Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Myelin Debris-Treated Microglial Cell Lines Activates the Gene Expression of Cholesterol Efflux Transporter ABCA1.

Aging is the major risk factor for Alzheimer's disease (AD). In the aged brain, myelin debris accumulates and is cleared by microglia. Phagocytosed myelin debris increases neutral lipid droplet content in microglia. Neutral lipids include cholesteryl esters (CE) and triacylglycerol (TAG). To examine the effects of myelin debris on neutral lipid content in microglia, we added myelin debris to human HMC3 and mouse N9 cells. The results obtained when using 3H-oleate as a precursor in intact cells reveal that myelin debris significantly increases the biosynthesis of CE but not TAG. Mass analyses have shown that myelin debris increases both CE and TAG. The increase in CE biosynthesis was abolished using inhibitors of the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1). ACAT1 inhibitors are promising drug candidates for AD treatment. In myelin debris-loaded microglia, treatment with two different ACAT1 inhibitors, K604 and F12511, increased the mRNA and protein content of ATP-binding cassette subfamily A1 (ABCA1), a protein that is located at the plasma membrane and which controls cellular cholesterol disposal. The effect of the ACAT1 inhibitor on ABCA1 was abolished by preincubating cells with the liver X receptor (LXR) antagonist GSK2033. We conclude that ACAT1 inhibitors prevent the accumulation of cholesterol and CE in myelin debris-treated microglia by activating ABCA1 gene expression via the LXR pathway.

Characterization of Stealth Liposome-Based Nanoparticles Encapsulating the ACAT1/SOAT1 Inhibitor F26: Efficacy and Toxicity Studies In Vitro and in Wild-Type Mice.

Cholesterol homeostasis is pivotal for cellular function. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), also abbreviated as SOAT1, is an enzyme responsible for catalyzing the storage of excess cholesterol to cholesteryl esters. ACAT1 is an emerging target to treat diverse diseases including atherosclerosis, cancer, and neurodegenerative diseases. F12511 is a high-affinity ACAT1 inhibitor. Previously, we developed a stealth liposome-based nanoparticle to encapsulate F12511 to enhance its delivery to the brain and showed its efficacy in treating a mouse model for Alzheimer's disease (AD). In this study, we introduce F26, a close derivative of F12511 metabolite in rats. F26 was encapsulated in the same DSPE-PEG2000/phosphatidylcholine (PC) liposome-based nanoparticle system. We employed various in vitro and in vivo methodologies to assess F26's efficacy and toxicity compared to F12511. The results demonstrate that F26 is more effective and durable than F12511 in inhibiting ACAT1, in both mouse embryonic fibroblasts (MEFs), and in multiple mouse tissues including the brain tissues, without exhibiting any overt systemic or neurotoxic effects. This study demonstrates the superior pharmacokinetic and safety profile of F26 in wild-type mice, and suggests its therapeutic potential against various neurodegenerative diseases including AD.

Personal Exposure to Sulfuric Acid in the Electroplating Industry: Development and Validation of a Predictive Model.

This study aimed to measure personal exposure to sulfuric acid in the electroplating industry to establish a predictive model and test its validation. We collected indoor air parameters and related information from four electroplating plants. Silica gel sorbents were used to collect air samples using high-performance ion chromatography. We collected air samples from three plants (i.e., Plant B, Plant C, and Plant D) and applied multiple linear regressions to build a predictive model. Eight samples collected from the fourth plant (i.e., Plant A) were used to validate the model. A total of 41 samples were collected with a mean of 25.0 ± 9.8 µg/m3 (range 12.1-51.7 µg/m3) in this study, including Plant A (8 samples, 17.5 ± 2.8 µg/m3, 13.0-22.0 µg/m3), Plant B (11 samples, 36.5 ± 9.7 µg/m3, 23.1-51.7 µg/m3), Plant C (11 samples, 16.4 ± 1.7 µg/m3, 12.1-17.8 µg/m3), and Plant D (11 samples, 27.4 ± 1.7 µg/m3, 24.1-29.9 µg/m3). Plant B was significantly higher in sulfuric acid than the other plants. Workers from the electroplating process plants were exposed to sulfuric acid at 29.0 ± 11.5 µg/m3. The predictive model for personal exposure to sulfuric acid fit the data well (r2 = 0.853; adjusted r2 = 0.837) and had an accuracy of 5.52 µg/m3 (bias ± precision; 4.98 ± 2.38 µg/m3), validated by the personal sampling of the fourth plant. This study observed that sulfuric acid exposure was lower than the permissible exposure level of 1000 µg/m3 in Taiwan and the United States, and only two samples were lower than the European Union standard of 50 µg/m3. The developed model can be applied in epidemiological studies to predict personal exposure to sulfuric acid in plants using electroplating.

Exposure and health risk assessment of volatile organic compounds among drivers and passengers in long-distance buses.

Exposure to volatile organic compounds (VOCs) such as benzene, toluene, ethylbenzene, xylene, and formaldehyde from long-distance buses has been reported to adversely affect human health. This study investigates the concentrations of these five VOCs and evaluates their health risks to drivers and passengers on board. Ten trips from Taipei to Taichung were performed during the warm and cold seasons of 2021-2022. Two locations inside the bus were established to collect air samples by a 6-liter canister for drivers and passengers. Exposure concentrations of benzene, toluene, ethylbenzene, and xylene were analyzed via gas chromatography with a flame ionization detector and the formaldehyde concentration was monitored using a formaldehyde meter. Subsequently, a Monte Carlo simulation was conducted to evaluate the carcinogenic and non-carcinogenic risks of the five VOCs. Formaldehyde emerged as the highest detected compound (9.06 ± 3.77 µg/m3), followed by toluene (median: 6.11 µg/m3; range: 3.86-14.69 µg/m3). In particular, formaldehyde was identified to have the significantly higher concentration during non-rush hours (10.67 ± 3.21 µg/m3) than that during rush hours (7.45 ± 3.41 µg/m3) and during the warm season (10.71 ± 2.97 µg/m3) compared with that during the cold season (7.41 ± 4.26 µg/m3). Regarding non-carcinogenic risks to drivers and passengers, the chronic hazard indices for these five VOCs were under 1 to indicate an acceptable risk. In terms of carcinogenic risk, the median risks of benzene and formaldehyde for drivers were 2.88 × 10-6 (95% confidence interval [CI]: 2.11 × 10-6 - 5.13 × 10-6) and 1.91 × 10-6 (95% CI: 4.54 × 10-7 - 3.44 × 10-6), respectively. In contrast, the median carcinogenic risks of benzene and formaldehyde for passengers were less than 1 × 10-6 to present an acceptable risk. This study suggests that benzene and formaldehyde may present carcinogenic risks for drivers. Moreover, the non-carcinogenic risk for drivers and passengers is deemed acceptable. We recommended that the ventilation frequency be increased to mitigate exposure to VOCs in long-distance buses.

Impact of occupational noise exposure on the hearing level in hospital staffs: a longitudinal study.

The study aimed to evaluate the impact of occupational noise on hearing loss among healthcare workers using audiometry. A longitudinal study was conducted with a six-month follow-up period in a hospital with 21 participants, divided into high-noise-exposure (HNE) and low-noise-exposure (LNE) groups. Mean noise levels were higher in the HNE group (70.4 ± 4.5 dBA), and hearing loss was measured using pure-tone audiometry at baseline and follow-up. The HNE group had significantly higher mean threshold levels at frequencies of 0.25 kHz, 0.5 kHz, 4.0 kHz, and an average of 0.5, 1, 2, and 4 kHz (all p-values < 0.05) after the follow-up period. After adjusting for confounding factors, the HNE group had significantly higher hearing loss levels at 0.25 kHz, 0.5 kHz, and average frequencies of 0.5, 1, 2, and 4 kHz compared to the LNE group at the second measurement. Occupational noise levels above 65 dBA over six months were found to cause significant threshold changes at frequencies of 0.25 kHz, 0.5 kHz, and an average of 0.5-4.0 kHz. This study highlights the risk of noise-induced hearing loss among healthcare workers and emphasizes the importance of implementing effective hearing conservation programs in the workplace. Regular monitoring and assessment of noise levels and hearing ability, along with proper use of personal protective equipment, are crucial steps in mitigating the impact of occupational noise exposure on the hearing health of healthcare workers.

Application of artificial intelligence algorithms and low-cost sensors to estimate respirable dust in the workplace.

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.

Climate change, air quality, and respiratory health: a focus on particle deposition in the lungs.

This 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.

Climate change influences particle deposition in the lungs by modifying the physicochemical properties of particulate air pollution, thereby escalating the risk of respiratory disease development.It is crucial for healthcare providers to educate patients about the relationship between climate change and respiratory health.People with conditions such as asthma, COPD, and allergies must understand how changes in weather, air pollution, and allergens can exacerbate their symptoms.Instruction on understanding air quality indices and pollen predictions, along with recommendations on adapting everyday activities and medication regimens in response, is essential.

The impact of air pollution on respiratory diseases in an era of climate change: A review of the current evidence.

The impacts of climate change and air pollution on respiratory diseases present significant global health challenges. This review aims to investigate the effects of the interactions between these challenges focusing on respiratory diseases. Climate change is predicted to increase the frequency and intensity of extreme weather events amplifying air pollution levels and exacerbating respiratory diseases. Air pollution levels are projected to rise due to ongoing economic growth and population expansion in many areas worldwide, resulting in a greater burden of respiratory diseases. This is especially true among vulnerable populations like children, older adults, and those with pre-existing respiratory disorders. These challenges induce inflammation, create oxidative stress, and impair the immune system function of the lungs. Consequently, public health measures are required to mitigate the effects of climate change and air pollution on respiratory health. The review proposes that reducing greenhouse gas emissions contribute to slowing down climate change and lessening the severity of extreme weather events. Enhancing air quality through regulatory and technological innovations also helps reduce the morbidity of respiratory diseases. Moreover, policies and interventions aimed at improving healthcare access and social support can assist in decreasing the vulnerability of populations to the adverse health effects of air pollution and climate change. In conclusion, there is an urgent need for continuous research, establishment of policies, and public health efforts to tackle the complex and multi-dimensional challenges of climate change, air pollution, and respiratory health. Practical and comprehensive interventions can protect respiratory health and enhance public health outcomes for all.

Stealth Liposomes Encapsulating a Potent ACAT1/SOAT1 Inhibitor F12511: Pharmacokinetic, Biodistribution, and Toxicity Studies in Wild-Type Mice and Efficacy Studies in Triple Transgenic Alzheimer's Disease Mice.

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-PEG2000 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.

Associations of particulate matter, gaseous pollutants, and road traffic noise with the prevalence of asthma in children.

The purposes of this study were to elucidate the associations between exposure to particulate matter, gaseous pollutants, and road traffic noise and asthma prevalence and to determine the interaction between exposure to multiple pollutants and asthma in children. A total of 3,246 children were recruited from 11 kindergartens in New Taipei City, Taiwan. Land use regression (LUR) was used to establish predictive models for estimating individual exposure levels of particulate matter, gaseous pollutants, and the 24 h A-weighted equivalent sound pressure level (LAeq,24). Multiple logistic regression was performed to test the associations between exposure to these environmental factors and asthma prevalence in children. Multiple-exposure models revealed that an interquartile-range (IQR) increase in PM2.5 (1.17 µg/m3) and PM10 (10.69 µg/m3) caused a 1.34-fold (95% confidence interval [CI] = 1.05-1.70) and 1.17-fold (95% CI = 1.01-1.36) increase in risk of asthma prevalence in children after adjusting for LAeq,24 and NO2. Co-exposure to PM2.5, LAeq,24, and O3, SO2, or CO, as well as co-exposure to PM10, LAeq,24, and CO produced similar findings. Only exposure to one IQR of SO2 (0.15 ppb) was observed a significant association (odds ratio = 1.16, 95% CI = 1.00-1.34) with the asthma prevalence in children after adjusting for PM10 and LAeq,24. Exposure to PM2.5, PM10, and SO2 may be associated with a higher asthma prevalence in children, while other gaseous pollutants and road traffic noise did not demonstrate significant associations. The interaction of exposure to air pollutants and road traffic noise on asthma prevalence in children was not observed in this study.

Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity.

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.

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

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.

Associations of road traffic noise and its frequency spectrum with prevalent depression in Taichung, Taiwan.

Introduction: Exposure to road traffic noise has been reported to be associated with depression in many epidemiological studies, but the association between noise frequency spectrum and depression remains unclear. This community-based study investigated the associations between road traffic noise exposure and its frequency components with prevalent depression. Methods: A total of 3,191 residents living in Taichung who participated in the Taiwan Biobank between 2010 and 2017, were included as study participants. The land-use regression models were used to evaluate individual annual average values of A-weighted equivalent sound level over 24 h (Leq,24h) and particulate matter with an aerodynamic diameter <2.5 µm (PM2.5) using the geographic information system. Multiple logistic regression was applied to estimate the odds ratios (ORs) for depression after adjusting for potential risk factors and PM2.5. Results: An interquartile range increase in Leq,24h at full frequency (4.7 dBA), 1,000 Hz (5.2 dB), and 2,000 Hz (4.8 dB) was significantly associated with an elevated risk for depression with ORs of 1.62 (95% confidence interval [CI]: 1.03, 2.55), 1.58 (95% CI: 1.05, 2.37), and 1.58 (95% CI:1.03, 2.43), respectively, by controlling for PM2.5. The high-exposure group (≥3rd quartile median of noise levels) at full frequency, 1,000 Hz, and 2,000 Hz had an increased risk for depression with ORs of 2.65 (95% CI: 1.16-6.05), 2.47 (95% CI: 1.07-5.70), and 2.60 (95% CI: 1.10-6.12), respectively, compared with the reference group (<1st quartile of noise levels) after adjustment for PM2.5. Significant exposure-response trends were observed between the prevalent depression and noise exposure by quartiles at full frequency, 1,000 Hz, and 2,000 Hz (all p < 0.05). Conclusion: Exposure to road traffic noise may be associated with an increased prevalence of depression, particularly at 1,000 and 2,000 Hz.

Ambient relative humidity-dependent obstructive sleep apnea severity in cold season: A case-control study.

BACKGROUND: The objective of this study was to examine associations of daily averages and daily variations in ambient relative humidity (RH), temperature, and PM2.5 on the obstructive sleep apnea (OSA) severity. METHODS: A case-control study was conducted to retrospectively recruit 8628 subjects in a sleep center between January 2015 and December 2021, including 1307 control (apnea-hypopnea index (AHI) < 5 events/h), 3661 mild-to-moderate OSA (AHI of 5-30 events/h), and 3597 severe OSA subjects (AHI > 30 events/h). A logistic regression was used to examine the odds ratio (OR) of outcome variables (daily mean or difference in RH, temperature, and PM2.5 for 1, 7, and 30 days) with OSA severity (by the groups). Two-factor logistic regression models were conducted to examine the OR of RH with the daily mean or difference in temperature or PM2.5 with OSA severity. An exposure-response relationship analysis was conducted to examine the outcome variables with OSA severity in all, cold and warm seasons. RESULTS: We observed associations of mean PM2.5 and RH with respective increases of 0.04-0.08 and 0.01-0.03 events/h for the AHI in OSA patients. An increase in the daily difference of 1 % RH increased the AHI by 0.02-0.03 events/h in OSA patients. A daily PM2.5 decrease of 1 µg/m3 reduced the AHI by 0.03 events/h, whereas a daily decrease in the RH of 1 % reduced the AHI by 0.03-0.04 events/h. The two-factor model confirmed the most robust associations of ambient RH with AHI in OSA patients. The exposure-response relationship in temperature and RH showed obviously seasonal patterns with OSA severity. CONCLUSION: Short-term ambient variations in RH and PM2.5 were associated with changes in the AHI in OSA patients, especially RH in cold season. Reducing exposure to high ambient RH and PM2.5 levels may have protective effects on the AHI in OSA patients.

Exposure and health risk assessment of indoor volatile organic compounds in a medical university.

Many volatile organic compounds (VOCs) are used for experiments at universities, and most of them contain benzene, toluene, ethylbenzene, xylene, and an extraction solvent of dichloromethane. This study aimed to investigate the indoor concentrations of these five compounds in different locations on campus and to evaluate possible health risks for faculty members and students in a medical university. We selected 10 locations as sampling sites to conduct 4-h monitoring sessions on weekdays each season during 2019-2020. We used a 6-liter canister to collect air samples and analyzed these five VOCs via gas chromatography with a flame ionization detector. Monte Carlo simulation was performed to evaluate the carcinogenic and noncarcinogenic risks of these five VOCs. We found that dichloromethane was the most highly detected compound (median: 621.07 µg/m3; range: 44.01-8523.91 µg/m3), and the Department of Medicine had the highest concentration of the total of these VOCs among all of the locations (median: 5595.29 µg/m3; range: 1565.67-7398.66 µg/m3). The median carcinogenic risks of dichloromethane and benzene were 6.36 × 10-5 (95% confidence interval [CI]: 6.83 × 10-6-7.37 × 10-4) and 5.47 × 10-6 (95% CI: 4.03 × 10-7-2.42 × 10-5), respectively, for faculty members, and the lower risks of 3.14 × 10-5 (95% CI: 3.39 × 10-6-3.64 × 10-4) and 2.69 × 10-6 (95% CI: 1.97 × 10-7-1.19 × 10-5) were estimated for the students. The chronic noncarcinogenic risks of four VOCs were less than one, except for dichloromethane with a median hazard index of 1.92 (95% CI: 2.11 × 10-1-2.22 × 101). This study observed the spatial variation in the concentrations of the total of five VOCs and dichloromethane. The carcinogenic risks were classified as being at the possible level, and the noncarcinogenic risk of dichloromethane was greater than the acceptable level. Increasing local exhaust ventilation during the experiment and reducing the using amount of dichloromethane are recommended actions to reduce VOCs exposures in the medical university.

Acat1/Soat1 knockout extends the mutant Npc1 mouse lifespan and ameliorates functional deficiencies in multiple organelles of mutant cells.

Multiple membrane organelles require cholesterol for proper function within cells. The Niemann-Pick type C (NPC) proteins export cholesterol from endosomes to other membrane compartments, including the endoplasmic reticulum (ER), plasma membrane (PM), trans-Golgi network (TGN), and mitochondria, to meet their cholesterol requirements. Defects in NPC cause malfunctions in multiple membrane organelles and lead to an incurable neurological disorder. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), a resident enzyme in the ER, converts cholesterol to cholesteryl esters for storage. In mutant NPC cells, cholesterol storage still occurs in an NPC-independent manner. Here we report the interesting finding that in a mutant Npc1 mouse (Npc1nmf), Acat1 gene (Soat1) knockout delayed the onset of weight loss, motor impairment, and Purkinje neuron death. It also improved hepatosplenic pathology and prolonged lifespan by 34%. In mutant NPC1 fibroblasts, ACAT1 blockade (A1B) increased cholesterol content associated with TGN-rich membranes and mitochondria, while decreased cholesterol content associated with late endosomes. A1B also restored proper localization of syntaxin 6 and golgin 97 (key proteins in membrane trafficking at TGN) and improved the levels of cathepsin D (a key protease in lysosome and requires Golgi/endosome transport for maturation) and ABCA1 (a key protein controlling cholesterol release at PM). This work supports the hypothesis that diverting cholesterol from storage can benefit multiple diseases that involve cholesterol deficiencies in cell membranes.

The impacts of ambient relative humidity and temperature on supine position-related obstructive sleep apnea in adults.

Obstructive sleep apnea (OSA) is associated with seasonal variations. The objective of this study was to examine associations of ambient relative humidity (RH) and temperature on sleep parameters. We conducted a cross-sectional study by retrospectively recruiting 5204 adults from a sleep center in Taipei, Taiwan. Associations of 1-night polysomnography with ambient RH and temperature in 1-day, 7-day, 1-month, 6-month, and 1-year averages were examined using linear regression models and a mediation analysis. RH increase was associated with snoring index decrease and apnea/hypopnea index (AHI) increase. Temperature increase was associated with decreases in sleep efficiency and the AHI, and increases in the wake time after sleep onset and snoring index. RH increase was inversely associated with non-rapid eye movement (NREM) sleep stage I (N1), III (N3), and rapid eye movement (REM) sleep, but positively associated with the NREM sleep stage II (N2) stage. Temperature increase was associated with N1, N2, and N3 sleep. An increase in RH was associated with an increase in the arousal index and a decrease in the < 95% arterial oxygen saturation (SaO2) among total, REM, and NREM sleep, whereas a temperature increase was associated with a decrease in the arousal index and an increase in < 95% SaO2 among total, REM, and NREM sleep. An increase in RH was associated with increases in the time spent in a supine posture and the supine AHI. An increase in temperature was associated with decreases in the supine posture, supine AHI, and non-supine AHI. The N3 sleep stage was an important mediator in increasing the supine AHI with a long-term increase in RH. But the N1 and N2 sleep stages mediated a decrease in the supine AHI with an increase in RH. In conclusion, ambient RH and temperature were associated with alterations in sleep parameters in adults, which were mediated by the sleep cycle. An understanding of outdoor environments has important implications for diagnostic classifications in the supine dominance of OSA in adults.

Air pollution associated with cognitive decline by the mediating effects of sleep cycle disruption and changes in brain structure in adults.

The effects of air pollution on sleep and dementia remain unclear. The objective of this study was to investigate the effects of air pollution on cognitive function as mediated by the sleep cycle. A cross-sectional study design was conducted to recruit 4866 subjects on which PSG had been performed. Fifty of them were further given a cognitive function evaluation by the MMSE and CASI as well as brain images by CT and MRI. Associations of 1-year air pollution parameters with sleep parameters, cognitive function, and brain structure were examined. We observed that O3 was associated with a decrease in arousal, an increase in the N1 stage, and a decrease in the N2 stage of sleep. NO2 was associated with an increase in the N1 stage, a decrease in the N2 stage, and an increase in REM. PM2.5 was associated with a decrease in the N1 stage, increases in the N2 and N3 stages, and a decrease in REM. The N1 and N2 stages were associated with cognitive decline, but REM was associated with an increase in cognitive function. The N1 stage was a mediator of the effects of PM2.5 on the concentration domain of the MMSE. O3 was associated with an increase in the pars orbitalis volume of the left brain. NO2 was associated with increases in the rostral middle frontal volume, supramarginal gyrus volume, and transverse temporal volume of the left brain, and the pars opercularis volume of the right brain. PM2.5 was associated with increases in the pars triangularis volume of the left brain and the fusiform thickness of the right brain. In conclusion, we observed that air pollution was associated with cognitive decline by mediating effects on the sleep cycle with changes in the brain structure in controlling executive, learning, and language functions in adults.

Association of long-term indoor exposure to fine particles with pulmonary effects in Northern Taiwan.

An association between short-term indoor exposure to fine particles (PM2.5) and acute respiratory effects has been reported. It is still unclear whether long-term indoor exposure to PM2.5 is associated with pulmonary events. This study recruited 1023 healthy adult homeworkers to conduct a prospective observational study from 2010 to 2021. Four repeated home visits per year were conducted for each participant to measure 24-hour PM2.5 and peak expiratory flow rate (PEFR) and to collect blood samples for absolute eosinophil count (AEC) and carcinoembryonic antigen (CEA) analysis. Additionally, a questionnaire related to personal characteristics, health status and home characteristics was conducted for each participant. The mixed-effects models showed a significant association of PM2.5 with increased CEA and AEC and decreased % predicted PEFR. No significant association between low-level PM2.5 exposure (10-year mean level < 10 µg/m3) and adverse pulmonary effects was observed. The present study concluded that long-term indoor exposure to PM2.5 at a concentration higher than 10 µg/m3 was associated with adverse pulmonary effects among healthy adult homeworkers.

Facile method to incorporate high-affinity ACAT/SOAT1 inhibitor F12511 into stealth liposome-based nanoparticle and demonstration of its efficacy in blocking cholesteryl ester biosynthesis without overt toxicity in neuronal cell culture.

BACKGROUND: Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been considered as potential therapeutic agents to treat several diseases, including Alzheimer's disease, atherosclerosis, and cancer. While many ACAT inhibitors are readily available, methods to encapsulate them as nanoparticles have not been reported. NEW METHOD: We report a simple method to encapsulate ACAT inhibitors, using the potent hydrophobic ACAT inhibitor F12511 as an example. By mixing DSPE-PEG2000, egg phosphatidylcholine (PC), and F12511 in ethanol, followed by drying, resuspension and sonication in buffer, we show that F12511 can be encapsulated as stealth liposomes at high concentration. RESULTS: We successfully incorporated F12511 into nanoparticles and found that increasing PC in the nanoparticles markedly increased the amount of F12511 incorporated in stealth liposomes. The nanoparticles containing F12511 (Nanoparticle F) exhibit average size of approximately 200 nm and are stable at 4 ºC for at least 6 months. Nanoparticle F is very effective at inhibiting ACAT in human and mouse neuronal and microglial cell lines. Toxicity tests using mouse primary neuronal cells show that F12511 alone or Nanoparticle F added at concentrations from 2 to 10 µM for 24-, 48-, and 72-hours produces minimal, if any, toxicity. COMPARISON WITH EXISTING METHOD(S): Unlike existing methods, the current method is simple, cost effective, and can be expanded to produce tagged liposomes to increase specificity of delivery. This also offers opportunity to embrace water soluble agent(s) within the aqueous compartment of the nanoparticles for potential combinatorial therapy. CONCLUSIONS: This method shows promise for delivery of hydrophobic ACAT inhibitors at high concentration in vivo.