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Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of miRNAs. However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte–derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improved insulin secretion and glucose intolerance in db / db mice. Supporting the function of EV miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p–containing EVs showed their distribution in mouse pancreatic islets. Tracing the injected adeno-associated virus (AAV)-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat resulted in upregulating miR-27a-5p in EVs and serum and elicited mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targeted L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduced insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolished the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EV miR-27a-5p in visceral adipocyte–mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus. Article Highlights: miR-27a-5p expression in the islets is increased in obesity-associated diabetes mouse models. miR-27a-5p overexpression in β-cells impairs β-cell function in vitro and in vivo. Visceral adipocyte–derived extracellular vesicles and their cargo miR-27a-5p lead to β-cell insulin secretion injury and glucose intolerance by targeting L-type Ca2+ channel subtype CaV1.2. Blockage of visceral adipocyte extracellular vesicle miR-27a-5p expression improves β-cell insulin secretion and glucose tolerance in db / db mice. [ABSTRACT FROM AUTHOR]

The vertical variations and key drivers of ozone and its precursors, namely NOx and VOCs, in the atmospheric boundary layer, have vital impacts on surface ozone budgets but are poorly understood so far. Using online gradient measurements from a 356 m tower, we obtained continuous vertical profiles of ozone and its precursors, which exhibited strong gradients throughout the day. In the daytime, the vertical gradients of ozone precursors are significantly regulated by reactions with OH radicals. At night, our observations confirmed more intense VOC reactions with NO3 radicals in the residual layer than in the boundary layer. Additionally, we found that residual layer entrainment could contribute to over half of the boundary-layer ozone enhancements in the morning periods. Our results underscore the importance of considering vertical changes of ozone and its precursors in the atmospheric boundary layer when developing future ozone mitigation strategies. [ABSTRACT FROM AUTHOR]

Aim: To assess the expression and function of miR‐483‐5p in diabetic β cells. Methods: The expression of miR‐483‐5p was evaluated in the pancreatic islets of obesity mouse models by quantitative reverse transcription polymerase chain reaction. Dual‐luciferase activity, and western blotting assays, were utilized for miR‐483‐5p target gene verification. Mice with β cell‐specific miR‐483‐5p downregulation were studied under metabolic stress (i.e. a high‐fat diet) condition. Lineage tracing was used to determine β‐cell fate. Results: miR‐483‐5p increased in the islets of obese mouse models. Expression levels of miR‐483‐5p were significantly upregulated with the treatment of high glucose and palmitate, in both MIN6 cells and mouse islets. Overexpression of miR‐483‐5p in β cells results in impaired insulin secretion and β‐cell identity. Cell lineage‐specific analyses revealed that miR‐483‐5p overexpression deactivated β‐cell identity genes (insulin, Pdx1 and MafA) and derepressed β‐cell dedifferentiation (Ngn3) genes. miR‐483‐5p downregulation in β cells of high‐fat diet‐fed mice alleviated diabetes and improved glucose intolerance by enhancing insulin secretory capacity. These detrimental effects of miR‐483‐5p relied on its seed sequence recognition and repressed expression of its target genes Pdx1 and MafA, two crucial markers of β‐cell maturation. Conclusions: These findings indicate that the miR‐483‐5p–mediated reduction of mRNAs specifies β‐cell identity as a contributor to β‐cell dysfunction via the loss of cellular differentiation. [ABSTRACT FROM AUTHOR]

Understanding the near-ground vertical and temporal photochemical O 3 formation mechanism is important to mitigate O 3 pollution. Here, we measured the vertical profiles of O 3 and its precursors at six different heights, ranging from 5 to 335 m, using a newly built vertical observation system in the Pearl River Delta (PRD) region of China. The net photochemical ozone production rate (P (O 3) net) and O 3 formation sensitivities at various heights were diagnosed using an observation-based model coupled with the Master Chemical Mechanism (MCM v3.3.1). Moreover, to assess model performance and identify the causative factors behind O 3 pollution episodes, the P (O 3) net was measured at 5 m above ground level with a custom-built detection system. In total, three O 3 pollution episodes and two non-episodes were captured. The identified O 3 pollution episodes were found to be jointly influenced by both photochemical production and physical transport, with local photochemical reactions playing a major role. The high index of agreement (IOA) calculated by comparing the modelled and measured P (O 3) net values indicated the rationality of investigating the vertical and temporal variability in O 3 formation mechanisms using model results. However, the measured P (O 3) net values were generally higher than the modelled P (O 3) net values, particularly under high-NO x conditions, which may indicate a potential underestimation of total RO 2 by the model. Throughout the measurement period, the contribution of different reaction pathways to O 3 production remained consistent across various heights, with HO 2 + NO as the major O 3 production pathway, followed by RO 2 + NO. We observed that P (O 3) net decreased with an increase in measurement height, which was primarily attributed to the reduction in O 3 precursors, such as oxygenated volatile organic compounds (OVOCs) and non-methane hydrocarbons (NMHCs). The O 3 formation regimes were similar at different heights during both episodes and non-episodes, either being located in the VOC-sensitive regime or in the transition regime that is more sensitive to VOCs. Diurnally, photochemical O 3 formation typically remained in the VOC-sensitive regime during the morning and noon, but it transitioned to the transition regime and was more sensitive to VOCs in the afternoon at around 16:00 LT (local time). Vertical and temporal photochemical O 3 formation is most sensitive to OVOCs, suggesting that targeting specific VOCs for control measures is more practical and feasible at the observation site. The vertical temporal analysis of O 3 formation mechanisms near the ground surface in this study provides critical foundational knowledge that can be used to formulate effective short-term emergency and long-term control strategies to combat O 3 pollution in the PRD region of China. [ABSTRACT FROM AUTHOR]

Fulminant hepatitis (FH) is a life-threatening clinical liver syndrome characterized by substantial hepatocyte necrosis and severe liver damage. FH is typically associated with severe oxidative stress, inflammation, and mitochondrial dysfunction. Pyrroloquinoline quinone (PQQ), a naturally occurring redox cofactor, functions as an essential nutrient and antioxidant and reportedly inhibits oxidative stress and exerts potent anti-inflammatory effects. In the present study, we aimed to evaluate the therapeutic efficacy of PQQ in murine hepatitis virus strain 3 (MHV-3)-induced FH and examined the underlying mechanism. An MHV-3-induced FH mouse model was established for in vivo examination. Liver sinusoidal endothelial cells (LSECs) were used for in vitro experiments. Herein, we observed that PQQ supplementation significantly attenuated MHV-3-induced hepatic injury by suppressing inflammatory responses and reducing oxidative stress. Mechanistically, PQQ supplementation ameliorated MHV-3-induced hepatic damage by down-regulating the Keap1/Nrf2 signaling pathway in vivo and in vitro. Furthermore, Nrf2 small interfering RNA targeting LSECs abrogated the PQQ-mediated protective effects against MHV-3-related liver injury. Our results deepen our understanding of the hepatoprotective function of PQQ against MHV-3-induced liver injury and provide evidence that alleviating oxidative stress might afford a novel therapeutic strategy for treating FH. [ABSTRACT FROM AUTHOR]

To study the effects of caspase inhibitors on hemodynamics and inflammatory factors in acute respiratory distress syndrome (ARDS) model rats. Sixty healthy male Wistar rats were randomly divided into three groups, namely, the control group, ARDS group and ARDS + Caspase inhibitor group, with 20 rats in each group. The control group was intraperitoneally injected with 2 mL/kg saline, and the ARDS model group was established by intraperitoneally injecting 4 mg/kg Lipopolysaccharide (LPS), ARDS + Caspase inhibitor group was adminstered 20 mg/kg caspase inhibitor after intraperitoneal LPS injection. Changes in pulmonary arterial pressure (PAP) and mean arterial pressure (MAP) at 6 and 12 h before and after administration were recorded. Moreover, arterial blood gas was evaluated with a blood gas analyzer and changes in the partial pressure of O2 (PaO2), partial pressure of CO2 (PaCO2), partial pressure of O2/fraction of inspired O2 (PaO2/FiO2) were evaluated. In addition, the lung wet/dry weight (W/D) ratio and inflammatory factor levels in lung tissue were determined. Finally, pathological sections were used to determine the pulmonary artery media thickness (MT), MT percentage (MT%), and the degree of muscle vascularization. The pulmonary arterial pressure of rats was determined at several time points. Compared with the control group, the model group had a significantly increased pulmonary arterial pressure at each time point (P < 0.01), and the mean arterial pressure significantly increased at 6 h (P < 0.05). Compared with that of rats in the model group, the pulmonary arterial pressure of rats in drug administration group was significantly reduced at each time point after administration (P < 0.01), and the mean arterial pressure was significantly reduced at 6 h (P < 0.05). The arterial blood gas analysis showed that compared with those in the control group, PaO2, PaCO2 and PaO2/FiO2 in the model group were significantly reduced (P < 0.01), and PaO2, PaCO2 and PaO2/FiO2 were significantly increased after caspase inhibitor treatment (P < 0.05 or 0.01). The levels of the inflammatory mediators tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in the model group were significantly higher than those in the control group (P < 0.01), and they were significantly decreased after caspase inhibitor treatment (P < 0.01). In the model group, pulmonary artery MT, MT% and the degree of muscle vascularization were significantly increased (P < 0.05 or 0.01), and pulmonary artery MT and the degree of muscle vascularization were significantly reduced after caspase inhibitor treatment (P < 0.05 or 0.01). Apoptosis Repressor with a Caspase Recuitment Domain (ARC) can alleviate the occurrence and development of pulmonary hypertension (PH) by affecting hemodynamics and reducing inflammation. [ABSTRACT FROM AUTHOR]

Objective: To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL). Methods: A rat model for ALI/acute respiratory distress syndrome (ALI/ARDS) was established. Pathological examination of lung tissue was conducted to assess lung injury. Blood gas in the arteries was measured using a blood analyzer. Changes in PaO2, PaO2/FiO2, and lung wet/dry (W/D) weight ratio were carefully compared. ELISA assay was conducted to estimate cell adhesion and inflammation response. Finally, real-time reverse transcription polymerase chain reaction and western blotting assay was used to determine the activation of PI3K/AKT/mTOR pathway. Results: ARDS in vivo model was successfully constructed by LPS injection. Compared with the sham group, PaO2 and PaO2/FiO2 were significantly lower in the vehicle group, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8 andTNF-αwere significantly increased. After treatment with different doses of sivelestat sodium, we found PaO2, PaO2/FiO2 were prominently increased, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8, TNF-α levels were decreased in the dose-dependent manner. Meanwhile, compared with the vehicle group, the expression levels of Bax, PI3K, Akt and mTOR were significantly lower, and the expression of Bcl-2 was significantly higher after injection with sivelestat sodium. Conclusion: Sivelestat sodium has an interventional effect on ALI in sepsis by inhibiting the PI3K/AKT/mTOR signalling pathway. [ABSTRACT FROM AUTHOR]

Understanding the near-ground vertical and temporal photochemical O3 formation mechanism is important to mitigate the O3 pollution. Here, we measured the vertical profiles of O3 and its precursors at six different heights from 5-335 m using a newly built vertical observation system in Pearl River Delta (PRD) region, China. The net photochemical ozone production rate (P (O3)net) and O3 formation sensitivities at various heights were diagnosed using an observation-based model coupled with the Master Chemical Mechanism (MCM v3.3.1). Moreover, for the assessment of model performance and the causative factors behind O3 pollution episodes, the net photochemical ozone production rate (P (O3)net) was measured at 5 m ground level utilizing a custom-built detection system. In total three O3 pollution episodes and two non-episodes were captured. The identified O3 pollution episodes were found to be jointly influenced by both photochemical production and physical transport, with local photochemical reactions play a dominate role. The high index of agreement (IOA) calculated from comparing the modelled and measured P (O3)net values indicated the rationality to investigate the vertical and temporal variability of O3 formation mechanism using modelling results. However, the measured P (O3)net values were generally higher than the modelled P (O3)net values, particularly under high NOx conditions, which may indicate a potential underestimation of total RO2 by the model. Throughout the measurement period, the contribution of different reaction pathways to O3 production remained consistent across various heights, with HO2+NO as the major O3 production pathway, followed by RO2+NO. We saw P (O3)net decreased with the increase of the measurement height, primarily attributed to the decreased O3 precursors anthropogenic organic compounds (AVOC) and oxygenated volatile organic compounds (OVOC). O3 formation regimes were similar at different heights during both episodes and non-episodes, which was located either in volatile organic compounds (VOCs) sensitive regime or in transition regime and more sensitive to VOCs. Diurnally, photochemical O3 formation typically remained in the VOCs sensitive regime during the morning and noon time, but in the transitional regime and more sensitive to VOCs in the afternoon at around 16:00 LT. The vertical and temporal O3 formation are most sensitive to AVOC and OVOC, which suggests that targeting VOCs, especially AVOC and OVOC, for control measures is more practical and feasible at the observation site. The vertical temporal analysis of O3 formation mechanisms near the ground surface in this study provides critical foundational knowledge for formulating effective short-term emergency and long-term strategies to combat O3 pollution in the PRD region of China. [ABSTRACT FROM AUTHOR]

Current process-based research mainly uses box models to evaluate photochemical ozone production and destruction rates, and it is unclear to what extent the photochemical reaction mechanisms are elucidated. Here, we modified and improved a net photochemical ozone production rate (NPOPR, P (O 3) net) detection system based on the current dual-channel reaction chamber technique, which makes the instrument applicable to different ambient environments, and its various operating indicators were characterized, i.e., "airtightness", light transmittance, wall losses of the reaction and reference chambers, conversion rate of O 3 to NO 2 , air residence time, and performance of the reaction and reference chambers. The limits of detection of the NPOPR detection system were determined to be 0.07, 1.4, and 2.3 ppbv h -1 at sampling flow rates of 1.3, 3, and 5 L min -1 , respectively. We further applied the NPOPR detection system to field observations at an urban site in the Pearl River Delta (China). During the observation period, the maximum value of P (O 3) net was 34.1 ppbv h -1 , which was ∼ 0 ppbv h -1 at night within the system detection error and peaked at approximately noon local time. The daytime (from 06:00–18:00 LT) average value of P (O 3) net was 12.8 (± 5.5) ppbv h -1. We investigated the detailed photochemical O 3 formation mechanism in the reaction and reference chambers of the NPOPR detection system using a zero-dimensional box model. We found that the photochemical reactions in the reaction chamber were very close to those in ambient air, but there was not zero chemistry in the reference chamber because the reaction related to the production and destruction of RO 2 (= HO 2 + RO 2) continued in the reference chamber, which led to a small amount of P (O 3) net. Therefore, the P (O 3) net measured here can be regarded as the lower limit of the real P (O 3) net in the atmosphere; however, the measured P (O 3) net was still ∼ 7.5 to 9.3 ppbv h -1 higher than the modeled P (O 3) net value depending on different modeling methods, which may be due to the inaccurate estimation of HO 2 / RO 2 radicals in the modeling study. Short-lived intermediate measurements coupled with direct P (O 3) net measurements are needed in the future to better understand O 3 photochemistry. Our results show that the NPOPR detection system can achieve high temporal resolution and continuous field observations, which helps us to better understand photochemical O 3 formation and provides a key scientific basis for continuous improvement of air quality in China. [ABSTRACT FROM AUTHOR]

This work aimed to investigate the role of nuclear factor peroxisome proliferator-activated receptor α (PPARα) in modification of circadian clock and their relevance to development of nonalcoholic fatty liver disease (NAFLD). Both male wild-type (WT) and Pparα-null (KO) mice treated with high-fat diet (HFD) were used to explore the effect of PPARα and lipid diet on the circadian rhythm. WT, KO, and PPARα-humanized (hPPARα) mice were treated with PPARα agonist fenofibrate to reveal the hPPARα dependence of circadian locomotor output cycles kaput (CLOCK) down-regulation. The mouse model and hepatocyte experiments were designed to verify the action of PPARα in down-regulating CLOCK and lipid accumulation in vivo and in vitro. Strongest NAFLD developed in mice fed 45%HFD, and it was inhibited in WT mice. The activity rhythm of WT mice was found to be different from that of the KO mice on normal diet and HFD. The core circadian factor CLOCK was down-regulated by HFD in both WT and KO mice in the liver, not in the hypothalamus. More interestingly, hepatic CLOCK was down-regulated by basal PPARα and activated PPARα in dose dependence of fenofibrate. Accordingly, CLOCK down-regulation dependent of PPARα activity was involved in inhibition of lipid metabolism in hepatocytes. Down-regulation of hepatic CLOCK by basal PPARα contributes to tolerance against development of NAFLD. Inhibition of CLOCK by activated PPARα is involved in inhibition of NAFLD by PPARα agonists. Key messages: • PPARα inhibited NAFLD development induced by HFD. • PPARα mediated modifications of circadian rhythm and the hepatic circadian factor CLOCK in NAFLD models. • Down-regulation of hepatic CLOCK by basal PPARα contributed to tolerance against development of NAFLD. • Inhibition of CLOCK by activated PPARα was involved in therapeutic actions against fatty liver diseases by PPARα agonists. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptors (PPARs) have been suggested to play crucial roles in the pathology of NAFLD with a vague understanding of the underlying mechanism. Here, we integrated large-scale literature data and clinical data to explore the potential role of the PPAR-APOA1 signaling pathway in the pathology of NAFLD. First, the signaling pathway connecting PPARs, APOA1, and NAFLD was constructed. Then, we employed clinical data to explore the association between APOA1 levels and NAFLD. In addition, we built the APOA1-driven pathway analysis to explore the potential mechanism of the APOA1-NAFLD association. Pathway analysis showed that APOA1 serves as a hubprotein connecting PPARs and NAFLD through a beneficial modulation of 16 out of 21 NAFLD upstream regulators. Each relationship within the composed pathway was supported by results from multiple previous studies. Clinical data analysis showed that an increase of APOA1 level was associated with a significantly decreased NAFLD prevalence ( χ 2 = 292.109 ; P < 0.001). When other confounding factors were adjusted, serum APOA1 level was shown as an independent risk factor for the prevalence of NAFLD (P value<.0001; OR = 0.562). Our results suggested that the three PPARs (PPARA, PPARD, and PPARG) might promote the expression and molecular transportation of APOA1 to form a PPAR-APOA1 signaling pathway that demonstrated a beneficial role in the pathogenesis of NAFLD. [ABSTRACT FROM AUTHOR]

Aiming Liu,2,* Yin Jiang,2 Dandan Chen,1 Binbin Li,3 Can Yao,3 Rongchang Chen,1 Fei Shi31Key Laboratory of Shenzhen Respiratory Diseases, Institute of Shenzhen Respiratory Diseases, Shenzhen People's Hospital (The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University), Shenzhen, Guangdong, People's Republic of China; 2Shenzhen National Climate Observatory, Meteorological Bureau of Shenzhen Municipality, Shenzhen Key Laboratory of Severe Weather in South China, Shenzhen, Guangdong, People's Republic of China; 3Emergency Department, Institute of Shenzhen Respiratory Diseases, Shenzhen People's Hospital (The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University), Shenzhen, Guangdong, People's Republic of China*These authors contributed equally to this workCorrespondence: Rongchang Chen; Fei Shi Email [email protected] ; [email protected] Background: Reversible airflow obstruction (RO) and fixed airflow obstruction (FO) are two important clinical phenotypes of asthma. However, the relationship between air pollutant exposure and exacerbation of the two phenotypes is unknown. Objective: To study the effects of air pollutant exposure on exacerbation severity in asthma patients with or without FO. Methods: A total of 197 severe asthma patients were enrolled, and divided into two groups: the FO group (n=81) and the RO group (n=116). We collected the demographic data, laboratory parameters, pulmonary function test parameters, and the daily average concentrations of different air particles in Shenzhen on the different lag days of each subject. The receiver operating characteristic (ROC) curve was used to identify the effects of major air pollutants on the severity of asthma patients with RO. Results: Compared with the RO group, the FO group had fewer women, lower body mass index (BMI), longer disease duration, higher smoking history rate, allergic family history rate, FeNO level, and lower levels of large airway parameters. The median exposure levels of PM10 and PM2.5 in the severe RO subgroup were both higher than those in the mild-to-moderate RO subgroup on Lag0, 1 and 3, and the median exposure level of PM1 on Lag0 in the severe RO subgroup was significantly higher than that in the mild-to-moderate RO subgroup. Logistic regression modeling indicated exposure to PM2.5 and PM1.0 on Lag0, and PM10 on Lag0-2 were the independent risk factors for hospital admissions for asthma patients with RO. By performing an ROC curve analysis, PM2.5 on Lag0 (AUC = 0.645, p = 0.027) provided a best performance to predict severe asthma exacerbations with RO, with a sensitivity of 36.0% and a specificity of 91.2%. Conclusion: Short-term exposure to PM10, PM2.5 and PM1 may play a role in exacerbation severity among asthma patients with RO. [ABSTRACT FROM AUTHOR]

α-naphthylisothiocyanate (ANIT) is used to induce intrahepatic cholestasis and it is frequently used for investigations into the disease mechanism. The lithocholic acid (LCA) cholestatic model has also been extensively used in various studies; however, to the best of our knowledge, a comparative study determining the hepatotoxic mechanisms induced by these two models has not been previously conducted. In the present study, ICR mice were treated with ANIT or LCA to induce cholestatic liver injury. Biochemical analysis was used to determine the serum. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bile acid (TBA) levels, and histopathological assessment was used to examine the liver tissue. Metabolomic analysis was used for the serum biomarker identification. Reverse transcription-quantitative PCR analysis and western blotting were used to analyze the inflammation biomarkers. The serum metabolome of the ANIT group clustered away from of the LCA group, which was demonstrated by the different modifications of the BA components. ALP level was found to be preferentially increased in the ANIT group from 24 to 48 h. Total BA levels was only increased in the ANIT group at 24 h. In contrast, AST and ALT activity levels were preferentially increased in the LCA group. The bile ducts in the hepatic tissues of the ANIT group were observed to be severely dilated, whereas the presence of edematous hepatocytes around the necrotic lesions and neutrophil infiltration were identified in the LCA group. The expression levels of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase genes were significantly downregulated in the ANIT group compared with the LCA group, where a stronger adaptation of BA metabolism was supported by major differences in the concentration of the BA components. Despite the aforementioned etiological differences in the cholestasis induced by each treatment, the activation of the JNK/STAT3 signaling pathway was similar between the two cholestatic models. In conclusion, these data suggested that the liver injury induced by ANIT may be cholestatic, while the liver injury caused in the LCA model may be hepatocellular. Moreover, the downstream cholestatic liver injury in both models was indicated to be mediated by the JNK/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Objectives: Metabolic syndrome (MS) is the concurrence of at least three of five medical conditions: obesity, high blood pressure, insulin resistance, high serum triglyceride (TG) and low serum high‐density lipoprotein levels. While fibrates are used to treat disorders other than the lowering serum TG, the mechanism by which fibrates decrease MS has not been established. Methods: In this study, wild‐type and Ppara‐null mice fed a medium‐fat diet (MFD) were administered gemfibrozil and fenofibrate for 3 months respectively, to explore the effect and action mechanism. Key findings: In Ppara‐null mice, MFD treatment increased body weight, adipose tissue, serum TG and impaired glucose tolerance. These phenotypes were attenuated in two groups treated with gemfibrozil and fenofibrate. The STAT3 pathway was activated in adipose and hepatic tissues in positive control, and inhibited in groups treated with gemfibrozil and fenofibrate. The above phenotypes and inflammation were not observed in any wild‐type group. In 3T3‐L1 adipogenic stem cells treated with high glucose, STAT3 knockdown greatly decreased the number of lipid droplets. Conclusions: Low dose of clinical fibrates was effective against MS development independent of PPARα, and this action was mediated by STAT3 signalling inhibition in adipose tissue and, to a lesser extent, in hepatic tissues. [ABSTRACT FROM AUTHOR]

Remanufacturing is an effective way to realize the reutilization of resources. Disassembly, as an essential step of remanufacturing, is usually finished by manual work which is low efficiency and high labor cost. Robotic disassembly provides an alternative way to reduce labor intensity and disassembly cost. Disassembly line is an efficient method to deal with end-of-life products on a large scale. Balancing the workload of robotic workstations is the main objective of robotic disassembly line balancing problem. In this paper, an improved multi-objective discrete bees algorithm is proposed to solve robotic disassembly line balancing problem. The feasible disassembly sequence is obtained by space interference matrix method. It is used to generate robotic disassembly line solution by robotic workstation assignment method. After that, the multi-objective robotic disassembly line balancing problem is proposed. With the help of efficient non-dominated Pareto sorting method, the improved multi-objective discrete bees algorithm is proposed to find Pareto optimal solutions. Based on a gear pump and a camera, the performance of the improved multi-objective discrete bees algorithm is analyzed under different parameters and compared with the other optimization algorithms. In addition, Pareto fronts of robotic disassembly line balancing problem are also compared with those of the other two cases. The result shows the proposed method can find better solutions using comparable running time compared with the other optimization algorithms. [ABSTRACT FROM AUTHOR]

Gemfibrozil is a fibrate drug used widely for dyslipidemia associated with atherosclerosis. Clinically, both gemfibrozil and its phase II metabolite gemfibrozil 1-O-β-glucuronide (gem-glu) are involved in drug-drug interaction (DDI). But the DDI risk caused by gem-glu between human and mice has not been compared. In this study, six volunteers were recruited and took a therapeutic dose of gemfibrozil for 3 days for examination of the gemfibrozil and gem-glu level in human. Male mice were fed a gemfibrozil diet (0.75%) for 7 days, following which a cocktail-based inhibitory DDI experiment was performed. Plasma samples and liver tissues from mice were collected for determination of gemfibrozil, gem-glu concentration and cytochrome p450 enzyme (P450) induction analysis. In human, the molar ratio of gem-glu/gemfibrozil was 15% and 10% at the trough concentration and the concentration at 1.5 h after the 6th dose. In contrast, this molar ratio at steady state in mice was 91%, demonstrating a 6- to 9-fold difference compared with that in human. Interestingly, a net induction of P450 activity and in vivo inductive DDI potential in mice was revealed. The P450 activity was not inhibited although the gem-glu concentration was high. These data suggested species difference of relative gem-glu exposure between human and mice, as well as a net inductive DDI potential of gemfibrozil in mouse model. [ABSTRACT FROM AUTHOR]

Background and Purpose: Fenofibrate, a PPARα agonist, is the most widely prescribed drug for treating hyperlipidaemia. Although fibrate drugs are reported to be beneficial for cholestasis, their underlying mechanism has not been determined.Experimental Approach: Wild-type mice and Pparα-null mice were pretreated orally with fenofibrate for 3 days, following which α-naphthylisothiocyanate (ANIT) was administered to induce cholestasis. The PPARα agonist WY14643 and JNK inhibitor SP600125 were used to determine the role of PPARα and the JNK pathway, respectively, in cholestatic liver injury. The same fenofibrate regimen was applied to investigate its beneficial effects on sclerosing cholangitis in a DDC-induced cholestatic model.Key Results: Fenofibrate, 25 mg·kg-1 twice a day, totally attenuated ANIT-induced cholestasis and liver injury as indicated by biochemical and histological analyses. This protection occurred in wild-type, but not in Pparα-null, mice. Alterations in bile acid synthesis and transport were found to be an adaptive response rather than a direct effect of fenofibrate. WY14643 attenuated ANIT-induced cholestasis and liver injury coincident with inhibition of JNK signalling. Although SP600125 did not affect cholestasis, it inhibited liver injury in the ANIT model when the dose of fenofibrate used was ineffective. Fenofibrate was also revealed to have a beneficial effect in the sclerosing cholangitis model.Conclusions and Implications: These data suggest that the protective effects of fenofibrate against cholestasis-induced hepatic injury are dependent on PPARα and fenofibrate dose, and are mediated through inhibition of JNK signalling. This mechanism of fenofibrate protection against intrahepatic cholestasis may offer additional therapeutic opportunities for cholestatic liver diseases. [ABSTRACT FROM AUTHOR]

Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug–drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose–response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0.75% gemfibrozil-containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose-dependent manner by gemfibrozil. In Pparα-null mice, their mRNA level, protein level and activity were induced more than those in wild-type mice. So, gemfibrozil induced CYP, and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug–drug interactions and metabolic diseases treated with fibrates. [ABSTRACT FROM AUTHOR]

Background and Purpose: Currently, ursodeoxycholic acid and obeticholic acid are the only two FDA-approved drugs for cholestatic liver diseases. Thus, new therapeutic approaches need to be developed. Here we have evaluated the anti-cholestasis effects of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera.Experimental Approach: Hepatoprotective effect of SolB against intrahepatic cholestasis, induced by lithocholic acid (LCA), was evaluated in mice. Metabolomic analysis and gene analysis were used to assess involvement of pregnane X receptor (PXR). Molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the critical role of the PXR pathway in the anti-cholestasis effects of SolB.Key Results: SolB protected against LCA-induced intrahepatic cholestasis. Furthermore, therapeutic treatment with SolB decreased mortality in cholestatic mice. Metabolomics and gene analysis showed that SolB accelerated metabolism of bile acids, promoted bile acid efflux into the intestine, and induced hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1, and Oatp2, which are involved in bile acid homeostasis. Mechanistic studies showed that SolB activated human PXR and up-regulated PXR target genes in human cell lines. Additionally, SolB did not protect Pxr-null mice from liver injury induced by intrahepatic cholestasis, thus providing genetic evidence that the effect of SolB was PXR-dependent.Conclusion and Implications: These findings provide direct evidence for the hepatoprotective effects of SolB against cholestasis by activating PXR. Therefore, SolB may provide a new and effective approach to the prevention and treatment of cholestatic liver diseases. [ABSTRACT FROM AUTHOR]

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Perfluorodecanoic acid (PFDA) is widely used in production of many daily necessities based on their surface properties and stability. It was assigned as a Persistent Organic Pollutant in 2009 and became a public concern partly because of its potential for activation of the peroxisome proliferator-activated receptor alpha (PPARα). In this study, wild-type and Ppara-null mice were administered PFDA (80 mg/kg). Blood and liver tissues were collected and subjected to systemic toxicological and mechanistic analysis. UPLC-ESI-QTOFMS-based metabolomics was used to explore the contributing components of the serum metabolome that led to variation between wild-type and Pparα-null mice. Bile acid homeostasis was disrupted, and slight hepatocyte injury in wild-type mice accompanied by adaptive regulation of bile acid synthesis and transport was observed. The serum metabolome in wild-type clustered differently from that in Pparα-null, featured by sharp increases in bile acid components. Differential toxicokinetic tendency was supported by regulation of UDP-glucuronosyltransferases dependent on PPARα, but it did not contribute to the hepatotoxic responses. Increase in Il- 10 and activation of the JNK pathway indicated inflammation was induced by disruption of bile acid homeostasis in wild-type mice. Inhibition of p-p65 dependent on PPARα activation by PFDA stopped the inflammatory cascade, as indicated by negative response of Il- 6, Tnf- α, and STAT3 signaling. These data suggest disruptive and protective role of PPARα in hepatic responses induced by PFDA. [ABSTRACT FROM AUTHOR]

Objectives Chlorogenic acid ( CGA) is one of the most widely consumed polyphenols in diets and is recognized to be a natural hepatoprotective agent. Here, we evaluated the protective effect and the potential mechanism of CGA against ɑ-naphthylisothiocyanate ( ANIT)-induced cholestasis and liver injury. Methods Twenty-five male 129/Sv mice were administered with CGA, and ANIT challenge was performed at 75 mg/kg on the 4th day. Blood was collected and subjected to biochemical analysis; the liver tissues were examined using histopathological analysis and signalling pathways. Key findings Chlorogenic acid almost totally attenuated the ANIT-induced liver damage and cholestasis, compared with the ANIT group. Dose of 50 mg/kg of CGA significantly prevented ANIT-induced changes in serum levels of alanine aminotransferase, alkaline phosphatases, total bile acid, direct bilirubin, indirect bilirubin (5.3-, 6.3-, 18.8-, 158-, 41.4-fold, P<0.001) and aspartate aminotransferase (4.6-fold, P<0.01). Expressions of the altered bile acid metabolism and transport-related genes were normalized by cotreatment with CGA. The expressions of interleukin 6, tumour necrosis factor-α and suppressor of cytokine signalling 3 were found to be significantly decreased (1.2-fold, ns; 11.0-fold, P<0.01; 4.4-fold, P<0.05) in the CGA/ ANIT group. Western blot revealed that CGA inhibited the activation and expression of signal transducer and activator of transcription 3 and NFκB. Conclusions These data suggest that CGA inhibits both ANIT-induced intrahepatic cholestasis and the liver injury. This protective effect involves down-regulation of STAT3 and NFκB signalling. [ABSTRACT FROM AUTHOR]

Traditional medicinal formulation of Yin-zhi-huang (YZH) is widely used in the clinic for the treatment of jaundice and chronic liver diseases in East Asian countries. However, the pharmacologically active components of YZH and the underlying mechanism are still unknown. Geniposide (GEN) was recently identified as one of the most abundant circulating components in YZH. In this study, we investigated the protective effect of GEN against liver injuries induced by alpha-naphthylisothiocyanate (ANIT). 50mg/kg of GEN was administered to ICR mice once daily for 5 days, and challenge of ANIT 75mg/kg was performed on the 4th day. Blood and liver tissues were collected on day 6 and subjected to biochemical, histopathological and pathway analyses. The biochemical and pathological findings showed that GEN almost totally attenuated ANIT-induced cholestasis and liver injury compared with the vehicle/ANIT group. The altered gene transcription related to bile acid metabolism and transport was normalized by co-treatment with GEN. The expressions of tumor necrosis factor- and the suppressor of cytokine signaling 3 were significantly decreased in the GEN/ANIT group. Western blot revealed that GEN inhibited the activation and expression of STAT3 and NFB. These data suggest GEN inhibits ANIT-induced hepatotoxicity. The protective effect is associated with the downregulation of STAT3 and NFB signaling. [ABSTRACT FROM AUTHOR]

Amyloid-beta (Aβ) interacts with the serine/threonine protein kinase AKT (also known as protein kinase B)/glycogen synthase kinase 3β (GSK3β) pathway and deactivates GSK3β signaling, which result in microtubule protein tau phosphorylation. Atorvastatin, a HMG-CoA reductase inhibitor, has been proven to improve learning and memory performance, reduce Aβ and phosphorylated tau levels in mouse model of Alzheimer's disease (AD). However, it still remains unclear whether atorvastatin is responsible for regulation of AKT/GSK3β signaling and contributes to subsequent down-regulation of Aβ1-42 and phosphorylated tau in APP/PS1 transgenic (Tg APP/PS1) mice. Herein, we aimed to investigate the possible impacts of atorvastatin (10 mg/kg, p.o.) on the memory deficit by behavioral tests and changes of AKT/GSK3β signaling in hippocampus and prefrontal cortex by western blot test in Tg APP/PS1 mice. The results showed that treatment with atorvastatin significantly reversed the memory deficit in the Tg APP/PS1 mice in a novel object recognition and the Morris water maze tests. Moreover, atorvastatin significantly attenuated Aβ1-42 accumulation and phosphorylation of tau (Ser396) in the hippocampus and prefrontal cortex of Tg APP/PS1 mice. In addition, atorvastatin treatment also increased phosphorylation of AKT, inhibited GSK3β activity by increasing phosphorylation of GSK3β (Ser9) and decreasing the beta-site APP cleaving enzyme 1 (BACE1) expression. These results indicated that the memory ameliorating effect of atorvastatin may be, in part, by regulation the AKT/GSK3β signaling which may contribute to down-regulation of Aβ1-42 and tau hyperphosphorylation. [ABSTRACT FROM AUTHOR]

Inhibition of phosphodiesterase-4 or 5 (PDE4 or PDE5) increases cyclic adenosine monophosphate (cAMP)- or cyclic guanosine monophosphate (cGMP), respectively, which activates cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/neuropeptide VGF (non-acryonimic) signaling and produces antidepressant-like effects on behavior. However, causal links among these actions have not been established. In the present study, mice were evaluated for the effects of etazolate and sildenafil, the inhibitor of PDE4 or PDE5, respectively, on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) in the forced-swimming test (FST) and tail suspension test (TST), in the presence or absence of the inhibitor of protein kinase A (PKA) or protein kinase G (PKG) via intracerebroventricular (i.c.v.) infusions. The levels of cAMP, cGMP and expression of pCREB, CREB, BDNF and VGF in both the hippocampus and prefrontal cortex were determined. The results showed that etazolate at 5.0 mg/kg or sildenafil at 30 mg/kg significantly reversed CUMS-induced depressive-like behavior; the effects were paralleled with the increased levels of cAMP/pCREB/BDNF/VGF or cGMP/pCREB/BDNF/VGF signaling, respectively. These effects were completely abolished following inhibition of PKA or PKG, respectively. The results suggest that inhibition of PDE4 by etazolate or PDE5 by sildenafil produced antidepressant-like effects in CUMS-treated animals via cAMP or cGMP signaling, which shares the common downstream signal pathway of CREB/BDNF/VGF. [ABSTRACT FROM AUTHOR]

Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis. [ABSTRACT FROM AUTHOR]

Chitosan (Ch) is one of the most commonly used natural biomaterials. Osteodifferentiation of mesenchymal stem cells (MSCs) on Ch has drawn extensive interest. Hydroxyapatite (HA) is a component of skeleton and teeth with good biocompatibility. Combination with HA may be a good method to modify Ch to facilitate cellular behaviors and functions on it. In this study, Ch/HA film was prepared and characterized. Its potential to benefit cellular behaviors and osteodifferentiation of MSCs was evaluated. Resultantly, physical properties of composite Ch/HA, including water-in-air contact angle, tensile strength, elastic modulus, and breaking elongation were favorably modified. In cellular culture medium, Ch/HA films absorbed more Ca2+ than Ch films, and more HA crystalline growths on Ch/HA films. 3-(4,5-Dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and morphological features showed better proliferation and adhesion of MSCs on Ch/HA films. Osteodifferentiation of MSCs on Ch/HA was promoted, indicated by modified transcription level of osteocalcin, osteopontin, collagen I, alkaline phosphatase (ALP), and induced ALP activity. These data suggest biocompatibility of Ch is modified after being blended with HA, which promotes osteodifferentiation of MSCs. This can be a promising approach to modify Ch for its applications in bone tissue engineering. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 1202-1209, 2014. [ABSTRACT FROM AUTHOR]

ABSTRACT Drug-induced QT prolongation usually leads to torsade de pointes (TdP), thus for drugs in the early phase of development this risk should be evaluated. In the present study, we demonstrated a visualized transgenic zebrafish as an in vivo high-throughput model to assay the risk of drug-induced QT prolongation. Zebrafish larvae 48 h post-fertilization expressing green fluorescent protein in myocardium were incubated with compounds reported to induce QT prolongation or block the human ether-a-go-go-related gene (hERG) K+ current. The compounds sotalol, indapaminde, erythromycin, ofoxacin, levofloxacin, sparfloxacin and roxithromycin were additionally administrated by microinjection into the larvae yolk sac. The ventricle heart rate was recorded using the automatic monitoring system after incubation or microinjection. As a result, 14 out of 16 compounds inducing dog QT prolongation caused bradycardia in zebrafish. A similar result was observed with 21 out of 26 compounds which block hERG current. Among the 30 compounds which induced human QT prolongation, 25 caused bradycardia in this model. Thus, the risk of compounds causing bradycardia in this transgenic zebrafish correlated with that causing QT prolongation and hERG K+ current blockage in established models. The tendency that high logP values lead to high risk of QT prolongation in this model was indicated, and non-sensitivity of this model to antibacterial agents was revealed. These data suggest application of this transgenic zebrafish as a high-throughput model to screen QT prolongation-related cardio toxicity of the drug candidates. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Fibrates are widely used for the treatment of dyslipidemia. However, the contributions of the phase I and phase II metabolic pathways to the clearance of fibrates are unclear. In this study, we investigated the metabolism of gemfibrozil (Gem), clofibric acid (CA), fenofibric acid (FA) and bezafibrate (Beza) by cytochrome P450s (P450s) and UDP-glycosyltransferases (UGTs) using a substrate depletion approach. We also compared the metabolic characteristics of rat liver microsomes (RLM) and human liver microsomes (HLM). The intrinsic clearance rates mediated by P450s, UGTs and both were 172 ± 22, 643 ± 26, 798 ± 103 μL min mg, respectively, for Gem and 43 ± 11, 88 ± 12, 119 ± 15 μL min mg, respectively, for CA in RLM. The fractions metabolized by P450s and UGTs in RLM were 22% and 81% for Gem, 36% and 74% for CA. The P450- and UGT-mediated depletion rates for Gem were 303 and 1607 nmol min mg in RLM versus 86 and 243 nmol min mg in HLM. The corresponding rates for CA were 1.1 and 1.7 nmol min mg in RLM versus 0.025 and 0.038 nmol min mg in HLM. Accordingly, both P450s and UGTs substantially contribute to the clearance of Gem and CA, with UGTs playing a greater role. To avoid under-estimating the impact of these pathways, it is necessary to measure NADPH- and UDPGA-dependent metabolism. Although the fractions of these two pathways in RLM and HLM were similar, the depletion rate of Gem and CA in RLM was higher than that in HLM. The metabolism of FA and Beza by P450s and UGTs was too low to calculate intrinsic clearance in both RLM and HLM. These results indicate that fibrates are metabolized via similar pathways in rats and humans, and it is applicable to use RLM to predict the clearance of fibrates in human. [ABSTRACT FROM AUTHOR]

Ketoconazole (KTZ), a clinical antifungal agent, is a known inhibitor of CYP3A and permeability glycoprotein (P-gp). Berberine (BBR), a natural plant-derived product used for gastroenteritis, is a substrate of P-gp. Recently, a synergistic antifungal effect of KTZ combined with BBR has been revealed. In this study, we performed both in vivo and in vitro experiments to explore whether pharmacokinetic interactions between KTZ and BBR would benefit their phamacodynamic synergism. After oral co-administration of 10 mg/kg KTZ with 60 mg/kg BBR, the average area under the curve (AUC) and the maximum concentration ( Cmax) for KTZ increased to 215% and 449% (p < 0.05), respectively, in male rats and 157% and 172% ( p < 0.05), respectively, in female rats, compared with those administered KTZ alone. Area under the curve and Cmax for BBR increased to 173% and 142%, respectively, compared with those administered BBR alone. After intravenous co-administration of 0.5 mg/kg KTZ and 0.8 mg/kg BBR, the pharmacokinetic properties of KTZ remained the same, but AUC of BBR increased to 254% ( p < 0.05) compared with those administered BBR alone. In rat liver microsomes, inhibitory concentration (IC)50 of BBR inhibiting KTZ depletion was determined to be 103 µ m. These resulting pharmacokinetic interactions may benefit their pharmacodynamic synergism to a certain extent. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Topographical micro-structures of material surfaces are known to influence cell behavior. In this study, alignment and proliferation of mesenchymal stem cells (MSCs) on chitosan (CS) films with different microtopography was investigated. A modified solvent-non-solvent method was used to produce micro-well polystyrene films which were used as templates for preparation of micro-hilled CS films. The alignment and proliferation of MSCs on CS films were characterized by scanning electron microscopy and the MTT assay, respectively. Polystyrene films with different micro-well diameters were produced under different conditions. We successfully produced CS films with micro-hills of 10 μm (CS10) and 5-30 μm (CS5-30) by a molding approach. MSCs cultured on CS10 covered the tightly packed micro-hills and flattened polygonally. In contrast, MSCs on CS5-30 mostly adhered between loosely packed micro-hills and demonstrated elongated extensions. The proliferation rate of MSCs on CS5-30 was highest on day 4 (66% on CS5-30 versus 46% on CS10 and 24% on smooth CS) and day 8 (106% on CS5-30 versus 38% on CS10 and 72% on smooth CS). It is reasonable to suggest that spatially and dimensionally dispersed micro-hills on CS films facilitate the alignment and proliferation of MSCs. This may be used to physically modify CS for tissue-engineering applications. [ABSTRACT FROM AUTHOR]

The recombinant adeno-associated virus 8 (rAAV8) vector is a widely used tool in basic research and clinical trials. The cytomegalovirus immediate-early enhancer/chicken β-actin (CAG) promoter is a synthetic promoter used in adenoviral constructs with a wide spectrum and notable efficiency. The thyroxine binding globulin (TBG) promoter is a liver-specific promoter, which directs transgene expression in hepatocytes. However, the transduction efficiency of the rAAV vector is dependent on both the administration routes and the promoter elements. In the present study, the transduction efficiency in the liver following intraperitoneal (IP) and intravenous (IV) injections of rAAV8 with the CAG, TBG669 and TBG410 promoters was compared. Enhanced green fluorescent protein (EGFP) expression was used as the biomarker to indicate efficiency. Among the three different promoters, CAG exhibited the highest efficiency from both IV and IP injections. Following IV administration, EGFP expression, induced by the CAG promoter, was 67-fold higher compared with that in the TBG410 promoter group and 26-fold higher compared with that in the TBG669 promoter group. EGFP protein expression was higher with IV injection compared with that for IP injection for both the CAG and TBG669 promoters (P<0.05). With the CAG promoter, EGFP protein expression was 1.5-fold higher with the use of IV injection than with IP injection. With the TBG410 promoter, no differences were observed between the two administrations. In conclusion, these findings demonstrated that the CAG promoter was much more efficient at driving gene expression in the liver compared with that for the TBG promoters in rAAV8. In addition, IP administration produced comparable efficiency for gene delivery via the rAAV8 vector, particularly with the promoter TBG410. [ABSTRACT FROM AUTHOR]