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Article ; Online: ACAT1/SOAT1 Blockade Suppresses LPS-Mediated Neuroinflammation by Modulating the Fate of Toll-like Receptor 4 in Microglia

Haibo Li / Thao N. Huynh / Michael Tran Duong / James G. Gow / Catherine C. Y. Chang / Ta Yuan Chang

International Journal of Molecular Sciences, Vol 24, Iss 5616, p

2023 Volume 5616

Abstract: Cholesterol is stored as cholesteryl esters by the enzymes acyl-CoA:cholesterol acyltransferases/sterol O:acyltransferases (ACATs/SOATs). ACAT1 blockade (A1B) ameliorates the pro-inflammatory responses of macrophages to lipopolysaccharides (LPS) and ... ...

Abstract	Cholesterol is stored as cholesteryl esters by the enzymes acyl-CoA:cholesterol acyltransferases/sterol O:acyltransferases (ACATs/SOATs). ACAT1 blockade (A1B) ameliorates the pro-inflammatory responses of macrophages to lipopolysaccharides (LPS) and cholesterol loading. However, the mediators involved in transmitting the effects of A1B in immune cells is unknown. Microglial Acat1/Soat1 expression is elevated in many neurodegenerative diseases and in acute neuroinflammation. We evaluated LPS-induced neuroinflammation experiments in control vs. myeloid-specific Acat1/Soat1 knockout mice. We also evaluated LPS-induced neuroinflammation in microglial N9 cells with and without pre-treatment with K-604, a selective ACAT1 inhibitor. Biochemical and microscopy assays were used to monitor the fate of Toll-Like Receptor 4 (TLR4), the receptor at the plasma membrane and the endosomal membrane that mediates pro-inflammatory signaling cascades. In the hippocampus and cortex, results revealed that Acat1/Soat1 inactivation in myeloid cell lineage markedly attenuated LPS-induced activation of pro-inflammatory response genes. Studies in microglial N9 cells showed that pre-incubation with K-604 significantly reduced the LPS-induced pro-inflammatory responses. Further studies showed that K-604 decreased the total TLR4 protein content by increasing TLR4 endocytosis, thus enhancing the trafficking of TLR4 to the lysosomes for degradation. We concluded that A1B alters the intracellular fate of TLR4 and suppresses its pro-inflammatory signaling cascade in response to LPS.
Keywords	cholesterol ; cholesteryl esters ; acyl-CoA:cholesterol acyltransferase ; sterol O-acyltransferase ; ACAT inhibitor ; lipid rafts ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	630
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity

Taylor C. Harned / Radu V. Stan / Ze Cao / Rajarshi Chakrabarti / Henry N. Higgs / Catherine C. Y. Chang / Ta Yuan Chang

International Journal of Molecular Sciences, Vol 24, Iss 5525, p

2023 Volume 5525

Abstract: Cholesterol is a key component of all mammalian cell membranes. Disruptions in cholesterol metabolism have been observed in the context of various diseases, including neurodegenerative disorders such as Alzheimer’s disease (AD). The genetic and ... ...

Abstract	Cholesterol is a key component of all mammalian cell membranes. Disruptions in cholesterol metabolism have been observed in the context of various diseases, including neurodegenerative disorders such as Alzheimer’s disease (AD). The genetic and pharmacological blockade of acyl-CoA:cholesterol acyltransferase 1/sterol O-acyltransferase 1 (ACAT1/SOAT1), a cholesterol storage enzyme found on the endoplasmic reticulum (ER) and enriched at the mitochondria-associated ER membrane (MAM), has been shown to reduce amyloid pathology and rescue cognitive deficits in mouse models of AD. Additionally, blocking ACAT1/SOAT1 activity stimulates autophagy and lysosomal biogenesis; however, the exact molecular connection between the ACAT1/SOAT1 blockade and these observed benefits remain unknown. Here, using biochemical fractionation techniques, we observe cholesterol accumulation at the MAM which leads to ACAT1/SOAT1 enrichment in this domain. MAM proteomics data suggests that ACAT1/SOAT1 inhibition strengthens the ER-mitochondria connection. Confocal and electron microscopy confirms that ACAT1/SOAT1 inhibition increases the number of ER-mitochondria contact sites and strengthens this connection by shortening the distance between these two organelles. This work demonstrates how directly manipulating local cholesterol levels at the MAM can alter inter-organellar contact sites and suggests that cholesterol buildup at the MAM is the impetus behind the therapeutic benefits of ACAT1/SOAT1 inhibition.
Keywords	cholesterol ; ACAT1 ; SOAT1 ; ACAT inhibitors ; endoplasmic reticulum ; mitochondria-associated membrane (MAM) ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Application of artificial intelligence algorithms and low-cost sensors to estimate respirable dust in the workplace

Ta-Yuan Chang / Guan-Yu Chen / Jing-Jie Chen / Li-Hao Young / Li-Te Chang

Environment International, Vol 182, Iss , Pp 108317- (2023)

2023

Abstract: The Internet of Things (IoT) and low-cost sensor technology have become common tools for environmental exposure monitoring; however, their application in measuring respirable dust (RD) in the workplace remains limited. This study aimed to develop a ... ...

Abstract	The Internet of Things (IoT) and low-cost sensor technology have become common tools for environmental exposure monitoring; however, their application in measuring respirable dust (RD) in the workplace remains limited. This study aimed to develop a predictive model for RD using artificial intelligence (AI) algorithms and low-cost sensors and subsequently assess its validity using a standard sampling approach. Various low-cost sensors were combined into an RD sensor module and mounted on a portable aerosol monitor (GRIMM 11-D) for two weeks. AI algorithms were used to capture data per minute over 14 days to establish predictive RD models. The best-fitting model was validated using an aluminum cyclone equipped with an air pump and polytetrafluoroethylene filters to sample the 8-hour RD for 5 days at an aircraft manufacturing company. This module was continuously monitored for two weeks to evaluate its stability. The RD concentration measured by GRIMM 11-D in a general outdoor environment over two weeks was 28.1 ± 16.1 μg/m3 (range: 2.4–85.3 μg/m3). Among the various established models, random forest regression was observed to have the best prediction capacity (R2 = 0.97 and root mean square error = 2.82 μg/m3) in comparison to the other 19 methods. Field-based validation revealed that the predicted RD concentration (35.9 ± 4.1 μg/m3, range: 32.7–42.9 μg/m3) closely approximated the results obtained by the traditional method (38.1 ± 8.9 μg/m3, range: 28.1–52.5 μg/m3), and a strong positive Spearman correlation was observed between the two (rs = 0.70). The average bias was −2.2 μg/m3 and the precision was 5.8 μg/m3, resulting in an accuracy of 6.2 μg/m3 (94.2 %). Data completeness was 99.7 % during the continuous two-week monitoring period. The developed sensor module of RD exhibited excellent predictive performance and good data stability that can be applied to exposure assessments in occupational epidemiological studies.
Keywords	Artificial intelligence ; Internet of things ; Low-cost sensor ; Random forest method ; Respirable dust ; Environmental sciences ; GE1-350
Subject code	333
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A simple method to disrupt and restore subunit interaction of acyl-CoA:cholesterol acyltransferase 1

Bryan Neumann / Catherine C.Y. Chang / Ta-Yuan Chang

MethodsX, Vol 6, Iss , Pp 2242-

2019 Volume 2247

Abstract: Acyl-CoA:cholestereol acyltransferase 1 (ACAT1) is a two-fold dimer (homotetramer) and has two distinct dimerization domains. One domain is in an alpha-helical rich region near the cytoplasmic N-terminus. The other is proposed to be near the C-terminus ... ...

Abstract	Acyl-CoA:cholestereol acyltransferase 1 (ACAT1) is a two-fold dimer (homotetramer) and has two distinct dimerization domains. One domain is in an alpha-helical rich region near the cytoplasmic N-terminus. The other is proposed to be near the C-terminus where multiple transmembrane domains promote hydrophobic interactions between two ACAT1 subunits. The truncation of the ACAT1 N-terminal dimerization domain, Δ1-65, creates a dimer which is fully enzymatically active. It is currently not known how the C-terminal dimerization domain contributes to ACAT1 enzymatic activity. Here we describe a simple method that dissociates ACAT1 dimers through the addition of the non-ionic detergents Triton X-100 or octyl glucoside which disrupt the C-terminal dimerization domain. We also document the protocols for a method to exchange Triton X-100 with CHAPS to restore C-terminal dimerization of the ACAT1 protein, and an optimized liposomal assay to assess ACAT enzymatic activity. • This method can be applied to dissociate ACAT1 subunits by using Triton X-100 or octyl glucoside. • ACAT1 dimerization can be restored by exchanging Triton X-100 with CHAPS. • The liposomal ACAT activity assay conditions have been optimized. Method name: Dissociation of ACAT1 subunits by non-ionic detergents, Keywords: ACAT1, SOAT1, Two-fold dimer, MBOAT, Quaternary structure, Liposomes, Transmembrane, Cholesterol, Enzyme activity, Detergent
Keywords	Science ; Q
Subject code	572
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Application of land-use regression models to estimate sound pressure levels and frequency components of road traffic noise in Taichung, Taiwan

Ta-Yuan Chang / Chih-Hsiang Liang / Chang-Fu Wu / Li-Te Chang

Environment International, Vol 131, Iss , Pp - (2019)

2019

Abstract: Few studies have applied land-use regression to predict road traffic noise exposure, and there are few predictive models for different frequencies. This study aimed to measure 24-h average road traffic noise levels and to analyze the frequency components ...

Abstract	Few studies have applied land-use regression to predict road traffic noise exposure, and there are few predictive models for different frequencies. This study aimed to measure 24-h average road traffic noise levels and to analyze the frequency components over one year to establish land-use regression models of noise exposure. Fifty monitoring stations were set up to conduct 3 measurements for A-weighted equivalent sound pressure levels over 24 h (Leq,24h) and night equivalent sound pressure levels (Lnight), as well as octave-band analyses, during the 2013–2014 period. Noise measurements were integrated with land-use types, road and traffic information, meteorological data and geographic information systems to construct land-use regression models. Leave-one-out cross-validation was performed to test the validity of the predictive models. The annual means of Leq,24h and Lnight were 66.4 ± 4.7 A-weighed decibels (dBA) and 62.1 ± 6.0 dBA, respectively. Octave-band frequency analyses revealed that the highest means over 24 h and at night were 61.4 ± 5.3 decibels (dB) and 56.7 ± 6.6 dB (both at 1000 Hz), respectively. The model-explained variance (R2) of the full-frequency noise was 0.83 for Leq,24h and 0.79 for Lnight. The R2 values for octave-band-frequency noise ranged from 0.67 to 0.88 for Leq,24h and 0.65 to 0.85 for Lnight, with the highest R2 at 250 Hz for Leq,24h and at 125 Hz for Lnight. The differences between the model R2 and the leave-one-out cross-validation R2 ranged from 5% to 15% for both Leq,24h and Lnight at all frequencies. In the validation, the root mean squared error was 2.09 dBA and 2.80 dBA for the full-frequency Leq,24 and Lnight, respectively, and ranged from 1.89 to 2.62 dB and from 2.51 to 3.28 dB for the octave-band-frequency Leq,24h and Lnight, respectively. This study observed that the annual means of the measured Leq,24h and Lnight in Taichung were both above 60 dBA and had the highest level at 1000 Hz. The developed land-use regression models of Leq,24 and Lnight both had good ...
Keywords	Environmental sciences ; GE1-350
Subject code	519
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Stealth Liposomes Encapsulating a Potent ACAT1/SOAT1 Inhibitor F12511

Adrianna L. De La Torre / Thao N. Huynh / Catherine C. Y. Chang / Darcy B. Pooler / Dylan B. Ness / Lionel D. Lewis / Sanjana Pannem / Yichen Feng / Kimberley S. Samkoe / William F. Hickey / Ta Yuan Chang

International Journal of Molecular Sciences, Vol 24, Iss 11013, p

Pharmacokinetic, Biodistribution, and Toxicity Studies in Wild-Type Mice and Efficacy Studies in Triple Transgenic Alzheimer’s Disease Mice

2023 Volume 11013

Abstract: Cholesterol is essential for cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is catalyzed by the enzymes acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 being the primary isoenzyme in most cells in ...

Abstract	Cholesterol is essential for cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is catalyzed by the enzymes acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 being the primary isoenzyme in most cells in humans. In Alzheimer’s Disease, CEs accumulate in vulnerable brain regions. Therefore, ACATs may be promising targets for treating AD. F12511 is a high-affinity ACAT1 inhibitor that has passed phase 1 safety tests for antiatherosclerosis. Previously, we developed a nanoparticle system to encapsulate a large concentration of F12511 into a stealth liposome (DSPE-PEG 2000 with phosphatidylcholine). Here, we injected the nanoparticle encapsulated F12511 (nanoparticle F) intravenously (IV) in wild-type mice and performed an HPLC/MS/MS analysis and ACAT enzyme activity measurement. The results demonstrated that F12511 was present within the mouse brain after a single IV but did not overaccumulate in the brain or other tissues after repeated IVs. A histological examination showed that F12511 did not cause overt neurological or systemic toxicity. We then showed that a 2-week IV delivery of nanoparticle F to aging 3xTg AD mice ameliorated amyloidopathy, reduced hyperphosphorylated tau and nonphosphorylated tau, and reduced neuroinflammation. This work lays the foundation for nanoparticle F to be used as a possible therapy for AD and other neurodegenerative diseases.
Keywords	ACAT1/SOAT1 ; nanoparticles ; Alzheimer’s disease ; cholesterol ; cholesteryl ester ; amyloid ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	572
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Climate change, air quality, and respiratory health

Jer-Hwa Chang / Yueh-Lun Lee / Li-Te Chang / Ta-Yuan Chang / Ta-Chih Hsiao / Kian Fan Chung / Kin Fai Ho / Han-Pin Kuo / Kang-Yun Lee / Kai-Jen Chuang / Hsiao-Chi Chuang

Annals of Medicine, Vol 55, Iss

a focus on particle deposition in the lungs

2023 Volume 2

Abstract: AbstractThis review article delves into the multifaceted relationship between climate change, air quality, and respiratory health, placing a special focus on the process of particle deposition in the lungs. We discuss the capability of climate change to ... ...

Abstract	AbstractThis review article delves into the multifaceted relationship between climate change, air quality, and respiratory health, placing a special focus on the process of particle deposition in the lungs. We discuss the capability of climate change to intensify air pollution and alter particulate matter physicochemical properties such as size, dispersion, and chemical composition. These alterations play a significant role in influencing the deposition of particles in the lungs, leading to consequential respiratory health effects. The review paper provides a broad exploration of climate change’s direct and indirect role in modifying particulate air pollution features and its interaction with other air pollutants, which may change the ability of particle deposition in the lungs. In conclusion, climate change may play an important role in regulating particle deposition in the lungs by changing physicochemistry of particulate air pollution, therefore, increasing the risk of respiratory disease development.
Keywords	Air pollution ; asthma ; children ; COPD ; extreme weather ; secondary organic aerosol ; Medicine ; R
Subject code	333
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Taylor & Francis Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Determination and Prediction of Respirable Dust and Crystalline-Free Silica in the Taiwanese Foundry Industry

Ching-Tang Kuo / Fen-Fen Chiu / Bo-Ying Bao / Ta-Yuan Chang

International Journal of Environmental Research and Public Health, Vol 15, Iss 10, p

2018 Volume 2105

Abstract: Background: Respirable crystalline silica (RCS) has been recognized as a human carcinogen; however, the measurement and analysis of RCS in small-scale foundries is rare and difficult. This study aimed to measure respirable dust and RCS levels among 236 ... ...

Abstract	Background: Respirable crystalline silica (RCS) has been recognized as a human carcinogen; however, the measurement and analysis of RCS in small-scale foundries is rare and difficult. This study aimed to measure respirable dust and RCS levels among 236 foundry workers in Taiwan and used these data to establish predictive models for personal exposure. Methods: Personal sampling of various production processes were measured gravimetrically and analyzed using the X-ray diffraction method. Multiple linear regression was used to establish predictive models. Results: Foundry workers were exposed to geometric means and geometric standard deviations of 0.52 ± 4.0 mg/m3 and 0.027 ± 15 mg/m3 for respirable dust and RCS, respectively. The highest exposure levels were observed among workers in the sand blasting process, with geometric means of 1.6 mg/m3 and 0.099 mg/m3 for respirable dust and RCS, respectively. The predictive exposure model for respirable dust fitted the data well (R2 = 0.75; adjusted R2 = 0.64), and the predictive capacity for RCS was higher (R2 = 0.89; adjusted R2 = 0.84). Conclusions: Foundry workers in the sand blasting process may be exposed to the highest levels of respirable dust and RCS. The developed models can be applied to predict respirable dust and RCS levels adequately in small-scale foundry workers for epidemiological studies.
Keywords	crystalline silica ; exposure assessment ; foundry industry ; predictive model ; respirable dust ; Medicine ; R
Subject code	670
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Investigation of Microenvironmental Exposures to Particle-Bound Polycyclic Aromatic Hydrocarbons for Elementary School Children

Chin-Sheng Tang / Shih-Chun Candice Lung / Ta-Yuan Chang / Han-Hsiang Tu / Li-Te Chang

International Journal of Environmental Research and Public Health, Vol 16, Iss 22, p

2019 Volume 4390

Abstract: Polycyclic aromatic hydrocarbons (PAHs) are formed when organic matters incompletely combust and get distributed into the air in the form of vapor or the particular phase of absorption or condensation on the surface of respirable particles. Certain PAHs ... ...

Abstract	Polycyclic aromatic hydrocarbons (PAHs) are formed when organic matters incompletely combust and get distributed into the air in the form of vapor or the particular phase of absorption or condensation on the surface of respirable particles. Certain PAHs are considered as carcinogenic and mutagenic, and are primarily associated with the particulate phase. Therefore, the characterization of exposure to particle-bound PAHs (p-PAHs) is critical to assessing the health risks in our daily life. A panel study was conducted during the years 2004 and 2005 to assess microenvironmental exposures to p-PAHs for elementary school children living in Taipei metropolitan area. During the study, integrated filter samples were collected by a dust monitor (model 1.108, Grimm) for 17 p-PAH species analysis using gas chromatography with mass spectrometry (GC/MS). The sampling durations were five days. Overall, 52 samples for children’s microenvironmental exposures were included in the data analysis. Results showed that geometric mean (GM) levels (and geometric standard deviation) of p-PAH exposures were 4.443 (3.395) ng/m 3 for children. The top three highest proportions of p-PAH components were indeno[1,2,3-cd]pyrene (IND) (21.7%), benzo[g,h,i]perylene (BghiP) (18.5%), and dibenz[a,h]anthracene (DBA) (9.1%), all of which are 5- or 6-ring p-PAHs. In addition, results from diagnostic ratios and principal component analysis (PCA) found that traffic pollution, incense burning, and cooking emission were the major p-PAH exposure sources for children. The total benzo[a]pyrene equivalent (BaPeq) concentration was 1.07 ± 0.80 ng/m 3 (mean ± standard deviation), with a GM of 0.84 ng/m 3 . The GM value of the inhalation carcinogenic risk was 7.31 × 10 −5 with the range of 2.23 × 10 −5 to 3.11 × 10 −4 , which was higher than the U.S. Environmental Protection Administration guideline limit of 10 −6 . DBA accounted for 45.1% of the excess cancer risk, followed by benzo[a]pyrene (BaP) (33.5%) and IND (10.7%). In conclusion, the current study ...
Keywords	particle-bound polycyclic aromatic hydrocarbons ; microenvironmental exposure ; elementary school children ; benzo[a]pyrene equivalent concentration ; risk assessment ; Medicine ; R
Subject code	333
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor

Chengcheng Guan / Yange Niu / Si-Cong Chen / Yunlu Kang / Jing-Xiang Wu / Koji Nishi / Catherine C. Y. Chang / Ta-Yuan Chang / Tuoping Luo / Lei Chen

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 11

Abstract: Sterol O-acyltransferase 1 (SOAT1, also named ACAT1) is an endoplasmic reticulum resident enzyme which catalyzes the esterification of cholesterol to generate cholesteryl esters. Here, authors report cryo-EM structures of human SOAT1 which reveal the ... ...

Abstract	Sterol O-acyltransferase 1 (SOAT1, also named ACAT1) is an endoplasmic reticulum resident enzyme which catalyzes the esterification of cholesterol to generate cholesteryl esters. Here, authors report cryo-EM structures of human SOAT1 which reveal the binding site of the competitive inhibitor CI-976.
Keywords	Science ; Q
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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