in three brain regions of LOAD patients and significant positive correlation of PLCG2 expression with amyloid plaque density. These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases in Plcg2 expression associated with amyloid pathology. Of note, increased Plcg2 expression levels in 5xFAD mice were abolished by reducing microglia. Furthermore, using bulk RNA-Seq data, we performed differential expression analysis by comparing cognitively normal older adults (CN) with 75th percentile (high) and 25th percentile (low) PLCG2 gene expression levels to identify pathways related to inflammation and the inflammatory response. The findings in the human brain were validated by differential expression analyses between WT and plcg2 inactivated mice. PLCG2 co-expression network analysis of microglial single-cell RNA-Seq data identified pathways related to the inflammatory response including regulation of I-kappaB/NF-kappa B signaling and response to lipopolysaccharide.Our results provide further evidence that PLCG2 plays an important role in AD pathophysiology and may be a potential target for microglia-targeted AD therapies.

    View details for DOI 10.1186/s13073-022-01022-0

    View details for PubMedID 35180881

    View details for PubMedCentralID PMC8857783

  • Moderate Ethanol Pre-treatment Mitigates ICH-Induced Injury via ER Stress Modulation in Rats. Frontiers in molecular neuroscience Lin, P. B., Wang, P. K., Pang, C. Y., Hu, W. F., Tsai, A. P., Oblak, A. L., Liew, H. K. 2021; 14: 682775

    Abstract

    Intracerebral hemorrhage (ICH) is a life-threatening type of stroke that disrupts the normal neurological function of the brain. Clinical studies have reported a non-linear J-shaped association between alcohol consumption levels and the occurrence of cerebral stroke. Specifically, alcohol intoxication increases stroke incidence, while moderate alcohol pre-conditioning decreases stroke frequency and improves outcomes. Although alcohol pre-consumption is likely a crucial player in ICH, the underlying mechanism remains unclear. We performed 1-h alcohol pre-conditioning followed by ICH induction in Sprague-Dawley (SD) rats to investigate the role of alcohol pre-conditioning in ICH. Interestingly, behavioral test analysis found that ethanol intoxication (3 g/kg) aggravated ICH-induced neurological deficits, but moderate ethanol pre-conditioning (0.75 g/kg) ameliorated ICH-induced neurological deficits by reducing the oxidative stress and proinflammatory cytokines release. Moreover, we found that moderate ethanol pretreatment improved the striatal endoplasmic reticulum (ER) homeostasis by increasing the chaperone protein expression and reducing oxidative stress and apoptosis caused by ICH. Our findings show that the mechanism regulated by moderate ethanol pre-conditioning might be beneficial for ICH, indicating the importance of ER homeostasis, oxidative stress, and differential cytokines release in ICH.

    View details for DOI 10.3389/fnmol.2021.682775

    View details for PubMedID 34248500

    View details for PubMedCentralID PMC8267178

  • Rare CASP6N73T variant associated with hippocampal volume exhibits decreased proteolytic activity, synaptic transmission defect, and neurodegeneration. Scientific reports Zhou, L., Nho, K., Haddad, M. G., Cherepacha, N., Tubeleviciute-Aydin, A., Tsai, A. P., Saykin, A. J., Jesper Sjöström, P., LeBlanc, A. C. 2021; 11 (1): 12695

    Abstract

    Caspase-6 (Casp6) is implicated in Alzheimer disease (AD) cognitive impairment and pathology. Hippocampal atrophy is associated with cognitive impairment in AD. Here, a rare functional exonic missense CASP6 single nucleotide polymorphism (SNP), causing the substitution of asparagine with threonine at amino acid 73 in Casp6 (Casp6N73T), was associated with hippocampal subfield CA1 volume preservation. Compared to wild type Casp6 (Casp6WT), recombinant Casp6N73T altered Casp6 proteolysis of natural substrates Lamin A/C and α-Tubulin, but did not alter cleavage of the Ac-VEID-AFC Casp6 peptide substrate. Casp6N73T-transfected HEK293T cells showed elevated Casp6 mRNA levels similar to Casp6WT-transfected cells, but, in contrast to Casp6WT, did not accumulate active Casp6 subunits nor show increased Casp6 enzymatic activity. Electrophysiological and morphological assessments showed that Casp6N73T recombinant protein caused less neurofunctional damage and neurodegeneration in hippocampal CA1 pyramidal neurons than Casp6WT. Lastly, CASP6 mRNA levels were increased in several AD brain regions confirming the implication of Casp6 in AD. These studies suggest that the rare Casp6N73T variant may protect against hippocampal atrophy due to its altered catalysis of natural protein substrates and intracellular instability thus leading to less Casp6-mediated damage to neuronal structure and function.

    View details for DOI 10.1038/s41598-021-91367-0

    View details for PubMedID 34135352

    View details for PubMedCentralID PMC8209045

  • INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia. Neurobiology of disease Tsai, A. P., Lin, P. B., Dong, C., Moutinho, M., Casali, B. T., Liu, Y., Lamb, B. T., Landreth, G. E., Oblak, A. L., Nho, K. 2021; 153: 105303

    Abstract

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies recently highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase (INPP5D), also known as SHIP1, is selectively expressed in brain microglia and has been reported to be associated with LOAD. Although INPP5D is likely a crucial player in AD pathophysiology, its role in disease onset and progression remains unclear. We performed differential gene expression analysis to investigate INPP5D expression in AD and its association with plaque density and microglial markers using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression in the 5xFAD amyloid mouse model. Differential gene expression analysis found that INPP5D expression was upregulated in LOAD and positively correlated with amyloid plaque density. In addition, in 5xFAD mice, Inpp5d expression increased as the disease progressed, and selectively in plaque-associated microglia. Increased Inpp5d expression levels in 5xFAD mice were abolished entirely by depleting microglia with the colony-stimulating factor receptor-1 antagonist PLX5622. Our findings show that INPP5D expression increases as AD progresses, predominantly in plaque-associated microglia. Importantly, we provide the first evidence that increased INPP5D expression might be a risk factor in AD, highlighting INPP5D as a potential therapeutic target. Moreover, we have shown that the 5xFAD mouse model is appropriate for studying INPP5D in AD.

    View details for DOI 10.1016/j.nbd.2021.105303

    View details for PubMedID 33631273

    View details for PubMedCentralID PMC8082515

  • Metabolic Defects Caused by High-Fat Diet Modify Disease Risk through Inflammatory and Amyloidogenic Pathways in a Mouse Model of Alzheimer's Disease. Nutrients Reilly, A. M., Tsai, A. P., Lin, P. B., Ericsson, A. C., Oblak, A. L., Ren, H. 2020; 12 (10)

    Abstract

    High-fat diet (HFD) has been shown to accelerate Alzheimer's disease (AD) pathology, but the exact molecular and cellular mechanisms remain incompletely understood. Moreover, it is unknown whether AD mice are more susceptible to HFD-induced metabolic dysfunctions. To address these questions, we used 5xFAD mice as an Alzheimer's disease model to study the physiological and molecular underpinning between HFD-induced metabolic defects and AD pathology. We systematically profiled the metabolic parameters, the gut microbiome composition, and hippocampal gene expression in 5xFAD and wild type (WT) mice fed normal chow diet and HFD. HFD feeding impaired energy metabolism in male 5xFAD mice, leading to increased locomotor activity, energy expenditure, and food intake. 5xFAD mice on HFD had elevated circulating lipids and worsened glucose intolerance. HFD caused profound changes in gut microbiome compositions, though no difference between genotype was detected. We measured hippocampal mRNAs related to AD neuropathology and neuroinflammation and showed that HFD elevated the expression of apoptotic, microglial, and amyloidogenic genes in 5xFAD mice. Pathway analysis revealed that differentially regulated genes were involved in insulin signaling, cytokine signaling, cellular stress, and neurotransmission. Collectively, our results showed that 5xFAD mice were more susceptible to HFD-induced metabolic dysregulation and suggest that targeting metabolic dysfunctions can ameliorate AD symptoms via effects on insulin signaling and neuroinflammation in the hippocampus.

    View details for DOI 10.3390/nu12102977

    View details for PubMedID 33003412

    View details for PubMedCentralID PMC7600118

  • The Role of Urocortins in Intracerebral Hemorrhage. Biomolecules Choy, K. W., Tsai, A. P., Lin, P. B., Wu, M. Y., Lee, C., Alias, A., Pang, C. Y., Liew, H. K. 2020; 10 (1)

    Abstract

    Intracerebral hemorrhage (ICH) causes an accumulation of blood in the brain parenchyma that disrupts the normal neurological function of the brain. Despite extensive clinical trials, no medical or surgical therapy has shown to be effective in managing ICH, resulting in a poor prognosis for the patients. Urocortin (UCN) is a 40-amino-acid endogenous neuropeptide that belongs to the corticotropin-releasing hormone (CRH) family. The effect of UCN is activated by binding to two G-protein coupled receptors, CRH-R1 and CRH-R2, which are expressed in brain neurons and glial cells in various brain regions. Current research has shown that UCN exerts neuroprotective effects in ICH models via anti-inflammatory effects, which generally reduced brain edema and reduced blood-brain barrier disruption. These effects gradually help in the improvement of the neurological outcome, and thus, UCN may be a potential therapeutic target in the treatment of ICH. This review summarizes the data published to date on the role of UCN in ICH and the possible protective mechanisms underlined.

    View details for DOI 10.3390/biom10010096

    View details for PubMedID 31935997

    View details for PubMedCentralID PMC7022917

  • Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats. Cells Liew, H. K., Hu, W. F., Lin, P. B., Wang, P. K., Tsai, A. P., Pang, C. Y., Chen, T. Y. 2019; 8 (11)

    Abstract

    Neuroinflammation is a hallmark in intracerebral hemorrhage (ICH) that induces secondary brain injury, leading to neuronal cell death. ER stress-triggered apoptosis and proteostasis disruption caused neuroinflammation to play an important role in various neurological disorders. The consequences of ER stress and proteostasis disruption have rarely been studied during the course of ICH development.ICH was induced by collagenase VII-S intrastriatal infusion. Animals were sacrificed at 0, 3, 6, 24, and 72 h post-ICH. Rats were determined for body weight changes, hematoma volume, and neurological deficits. Brain tissues were harvested for molecular signaling analysis either for ELISA, immunoblotting, immunoprecipitation, RT-qPCR, protein aggregation, or for histological examination. A non-selective proteasome inhibitor, MG132, was administered into the right striatum three hours prior to ICH induction.ICH-induced acute proteasome over-activation caused the early degradation of the endoplasmic reticulum (ER) chaperone GRP78 and IκB protein. These exacerbations were accompanied by the elevation of pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP) and pro-inflammatory cytokines expression via nuclear factor-kappa B (NF-κB) signal activation. Pre-treatment with proteasome inhibitor MG132 significantly ameliorated the ICH-induced ER stress/proteostasis disruption, pro-inflammatory cytokines, neuronal cells apoptosis, and neurological deficits.ICH induced rapid proteasome over-activation, leading to an exaggeration of the ER stress/proteostasis disruption, and neuroinflammation might be a critical event in acute ICH pathology.

    View details for DOI 10.3390/cells8111326

    View details for PubMedID 31717886

    View details for PubMedCentralID PMC6912695

  • Contrast Media Induced Kounis Syndrome: A Case Report. Diagnostics (Basel, Switzerland) Chien, D. S., Tsai, A. P., Lin, P. C., Yiang, G. T., Wu, M. Y. 2019; 9 (4)

    Abstract

    Kounis syndrome is a rare anaphylactic reaction leading to coronary spasm, acute plaque rupture, or intrastent stenosis. Many types of medicine or environmental factors can potentially trigger Kounis syndrome by mast cell allergic reactions. In severe Kounis syndrome, reduced blood pressure or cardiac arrest may be accompanying symptoms. The treatment strategy for Kounis syndrome is usually difficult due to both cardiac dysfunction and allergic reactions. The delay to intervention to break the vicious circle may cause catastrophic complications. Therefore, early diagnosis is critical for physicians to outline detailed etiology for prevention and treat the cardiac and allergic symptoms in a timely manner. Here, we describe a case presenting rare severe Kounis syndrome with cardiac arrest which occurred after the administration of a contrast media.

    View details for DOI 10.3390/diagnostics9040154

    View details for PubMedID 31635242

    View details for PubMedCentralID PMC6963726

  • Severe Type of Minocycline-Induced Hyperpigmentation Mimicking Peripheral Arterial Occlusive Disease in a Bullous Pemphigoid Patient. Antibiotics (Basel, Switzerland) Wu, M. Y., Hou, Y. T., Yiang, G. T., Tsai, A. P., Lin, C. H. 2019; 8 (3)

    Abstract

    Minocycline is a tetracycline group antibiotic that is known to cause significant antibacterial and anti-inflammatory effects. Minocycline has been widely used to treat systemic infection, acne, dermatitis, and rosacea. However, various dose-related side effects of hyperpigmentation in whole body tissues have been reported. Three main types of minocycline-induced hyperpigmentation have been identified. In rare severe hyperpigmentation cases, drug-induced hyperpigmentation can mimic local cellulitis or peripheral arterial occlusive disease (PAOD). These processes require different therapeutic strategies. Therefore, early diagnosis is extremely important for physicians to determine the etiology of the hyperpigmentation, and subsequently discontinue the minocycline if indicated. We describe a rare case presenting a severe form of type III minocycline-induced hyperpigmentation mimicking peripheral arterial occlusive disease in a bullous pemphigoid patient.

    View details for DOI 10.3390/antibiotics8030093

    View details for PubMedID 31315305

    View details for PubMedCentralID PMC6783986

  • Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies. Journal of clinical medicine Li, C. J., Chen, C. S., Yiang, G. T., Tsai, A. P., Liao, W. T., Wu, M. Y. 2019; 8 (4)

    Abstract

    Cardiomyopathy is a group of heterogeneous cardiac diseases that impair systolic and diastolic function, and can induce chronic heart failure and sudden cardiac death. Cardiomyopathy is prevalent in the general population, with high morbidity and mortality rates, and contributes to nearly 20% of sudden cardiac deaths in younger individuals. Genetic mutations associated with cardiomyopathy play a key role in disease formation, especially the mutation of sarcomere encoding genes and ATP kinase genes, such as titin, lamin A/C, myosin heavy chain 7, and troponin T1. Pathogenesis of cardiomyopathy occurs by multiple complex steps involving several pathways, including the Ras-Raf-mitogen-activated protein kinase-extracellular signal-activated kinase pathway, G-protein signaling, mechanotransduction pathway, and protein kinase B/phosphoinositide 3-kinase signaling. Excess biomechanical stress induces apoptosis signaling in cardiomyocytes, leading to cell loss, which can induce myocardial fibrosis and remodeling. The clinical features and pathophysiology of cardiomyopathy are discussed. Although several basic and clinical studies have investigated the mechanism of cardiomyopathy, the detailed pathophysiology remains unclear. This review summarizes current concepts and focuses on the molecular mechanisms of cardiomyopathy, especially in the signaling from mutation to clinical phenotype, with the aim of informing the development of therapeutic interventions.

    View details for DOI 10.3390/jcm8040520

    View details for PubMedID 30995779

    View details for PubMedCentralID PMC6518034

  • Epithelial to Mesenchymal Transition and Cell Biology of Molecular Regulation in Endometrial Carcinogenesis. Journal of clinical medicine Chiu, H. C., Li, C. J., Yiang, G. T., Tsai, A. P., Wu, M. Y. 2019; 8 (4)

    Abstract

    Endometrial carcinogenesis is involved in several signaling pathways and it comprises multiple steps. The four major signaling pathways-PI3K/AKT, Ras/Raf/MEK/ERK, WNT/β-catenin, and vascular endothelial growth factor (VEGF)-are involved in tumor cell metabolism, growth, proliferation, survival, and angiogenesis. The genetic mutation and germline mitochondrial DNA mutations also impair cell proliferation, anti-apoptosis signaling, and epithelial⁻mesenchymal transition by several transcription factors, leading to endometrial carcinogenesis and distant metastasis. The PI3K/AKT pathway activates the ransforming growth factor beta (TGF-β)-mediated endothelial-to-mesenchymal transition (EMT) and it interacts with downstream signals to upregulate EMT-associated factors. Estrogen and progesterone signaling in EMT also play key roles in the prognosis of endometrial carcinogenesis. In this review article, we summarize the current clinical and basic research efforts regarding the detailed molecular regulation in endometrial carcinogenesis, especially in EMT, to provide novel targets for further anti-carcinogenesis treatment.

    View details for DOI 10.3390/jcm8040439

    View details for PubMedID 30935077

    View details for PubMedCentralID PMC6518354

  • An engineered arginine-rich α-helical antimicrobial peptide exhibits broad-spectrum bactericidal activity against pathogenic bacteria and reduces bacterial infections in mice. Scientific reports Yang, C. H., Chen, Y. C., Peng, S. Y., Tsai, A. P., Lee, T. J., Yen, J. H., Liou, J. W. 2018; 8 (1): 14602

    Abstract

    The increase in the prevalence of antibiotic-resistant bacteria has become a major public health concern. Antimicrobial peptides (AMPs) are emerging as promising candidates addressing this issue. In this study, we designed several AMPs by increasing α-helical contents and positive charges and optimizing hydrophobicity and amphipathicity in the Sushi 1 peptide from horseshoe crabs. A neural network-based bioinformatic prediction tool was used for the first stage evaluations of peptide properties. Among the peptides designed, Sushi-replacement peptide (SRP)-2, an arginine-rich and highly α-helical peptide, showed broad-spectrum bactericidal activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and multidrug-resistant Acinetobacter baumannii; nevertheless, it showed little hemolytic and cytotoxic activity against mammalian cells. Atomic force microscopy results indicated that SRP-2 should interact directly with cell membrane components, resulting in bacterial cell death. SRP-2 also neutralized LPS-induced macrophage activation. Moreover, in an intraperitoneal multidrug-resistant A. baumannii infection mouse model, SRP-2 successfully reduced the bacterial number in ascitic fluid and tumor necrosis factor-α production. Our study findings demonstrate that bioinformatic calculations can be powerful tools to help design potent AMPs and that arginine is superior to lysine for providing positive charges for AMPs to exhibit better bactericidal activity and selectivity against bacterial cells.

    View details for DOI 10.1038/s41598-018-32981-3

    View details for PubMedID 30279591

    View details for PubMedCentralID PMC6168480

  • Current Mechanistic Concepts in Ischemia and Reperfusion Injury. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology Wu, M. Y., Yiang, G. T., Liao, W. T., Tsai, A. P., Cheng, Y. L., Cheng, P. W., Li, C. Y., Li, C. J. 2018; 46 (4): 1650-1667

    Abstract

    Ischemia-reperfusion injury is associated with serious clinical manifestations, including myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. Ischemia-reperfusion injury is a critical medical condition that poses an important therapeutic challenge for physicians. In this review article, we present recent advances focusing on the basic pathophysiology of ischemia-reperfusion injury, especially the involvement of reactive oxygen species and cell death pathways. The involvement of the NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system are also described. When the blood supply is re-established after prolonged ischemia, local inflammation and ROS production increase, leading to secondary injury. Cell damage induced by prolonged ischemia-reperfusion injury may lead to apoptosis, autophagy, necrosis, and necroptosis. We highlight the latest mechanistic insights into reperfusion-injury-induced cell death via these different processes. The interlinked signaling pathways of cell death could offer new targets for therapeutic approaches. Treatment approaches for ischemia-reperfusion injury are also reviewed. We believe that understanding the pathophysiology ischemia-reperfusion injury will enable the development of novel treatment interventions.

    View details for DOI 10.1159/000489241

    View details for PubMedID 29694958

  • Energy Homeostasis and Abnormal RNA Metabolism in Amyotrophic Lateral Sclerosis. Frontiers in cellular neuroscience Liu, Y. J., Tsai, P. Y., Chern, Y. 2017; 11: 126

    Abstract

    Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that is clinically characterized by progressive muscle weakness and impaired voluntary movement due to the loss of motor neurons in the brain, brain stem and spinal cord. To date, no effective treatment is available. Ample evidence suggests that impaired RNA homeostasis and abnormal energy status are two major pathogenesis pathways in ALS. In the present review article, we focus on recent studies that report molecular insights of both pathways, and discuss the possibility that energy dysfunction might negatively regulate RNA homeostasis via the impairment of cytoplasmic-nuclear shuttling in motor neurons and subsequently contribute to the development of ALS.

    View details for DOI 10.3389/fncel.2017.00126

    View details for PubMedID 28522961

    View details for PubMedCentralID PMC5415567

  • Therapeutic effects of human urocortin-1, -2 and -3 in intracerebral hemorrhage of rats. Neuropeptides Liew, H. K., Huang, L. C., Yang, H. I., Peng, H. F., Li, K. W., Tsai, A. P., Chen, S. Y., Kuo, J. S., Pang, C. Y. 2015; 52: 89-96

    Abstract

    Urocortin exerts neuroprotective effects in intracerebral hemorrhage (ICH) of rats. For pre-clinical trial, we intended to study the neuroprotective efficacy of human UCN (hUCN)-1, -2 and -3 in treating ICH rats. ICH was induced by infusing bacterial collagenase VII (0.23 U in sterile saline) to the striatum. The hUCN-1, -2, and -3 were administrated (2.5μg/kg, i.p.) at 1h after ICH insult, respectively. Neurological deficits were evaluated by modified Neurological Severity Scores. Brain edema and hematoma expansion was evaluated by coronal T2-WI and DWI magnetic resonance imaging on 1, 3, 6, 24, and 56h after ICH insult. Blood-brain barrier permeability was evaluated by Evans blue assay on day 3 after ICH. Brain lesion volume was evaluated by morphormetric measurement on day 7 after ICH. Our results demonstrated that the hUCN-1 significantly reduced hematoma, blood-brain barrier disruption and neurological deficits on day 3, and brain lesion volume on day 7 after ICH insult. The prediction of secondary structure of the hUCNs clarifies that the percentage of alpha-helix, random coil and extended strand between rat-UCN (rUCN)-1 and hUCN-1 are the same. The structure similarity between human- and rat-UCN-1 may be one of the reasons that both can exert similar therapeutic potential in ICH rats.

    View details for DOI 10.1016/j.npep.2015.05.004

    View details for PubMedID 26055808

  • L-type calcium channels in sympathetic α3β2-nAChR-mediated cerebral nitrergic neurogenic vasodilation. Acta physiologica (Oxford, England) Wu, C. Y., Lee, R. H., Chen, P. Y., Tsai, A. P., Chen, M. F., Kuo, J. S., Lee, T. J. 2014; 211 (4): 544-58

    Abstract

    Nicotine stimulation of α3β2-nicotinic acetylcholine receptors (α3β2-nAChRs) located on sympathetic nerves innervating basilar arteries causes calcium-dependent noradrenaline release, leading to activation of parasympathetic nitrergic nerves and dilation of basilar arteries. This study aimed to investigate the major subtype of calcium channels located on cerebral peri-vascular sympathetic nerves, which is involved in nicotine-induced α3β2-nAChR-mediated nitrergic vasodilation in basilar arteries.Nicotine- and transmural nerve stimulation (TNS)-induced dilation of isolated porcine basilar arteries was examined using in vitro tissue bath. Nicotine-induced calcium influx, nicotine-induced noradrenaline release and nicotine-induced inward currents were evaluated in rat superior cervical ganglion (SCG) neurones, peri-vascular sympathetic nerves of porcine basilar arteries and α3β2-nAChRs-expressing oocytes respectively. mRNA and protein expression of Cav 1.2 and Cav 1.3 channels were detected by RT-PCR, Western blotting and immunohistochemistry.Nicotine-induced vasodilation was not affected by ω-agatoxin TK (selective P/Q-type calcium channel blocker) or ω-conotoxin GVIA (N-type calcium channel blocker). The vasodilation, however, was inhibited by nicardipine (L-type calcium channel blocker) in concentrations which did not affect TNS-induced vasodilation, suggesting the specific blockade. Nicardipine concentration-dependently inhibited nicotine-induced calcium influx in rat SCG neurones and reduced nicotine-induced noradrenaline release from peri-vascular sympathetic nerves of porcine basilar arteries. Nicardipine (10 μm), which significantly blocked nicotine-induced vasorelaxation by 70%, did not appreciably affect nicotine-induced inward currents in α3β2-nAChRs-expressing oocytes. Furthermore, the mRNAs and proteins of Cav 1.2 and Cav 1.3 channels were expressed in porcine SCG and peri-vascular nerve terminals.The sympathetic neuronal calcium influx through L-type calcium channels is modulated by α3β2-nAChRs. This calcium influx causes noradrenaline release, initiating sympathetic-parasympathetic (axo-axonal) interaction-induced nitrergic dilation of porcine basilar arteries.

    View details for DOI 10.1111/apha.12315

    View details for PubMedID 24825168

  • STAT1 mediates oroxylin a inhibition of iNOS and pro-inflammatory cytokines expression in microglial BV-2 cells. PloS one Liu, P. W., Chen, M. F., Tsai, A. P., Lee, T. J. 2012; 7 (12): e50363

    Abstract

    Microglia-mediated inflammation is implicated in pathogenesis of neurodegenerative diseases. Oroxylin A, a flavonoid isolated from Scutellariae baicalensis, has been shown to ameliorate microglia activation-mediated neurodegeneration in vivo. The molecular mechanism underlying the inhibitory effects of oroxylin A on microglia activation, however, remains unknown. In the present study, effects of oroxylin A co-treated with lipopolysaccharide (LPS, 100 ng/ml) on LPS-induced activation of cultured microglial BV-2 cells were examined. Nitric oxide (NO) production was determined by Greiss method. Expression of inducible nitric oxide synthase (iNOS), interleukin (IL)-1β and IL-6 was assessed using real-time RT-PCR or Western blot analysis. Furthermore, activation of the nuclear factor κB (NFκB) and the signal transducer and activator of transcription 1 (STAT1) was examined by Western blot analysis and transcription factor DNA-binding activity assay. Our results indicated that oroxylin A (10-100 µM) in a concentration-dependent manner inhibited LPS-induced NO production via blocking iNOS expression at both mRNA and protein levels without affecting the degradation rate of iNOS mRNA. Moreover, oroxylin A significantly attenuated LPS-induced late expression (20 hours after LPS challenge) of IL-1β and IL-6. Furthermore, oroxylin A significantly suppressed LPS-induced JAK2-mediated STAT1 phosphorylation without affecting LPS-induced NFκB-p65 nuclear translocation or NFκB-p65 DNA-binding activity. This is consistent with the finding that AG490, a specific JAK2 inhibitor, significantly inhibited LPS-induced STAT1 phosphorylation with almost completely diminished iNOS expression. These results suggest that oroxylin A, via suppressing STAT1 phosphorylation, inhibits LPS-induced expression of pro-inflammatory genes in BV-2 microglial cells.

    View details for DOI 10.1371/journal.pone.0050363

    View details for PubMedID 23236370

    View details for PubMedCentralID PMC3516518