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High-valent iron (Fe(IV/V/VI)) has been widely applied in water decontamination. However, common Fe(II)-activating oxidants including hydrogen peroxide (H2O2) and persulfate react slowly with Fe(II) and exhibit low selectivity for Fe(IV) production due to the cogeneration of radicals. Herein, we report peroxyacids (POAs; R-C(O)OOH) that can react with Fe(II) more than 3 orders of magnitude faster than H2O2, with high selectivity for Fe(IV) generation. Rapid degradation of bisphenol A (BPA, an endocrine disruptor) was achieved by the combination of Fe(II) with performic acid (PFA), peracetic acid (PAA), or perpropionic acid (PPA) within one second. Experiments with phenyl methyl sulfoxide (PMSO) and tert-butyl alcohol (TBA) revealed Fe(IV) as the major reactive species in all three Fe(II)-POA systems, with a minor contribution of radicals (i.e., •OH and R-C(O)O•). To understand the exceptionally high reactivity of POAs, a detailed computational comparison among the Fenton-like reactions with step-by-step thermodynamic evaluation was conducted. The high reactivity is attributed to the lower energy barriers for O-O bond cleavage, which is determined as the rate-limiting step for the Fenton-like reactions, and the thermodynamically favorable bidentate binding pathway of POA with iron. Overall, this study advances knowledge on POAs as novel Fenton-like reagents and sheds light on computational chemistry for these systems.

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Age-related macular degeneration (AMD) causes severe blindness in the elderly due to choroidal neovascularization (CNV), which results from the dysfunction of the retinal pigment epithelium (RPE). While normal RPE depends exclusively on mitochondrial oxidative phosphorylation for energy production, the inflammatory conditions associated with metabolic reprogramming of the RPE play a pivotal role in CNV. Although mitochondrial pyruvate dehydrogenase kinase (PDK) is a central node of energy metabolism, its role in the development of CNV in neovascular AMD has not been investigated. In the present study, we used a laser-induced CNV mouse model to evaluate the effects of Pdk4 gene ablation and treatment with pan-PDK or specific PDK4 inhibitors on fluorescein angiography and CNV lesion area. Among PDK isoforms, only PDK4 was upregulated in the RPE of laser-induced CNV mice, and Pdk4 gene ablation attenuated CNV. Next, we evaluated mitochondrial changes mediated by PDK1-4 inhibition using siRNA or PDK inhibitors in inflammatory cytokine mixture (ICM)-treated primary human RPE (hRPE) cells. PDK4 silencing only in ICM-treated hRPE cells restored mitochondrial respiration and reduced inflammatory cytokine secretion. Likewise, GM10395, a specific PDK4 inhibitor, restored oxidative phosphorylation and decreased ICM-induced upregulation of inflammatory cytokine secretion. In a laser-induced CNV mouse model, GM10395 significantly alleviated CNV. Taken together, we demonstrate that specific PDK4 inhibition could be a therapeutic strategy for neovascular AMD by preventing mitochondrial metabolic reprogramming in the RPE under inflammatory conditions.

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Objective: To investigate temporal trends in mortality rates and underlying causes of death in persons with disabilities before and during the coronavirus disease 2019 (COVID-19) pandemic. Methods: Annual mortality rates and causes of death were analyzed using data covering the 2017-2022 period. Results: The mortality rate among people with disabilities increased from 2017 to 2022; the rate was five times higher during COVID-19 in this population than in the general population. When analyzing the cause of death, the incidence of infectious diseases and tuberculosis decreased after COVID-19. In contrast, the incidence of other bacillary disorders (A30-A49) increased. The incidence of respiratory system diseases (J00-J99), influenza and pneumonia (J09-J18), and other acute lower respiratory infections (J20-J22) decreased before COVID-19, while the incidence of lung diseases due to external agents (J60-J70), other respiratory diseases principally affecting the interstitium (J80-J84), and other diseases of the pleura (J90-J94) increased during the pandemic. The risk of COVID-19 death among people with disabilities was 1.1-fold higher for female patients (95% CI = 1.06-1.142), 1.41-fold for patients aged 70 years and older (95% CI = 1.09-1.82), and 1.24-fold higher for people with severe disabilities (95% CI = 1.19-1.28). Conclusions: The mortality rate in people with disabilities significantly increased during COVID-19, compared with that before the pandemic. People with disabilities had a higher mortality rate during COVID-19 compared with the general population. Risk factors must be reduced to prevent high mortality rates in this population.

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Excessive reactive oxygen species (ROS) in cellular environments leads to oxidative stress, which underlies numerous diseases, including inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, and cancer. Oxidative stress can be particularly damaging to biological membranes such as those found in mitochondria, which are abundant with polyunsaturated fatty acids (PUFAs). Oxidation of these biological membranes results in concomitant disruption of membrane structure and function, which ultimately leads to cellular dysfunction. Graphene quantum dots (GQDs) have garnered significant interest as a therapeutic agent for numerous diseases that are linked to oxidative stress. Specifically, GQDs have demonstrated an ability to protect mitochondrial structure and function under oxidative stress conditions. However, the fundamental mechanisms by which GQDs interact with membranes in oxidative environments are poorly understood. Here, we used C11-BODIPY, a fluorescent lipid oxidation probe, to develop quantitative fluorescence assays that determine both the extent and rate of oxidation that occurs to PUFAs in biological membranes. Based on kinetics principles, we have developed a generalizable model that can be used to assess the potency of antioxidants that scavenge ROS in the presence of biological membranes. By augmenting our fluorescence assays with 1H NMR spectroscopy, the results demonstrate that GQDs scavenge nascent hydroxyl and peroxyl ROS that interact with membranes and that GQDs are potent inhibitors of ROS-induced lipid oxidation in PUFA-containing biological membranes. The antioxidant potency of GQDs is comparable to or even greater than established antioxidant molecules, such as ascorbic acid and Trolox. This work provides mechanistic insights into the mitoprotective properties of GQDs under oxidative stress conditions, as well as a quantitative framework for assessing antioxidant interactions in biological membrane systems.

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Lithium batteries with solid-state electrolytes are an appealing alternative to state-of-the-art non-aqueous lithium-ion batteries with liquid electrolytes because of safety and energy aspects. However, engineering development at the cell level for lithium batteries with solid-state electrolytes is limited. Here, to advance this aspect and produce high-energy lithium cells, we introduce a cell design based on advanced parametrization of microstructural and architectural parameters of electrode and electrolyte components. To validate the cell design proposed, we assemble and test (applying a stack pressure of 3.74 MPa at 45 °C) 10-layer and 4-layer solid-state lithium pouch cells with a solid polymer electrolyte, resulting in an initial specific energy of 280 Wh kg-1 (corresponding to an energy density of 600 Wh L-1) and 310 Wh kg-1 (corresponding to an energy density of 650 Wh L-1) respectively.

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OBJECTIVE: The fresh-market tomato (Solanum lycopersicum) is bred for direct human consumption. It is selected for specific traits to meet market demands and production systems, and unique genetic variations underlying fresh-market tomato yields have been recently identified. However, DNA sequence variant-trait associations are not yet fully examined even for major traits. To provide a rich genome sequence resource for various genetics and breeding goals for fresh-market tomato traits, we report whole genome sequence data of a pool of contemporary U.S. fresh-market tomatoes. DATA DESCRIPTION: Eighty-one tomatoes were nominated by academic tomato breeding programs in the U.S. Of the 81 tomatoes, 68 were contemporary fresh-market tomatoes, whereas the remaining 13 were relevant fresh-market tomato breeding and germplasm accessions. Whole genome sequencing (WGS) of the 81 tomatoes was conducted using the Illumina next-generation sequencing technology. The polymerase chain reaction (PCR)-free, paired-end sequencing libraries were sequenced on an average depth per sequenced base of 24 × for each tomato. This data note enhances visibility and potential for use of the more diverse, freely accessible whole genome sequence data of contemporary fresh-market tomatoes.

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While many gene expression studies have focused on male pattern baldness (MPB), few studies have investigated the genetic differences between bald and non-bald hair follicles in female pattern hair loss (FPHL). This study aimed to identify molecular biomarkers associated with FPHL through genetic analysis of paired bald and non-bald hair follicles from 18 FPHL patients, using next-generation sequencing (NGS) techniques. RNA transcriptome analysis was performed to identify differentially expressed genes (DEGs) between bald and non-bald hair follicles in FPHL. The DEGs were validated using real-time PCR, and protein expression was confirmed through immunohistochemistry and western blot analysis. Our findings suggest that HOXB13, SFRP2, PTGDS, CXCR3, SFRP4, SOD3, and DCN are significantly upregulated in bald hair follicles compared to non-bald hair follicles in FPHL. SFRP2 and PTGDS were found to be consistently highly expressed in bald hair follicles in all 18 samples. Additionally, elevated protein levels of SFRP2 and PTGDS were confirmed through western blot and immunohistochemical analysis. Our study identified SFRP2 and PTGDS as potential biomarkers for FPHL and suggests that they may play a role in inducing hair loss in this condition. These findings provide a foundation for further research on the pathogenesis of FPHL and potential therapeutic targets.

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INTRODUCTION: Hair loss is driven by multiple factors, including genetics. Androgenetic alopecia (AGA) is a condition in which treatments necessitate prolonged compliance with prescribed medications. We have developed IVL3001, a long-acting injectable (LAI) formulation of finasteride encapsulated within poly lactic-co-glycolic acid microspheres, to enhance the efficacy of the finasteride and to achieve consistent positive outcomes in adults. An open-label, sequential, single-dose phase I clinical trial was designed to evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) of IVL3001. METHODS: A total of 40 non-smoking, healthy adult males were divided into three cohorts where the IVL3001 group received a single subcutaneous injection of 12-36 mg IVL3001 and 1 mg finasteride (Propecia®) once daily for 28 days. The plasma concentrations of finasteride, dihydrotestosterone (DHT), and testosterone were measured using liquid chromatography-tandem mass spectrometry. The tolerability of the injections was assessed, and compartment models were developed to predict the effective dose and assess PK/PD profiles. RESULTS: IVL3001 and finasteride 1 mg tablets were well tolerated. IVL3001 showed consistent plasma concentrations without bursts or fluctuations. Consistent with its mechanism of action, IVL3001 reduced DHT levels. Simulation data showed that the administration of 12-36 mg of IVL3001 every 4 weeks achieved plasma concentrations similar to finasteride, with comparable DHT reduction. CONCLUSION: The present study represents the first clinical trial to evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD), and tolerability of finasteride long-acting injectables (LAI) in adults. The rapid onset of action sustained effective drug concentration and the prolonged half-life of IVL3001 suggest that it offers multiple benefits over conventional oral formulations in terms of therapeutic response and compliance. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04945226.

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Graphene oxide quantum dots (GOQDs) are promising candidates for biomedical applications since they have lower toxicity and higher biocompatibility than traditional semiconductor quantum dots. However, oxygen functional groups such as epoxy and hydroxyl groups usually induce nonradiative relaxation, which leads to GOQDs exhibiting nonemissive properties. For the enhancement of the emission efficiency of GOQDs, the number of nonradiative relaxation sites should be reduced. This paper reports the synthesis of highly luminescent reduced GOQDs prepared by liquid-phase photoreduction (LPP-rGOQDs). First, GOQDs was fabricated from single-walled carbon nanotubes through chlorate-based oxidation and separation after acoustic cavitation. Subsequently, LPP-rGOQDs were obtained by liquid-phase photoreduction of the GOQD suspension under intense pulsed light irradiation. Liquid-phase photoreduction selectively reduced epoxy groups present on the basal plane of GOQDs, and hydrogenated the basal plane without removal of carbonyl and carboxyl groups at the edges of the GOQDs. Such selective removal of oxidative functional groups was used to control the reduction degree of GOQDs, closely related to their optical properties. The optimized LPP-rGOQDs were bright blue in color and showed quantum yields up to about 19.7%, which was 10 times the quantum yield of GOQDs. Furthermore, the LPP-rGOQDs were utilized to image a human embryonic kidney (HEK293A), and a low cytotoxicity level and satisfactory cell imaging performance were observed.

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External ventricular drainage is one of the most common neurosurgical procedures in the world for acute hydrocephalus, which must be performed carefully by a neurosurgeon. Although various neuromonitoring external ventricular drain (EVD) catheters have been utilized, they still suffer from rigidity and bulkiness to mitigate post-EVD placement trauma. Here, we introduce a flexible and low-profile smart EVD catheter using a class of technologies with sensitive electrical materials, seamless integration, and flexible mechanics, which serves as a highly soft and minimally invasive device to monitor electrical brain signals. This device reliably captures biopotentials in real time while exhibiting remarkable flexibility and reliability. The seamless integration of its sensory system promises a minimally invasive EVD placement on brain tissue. This work validates the device's distinct characteristics and performances through in vitro experiments and computational analysis. Collectively, this device's exceptional patient- and user-friendly attributes highlight its potential as one of the most practical EVD catheters.

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BACKGROUND: People with disabilities face challenges in daily life during the COVID-19 pandemic, including limited access to care, exposure to lifestyle-related diseases, and difficulties in regular exercise. Therefore, it is important to establish health safety nets using Information and Communication Technology (ICT) in communities. OBJECTIVE: This study aimed to develop an m-Health-based personalized lifestyle intervention algorithm targeting high-risk groups of lifestyle-related diseases (including hypertension, diabetes, and obesity) among people with hemiplegic disabilities, and to verify its feasibility. METHODS: Six people at a high risk of lifestyle-related diseases participated in an 8-week lifestyle intervention using a wearable device and the S-Health program. The self-health management areas included walking, moderate-intensity exercise, weight, blood pressure, blood sugar, diet, calorie intake, heart rate, sobriety, no smoking. Health, physical, psychological, and social changes were measured before and after the study. RESULTS: The intervention had a positive impact on the participants' health, with statistically significant differences found in fasting blood glucose, highest systolic blood pressure, grip strength, and motor function assessment. Quality of life, health-related quality of life, and self-efficacy improved post-intervention. CONCLUSION: Our findings can be used as preliminary evidence for establishing m-Health-based health safety net systems for people with disabilities who live in communities.

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BACKGROUND AND AIMS: The incidence of statin-induced new-onset diabetes (NOD) is increasing but its underlying mechanisms remain unclear. We aimed to investigate the effects of various doses of atorvastatin (ATO)-induced autophagy on the development of NOD. METHODS AND RESULTS: The isolated rat islets and MIN6 cells-treated with ATO, exhibited impaired glucose-stimulated insulin secretion, reduced insulin content, and induced apoptosis. Additionally, autophagy was induced at all doses (in vitro: 5, 10, 20 µM; in vivo: 10, 15, 20 mg/kg) in ATO-treated MIN6 cells or western diet (WD)-fed mice. In contrast to normal glucose-tolerant mice administered a low-dose (10 mg/kg) ATO, those treated with high-doses (15 or 20 mg/kg) exhibited impaired glucose tolerance. Furthermore, high-dose ATO-treated mice showed decreased ß-cell mass and increased apoptosis compared to that of vehicle-treated mice. We also observed that the number of vesicophagous cells in the pancreas of 20 mg/kg ATO-treated WD-fed mice was higher than in vehicle-treated WD-fed mice. Inhibiting autophagy using 3-methyladenine (3-MA) and siAtg5 improved glucose tolerance in vivo and in vitro by preventing apoptotic ß-cell death and restoring insulin granules. CONCLUSION: These results indicate that high doses of ATO induced hyperactivated autophagy in pancreatic cells, leading to impaired insulin storage, decreased cell viability, and reduced functional cell mass, ultimately resulting in NOD development.

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Formalin-fixed, paraffin-embedded (FFPE) tissue specimens are routinely used in pathological diagnosis, but their large number of artifactual mutations complicate the evaluation of companion diagnostics and analysis of next-generation sequencing data. Identification of variants with low allele frequencies is challenging because existing FFPE filtering tools label all low-frequency variants as artifacts. To address this problem, we aimed to develop DEEPOMICS FFPE, an AI model that can classify a true variant from an artifact. Paired whole exome sequencing data from fresh frozen and FFPE samples from 24 tumors were obtained from public sources and used as training and validation sets at a ratio of 7:3. A deep neural network model with three hidden layers was trained with input features using outputs of the MuTect2 caller. Contributing features were identified using the SHapley Additive exPlanations algorithm and optimized based on training results. The performance of the final model (DEEPOMICS FFPE) was compared with those of existing models (MuTect filter, FFPolish, and SOBDetector) by using well-defined test datasets. We found 41 discriminating properties for FFPE artifacts. Optimization of property quantification improved the model performance. DEEPOMICS FFPE removed 99.6% of artifacts while maintaining 87.1% of true variants, with an F1-score of 88.3 in the entire dataset not used for training, which is significantly higher than those of existing tools. Its performance was maintained even for low-allele-fraction variants with a specificity of 0.995, suggesting that it can be used to identify subclonal variants. Different from existing methods, DEEPOMICS FFPE identified most of the sequencing artifacts in the FFPE samples while retaining more of true variants, including those of low allele frequencies. The newly developed tool DEEPOMICS FFPE may be useful in designing capture panels for personalized circulating tumor DNA assay and identifying candidate neoepitopes for personalized vaccine design. DEEPOMICS FFPE is freely available on the web ( http://deepomics.co.kr/ffpe ) for research.

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Background: Environmental exposure to metal mixtures is common and may be associated with increased risk for neurodegenerative disorders including Alzheimer's disease. Objective: This study examined associations of mixed metal exposures with medial temporal lobe (MTL) MRI structural metrics and neuropsychological performance. Methods: Metal exposure history, whole blood metal, and neuropsychological tests were obtained from subjects with/without a history of mixed metal exposure from welding fumes (42 exposed subjects; 31 controls). MTL structures (hippocampus, entorhinal and parahippocampal cortices) were assessed by morphologic (volume, cortical thickness) and diffusion tensor imaging [mean (MD), axial (AD), radial diffusivity (RD), and fractional anisotropy (FA)] metrics. In exposed subjects, correlation, multiple linear, Bayesian kernel machine regression, and mediation analyses were employed to examine effects of single- or mixed-metal predictor(s) and their interactions on MTL structural and neuropsychological metrics; and on the path from metal exposure to neuropsychological consequences. Results: Compared to controls, exposed subjects had higher blood Cu, Fe, K, Mn, Pb, Se, and Zn levels (p's<0.026) and poorer performance in processing/psychomotor speed, executive, and visuospatial domains (p's<0.046). Exposed subjects displayed higher MD, AD, and RD in all MTL ROIs (p's<0.040) and lower FA in entorhinal and parahippocampal cortices (p's<0.033), but not morphological differences. Long-term mixed-metal exposure history indirectly predicted lower processing speed performance via lower parahippocampal FA (p=0.023). Higher whole blood Mn and Cu predicted higher entorhinal diffusivity (p's<0.043) and lower Delayed Story Recall performance (p=0.007) without overall metal mixture or interaction effects. Discussion: Mixed metal exposure predicted MTL structural and neuropsychological features that are similar to Alzheimer's disease at-risk populations. These data warrant follow-up as they may illuminate the path for environmental exposure to Alzheimer's disease-related health outcomes.

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Activation of hypoxia-inducible factor 1α (HIF1α) contributes to blood-retinal barrier (BRB) breakdown and pathological neovascularization responsible for vision loss in ischemic retinal diseases. During disease progression, mitochondrial biology is altered to adapt to the ischemic environment created by initial vascular dysfunction, but the mitochondrial adaptive mechanisms, which ultimately contribute to the pathogenesis of ischemic retinopathy, remain incompletely understood. In the present study, it is identified that expression of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) is essential for BRB breakdown and pathologic retinal neovascularization in mouse models mimicking ischemic retinopathies. Genetic Trap1 ablation or treatment with small molecule TRAP1 inhibitors, such as mitoquinone (MitoQ) and SB-U015, alleviate retinal pathologies via proteolytic HIF1α degradation, which is mediated by opening of the mitochondrial permeability transition pore and activation of calcium-dependent protease calpain-1. These findings suggest that TRAP1 can be a promising target for the development of new treatments against ischemic retinopathy, such as retinopathy of prematurity and proliferative diabetic retinopathy.

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South Korea has legislated "2050 carbon neutrality" in 2021 and is currently implementing it, and debate is brewing over which to focus on as the main means of achieving it in the power generation sector: renewable energy (RE) or nuclear power (NP). This article aims to collect and analyze data on the public preference for RE versus NP. In a national survey of 1000 people, respondents were first asked which was preferred, RE or NP, and then asked to indicate the preference intensity along a 5-point scale. Of all the respondents, 60.3% preferred RE and 27.7% preferred NP. The preference for the former was about 2.2 times more than that for the latter. However, the intensity of the preference for NP was 1.3 times more than that for RE. Both the two-limit Tobit model and ordered probit model have been applied to analyzing the factors influencing the preference. The effects of some variables on the preference for RE over NP are explained, and implications from this are discussed. The findings can be used as a reference to determine the main means of implementation of carbon neutrality or to increase the public acceptance of the specified means.

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In this study, it is demonstrated that CsPbBr3 perovskite nanocrystals (NCs) can enhance the overall performances of photomultiplication-type organic photodiodes (PM-OPDs). The proposed approach enables the ionic-polarizable CsPbBr3 NCs to be evenly distributed throughout the depletion region of Schottky junction interface, allowing the entire trapped electrons within the depletion region to be stabilized, in contrast to previously reported interface-limited strategies. The optimized CsPbBr3 -NC-embedded poly(3-hexylthiophene-diyl)-based PM-OPDs exhibit exceptionally high external quantum efficiency, specific detectivity, and gain-bandwidth product of 2,840,000%, 3.97 × 1015 Jones, and 2.14 × 107  Hz, respectively. 2D grazing-incidence X-ray diffraction analyses and drift-diffusion simulations combined with temperature-dependent J-V characteristic analyses are conducted to investigate the physics behind the success of CsPbBr3 -NC-embedded PM-OPDs. The results show that the electrostatic interactions generated by the ionic polarization of NCs effectively stabilize the trapped electrons throughout the entire volume of the photoactive layer, thereby successfully increasing the effective energy depth of the trap states and allowing efficient PM mechanisms. This study demonstrates how a hybrid-photoactive-layer approach can further enhance PM-OPD when the functionality of inorganic inclusions meets the requirements of the target device.

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BACKGROUND AND AIMS: Chronic hepatitis B virus (HBV) infection is associated with a reduced risk of dyslipidaemia. Using a human faecal microbiota transplantation (FMT), we compared changes in gut microbiota and lipid profiles in mice transplanted with human faeces from HBV-infected and non-infected individuals. APPROACH AND RESULTS: A total of 19 mice received human FMT from four HBV-infected individuals and were categorised into the HBV-positive mice group, while 20 mice received FMT from four HBV-non-infected individuals into the HBV-negative one. In the analysis of gut microbiota in FMT mice, we observed a robust increase in alpha diversity and abundance of Akkermansia muciniphila in HBV-positive mice, compared to that in HBV-negative. Functional inference analysis revealed that the pathways involved in glycerolipid metabolism were more enriched in HBV-positive mice. At 5 weeks of FMT, the reduced triglyceride (TG) level was predominantly observed in HBV-positive mice. CONCLUSIONS: Altered gut microbiota accompanied by HBV infection was associated with a robust increase in alpha diversity and butyrate producers, which resulted in a reduced level of TG at 5 weeks post-FMT. This indicates that the reduced risk of dyslipidaemia in chronic HBV infection may be due to the altered gut microbiota accompanied by HBV infection.

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This study investigated the impact of NaCl on the physical properties of cornstarch-methyl cellulose (CS-MC) mixtures and their gels prepared with rice flour in a model system. Opposite trends were observed, showing that NaCl led to decreased viscosity of the CS-MC mixtures (liquid-based), whereas a more stable and robust structure was observed for the rice-flour-added gels (solid-based) with the addition of NaCl. The interference of NaCl with the CS-MS blend's ability to form a stable gel network resulted in a thinner consistency, as the molecules of the CS-MS blend may not bind together as effectively. On the contrary, NaCl showed the potential to enhance the protein network within CS-MC gels prepared with rice flour, thereby contributing to an augmentation in the stability or firmness of the cooked gels. Careful utilization of NaCl to optimize the physical properties of the CS-MC blends, as well as the gels based on rice flour, should be performed.

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OBJECTIVE: Abnormal autophagic function and activated inflammasomes are typical features in the liver of patients with non-alcoholic steatohepatitis (NASH). Here, we explored whether gemigliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor for treatment of type 2 diabetes, can induce autophagy and regulate inflammasome activation as a potential NASH treatment independent of its anti-diabetic effect. METHODS: Expression analysis was performed using human liver samples obtained from 18 subjects who underwent hepatectomy. We explored the function and mechanism of gemigliptin using a methionine- and choline-deficient diet (MCD)-induced NASH mouse model and HepG2 cells cultured in MCD-mimicking medium. RESULTS: Autophagy was suppressed by marked decreases in the expression of ULK1 and LC3II/LC3I ratio in human NAFLD/NASH patients, a NASH mouse model, and HepG2 cells cultured with MCD-mimicking media. Surprisingly, we found that the expression of p-AMPK decreased in liver tissues from patients with steatosis but was restored in NASH patients. The expression of p-AMPK in the NASH mouse model was similar to that of the control group. Hence, these results indicate that autophagy was reduced in NASH via an AMPK-independent pathway. However, gemigliptin treatment attenuated lipid accumulation, inflammation, and fibrosis in the liver of MCD diet-fed mice with restoration of ULK1 expression and autophagy induction. In vitro, gemigliptin alleviated inflammasome activation through induction of ULK1-dependent autophagy. Furthermore, gemigliptin treatment upregulated ULK1 expression and activated AMPK even after siRNA-mediated knockdown of AMPKα1/2 and ULK1, respectively. CONCLUSIONS: Collectively, these results suggest that gemigliptin ameliorated NASH via AMPK-independent, ULK1-mediated effects on autophagy.

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