xQTLatlas: a comprehensive resource for human cellular-resolution multi-omics genetic regulatory landscape.

Understanding how genetic variants influence molecular phenotypes in different cellular contexts is crucial for elucidating the molecular and cellular mechanisms behind complex traits, which in turn has spurred significant advances in research into molecular quantitative trait locus (xQTL) at the cellular level. With the rapid proliferation of data, there is a critical need for a comprehensive and accessible platform to integrate this information. To meet this need, we developed xQTLatlas (http://www.hitxqtl.org.cn/), a database that provides a multi-omics genetic regulatory landscape at cellular resolution. xQTLatlas compiles xQTL summary statistics from 151 cell types and 339 cell states across 55 human tissues. It organizes these data into 20 xQTL types, based on four distinct discovery strategies, and spans 13 molecular phenotypes. Each entry in xQTLatlas is meticulously annotated with comprehensive metadata, including the origin of the tissue, cell type, cell state and the QTL discovery strategies utilized. Additionally, xQTLatlas features multiscale data exploration tools and a suite of interactive visualizations, facilitating in-depth analysis of cell-level xQTL. xQTLatlas provides a valuable resource for deepening our understanding of the impact of functional variants on molecular phenotypes in different cellular environments, thereby facilitating extensive research efforts.

Mechanistic Understanding of Dexamethasone-Mediated Protection against Remdesivir-Induced Hepatotoxicity.

Remdesivir (RDV), a broad-spectrum antiviral agent, is often used together with dexamethasone (DEX) for hospitalized COVID-19 patients requiring respiratory support. Potential hepatic adverse drug reaction is a safety concern associated with the use of RDV. We previously reported that DEX cotreatment effectively mitigates RDV-induced hepatotoxicity and reduces elevated serum alanine aminotransferase and aspartate aminotransferase levels in cultured human primary hepatocytes (HPH) and hospitalized COVID-19 patients, respectively. Yet, the precise mechanism behind this protective drug-drug interaction remains largely unknown. Here, we show that through the activation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling, RDV induces apoptosis (cleavage of caspases 8, 9, and 3), autophagy (increased autophagosome and LC3-II), and mitochondrial damages (decreased membrane potential, respiration, ATP levels, and increased expression of Bax and the released cytosolic cytochrome C) in HPH. Importantly, cotreatment with DEX partially reversed RDV-induced apoptosis, autophagy, and cell death. Mechanistically, DEX deactivates/dephosphorylates p38, JNK, and ERK1/2 signaling by enhancing the expression of dual specificity protein phosphatase 1 (DUSP1), a mitogen-activated protein kinase (MAPK) phosphatase, in a glucocorticoid receptor (GR)-dependent manner. Knockdown of GR in HPH attenuates DEX-mediated DUSP1 induction, MAPK dephosphorylation, as well as protection against RDV-induced hepatotoxicity. Collectively, our findings suggest a molecular mechanism by which DEX modulates the GR-DUSP1-MAPK regulatory axis to alleviate the adverse actions of RDV in the liver. SIGNIFICANCE STATEMENT: The research uncovers the molecular mechanisms by which dexamethasone safeguards against remdesivir-associated liver damage in the context of COVID-19 treatment.

Synergistic effects of graphene microgrooves and electrical stimulation on M2 macrophage polarization.

Macrophages play a crucial role in host response and wound healing, with M2 polarization contributing to the reduction of foreign-body reactions induced by the implantation of biomaterials and promoting tissue regeneration. Electrical stimulation (ES) and micropatterned substrates have a significant impact on the macrophage polarization. However, there is currently a lack of well-established cell culture platforms for studying the synergistic effects of these two factors. In this study, we prepared a graphene free-standing substrate with 20 µm microgrooves using capillary forces induced by water evaporation. Subsequently, we established an ES cell culture platform for macrophage cultivation by integrating a self-designed multi-well chamber cell culture device. We observed that graphene microgrooves, in combination with ES, significantly reduce cell spreading area and circularity. Results from immunofluorescence, ELISA, and flow cytometry demonstrate that the synergistic effect of graphene microgrooves and ES effectively promotes macrophage M2 phenotypic polarization. Finally, RNA sequencing results reveal that the synergistic effects of ES and graphene microgrooves inhibit the macrophage actin polymerization and the downstream PI3K signaling pathway, thereby influencing the phenotypic transition. Our results demonstrate the potential of graphene-based microgrooves and ES to synergistically modulate macrophage polarization, offering promising applications in regenerative medicine.

Plasmonic nanosensor and pressure-induced transparency based on coupled resonator in a nanoscale system.

Plasmonic nanosensors and the dynamic control of light fields are of the utmost significance in the field of micro- and nano-optics. Here, our study successfully demonstrates a plasmonic nanosensor in a compact coupled resonator system and obtains the pressure-induced transparency phenomenon for the first time to our knowledge. The proposed structure consists of a groove and slot cavity coupled in the metal-insulator-metal waveguide, whose mechanical and optical characteristics are investigated in detail using the finite element method. Simulation results show that we construct a quantitative relationship among the resonator deformation quantity, the applied pressure variation, and the resonant wavelength offset by combining the mechanical and optical properties of the proposed system. The physical features contribute to highly efficient plasmonic nanosensors for refractive index and optical pressure sensing with sensitivity of 1800 nm/RIU and 7.4 nm/MPa, respectively. Furthermore, the light waves are coupled to each other in the resonators, which are detuned due to the presence of pressure, resulting in the pressure-induced transparency phenomenon. It is noteworthy to emphasize that, unlike previously published works, our numerical results take structural deformation-induced changes in optical properties into account, making them trustworthy and practical. The proposed structure introduces a novel, to the best of our knowledge, approach for the dynamic control of light fields and has special properties that can be utilized for the realization of various integrated components.

Lieb-Schultz-Mattis Theorem for 1D Quantum Magnets with Antiunitary Translation and Inversion Symmetries.

We study quantum many-body systems in the presence of an exotic antiunitary translation or inversion symmetry involving time reversal. Based on a symmetry-twisting method and spectrum robustness, we propose that a half-integer spin chain that respects any of these two antiunitary crystalline symmetries in addition to the discrete Z_{2}×Z_{2} global spin-rotation symmetry must either be gapless or possess degenerate ground states. This explains the gaplessness of a class of chiral spin models not indicated by the Lieb-Schultz-Mattis theorem and its known extensions. Moreover, we present symmetry classes with minimal sets of generators that give nontrivial Lieb-Schultz-Mattis-type constraints, argued by the bulk-boundary correspondence in 2D symmetry-protected topological phases as well as lattice homotopy. Our results for detecting the ingappability of 1D quantum magnets from the interplay between spin-rotation symmetries and magnetic space groups are applicable to systems with a broader class of spin interactions, including Dzyaloshinskii-Moriya and triple-product interactions.

Investigating the effects of indoor lighting on measures of brain health in older adults: protocol for a cross-over randomized controlled trial.

BACKGROUND: The worldwide number of adults aged 60 years and older is expected to double from 1 billion in 2019 to 2.1 billion by 2050. As the population lives longer, the rising incidence of chronic diseases, cognitive disorders, and behavioral health issues threaten older adults' health span. Exercising, getting sufficient sleep, and staying mentally and socially active can improve quality of life, increase independence, and potentially lower the risk for Alzheimer's disease or other dementias. Nonpharmacological approaches might help promote such behaviors. Indoor lighting may impact sleep quality, physical activity, and cognitive function. Dynamically changing indoor lighting brightness and color throughout the day has positive effects on sleep, cognitive function, and physical activity of its occupants. The aim of this study is to investigate how different indoor lighting conditions affect such health measures to promote healthier aging. METHODS: This protocol is a randomized, cross-over, single-site trial followed by an exploratory third intervention. Up to 70 older adults in independent living residences at a senior living facility will be recruited. During this 16-week study, participants will experience three lighting conditions. Two cohorts will first experience a static and a dynamic lighting condition in a cluster-randomized cross-over design. The static condition lighting will have fixed brightness and color to match lighting typically provided in the facility. For the dynamic condition, brightness and color will change throughout the day with increased brightness in the morning. After the cross-over, both cohorts will experience another dynamic lighting condition with increased morning brightness to determine if there is a saturation effect between light exposure and health-related measures. Light intake, sleep quality, and physical activity will be measured using wearable devices. Sleep, cognitive function, mood, and social engagement will be assessed using surveys and cognitive assessments. DISCUSSION: We hypothesize participants will have better sleep quality and greater physical activity during the dynamic lighting compared to the static lighting condition. Additionally, we hypothesize there is a maximal threshold at which health-outcomes improve based on light exposure. Study findings may identify optimal indoor lighting solutions to promote healthy aging for older adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05978934.

Human constitutive androstane receptor represses liver cancer development and hepatoma cell proliferation by inhibiting erythropoietin signaling.

The constitutive androstane receptor (CAR) is a nuclear receptor that plays a crucial role in regulating xenobiotic metabolism and detoxification, energy homeostasis, and cell proliferation by modulating the transcription of numerous target genes. CAR activation has been established as the mode of action by which phenobarbital-like nongenotoxic carcinogens promote liver tumor formation in rodents. This paradigm, however, appears to be unrelated to the function of human CAR (hCAR) in hepatocellular carcinoma (HCC), which remains poorly understood. Here, we show that hCAR expression is significantly lower in HCC than that in adjacent nontumor tissues and, importantly, reduced hCAR expression is associated with a worse HCC prognosis. We also show overexpression of hCAR in human hepatoma cells (HepG2 and Hep3B) profoundly suppressed cell proliferation, cell cycle progression, soft-agar colony formation, and the growth of xenografts in nude mice. RNA-Seq analysis revealed that the expression of erythropoietin (EPO), a pleiotropic growth factor, was markedly repressed by hCAR in hepatoma cells. Addition of recombinant EPO in HepG2 cells partially rescued hCAR-suppressed cell viability. Mechanistically, we showed that overexpressing hCAR repressed mitogenic EPO-EPO receptor signaling through dephosphorylation of signal transducer and activator of transcription 3, AKT, and extracellular signal-regulated kinase 1/2. Furthermore, we found that hCAR downregulates EPO expression by repressing the expression and activity of hepatocyte nuclear factor 4 alpha, a key transcription factor regulating EPO expression. Collectively, our results suggest that hCAR plays a tumor suppressive role in HCC development, which differs from that of rodent CAR and offers insight into the hCAR-hepatocyte nuclear factor 4 alpha-EPO axis in human liver tumorigenesis.

Tunable electromagnetically induced absorption based on coupled-resonators in a compact plasmonic system.

Electromagnetically induced absorption (EIA) exhibits abnormal dispersion and novel fast-light features, making it a crucial aspect of nanophotonics. Here, the EIA phenomenon is numerically predicted in a compact plasmonic waveguide system by introducing a slot resonator above a square cavity. Simulation results reveal that the EIA response can be easily tuned by altering the structure's parameters, and double EIA valleys can be observed with an additional slot resonator. Furthermore, the investigated structures demonstrate a fast-light effect with an optical delay of ∼ -1.0 ps as a result of aberrant dispersion at the EIA valley, which enable promising applications in the on-chip fast-light area. Finally, a plasmonic nanosensor with a sensitivity of ∼1200 nm/RIU and figure of merit of ∼16600 is achieved based on Fano resonance. The special features of our suggested structure are applicable in realization of various integrated components for the development of multifunctional high-performance nano-photonic devices.

Plug-and-play algorithm for imaging through scattering media under ambient light interference.

Imaging through scattering media is a fascinating subject in the computational imaging domain. The methods based on speckle correlation imaging have found tremendous versatility. However, a darkroom condition without any stray light is required because the speckle contrast is easily disturbed by ambient light, which can lead to the reduction in object reconstruction quality. Here, we report a plug-and-play (PnP) algorithm to restore the object through scattering media under the non-darkroom environment. Specifically, the PnPGAP-FPR method is established via the generalized alternating projection (GAP) optimization framework, Fienup phase retrieval (FPR) method, and FFDNeT. The proposed algorithm is demonstrated experimentally and shows significant effectiveness and flexible scalability, which describe the potential for its practical applications.

Recursion-driven bispectral imaging for dynamic scattering scenes.

Imaging dynamic strongly scattering scenes remains a significant challenge because it is typically believed that moving objects and dynamic media provide huge barriers. Instead, we use the dynamics of objects and media and put forward a recursion-driven bispectral imaging (ReDBI) framework here for the reconstruction of a stationary or moving object hidden behind the dynamic media. ReDBI avoids the errors introduced by speckle modulation and phase-retrieval algorithms in the existing studies. We also quantitatively assess the reconstruction difficulty of character and shape objects with the benchmark of the minimum number of speckle images (MNSI) required to achieve a high-quality reconstruction, which can help to comprehend the media's transfer properties.

Electroceramics for High-Energy Density Capacitors: Current Status and Future Perspectives.

Materials exhibiting high energy/power density are currently needed to meet the growing demand of portable electronics, electric vehicles and large-scale energy storage devices. The highest energy densities are achieved for fuel cells, batteries, and supercapacitors, but conventional dielectric capacitors are receiving increased attention for pulsed power applications due to their high power density and their fast charge-discharge speed. The key to high energy density in dielectric capacitors is a large maximum but small remanent (zero in the case of linear dielectrics) polarization and a high electric breakdown strength. Polymer dielectric capacitors offer high power/energy density for applications at room temperature, but above 100 °C they are unreliable and suffer from dielectric breakdown. For high-temperature applications, therefore, dielectric ceramics are the only feasible alternative. Lead-based ceramics such as La-doped lead zirconate titanate exhibit good energy storage properties, but their toxicity raises concern over their use in consumer applications, where capacitors are exclusively lead free. Lead-free compositions with superior power density are thus required. In this paper, we introduce the fundamental principles of energy storage in dielectrics. We discuss key factors to improve energy storage properties such as the control of local structure, phase assemblage, dielectric layer thickness, microstructure, conductivity, and electrical homogeneity through the choice of base systems, dopants, and alloying additions, followed by a comprehensive review of the state-of-the-art. Finally, we comment on the future requirements for new materials in high power/energy density capacitor applications.

Effects of Overexpression of Fibroblast Growth Factor 15/19 on Hepatic Drug Metabolizing Enzymes.

Fibroblast growth factors 15 (FGF15) and 19 (FGF19) are endocrine growth factors that play an important role in maintaining bile acid homeostasis. FGF15/19-based therapies are currently being tested in clinical trials for the treatment of nonalcoholic steatohepatitis and cholestatic liver diseases. To determine the physiologic impact of long-term elevations of FGF15/19, a transgenic mouse model with overexpression of Fgf15 (Fgf15 Tg) was used in the current study. The RNA sequencing (RNA-seq) analysis revealed elevations of the expression of several genes encoding phase I drug metabolizing enzymes (DMEs), including Cyp2b10 and Cyp3a11, in Fgf15 Tg mice. We found that the induction of several Cyp2b isoforms resulted in increased function of CYP2B in microsomal metabolism and pharmacokinetics studies. Because the CYP2B family is known to be induced by constitutive androstane receptor (CAR), to determine the role of CAR in the observed inductions, we crossed Fgf15 Tg mice with CAR knockout mice and found that CAR played a minor role in the observed alterations in DME expression. Interestingly, we found that the overexpression of Fgf15 in male mice resulted in a phenotypical switch from the male hepatic expression pattern of DMEs to that of female mice. Differences in secretion of growth hormone (GH) between male and female mice are known to drive sexually dimorphic, STAT5b-dependent expression patterns of hepatic genes. We found that male Fgf15 Tg mice presented with many features similar to GH deficiency, including lowered body length and weight, Igf-1 and Igfals expression, and STAT5 signaling. SIGNIFICANCE STATEMENT: The overexpression of Fgf15 in mice causes an alteration in DMEs at the mRNA, protein, and functional levels, which is not entirely due to CAR activation but associated with lower GH signaling.

Androgen-induced insulin resistance is ameliorated by deletion of hepatic androgen receptor in females.

Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in ARfl/fl mice (adLivARKO). We observed normal metabolic function in littermate female Control (ARfl/fl ) and LivARKO (ARfl/fl ; Cre+/- ) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Furthermore, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR.

Two-dimensional group-III nitrides and devices: a critical review.

As third-generation semiconductors, group-III nitrides are promising for high power electronic and optoelectronic devices because of their wide bandgap, high electron saturation mobility, and other unique properties. Inspired by the thickness-dependent properties of two-dimensional (2D) materials represented by graphene, it is predicted that the 2D counterparts of group-III nitrides would have similar properties. However, the preparation of 2D group-III nitride-based materials and devices is limited by the large lattice mismatch in heteroepitaxy and the low rate of lateral migration, as well as the unsaturated dangling bonds on the surfaces of group-III nitrides. The present review focuses on theoretical and experimental studies on 2D group-III nitride materials and devices. Various properties of 2D group-III nitrides determined using simulations and theoretical calculations are outlined. Moreover, the breakthroughs in their synthesis methods and their underlying physical mechanisms are detailed. Furthermore, devices based on 2D group-III nitrides are discussed accordingly. Based on recent progress, the prospect for the further development of the 2D group-III nitride materials and devices is speculated. This review provides a comprehensive understanding of 2D group-III nitride materials, aiming to promote the further development of the related fields of nano-electronic and nano-optoelectronics.

Inside-Out-Oriented Cell Membrane Biomimetic Magnetic Nanoparticles for High-Performance Drug Lead Discovery.

Biomimetic cell membrane-coated nanoparticles have been broadly applied because of their superior biochemical properties. The right-side-out cell membrane coating manner provides nanoparticles with an immune-evasive stealth function in vivo. However, this acts as a drag for drug discovery when the drug targets are the intracellular domain of transmembrane receptors. Herein, inside-out-oriented cell membrane-coated nanoparticles were prepared for screening tyrosine kinase inhibitors, which specifically interacted with the intracellular kinase domain of the epidermal growth factor receptor. Biotinylated human lung adenocarcinoma epithelial cell membranes specifically interacted with streptavidin-immobilized Fe3O4 magnetic nanoparticles and then formed inside-out-oriented cell membrane-coated magnetic nanoparticles (IOCMMNPs). The cell membrane orientation of the IOCMMNPs was successfully confirmed by immunogold electron microscopy, fluorescently labeled confocal microscopy, sialic acid quantification assay, and the adsorption capacity assay. Moreover, IOCMMNPs possessed satisfactory binding capacity, selectivity, and high sensitivity (limit of detection = 0.4 × 10-3 µg mL-1). Ultimately, IOCMMNPs successfully targeted two main compounds from Strychnos nux-vomica whose potential antitumor activities were further validated by pharmacological studies. The application of the inside-out cell membrane coating strategy further enhances the drug screening efficiency and broadens the insight and methodologies for drug lead discovery. This inside-out cell membrane coating concept also provides a method for the future development of engineered cell membrane-coated nanotechnology.

Molecular characterization of structural protein genes of dengue virus serotype 1 epidemic in Yunnan, Southwest China, in 2018.

A dengue virus serotype 1 (DENV-1) epidemic occurred from October to December 2018 in Xishuangbanna, Yunnan, Southwest China, neighboring Myanmar, Laos, and Vietnam. In this study, we investigated the molecular characteristics, evolution, and potential source of DENV from Xishuangbanna. The C (capsid), prM (premembrane), and E (envelope) genes of DENV isolated from 87 serum samples obtained from local patients were amplified and sequenced, and the sequences were evaluated by identification of mutations, phylogenetic and homologous recombination analysis, and secondary structure prediction. Phylogenetic analysis showed that all of the epidemic DENV strains from Xishuangbanna could be grouped in a branch with DENV-1 isolates, and were most similar to the Fujian 2005 (China, DQ193572) and Singapore 2016 (MF314188) strains. When compared with DENV-1SS (the standard strain), there were 31 non-synonymous mutations, but no obvious homologous recombination signal was found. Secondary structure prediction showed that some changes had occurred in a helical region in proteins of the MN123849 and MN123854 strains, but there were few changes in the disordered region. This study reveals the molecular characteristics of the structural genes of the Xishuangbanna epidemic strains in 2018 and provides a reference for molecular epidemiology, infection, and pathogenicity research and vaccine development.

Electrical properties of yttria-stabilised hafnia ceramics.

Cubic, yttria-stabilised hafnia, YSH, ceramics of general formula, YxHf1-xO2-x/2: x = 0.15, 0.30 and 0.45 were sintered at 1650-1750 °C and characterised by impedance spectroscopy. All three compositions are primarily oxide ion conductors with a small amount of p-type conductivity that depends on atmospheric conditions and appears to increase with x. The electronic conductivity is attributed to hole location on under-bonded oxide ions and the absorption of oxygen molecules by oxygen vacancies, both of which occur on substitution of Hf4+ by Y3+. Composition x = 0.15 has the highest total conductivity and shows curvature in the Arrhenius plot at high temperatures, similar to that of the most conductive yttria-stabilised zirconia.

High oxide-ion conductivity in acceptor-doped Bi-based perovskites at modest doping levels.

A combination of impedance spectroscopy, time-of-flight secondary ion mass spectrometry and literature data are used to show that, (i) the bulk oxide ion conductivity of A-site, alkaline earth-doped BiFeO3 (BF) is independent of the ionic radius of the alkaline earth ion (Ca, Sr, Ba) and, (ii) despite very different A-site environments in (Na1/2Bi1/2)TiO3 and BF, similar high levels and optimisation of bulk oxide ion conductivity in these Bi-based tilted perovskites is achieved at modest acceptor doping levels of ∼1-10%. These results clearly demonstrate that optimisation of oxide ion conductivity in these materials requires concepts beyond a simple crystallochemical approach based on matching the ionic radii of acceptor dopant and host lattice ions.

Quantification of common and planar bile acids in tissues and cultured cells.

Bile acids (BAs) have been established as ubiquitous regulatory molecules implicated in a large variety of healthy and pathological processes. However, the scope of BA heterogeneity is often underrepresented in current literature. This is due in part to inadequate detection methods, which fail to distinguish the individual constituents of the BA pool. Thus, the primary aim of this study was to develop a method that would allow the simultaneous analysis of specific C24 BA species, and to apply that method to biological systems of interest. Herein, we describe the generation and validation of an LC-MS/MS assay for quantification of numerous BAs in a variety of cell systems and relevant biofluids and tissue. These studies included the first baseline level assessment for planar BAs, including allocholic acid, in cell lines, biofluids, and tissue in a nonhuman primate (NHP) laboratory animal, Macaca mulatta, in healthy conditions. These results indicate that immortalized cell lines make poor models for the study of BA synthesis and metabolism, whereas human primary hepatocytes represent a promising alternative model system. We also characterized the BA pool of M. mulatta in detail. Our results support the use of NHP models for the study of BA metabolism and pathology in lieu of murine models. Moreover, the method developed here can be applied to the study of common and planar C24 BA species in other systems.

Hepatic steroid sulfatase critically determines estrogenic activities of conjugated equine estrogens in human cells in vitro and in mice.

Conjugated equine estrogens (CEEs), whose brand name is Premarin, are widely used as a hormone-replacement therapy (HRT) drug to manage postmenopausal symptoms in women. Extracted from pregnant mare urine, CEEs are composed of nearly a dozen estrogens existing in an inactive sulfated form. To determine whether the hepatic steroid sulfatase (STS) is a key contributor to the efficacy of CEEs in HRT, we performed estrogen-responsive element (ERE) reporter gene assay, real-time PCR, and UPLC-MS/MS to assess the STS-dependent and inflammation-responsive estrogenic activity of CEEs in HepG2 cells and human primary hepatocytes. Using liver-specific STS-expressing transgenic mice, we also evaluated the effect of STS on the estrogenic activity of CEEs in vivo We observed that CEEs induce activity of the ERE reporter gene in an STS-dependent manner and that genetic or pharmacological inhibition of STS attenuates CEE estrogenic activity. In hepatocytes, inflammation enhanced CEE estrogenic activity by inducing STS gene expression. The inflammation-responsive estrogenic activity of CEEs, in turn, attenuated inflammation through the anti-inflammatory activity of the active estrogens. In vivo, transgenic mice with liver-specific STS expression exhibited markedly increased sensitivity to CEE-induced estrogenic activity in the uterus resulting from increased levels of liver-derived and circulating estrogens. Our results reveal a critical role of hepatic STS in mediating the hormone-replacing activity of CEEs. We propose that caution needs to be applied when Premarin is used in patients with chronic inflammatory liver diseases because such patients may have heightened sensitivity to CEEs due to the inflammatory induction of STS activity.