MLKL deficiency alleviates acute alcoholic liver injury via inhibition of NLRP3 inflammasome.

Mixed lineage kinase domain-like protein (MLKL) is identified as the terminal executor of necroptosis. However, its role in acute alcoholic liver injury remains unclear. This study elucidates that MLKL can contribute to acute alcoholic liver injury independently of necroptosis. Although the expression of MLKL was upregulated, no significant increase in its phosphorylation or membrane translocation was observed in the liver tissues of mice treated with ethanol. This finding confirms that alcohol intake does not induce necroptosis in mouse liver tissue. Additionally, the deletion of Mlkl resulted in the downregulation of NLRP3 expression, which subsequently inhibited the activation of the NLRP3 inflammasome and the ensuing inflammatory response, thereby effectively mitigating liver injury induced by acute alcohol consumption. The knockout of Nlrp3 did not affect the expression of MLKL, further confirming that MLKL acts upstream of NLRP3. Mechanistically, inhibiting the nuclear translocation of MLKL reduced the nuclear entry of p65, the principal transcriptional regulator of NLRP3, thereby limiting the transcription of Nlrp3 mRNA and subsequent NLRP3 expression. Overall, this study unveils a novel mechanism of MLKL regulates the activation of NLRP3 inflammasomes in a necroptosis independent way in acute alcoholic liver injury.

Single-Pixel Imaging Based on Deep Learning Enhanced Singular Value Decomposition.

We propose and demonstrate a single-pixel imaging method based on deep learning network enhanced singular value decomposition. The theoretical framework and the experimental implementation are elaborated and compared with the conventional methods based on Hadamard patterns or deep convolutional autoencoder network. Simulation and experimental results show that the proposed approach is capable of reconstructing images with better quality especially under a low sampling ratio down to 3.12%, or with fewer measurements or shorter acquisition time if the image quality is given. We further demonstrate that it has better anti-noise performance by introducing noises in the SPI systems, and we show that it has better generalizability by applying the systems to targets outside the training dataset. We expect that the developed method will find potential applications based on single-pixel imaging beyond the visible regime.

Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury.

Nuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.

High-efficiency terahertz single-pixel imaging based on a physics-enhanced network.

As an alternative solution to the lack of cost-effective multipixel terahertz cameras, terahertz single-pixel imaging that is free from pixel-by-pixel mechanical scanning has been attracting increasing attention. Such a technique relies on illuminating the object with a series of spatial light patterns and recording with a single-pixel detector for each one of them. This leads to a trade-off between the acquisition time and the image quality, hindering practical applications. Here, we tackle this challenge and demonstrate high-efficiency terahertz single-pixel imaging based on physically enhanced deep learning networks for both pattern generation and image reconstruction. Simulation and experimental results show that this strategy is much more efficient than the classical terahertz single-pixel imaging methods based on Hadamard or Fourier patterns, and can reconstruct high-quality terahertz images with a significantly reduced number of measurements, corresponding to an ultra-low sampling ratio down to 1.56%. The efficiency, robustness and generalization of the developed approach are also experimentally validated using different types of objects and different image resolutions, and clear image reconstruction with a low sampling ratio of 3.12% is demonstrated. The developed method speeds up the terahertz single-pixel imaging while reserving high image quality, and advances its real-time applications in security, industry, and scientific research.

Suppression of SIRT1/FXR signaling pathway contributes to oleanolic acid-induced liver injury.

Oleanolic acid (OA) is a pentacyclic triterpenoid compound used clinically for acute and chronic hepatitis. However, high dose or long-term use of OA causes hepatotoxicity, which limits its clinical application. Hepatic Sirtuin (SIRT1) participates in the regulation of FXR signaling and maintains hepatic metabolic homeostasis. This study was designed to determine whether SIRT1/FXR signaling pathway contributes to the hepatotoxicity caused by OA. C57BL/6J mice were administered with OA for 4 consecutive days to induce hepatotoxicity. The results showed that OA suppressed the expression of FXR and its downstream targets CYP7A1, CYP8B1, BSEP and MRP2 at both mRNA and protein levels, breaking the homeostasis of bile acid leading to hepatotoxicity. However, treatment with FXR agonist GW4064 noticeably attenuated hepatotoxicity caused by OA. Furthermore, it was found that OA inhibited protein expression of SIRT1. Activation of SIRT1 by its agonist SRT1720 significantly improved OA-induced hepatotoxicity. Meanwhile, SRT1720 significantly reduced the inhibition of protein expression of FXR and FXR-downstream proteins. These results suggested that OA may cause hepatotoxicity through SIRT1 dependent suppression of FXR signaling pathway. In vitro experiments confirmed that OA suppressed protein expressions of FXR and its targets through inhibition of SIRT1. It was further revealed that silencing of HNF1α with siRNA significantly weakened regulatory effects of SIRT1 on the expression of FXR as well as its target genes. In conclusion, our study reveals that SIRT1/FXR pathway is crucial in OA-induced hepatotoxicity. Activation of SIRT1/HNF1α/FXR axis may represent a novel therapeutic target for ameliorating OA and other herb-induced hepatotoxicity.

AMP-activated protein kinase-farnesoid X receptor pathway contributes to oleanolic acid-induced liver injury.

Natural pentacyclic triterpenoid oleanolic acid (OA) is used as an over-the-counter drug for acute and chronic hepatitis. However, clinical use of OA-containing herbal medicines has been reported to cause cholestasis, and the specific mechanism is unknown. The purpose of this study was to explore how OA causes cholestatic liver injury via the AMP-activated protein kinase (AMPK)-farnesoid X receptor (FXR) pathway. In animal experiments, it was found that OA treatment activated AMPK and decreased FXR and bile acid efflux transport proteins expression. When intervened with the specific inhibitor Compound C (CC), it was observed that AMPK activation was inhibited, the reduction of FXR and bile acid efflux transport protein expression was effectively alleviated, serum biochemical indicators were significantly reduced, and liver pathological damage brought about by OA was effectively ameliorated. In addition, OA was found to downregulate the expression of FXR and bile acid efflux transport proteins by activating the ERK1/2-LKB1-AMPK pathway in cellular experiments. The ERK1/2 inhibitor U0126 was used to pretreat primary hepatocytes, and this drastically reduced the phosphorylation levels of LKB1 and AMPK. The inhibition effects of OA on FXR and bile acid efflux transport proteins were also effectively alleviated after pretreatment with CC. In addition, OA-induced downregulation of FXR gene and protein expression levels was significantly prevented after silencing AMPKα1 expression in AML12 cells. Our study demonstrated that OA inhibited FXR and bile acid efflux transporters through the activation of AMPK, thus leading to cholestatic liver injury.

miR-16-5p Is a Novel Mediator of Venous Smooth Muscle Phenotypic Switching.

Vein graft failure after coronary artery bypass grafting (CABG) is primarily caused by intimal hyperplasia, which results from the phenotypic switching of venous smooth muscle cells (SMCs). This study investigates the role and underlying mechanism of miR-16-5p in the phenotypic switching of venous SMCs. In rats, neointimal thickness and area increased over time within 28 days after CABG, as did the time-dependent miR-16-5p downregulation and SMC phenotypic switching. Platelet-derived growth factor-BB-induced miR-16-5p downregulation in HSVSMCs was accompanied by and substantially linked with alterations in phenotypic switching indicators. Furthermore, miR-16-5p overexpression increased SMCs differentiation marker expression while suppressing HSVSMCs proliferation and migration and drastically inhibiting neointimal development in vein grafts. The miR-16-5p inhibited zyxin expression, which was necessary for HSVSMCs phenotypic switching. The miR-16-5p/zyxin axis is a novel, potentially therapeutic target for preventing and treating venous graft intimal hyperplasia.

Extremely Narrow and Actively Tunable Mie Surface Lattice Resonances in GeSbTe Metasurfaces: Study.

Mie surface lattice resonances (SLRs) supported by periodic all-dielectric nanoparticles emerge from the radiative coupling of localized Mie resonances in individual nanoparticles through Rayleigh anomaly diffraction. To date, it remains challenging to achieve narrow bandwidth and active tuning simultaneously. In this work, we report extremely narrow and actively tunable electric dipole SLRs (ED-SLRs) in Ge2Se2Te5 (GST) metasurfaces. Simulation results show that, under oblique incidence with TE polarization, ED-SLRs with extremely narrow linewidth down to 12 nm and high quality factor up to 409 can be excited in the mid-infrared regime. By varying the incidence angle, the ED-SLR can be tuned over an extremely large spectral region covering almost the entire mid-infrared regime. We further numerically show that, by changing the GST crystalline fraction, the ED-SLR can be actively tuned, leading to nonvolatile, reconfigurable, and narrowband filtering, all-optical multilevel modulation, or all-optical switching with high performance. We expect that this work will advance the engineering of Mie SLRs and will find intriguing applications in optical telecommunication, networks, and microsystems.

Farnesoid X receptor contributes to oleanolic acid-induced cholestatic liver injury in mice.

Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug-induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a long-term use. The present study aimed to investigate the role of FXR in OA-induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR-/- ) mice. The results showed that a significant alleviation in OA-induced cholestatic liver injury was observed in FXR-/- mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC-MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR-/- mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR-/- mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR-/- mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA-induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes.

Suppressed farnesoid X receptor by iron overload in mice and humans potentiates iron-induced hepatotoxicity.

BACKGROUND AND AIMS: Iron overload (IO) is a frequent finding in the general population. As the major iron storage site, the liver is subject to iron toxicity. Farnesoid X receptor (FXR) regulates bile acid metabolism and is implicated in various liver diseases. We aimed to determine whether FXR plays a role in regulating iron hepatotoxicity. APPROACH AND RESULTS: Human and mouse hepatocytes were treated with ferric ammonium citrate or iron dextran (FeDx). Mice were orally administered ferrous sulfate or injected i.p. with FeDx. Wild-type and Fxr-/- mice were fed an iron-rich diet for 1 or 5 weeks. Mice fed an iron-rich diet were coadministered the FXR agonist, GW4064. Forced expression of FXR was carried out with recombinant adeno-associated virus 1 week before iron-rich diet feeding. Serum levels of bile acids and fibroblast growth factor 19 (FGF19) were quantified in adults with hyperferritinemia and children with ß-thalassemia. The data demonstrated that iron suppressed FXR expression and signaling in human and mouse hepatocytes as well as in mouse liver and intestine. FXR deficiency potentiated iron hepatotoxicity, accompanied with hepatic steatosis as well as dysregulated iron and bile acid homeostasis. FXR negatively regulated iron-regulatory proteins 1 and 2 and prevented hepatic iron accumulation. Forced FXR expression and ligand activation significantly suppressed iron hepatotoxicity in iron-fed mice. The FXR agonist, GW4064, almost completely restored dysregulated bile acid signaling and metabolic syndrome in iron-fed mice. Conjugated primary bile acids were increased and FGF19 was decreased in serum of adults with hyperferritinemia and children with ß-thalassemia. CONCLUSIONS: FXR plays a pivotal role in regulating iron homeostasis and protects mice against iron hepatotoxicity. Targeting FXR may represent a therapeutic strategy for IO-associated chronic liver diseases.

Ultra-broadband terahertz bandpass filter with dynamically tunable attenuation based on a graphene-metal hybrid metasurface.

We propose an ultra-broadband terahertz bandpass filter with dynamically tunable attenuation based on a graphene-metal hybrid metasurface. The metasurface unit cell is composed of two metal stripes enclosed with a graphene rectangular ring. Results show that when the metasurface is normally illuminated by a terahertz wave polarized along the metal stripes, it can act as an ultra-broadband bandpass filter over the spectral range from 1.49 THz to 4.05 THz, corresponding to a fractional bandwidth of 92%. Remarkably, high transmittance above 90% covering the range from 1.98 THz to 3.95 THz can be achieved. By changing the Fermi level of graphene, we find that the attenuation within the passband can be dynamically tuned from 2% to 66%. We expect that the proposed ultra-broadband terahertz bandpass filter with tunable attenuation will find applications in terahertz communication and detection and sensing systems.

Cinnabar protects serum-nutrient starvation induced apoptosis by improving intracellular oxidative stress and inhibiting the expression of CHOP and PERK.

Cinnabar has been used for treatment of various disorders for thousands of years. The medical use of cinnabar, however, has been controversial because of its heavy metal mercury content. A large quantity of studies indicate that the toxicity of cinnabar is far below other inorganic or organic mercury-containing compounds. Yet, the underlying molecular basis has remained unresolved. Here, we investigated the beneficial effects of cinnabar on serum-nutrient starvation-elicited cell injury. Our findings showed that treatment of human renal proximal tubular cells (HK-2) with 4 nM cinnabar effectively inhibited nutrient deprivation induced apoptosis, reduced intracellular reactive oxygen species generation and increased GSH content, which was contrary to the exacerbated apoptotic cell death and oxidative stress in cells treated with HgCl2 at equal mercury concentration. In addition, cinnabar exerted robust antioxidative and antiapoptotic effects in cells under dual challenges of nutrient deprivation and treatment of H2O2. The protein expression levels of both CHOP and PERK were remarkably down-regulated in the cells treated with cinnabar compared to the control cells or cells treated with HgCl2. Overall, our data indicates that cinnabar at low concentration exerts anti-oxidative stress and anti-apoptosis effects by inhibiting the expression of the endoplasmic reticulum stress pathway proteins CHOP and PERK.

Potentiation of flutamide-induced hepatotoxicity in mice by Xian-Ling-Gu-Bao through induction of CYP1A2.

ETHNOPHARMACOLOGICAL RELEVANCE: Xian-Ling-Gu-Bao (XLGB) Fufang is herbal formula widely used to treat osteoporosis and other bone disorders. Because of its commonality in the clinical use, there is a safety concern over the use of XLGB combined with other androgen deprivation therapy (ADT) drugs such as flutamide (FLU) that is associated with reduced bone density. To date, there have been no evaluations on the side effects of the drug-drug interaction between XLGB and FLU. AIM OF THE STUDY: The present study was designed to investigate the hepatotoxicity in the context of the combined treatment of XLGB and FLU in a mouse model, and to determine whether the metabolic activation of FLU through induction of CYP1A2 plays a role in the increased hepatoxicity caused by the combination of XLGB and FLU. MATERIALS AND METHODS: C57 mice were administered with either XLGB (6,160 mg/kg), FLU (300 mg/kg), or with the combination of the two drugs. Animals were treated with XLGB for 5 days before the combined administration of XLGB and FLU for another 4 days. The serum of mice from single or the combined administration groups was collected for biochemical analysis. The mouse liver was collected to examine liver morphological changes, evaluate liver coefficient, as well as determine the mRNA expression of P450 isozymes (Cyp1a2, Cyp3a11 and Cyp2c37). For metabolism analysis, mice were treated with XLGB, FLU, or the combination of XLGB and FLU for 24 h. The urine samples were collected for the analysis of FLU-NAC conjugate by UPLC-Q-Orbitrap MS. The liver microsomes were prepared from fresh livers to determine the activity of metabolizing enzyme CYP1A2. RESULTS: The combined treatment of XLGB and FLU caused loss of mice body weight and elicited significant liver toxicity as evidenced by an increased liver coefficient and serum lactate dehydrogenase (LDH) activity as well as pathological changes of fatty lesion of liver tissue. FLU increased hepatic expression of Cyp1a2 mRNA that was further elevated in the liver of mice when administered with both FLU and XLGB. Treatment of FLU resulted in an increase in the expression of Cyp3a11 mRNA that was negated when mice were co-treated with FLU and XLGB. No significant difference in Cyp2c37 mRNA expression was observed among the different treatment groups as compared to the control. Analysis of metabolic activity showed that the combined administration caused a synergic effect in elevating the activity of the CYP1A2 enzyme. Mass spectrometry analysis identified the presence of FLU reactive metabolite derived FLU-NAC conjugate in the urine of mice treated with FLU. Strikingly, about a two-fold increase of the FLU-NAC conjugate was detected when treated with both FLU and XLGB, indicating an elevated amount of toxic metabolite produced from FLU in the present of XLGB. CONCLUSION: FLU and XLGB co-treatment potentiated FLU-induced hepatoxicity. This increased hepatoxicity was mediated through the induction of CYP1A2 activity which in turn enhanced bioactivation of FLU leading to over production of FLU-NAC conjugate and oxidative stress. These results offer warnings about serious side effects of the FLU-XLGB interaction in the clinical practice.

Dendrobium nobile Lindl. alkaloids alleviate Mn-induced neurotoxicity via PINK1/Parkin-mediated mitophagy in PC12 cells.

Modern pharmacological studies have demonstrated that Dendrobium nobile Lindl. Alkaloids (DNLA), the main active ingredients of Dendrobium nobile, is valuable as an anti-aging and neuroprotective herbal medicine. The present study was designed to determine whether DNLA confers protective function over neurotoxicant manganese (Mn)-induced cytotoxicity and the mechanism involved. Our results showed that pretreatment of PC12 cells with DNLA alleviated cell toxicity induced by Mn and improved mitochondrial respiratory capacity and oxidative status. Mn treatment increased apoptotic cell death along with a marked increase in the protein expression of Bax and a decrease in the expression of Bcl-2 protein, all of which were noticeably reversed by DNLA. Furthermore, DNLA significantly abolished the decrease in protein levels of both PINK1 and Parkin, and mitigated the increased expression of autophagy marker LC3-II and accumulation of p62 caused by Mn. These results demonstrate that DNLA inhibits Mn induced cytotoxicity, which may be mediated through modulating PINK1/Parkin-mediated autophagic flux and improving mitochondrial function.

Expression of cytochrome P450 isozyme transcripts and activities in human livers.

Individual differences in cytochrome P450 (CYP) enzymes contribute to responses to drugs and environmental chemicals. The expression of CYPs is influenced by sex, age, and ethnicity. Human CYP studies are often conducted with human liver microsomes and liver cells to evaluate chemical induction and drug interactions. However, the basal or constitutive expression of CYP transcripts and enzyme activities in the intact liver are also important in our understanding of individual variation in CYPs. This study utilised 100 human liver samples to profile the constitutive expression of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 4A11 enzyme activity and transcript levels. The mRNA expression of the CYPs and xenobiotic receptors AhR, CAR, and PXR was examined via qPCR. Results showed that there was greater inter-individual variation in mRNA expression than in enzyme activities, except for CYP2C19. Females had higher CYP3A4 activity than males. Children had lower CYP4A14 activity, while elderly had lower P450 oxidoreductase activity. Compared to Caucasians, Hispanics had higher CYP2C8 activity and higher CYP2B6, CYP2C9, and CYP2C19 mRNA expression, whereas African Americans had lower CYP2D6 mRNA expression. These results add to our understanding of individual variations in xenobiotic metabolism and toxicology.

A novel LC-MS/MS method for quantification of unstable endogenous 3,4-dihydroxyphenylacetaldehyde in rat brain after chemical derivatization.

3,4-dihydroxyphenylacetaldehyde (DOPAL), a toxic intermediary metabolite of dopamine (DA), causes catecholaminergic neurodegeneration via covalent binding with functional proteins or other biomolecules. Accurate quantification of DOPAL is essential to investigate the etiological factors associated with DOPAL and the pathogenetic role of DOPAL in Parkinson's disease (PD). However, no validated quantitative methods are available. Quantification of DOPAL in biosample is challenging since it is a reactive endogenous aldehyde with poor ionization efficiency and chromatographic behavior in the LC-MS system. Here, a sensitive, simple, and robust UPLC-MS/MS method has been established and validated for the determination of DOPAL in rat brain tissue specimens. DOPAL was found to be unstable in biosample due to reactive aldehyde whereas it was stable in acidic condition. The analyte was stabilized by pH and temperature control during the sample preparation and derivatization. Then, a chemical derivatization method that can be readily performed in acidic conditions and at low temperature was employed using 2-hydrazino-4-(trifluoromethyl)-pyrimidine (HTP) to block the reactive aldehyde and improve the detection sensitivity (about 100-fold increase) and chromatographic retention. Bovine serum albumin was used as a surrogate matrix, which was validated by the parallelism assay and post-column infusion experiment. This method was fully validated and the lower limit of quantification (LLOQ) was 0.5 ng/mL. With the method, a significant increase of DOPAL level was found in striatum region of rats received 6-hydroxydopamine (6-OHDA) injection for 12 h, indicating DOPAL may play a pathogenic role in 6-OHDA-induced PD model.

Changes in global Orchidaceae disease geographical research trends: recent incidences, distributions, treatment, and challenges.

Many of the Orchidaceae species are threatened due to environmental changes and over exploitation for full fill global demands. The main objective of this article was critically analyzed the recent global distribution of Orchidaceae diversity, its disease patterns, microbial disease identification, detection, along with prevention and challenges. Critical analysis findings revealed that Orchidaceae growth and developments were affected indirectly or directly as a result of complex microbial ecological interactions. Studies have identified many species associated with orchids, some are pathogenic and cause symptoms such as soft rot, brown rot, brown spot, black rot, wilt, foliar, root rot, anthracnose, leaf spot. The review was provided the comprehensive data to evaluate the identification and detection of microbial disease, which is the most important challenge for sustainable cultivation of Orchidaceae diversity. Furthermore, this article is the foremost of disease triggering microbes, orchid relations, and assimilates various consequences that both promoted the considerate and facts of such disease multipart, and will permit the development of best operative disease management practices.

Sex-, Age-, and Race/Ethnicity-Dependent Variations in Drug-Processing and NRF2-Regulated Genes in Human Livers.

Individual variations in xenobiotic metabolism affect the sensitivity to diseases. In this study, the impacts of sex, age, and race/ethnicity on drug-processing genes and nuclear factor erythroid 2-related factor 2 (NRF2) genes in human livers were examined via QuantiGene multiplex suspension array (226 samples) and quantitative polymerase chain reaction (qPCR) (247 samples) to profile the expression of nuclear receptors, cytochrome P450s, conjugation enzymes, transporters, bile acid metabolism, and NRF2-regulated genes. Sex differences were found in expression of about half of the genes, but in general the differences were not large. For example, females had higher transcript levels of catalase, glutamate-cysteine ligase catalytic subunit (GCLC), heme oxygenase 1 (HO-1), Kelch-like ECH-associated protein 1 (KEAP1), superoxide dismutase 1, and thioredoxin reductase-1 compared with males via qPCR. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subunit (GCLM) and elderly had higher multidrug resistance protein 3. African Americans had lower expression of farnesoid X receptor (FXR) but higher expression of HO-1, Caucasians had higher expression of organic anion transporter 2, and Hispanics had higher expression of FXR, SULT2A1, small heterodimer partner, and bile salt export pump. An examination of 34 diseased and control human liver samples showed that compared with disease-free livers, fibrotic livers had higher NAD(P)H-quinone oxidoreductase 1 (NQO1), GCLC, GCLM, and NRF2; hepatocellular carcinoma had higher transcript levels of NQO1 and KEAP1; and steatotic livers had lower GCLC, GCLM, and HO-1 expression. In summary, in drug-processing gene and NRF2 genes, sex differences were the major findings, and there were no apparent age differences, and race/ethnicity differences occurred for a few genes. These descriptive findings could add to our understanding of the sex-, age-, and race/ethnicity-dependent differences in drug-processing genes as well as NRF2 genes in normal and diseased human livers. SIGNIFICANCE STATEMENT: In human liver drug-processing and nuclear factor erythroid 2-related factor 2 genes, sex differences were the main finding. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subunit, and elderly had higher multidrug resistance protein 3. African Americans had lower expression of farnesoid X receptor (FXR) but higher expression of heme oxygenase 1, Caucasians had higher expression of organic anion transporter 2, and Hispanics had higher expression of FXR, small heterodimer partner, SULT2A1, and bile salt export pump.

Switchable broadband and wide-angular terahertz asymmetric transmission based on a hybrid metal-VO2 metasurface.

We propose a switchable broadband and wide-angular terahertz asymmetric transmission based on a spiral metasurface composed of metal and VO2 hybrid structures. Results show that asymmetric transmission reaching up to 15% can be switched on or off for circularly polarized terahertz waves when the phase of VO2 transits from the insulting state to the conducting state or reversely. Strikingly, we find that relatively high asymmetric transmission above 10% can be maintained over a broad bandwidth of 2.6-4.0 THz and also over a large incident angular range of 0°-45°. We further discover that as the incident angle increases, the dominant chirality of the proposed metasurface with VO2 in the conducting state can shift from intrinsic to extrinsic chirality. We expect this work will advance the engineering of switchable chiral metasurfaces and promote terahertz applications.

LC-MS-Based Metabolomic Study of Oleanolic Acid-Induced Hepatotoxicity in Mice.

Oleanolic acid (OA), a natural triterpenoid, which has the development prospects in anti-tumor therapy is a widely used hepatoprotective drug in China. It has been reported that OA can cause liver toxicity after higher doses or longer-term use. Therefore, the study aims to explore the possible hepatotoxicity mechanism based on liver metabolic profiles. Liver metabolic profiles were obtained from untargeted ultrahigh performance liquid chromatography (UHPLC)-Q Exactive Orbitrap mass spectrometry (MS) technique. It was found that altered bile acid, amino acid, and energy metabolism might be at least partly responsible for OA-induced hepatotoxicity. Bile acid metabolism, as the most important pathway, was verified by using UHPLC-TSQ-MS, indicating that conjugated bile acids were the main contributors to OA-induced liver toxicity. Our findings confirmed that increased bile acids were the key element of OA hepatotoxicity, which may open new insights for OA hepatotoxicity in-depth investigations, as well as provide a reference basis for more hepatotoxic drug mechanism research.