G-quadruplex DNA-based colorimetric biosensor for the ultrasensitive visual detection of strontium ions using MnO2 nanorods as oxidase mimetics.

Strontium-90 (90Sr) is a major radioactive component that has attracted great attention, but its detection remains challenging since there are no specific energy rays indicative of its presence. Herein, a biosensor that is capable of rapidly detecting Sr2+ ions is demonstrated. Simple colorimetric method for sensitive detection of Sr2+ with the help of single-stranded DNA was developed by preparing MnO2 nanorods as oxidase mimic catalysis 3,3',5,5'-tetramethylbenzidine (TMB). Under weakly acidic conditions, MnO2 exhibited a strong oxidase-mimicking activity to oxidize colorless TMB into blue oxidation products (oxTMB) with discernible absorbance signals. Nevertheless, the introduction of a guanine-rich DNA aptamer inhibited MnO2-mediated TMB oxidation and reduced oxTMB formation, resulting in blue fading and diminished absorbance. Upon the addition of strontium ions to the system, the aptamers formed a stable G-quadruplex structure with strontium ions, thereby restoring the oxidase-mimicking activity of MnO2. Under the best experimental conditions, the absorbance exhibits a linear relationship with the Sr2+ concentration within the range 0.01-200 µM, with a limit of detection of 0.0028 µM. When the concentration of Sr2+ from 10-8 to 10-6 mol L-1, a distinct color change gradient could be observed in paper-based sensor. We successfully applied this approach to determine Sr2+ in natural water samples, obtaining recoveries ranging from 97.6 to 103% with a relative standard deviation of less than 5%. By providing technical solutions for detection, our work contributed to the effective monitoring of transportation of radioactive Sr in the environment.

Solvent-controlled two-step one-pot syntheses of α-X (X = Br or Cl) enamino ketones/esters and 3-(2,5-dioxopyrrolidin-1-yl)acrylate by using terminal carbonyl alkynes.

A new two-step one-pot aminobromination/chlorination of carbonyl alkynes has been achieved via a Michael addition of aliphatic secondary amines and subsequent ß-bromination/chlorination of the obtained enamines to afford various α-X (X = Br or Cl) enamino ketones/esters in moderate to good yields. A solvent-controllable protocol has been developed to produce versatile 3-(2,5-dioxopyrrolidin-1-yl)acrylates in moderate yields by using toluene as the solvent and chain alkyl propiolates as alkynyl substrates.

Low abundance of TFPI-2 by both promoter methylation and miR-27a-3p regulation is linked with poor clinical outcome in gastric cancer.

BACKGROUND: The tumor suppressor role of tissue factor pathway inhibitor 2 (TFPI-2) has been reported in various tumors. The present study aimed to improve the understanding of the oncogenic properties of TFPI-2 in gastric cancer. METHODS: Relative expression of TFPI-2 was determined by a real-time polymerase chain reaction (PCR) and western blotting, respectively. Cell viability was measured via a cell counting kit-8 assay and proliferation was evaluated by a colony formation assay. Cell apoptosis was assessed with a caspase-3 activity kit and invasion was evaluated by a transwell chamber assay. The methylation level of TFPI-2 promoter was assayed by methylation-specific PCR. The regulatory effect of miR-27a-3p on TFPI-2 was analyzed with a luciferase reporter assay. The direct association between miR-27a-3p and TFPI-2 was shown by biotin-labelling pulldown. RESULTS: TFPI-2 was down-regulated in gastric cancer, which associated with an unfavorable prognosis clinically. Ectopic introduction of TFPI-2 greatly compromised cell viability, colony formation and invasive capacity, and also induced cell apoptosis simultaneously. The promoter region of TFPI-2 was extensively methylated in gastric cancer tissues compared to normal tissues, suggesting the epigenetic inhibition of TFPI-2 expression. We further identified that TFPI-2 functioned as sponge RNA against miR-27a-3p. Most importantly, miR-27a-3p-specific inhibitor significantly exerted a tumor suppressor function akin to TFPI-2 itself, and the anti-tumoral activities were completely abolished by TFPI-2 knockdown. CONCLUSIONS: We found that the epigenetically suppressed TFPI-2 compromised sponging effects with respect to miR-27a-3p in gastric cancer, which consequently and mechanistically contributed to the tumor biology of gastric cancer.

Dietary Glycyrrhiza uralensis extracts supplementation elevated growth performance, immune responses and disease resistance against Flavobacterium columnare in yellow catfish (Pelteobagrus fulvidraco).

The present study was conducted to evaluate the influence of Glycyrrhiza uralensis (G. uralensis) extracts on the growth performance, histological structure, immune response and disease resistance against Flavobacterium columnare (F. columnare) of yellow catfish. Fish were fed with two different diets, i.e., basal diet as control group (CG) and diet containing G. uralensis extracts as experimental group (GG). After 60 days feeding, growth performance of GG fish was significantly improved, with increased WG and SGR but decreased FCR compared to CG fish. Fish were then challenged with F. columnare for two times, as fish showed rare mortality after the first infection. GG fish showed significantly lower cumulative mortality during F. cloumnare infection than CG fish after 21 days infection (dpi). Epithelial cell exfoliation and obvious cellular vacuolization in the skin and congestion of gill lamellae were detected in CG fish, while GG fish showed increased width of epidermis and mucous cells number in skin, and increased length of secondary lamina in gill. GG fish also exhibited higher enzyme activity of lysozyme in serum and mRNA expression of lysozyme in head kidney than CG fish at most time points post infection. G. uralensis extracts supplementation also induced earlier serum anti-oxidative responses, with increased superoxide dismutase activity and total antioxidant capacity in GG fish at 1 dpi. Compared to CG fish, GG fish showed increased expression level of genes involved in TLRs-NFκB signaling (TLR2, TLR3, TLR5, TLR9, Myd88, and p65NFκB), resulting in higher expression levels of pro-inflammatory cytokines (IL-1ß and IL-8) in the head kidney post infection. However, these genes showed deviation in the gill of GG fish, which increased at some time points but decreased at other time points. Moreover, G. uralensis extracts supplementation also significantly unregulated the expression levels of IgM and IgD in head kidney, and the expression levels of IgM in the gill of yellow catfish, suggesting the elevated humoral immune response during F. columnare infection. All these results contributed to the elevated disease resistance ability against F. cloumnare infection of yellow catfish after dietary G. uralensis extracts supplementation.

Specific diacylglycerols generated by hepatic lipogenesis stimulate the oncogenic androgen receptor activity in male hepatocytes.

BACKGROUND: Obesity-induced hepatocellular carcinoma (HCC) is more prevalent in males than in females, but the underlying mechanism remains unclear. The influence of hepatic androgen receptor (AR) pathway on the gender difference of HCC has been well documented. Here we investigated the role of hepatic lipogenesis, which is elevated in the livers of obese and nonalcoholic fatty liver disease (NAFLD) patients, in stimulating the AR pathway for the male preference of obesity induced HCC. METHODS: Male C57BL/6J mice were fed a fructose-rich high carbohydrate diet (HCD) to induce hepatic lipogenesis. The effect of hepatic lipogenesis on AR was examined by the expression of hydrodynamically injected AR reporter and the endogenous AR target gene; the mechanism was delineated in hepatoma cell lines and validated in male mice. RESULTS: The hepatic lipogenesis induced by a fructose-rich HCD enhanced the transcriptional activity of hepatic AR in male mice, which did not happen when fed a high fat diet. This AR activation was blocked by sh-RNAs or inhibitors targeting key enzymes in lipogenesis, either acetyl-CoA carboxylase subunit alpha (ACCα), or fatty acid synthase (FASN), in vivo and in vitro. Further mechanistic study identified that specific unsaturated fatty acid, the oleic acid (C18:1 n-9), incorporated DAGs produced by hepatic lipogenesis are the key molecules to enhance the AR activity, through activation of Akt kinase, and this novel mechanism is targeted by metformin. CONCLUSIONS: Our study elucidates a novel mechanism underlying the higher risk of HCC in obese/NAFLD males, through specific DAGs enriched by hepatic lipogenesis to increase the transcriptional activity of hepatic AR, a confirmed risk factor for male HCC.

Hypoxia-activated cytotoxic agent tirapazamine enhances hepatic artery ligation-induced killing of liver tumor in HBx transgenic mice.

Transarterial chemoembolization (TACE) is the main treatment for intermediate stage hepatocellular carcinoma (HCC) with Barcelona Clinic Liver Cancer classification because of its exclusive arterial blood supply. Although TACE achieves substantial necrosis of the tumor, complete tumor necrosis is uncommon, and the residual tumor generally rapidly recurs. We combined tirapazamine (TPZ), a hypoxia-activated cytotoxic agent, with hepatic artery ligation (HAL), which recapitulates transarterial embolization in mouse models, to enhance the efficacy of TACE. The effectiveness of this combination treatment was examined in HCC that spontaneously developed in hepatitis B virus X protein (HBx) transgenic mice. We proved that the tumor blood flow in this model was exclusively supplied by the hepatic artery, in contrast to conventional orthotopic HCC xenografts that receive both arterial and venous blood supplies. At levels below the threshold oxygen levels created by HAL, TPZ was activated and killed the hypoxic cells, but spared the normoxic cells. This combination treatment clearly limited the toxicity of TPZ to HCC, which caused the rapid and near-complete necrosis of HCC. In conclusion, the combination of TPZ and HAL showed a synergistic tumor killing activity that was specific for HCC in HBx transgenic mice. This preclinical study forms the basis for the ongoing clinical program for the TPZ-TACE regimen in HCC treatment.

Residual bone fragments in tibiofibular joint and postoperative local recurrence: an analysis of 21 cases of proximal fibular giant cell tumour.

BACKGROUND: Currently, there are no known reports on the aetiology of local giant cell tumour (GCT) recurrence in the proximal fibula following en bloc resection. We analysed 21 cases of proximal fibular GCT, focusing on the presence of residual bone in the tibiofibular joint, its causes and its impact on postoperative recurrence. METHODS: We retrospectively analysed 21 cases with proximal fibular GCT occurring between 2000 and 2017. RESULTS: There were 14 males and 7 females. The average patient age was 25.0 years. Seventeen patients were diagnosed and treated at our facility, while 4 were referred after local recurrence. Six patients presented with residual bone fragments in the tibiofibular joint during their first month of follow-up. Patients with residual bone fragments had a higher local recurrence rate (83.3%) than those without (0%, p = 0.0003). Upon further analysis, patients with a preoperative Campanacci grade III tumour (p = 0.0055) and pathological fractures (p = 0.0109) were at a higher risk of exhibiting postoperative residual bone fragments. CONCLUSIONS: The presence of residual bone fragments in the tibiofibular joint was the main cause of postoperative local recurrence. The presence of residual bone fragments may be related to the preoperative Campanacci grade and pathological fractures. Therefore, close attention should be paid to postoperative follow-up examinations, and if recurrence is suspected, surgical resection should be planned.

Identification of autophagy-related signatures in nonalcoholic fatty liver disease and correlation with non-parenchymal cells of the liver.

Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disease. The incidence and prevalence of NAFLD have increased greatly in recent years, and there is still a lack of effective drugs. Autophagy plays an important role in promoting liver metabolism and maintaining liver homeostasis, and defects in autophagy levels are considered to be related to the development of NAFLD. However, the molecular mechanisms of autophagy in NAFLD still remain unknown. In this study, we identified 6 autophagy-associated hub genes using gene expression profiles obtained from the GSE48452 and GSE89632 datasets. Biomarkers were screened according to gene significance (GS) and module membership (MM) using weighted gene co-expression network analysis (WGCNA), and the immune infiltration landscape of the liver in NAFLD patients was explored using the CIBERSORT algorithm. Subsequently, we analyzed the relationship between liver non-parenchymal cells and autophagy-related hub genes using scRNA-seq data (GSE129516). Finally, we separated the NAFLD patients into two groups based on 6 hub genes by consensus clustering and screened 10 potential autophagy-related small molecules based on the cMAP database.

Biomolecular Condensates Based on Amino Acid for Enhancing Oral Bioavailability and Therapeutic Efficacy of Hydrophobic Drugs.

The oral administration of chemo- or immunotherapeutic drugs presents a compelling alternative for patients with malignant colorectal cancer, offering a convenient and patient-compliant "hospital-free" strategy. Unfortunately, the hydrophobic nature of many drug candidates, alongside the harsh conditions of the gastrointestinal tract, frequently results in suboptimal bioavailability and heightened systemic toxicity. To address these challenges, we harnessed the unique properties of biomolecular condensates, which form through a liquid-liquid phase separation mechanism, to develop a versatile platform for drug encapsulation and delivery. In this study, we introduce a reliable and effective amorphous oral drug delivery system based on biomolecular condensates derived from the amino acid derivative N-(benzyloxycarbonyl)-l-proline (ZP). These ZP condensates exhibit dynamic intermolecular interactions and possess unique physicochemical attributes such as fluidity and viscoelasticity. They significantly improve the solubility of hydrophobic drugs, ensuring enhanced stability and optimized pharmacokinetics under physiological and gastrointestinal conditions. By maintaining drugs in an amorphous state, we substantially increased drug bioavailability and markedly improved pharmacokinetics. Furthermore, the ZP condensates demonstrate potential as an integrated therapeutic platform capable of potentiating the synergies between chemotherapy and immunotherapy while concurrently reducing systemic toxicity. This has resulted in a significant enhancement of chemo-immunotherapy efficacy in the treatment of colorectal cancer, representing a notable advancement in drug delivery and oncology.

Bimetallic mutual-doping magnetic aerogels for iodine reduction capture and immobilization.

Adsorption is considered to be one of the most effective methods to remove radioiodine from the solution. However, developing highly efficient adsorbents and the rapid recovery of the used adsorbents is still a challenge. Here, a series of Cu/Fe3O4 bimetallic mutual-doping magnetic aerogels (Cu/Fe3O4-BMMA) were synthesized. Based on the in-situ bimetallic co-gelation process, the high dispersion of Cu in the aerogel was realized, providing conditions for the efficient elimination of I2. The Fe3+ in the initial gel was reduced to magnetic Fe3O4 during the preparation process, allowing for the quick recovery of the adsorbent through the application of a magnetic field. The adsorption experiments showed that Cu/Fe3O4-BMMA has good I2 adsorption capacity (631.3 mg/g) and fast capture kinetics (equilibrium time < 30 min). In addition, Cu/Fe3O4-BMMA was able to effectively remove trace I2 in the solution from ppm level (1.0 ppm) down to ppb level (≤30 ppb). The adsorbed I2 was converted into stable CuI, avoiding secondary pollution due to desorption. Overall, this study provides a potentially efficient iodine capture material for long-term decay storage of radioactive iodine.

Combining Gut Microbiota Modulation and Enzymatic-Triggered Colonic Delivery by Prebiotic Nanoparticles Improves Mouse Colitis Therapy.

The efficacy of ulcerative colitis (UC) therapy is closely connected to the composition of gut microbiota in the gastrointestinal tract. Prebiotic-based nanoparticles (NPs) provide a more precise approach to alleviate UC via modulating gut microbiota dysbiosis. The present study develops an efficient prebiotic-based colon-targeted drug delivery system (PCDDS) by using prebiotic pectin (Pcn) and chitosan (Csn) polysaccharides as a prebiotic shell, with the anti-inflammatory drug sulfasalazine (SAS) loaded into a poly(lactic-co-glycolic acid) (PLGA) core to construct SAS@PLGA-Csn-Pcn NPs. Then, we examine its characterization, cellular uptake, and in vivo therapeutic efficacy. The results of our study indicate that the Pcn/Csn shell confers efficient pH-sensitivity properties. The gut microbiota-secreted pectinase serves as the trigger agent for Pcn/Csn shell degradation, and the resulting Pcn oligosaccharides possess a substantial prebiotic property. Meanwhile, the formed PCDDSs exhibit robust biodistribution and accumulation in the colon tissue, rapid cellular uptake, efficient in vivo therapeutic efficacy, and modulation of gut microbiota dysbiosis in a mouse colitis model. Collectively, our synthetic PCDDSs demonstrate a promising and synergistic strategy for UC therapy.

Stachyose Exerts Anticolitis Efficacy by Re-balancing Treg/Th17 and Activating the Butyrate-Derived PPARγ Signaling Pathway.

Ulcerative colitis (UC) is a complex chronic inflammatory disease closely associated with gut homeostasis dysfunction. The previous studies have shown that stachyose, a functional food additive, has the potential to enhance gut health and alleviate UC symptoms. However, the underlying mechanism of its effects remains unknown. In this study, our findings showed that dietary supplements of stachyose had a significant dose-dependent protective effect on colitis symptoms, regulation of gut microbiota, and restoration of the Treg/Th17 cell balance in dextran sulfate sodium (DSS) induced colitis mice. To further validate these findings, we conducted fecal microbiota transplantation (FMT) to treat DSS-induced colitis in mice. The results showed that microbiota from stachyose-treated mice exhibited a superior therapeutic effect against colitis and effectively regulated the Treg/Th17 cell balance in comparison to the control group. Moreover, both stachyose supplementation and FMT resulted in an increase in butyrate production and the activation of PPARγ. However, this effect was partially attenuated by PPARγ antagonist GW9662. These results suggested that stachyose alleviates UC symptoms by modulating gut microbiota and activating PPARγ. In conclusion, our work offers new insights into the benefical effects of stachyose on UC and its potential role in modulating gut microbiota.

Sulfur vacancy-rich bismuth sulfide nanowire derived from CAU-17 for radioactive iodine capture in complex environments: Performance and intrinsic mechanisms.

Effective capture and immobilization of volatile radioiodine from the off-gas of post-treatment plants is crucial for nuclear safety and public health, considering its long half-life, high toxicity, and environmental mobility. Herein, sulfur vacancy-rich Vs-Bi2S3@C nanocomposites were systematically synthesized via a one-step solvothermal vulcanization of CAU-17 precursor. Batch adsorption experiments demonstrated that the as-synthesized materials exhibited superior iodine adsorption capacity (1505.8 mg g-1 at 200 °C), fast equilibrium time (60 min), and high chemisorption ratio (91.7%), which might benefit from the nanowire structure and abundant sulfur vacancies of Bi2S3. Furthermore, Vs-Bi2S3@C composites exhibited excellent iodine capture performance in complex environments (high temperatures, high humidity and radiation exposure). Mechanistic investigations revealed that the I2 capture by fabricated materials primarily involved the chemical adsorption between Bi2S3 and I2 to form BiI3, and the interaction of I2 with electrons provided by sulfur vacancies to form polyiodide anions (I3-). The post-adsorbed iodine samples were successfully immobilized into commercial glass fractions in a stable form (BixOyI), exhibiting a normalized iodine leaching rate of 3.81 × 10-5 g m-2 d-1. Overall, our work offers a novel strategy for the design of adsorbent materials tailed for efficient capture and immobilization of volatile radioiodine.

The intention of utilization and experience toward traditional Chinese medicine among breast cancer patients in the early and late stages: a qualitative study.

BACKGROUND: In Taiwan, breast cancer patients usually take conventional medicine and traditional Chinese medicine simultaneously. The utilization of traditional Chinese medicine among breast cancer patients at various stages has not been examined. This study aims to compare the intention of utilization and experience toward traditional Chinese medicine among early- and late-stage breast cancer patients. METHOD: This qualitative research collected data from breast cancer patients through focus groups interview by convenience sampling. Conducted in 2 branches of Taipei City Hospital, a public hospital managed by the Taipei City government. Breast cancer patients > 20 years old and had used TCM for breast cancer therapy for at least 3 months were included in the interview. A semi-structured interview guide was adopted in each focus group interview. In the following data analysis, stages I and II were considered early-stage, and stages III and IV were late-stage. For analyzing the data and reporting the results, we used qualitative content analysis as the approach for data analysis, assisted by NVivo 12. Categories and subcategories were identified through content analysis. RESULTS: Twelve and seven early- and late-stage breast cancer patients were included in this study, respectively. The side effects were the main intention of utilizing traditional Chinese medicine. Improving side effects and constitution was the main benefit for patients in both stages. Additionally, early-stage breast cancer patients used traditional Chinese medicine to prevent recurrence or metastasis. Late-stage breast cancer patients responded more frequently to the use of traditional Chinese medicine due to the side effects of western medicine. However, some of their symptoms were not fully relieved. CONCLUSIONS: Breast cancer staging may influence the intention and utilization of traditional Chinese medicine. Health policymakers should consider the results of this research and the evidence-based illustrations to establish guidelines for integrating traditional Chinese medicine among various stages of breast cancer to improve the outcome and quality of care for cancer patients.

Synthesis and characterization of Ag@Cu-based MOFs as efficient adsorbents for iodine anions removal from aqueous solutions.

Due to the critical importance of capturing radioiodine from aquatic environments for human health and ecosystems, developing highly efficient adsorbent materials with rapid kinetics for capturing iodide ions in aqueous solutions is urgently needed. Although extensive research has been conducted on iodine adsorption in gas and organic phases, limited research has been dedicated to adsorption in aqueous solutions. An effective technique for removing iodide was proposed using Ag@Cu-based MOFs synthesized by incorporating Ag into calcined HKUST-1 with varying mass ratios of Ag/Cu-C. Extensive characterization using SEM, XRD, XPS, and nitrogen adsorption-desorption analysis confirmed successful incorporation of Ag in Cu-C. Batch adsorption experiments were conducted, demonstrating that the 5% Ag@Cu-C material exhibited a high adsorption capacity of 247.1 mg g-1 at pH 3. Mechanism investigations revealed that Cu0 and dissolved oxygen in water generate Cu2O and H2O2, while Ag and a small amount of CuO generate Ag2O and Cu2O. Furthermore, iodide ions in the solution are captured by Cu+ and Ag+ adsorption sites. These findings highlighted the potential of Ag@Cu-based MOFs as highly effective adsorbents for iodine anions removal in radioactive wastewater.

Synchronous Interventions of Glucose and Mitochondrial Metabolisms for Antitumor Bioenergetic Therapy.

Hydrogen sulfide (H2 S)-based mitochondrial bioenergetic intervention is an attractive therapeutic modality. However, its therapeutic efficacy is limited owing to metabolic plasticity, which allows tumors to shift their metabolic phenotype between oxidative phosphorylation and glycolysis for energy compensation. To overcome this flexibility, a glycopolymer containing a caged H2 S and hydrogen peroxide (H2 O2 ) dual-donor (1-thio-ß-D-glucose [thioglucose]) is synthesized to wrap glucose oxidase (GOx) for complete depletion of tumorigenic energy sources. The loaded GOx catalyzes the glutathione-activated thioglucose to generate cytotoxic H2 S/H2 O2 , which further induces synergistic defects in mitochondrial function by suppressing cytochrome c oxidase expression and damaging the mitochondrial membrane potential. GOx also blocks glycolysis by depleting endogenous glucose. This synchronous intervention strategy exhibits good anticancer performance, broadening the horizon of antitumor bioenergetic therapy.

Cu/Al2O3 aerogels for high-efficiency and rapid iodide elimination from water.

Cu-based functional materials are excellent candidates for the elimination of iodine anions. However, the low utilization rate of Cu and its unsatisfactory adsorption performance limit its large-scale practical applications. This paper proposes a co-gelation method to obtain Cu/Al2O3 aerogels with a high specific area (537 m2/g). Cu/Al2O3 aerogels have a hierarchical porous structure and contain a high proportion of Cu (20.5 wt%). The high dispersibility of Cu, which is based on an in-situ gel process, provides conditions for the high-efficiency elimination of iodide anions. We conducted adsorption experiments that demonstrated that the fabricated Cu/Al2O3 aerogel had an ultrahigh adsorption capacity (407.6 mg/g) and a fast adsorption equilibrium time (0.5 h) for iodide anions. Additionally, the Cu/Al2O3 aerogel could selectively capture iodine anions even in the presence of high concentrations of competing ions (NO3-, SO42-, and Cl- at 60 mmol/L). Importantly, the aerogel can operate in a wide pH range of 3-11 without causing secondary pollution. This work demonstrates that low-cost Cu/Al2O3 aerogels exhibit great potential for eliminating radioactive iodine anions.

SARS-CoV-2 variants - Evolution, spike protein, and vaccines.

Despite the rising natural and vaccines mediated immunity, several countries have experienced a resurgence of the Coronavirus disease of 2019 (COVID-19) due to the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. From Alpha to Omicron, the variants of concern (VOC) have evolved several spike protein mutations that may have an impact on virus characteristics, such as transmissibility and antigenicity. In this review, we describe the evolution of SARS-CoV-2, summarize current knowledge of epidemiological and clinical features of the variants, and discuss the response strategies in terms of vaccines to reduce the burden of COVID-19.

Androgen receptor functions in pericentral hepatocytes to decrease gluconeogenesis and avoid hyperglycemia and obesity in male mice.

BACKGROUND: Although the impact of hepatic androgen receptor (AR) pathway on liver pathogenesis was documented, its physiological function in normal liver is remained unclear. This study aims to investigate if hepatic AR acts on metabolism, the major liver function, using a hepatic-specific AR-transgenic (H-ARTG) mouse model. METHODS: We established the albumin promoter driven H-ARTG mice and included wild type (WT) and H-ARKO mice for study. The body weight, specific metabolic parameters and results from various tolerance tests were compared in different groups of mice fed a chow diet, from 2 to 18 months of age. Glucose feeding and insulin treatment were used to study the expression and zonal distribution pattern of AR and related genes in liver at different prandial stages. RESULTS: The body weight of H-ARTG mice fed a chow diet was 15 % lower than that of wild-type mice, preceded by lower blood glucose and liver triglyceride levels caused by AR reduced hepatic gluconeogenesis. The opposite phenotypes identified in H-ARKO and castrated H-ARTG mice support the critical role of activated AR in decreasing gluconeogenesis and triglyceride levels in liver. Hepatic AR acting by enhancing the expression of cytosolic glycerol-3-phosphate dehydrogenase (cGPDH), a key of glycerophosphate shuttle, was identified as one mechanism to decrease gluconeogenesis from glycerol. We further found AR normally expressed in zone 3 of hepatic lobules. Its level fluctuates dependent on the demand of glucose, decreased by fasting but increased by glucose uptake or insulin stimulation. CONCLUSION: AR is a newly identified zone 3 hepatic gene with function in reducing blood glucose and body weight in mice. It suggests that stabilization of hepatic AR is a new direction to prevent hyperglycemia, obesity and nonalcoholic fatty liver disease (NAFLD) in males.