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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]

· A lightweight network enhances tile and bolt detection in CFETR. · Improving YOLOv5s with C3Ghost, SimSPPF, and EIOU structures. · GSE-YOLOv5s with higher mAP, fewer parameters, and less FLOPS. The detection of the first wall tile and bolts (holes) of CFETR is crucial for improving the efficiency of remote operation maintenance. The internal environment of CFETR is complex, and the existing target detection algorithms lack precision, are prone to missed detection, and occupy substantial computational resources. We introduce a method for detecting tiles and bolts (holes) using a lightweight network. First, a preliminary research platform is established to build a dataset. Secondly, based on YOLOv5s, the GhostBottleNeck module replaces the BottleNeck in the C3 module to build a C3Ghost structure, reducing model computation and parameters. A fast spatial pooling pyramid structure, SimSPPF module, is proposed to replace the SPPF module, increasing model speed. The replacement of the CIOU loss function with EIOU enhances positional accuracy. Comparative experimental results indicate this network outperforms baseline YOLOv5s by increasing the mAP by 1.4 %, decreasing parameters by 13.8 %, and reducing floating-point operations (FLOPS) by 13.2 %. This study holds considerable reference value for future remote visual maintenance in CFETR. [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]

• Combined model method is utilized to construct the virtual scene. • The force sensor is calibrated to compensate the installation error and gravity effect. • The proposed method is validated both on a virtual and a physical assembly platform. To fulfil in-vessel maintenance in the China Fusion Engineering Test Reactor (CFETR), a Master-Slave remote handling system with high reliability, stability, and flexibility is required. Due to the complexity of CFETR's internal environment and the robot system, operators need to be well trained before any physical maintenance is conducted. It is of high risk, high cost, and low efficiency that operators are trained in physical environment. The above problems can be avoided when operators are trained in a virtual environment. However, it is difficult to achieve the realization in the master side and contact force in the slave side. In this paper, we develop a new Virtual Assembly Simulation Platform with high quality realization of the contact force and the operator's telepresence. The platform consists of a master-slave robot system and a simulation environment build upon CoppeliaSim. To remove the influence of the tool's gravity on the feedback force obtained by the force sensor installed at the end of robot. We propose a least square method-based gravity compensation algorithm. The replaceability of the virtual platform to the physical platform and the effectiveness of the algorithm are demonstrated by the peg-in-hole assembly experiment. [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]

Overdose of acetaminophen (APAP) can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. The traditional Chinese herb Bupleurum falcatum has been widely used for the treatment of several liver diseases in eastern Asian countries, and saikosaponin d (SSd) is one of its major pharmacologically-active components. However, the efficacy of Bupleurum falcatum or SSd on APAP toxicity remains unclear. C57/BL6 mice were administered SSd intraperitoneally once daily for 5 days, followed by APAP challenge. Biochemical and pathological analysis revealed that mice treated with SSd were protected against APAP-induced hepatotoxicity. SSd markedly suppressed phosphorylation of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) and reversed the APAP-induced increases in the target genes of NF-κB, such as pro-inflammatory cytokine Il6 and Ccl2 , and those of STAT3, such as Socs3 , Fga , Fgb and Fgg . SSd also enhanced the expression of the anti-inflammatory cytokine Il10 mRNA. Collectively, these results demonstrate that SSd protects mice from APAP-induced hepatotoxicity mainly through down-regulating NF-κB- and STAT3-mediated inflammatory signaling. This study unveils one of the possible mechanisms of hepatoprotection caused by Bupleurum falcatum and/or SSd. [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]

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]

Abstract: Phenotypic modifications of vascular smooth muscle cells (VSMCs) contribute to pathological changes in atherosclerosis where modulation of intracellular calcium plays an important role. In this study, three fibrate drugs, namely gemfibrozil (Gem), fenofibric acid (Fa) and bezafibrate (Beza), were revealed to relax thoracic aorta associated with their potency to reduce intracellular calcium ([Ca2+]i) in cultured VSMCs. Relaxation effect of Gem, Fa and Beza was assayed on precontracted rat aortic rings. [Ca2+]i level in VSMCs following addition of these fibrates was measured by laser scanning confocal microscopy or flow cytometry. Resultantly, three fibrates showed activity for vasodilation with potency order of Gem>Fa>Beza. Sustained potent reduction of [Ca2+]i was observed with Gem 50mg/L and mild reduction with Fa 400–600mg/L, while no effect had been detected for Beza under our current system. Thus, the potency of these fibrates to relax aortic rings correlate well with their effect on [Ca2+]i reduction, strongly implicating an underlying causal relationship. Considering that Gem potently reduces [Ca2+]i in its clinical concentration range, this study suggests an insight to in situ pharmacological effects of anti-atherosclerosis and clinical toxicity risk. [Copyright &y& Elsevier]

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]

Abstract: Fibrate drugs are PPARα agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPARα agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey #2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly, they exhibited a much higher incidence of myotoxicity than that of humans. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity. [Copyright &y& Elsevier]

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]

Nitrogen oxides (NO x) are crucial in tropospheric photochemical ozone (O 3) production and oxidation capacity. Currently, the widely used NO x measurement technique is chemiluminescence (CL) (CL-NO x), which tends to overestimate NO 2 due to atmospheric oxidation products of NO x (i.e., NO z). We developed and characterized a NO x measurement system using the cavity attenuated phase shift (CAPS) technique (CAPS-NO x), which is free from interferences with nitrogen-containing species. The NO x measured by the CAPS-NO x and CL-NO x analyzers were compared. Results show that both analyzers showed consistent measurement results for NO, but the NO 2 measured by the CAPS-NO x analyzer (NO 2_CAPS) was mostly lower than that measured by the CL-NO x analyzer (NO 2_CL), which led to the deviations in O 3 formation sensitivity regime and O x (= O 3 + NO 2) sources (i.e., regional background and photochemically produced O x) determined by the ozone production efficiencies (OPE) calculated from NO 2_CL and NO 2_CAPS. Overall, OPE _CL exceeded OPE _CAPS by 18.9%, which shifted 3 out of 13 observation days from the VOCs-limited to the transition regime when judging using OPE _CL , as compared to calculations using OPE _CAPS. During the observation period, days dominated by regional background O x accounted for 46% and 62% when determined using NO 2_CL and NO 2_CAPS , respectively. These findings suggest that the use of the CL-NO x analyzer tends to underestimate both the VOCs-limited regime and the regional background Ox dominated days. The newly built CAPS-NO x analyzer here can promote the accurate measurement of NO 2 , which is meaningful for diagnosing O 3 formation regimes and O x sources. [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]

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]

The development of cholestatic liver injury (CLI) involves inflammation, but the dominant pathway mediating the chemotaxis is not yet established. This work explored key signaling pathway mediating chemotaxis in CLI and the role of Kupffer cells in the inflammatory liver injury. Probe inhibitors T-5224 (100 mg/kg) for AP-1 and C188–9 (100 mg/kg) for STAT3 were used to validate key inflammatory pathways in alpha-naphthylisothiocyanate (ANIT, 100 mg/kg)-induced CLI. Two doses of GdCl 3 (10 mg/kg and 40 mg/kg) were used to delete Kupffer cells and explore their role in CLI. Serum and liver samples were collected for biochemical and mechanism analysis. The liver injury in ANIT-treated mice were significantly increased supported by biochemical and histopathological changes, and neutrophils gathering around the necrotic loci. Inhibitor treatments down-regulated liver injury biomarkers except the level of total bile acid. The chemokine Ccl2 increased by 170-fold and to a less degree Cxcl2 by 45-fold after the ANIT treatment. p-c-Jun and p-STAT3 were activated in the group A but inhibited by the inhibitors in western blot analysis. The immunofluorescence results showed AP-1 not STAT3 responded to inhibitors in ANIT-induced CLI. With or without GdCl 3 , there was no significant difference in liver injury among the CLI groups. In necrotic loci in CLI, CXCL2 colocalized with hepatocyte biomarker Albumin, not with the F4/80 in Kupffer cells. Conclusively, AP-1 played a more critical role in the inflammation cascade than STAT3 in ANIT-induced CLI. Hepatocytes, not the Kupffer cells released chemotactic factors mediating the chemotaxis in CLI. [Display omitted] • AP-1 inhibitor T-5224 and STAT3 inhibitor C188-9 deleted cholestatic liver injury respectively. • Activation of AP-1 correlated more to cholestatic liver injury than STAT3. • Chemokines mediating the chemotaxis in cholestatic liver injury was released by hepatocytes not the Kupffer cells. • Kupffer cells in cholestatic liver injury were neither protective nor disruptive. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Hypaconitine is one of the main aconitum alkaloids in traditional Chinese medicines prepared with herbs from the genus Acotinum. These herbs are widely used for the treatment of cardiac insufficiency and arrhythmias. However, Acotinum alkaloids are known for their toxicity as well as their pharmacological activity, especially cardiotoxicity including QT prolongation, and the mechanism of this toxicity is not clear. Material and methods In this study, hypaconitine was administered orally to conscious Beagle dogs, and electrocardiograms were recorded by telemetry. Pharmacokinetic studies (6 h) were conducted to evaluate the relationship between QT prolongation and exposure level. HEK293 cells stably transfected with KCNH 2 ( hERG ) cDNA were used to examine the effects of hypaconitine on the KCNH2 channel by using the manual patch clamp technique. Results In the conscious dogs, all doses of hypaconitine induced QTcV (QT interval corrected according to the Van de Water formula) prolongation by more than 23% (67 ms) of control in a dose-dependent manner. The maximum QTcV prolongation was observed at 2 h after dosing. Maximum prolongation percentages were plotted against plasma concentrations of hypaconitine and showed a strong correlation ( R 2 =0.789). In the in vitro study in HEK293 cells, hypaconitine inhibited the KCNH2 currents in a concentration-dependent manner with an IC 50 of 8.1 nM. Conclusion These data suggest that hypaconitine inhibits KCNH2 potassium channels and this effect might be the molecular mechanism underlying QT prolongation in conscious dogs. [ABSTRACT FROM AUTHOR]

Casein (CN) is a common allergen that is challenging to avoid in modern foods. The effect of cold argon plasma (CAP) on reducing CN antigenicity was investigated, focusing on alterations in epitope structure and sequence. CAP mainly contains hydroxyl radicals (∙OH). After a 12-min CAP treatment, the result of ELISA demonstrated an 80.46 % reduction in antigenicity. Transmission electron microscopy and electrophoresis revealed that certain CN aggregated, while multispectral analysis indicated that part of CN was fragmented into smaller peptides. The predictive 3D model suggested the disruption of linear epitopes located in the α-helix region might contribute to the reduced allergenicity. The peptide sequences were compared to the linear epitopes predicted by immunoinformatics approaches, revealing some reduction or breakage of key allergic sequences. Meanwhile, amino acids with aromatic side chains and hydrophobic groups were susceptible to CAP-induced modifications. This investigation demonstrated CAP could be beneficial for processing hypoallergenic foods. [Display omitted] • Cold argon plasma (CAP) was utilized to reduce casein antigenicity. • CAP mainly contains reactive oxygen species (ROS), particularly high levels of ∙OH. • CAP causes casein's main chain to cleave, side chains to oxidize and aggregate. • 3D modelling and peptide sequencing was used to evaluate epitope alterations. • Aromatic and hydrophobic amino acids maybe susceptible to CAP-induced modification. [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]

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]

• To enhance the immersive operating experience by reducing time delays, a control system based on OROCOS and DDS has been presented to rapidly establish the bilateral teleoperation system with real-time performance. • A bilateral control algorithm combining closed-loop pose tracking and force feedback is proposed to improve the pose tracking accuracy of the slave robot and enhance the sense of telepresence. • A lightweight experimental setup has been constructed based on the maintenance scenario in EAST. Relative experiments have been conducted to validate the accuracy and effectiveness of the bilateral teleoperation system. Bilateral teleoperation is a control strategy used in remote handling (RH) to enable an operator to control a robot or system while perceiving the interactive force in the environment. To enhance the immersive operating experience by reducing time delays, a control system based on OROCOS and DDS has been presented to rapidly establish the bilateral teleoperation system with real-time performance. Additionally, a bilateral control algorithm combining closed-loop pose tracking and force feedback is proposed to improve the pose tracking accuracy of the slave robot and enhance the sense of telepresence. As a part of the pre-study on the tile assembly conducted by CMOR in Chinese Fusion Engineering Test Reactor (CFETR), a lightweight experimental setup has been constructed based on the maintenance scenario in EAST. Relative experiments have been conducted to validate the accuracy and effectiveness of the bilateral teleoperation system. The results demonstrate low latency and smooth control during the bilateral teleoperation process. [ABSTRACT FROM AUTHOR]

Highlights • In chronic cholestsis, bile acid metabolism adaptation is inhibited in wild-type mice but not in Ppara -null mice. • FXR pathway is activated in Ppara -null mice, not in wild-type mice. • Cross-talk between basal PPARα and FXR inhibit bile acid metabolism adaptation in chronic cholestasis. Abstract Cholestasis is one of the most challenging diseases to be treated in current hepatology. However little is known about the adaptation difference and the underlying mechanism between acute and chronic cholestasis. In this study, wild-type and Pparα -null mice were orally administered diet containing 0.05% ANIT to induce chronic cholestasis. Biochemistry, histopathology and serum metabolome analysis exhibited the similar toxic phenotype between wild-type and Pparα -null mice. Bile acid metabolism was strongly adapted in Pparα -null mice but not in wild-type mice. The Shp and Fxr mRNA was found to be doubled in cholestatic Pparα -null mice compared with the control group. Western blot confirmed the up-regulated expression of FXR in Pparα -null mice treated with ANIT. Inflammation was found to be stronger in Pparα -null mice than those in wild-type mice in chronic cholestasis. These data chain indicated that bile acid metabolism and inflammation signaling were different between wild-type and Pparα -null mice developing chronic cholestasis, although their toxic phenotypes could not be discriminated. So basal PPARα cross-talked with FXR and inhibited bile acid metabolism adaptation in chronic cholestasis. [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]

EAST Optical Diagnostic Beam Orientation Robot (EODBOR) is designed for the calibration of the visible optical diagnostic system before the plasma experiment, which can orientate light beams with high precision. At present, the motion of EODBOR is purely controlled by the operators during the whole calibration process since planning algorithms based on prior knowledge of the environment cannot be adopted due to the intrinsically unstructured property of EAST's vacuum vessel. To automate the calibration, we upgraded our previous system and propose a method for environment-aware motion planning based on Robot Operating System (ROS). In this method, the probabilistic octree is used to represent unknown objects in the environment, which is updated with point clouds from an RGB-D camera mounted at the end of the manipulator. We verify the feasibility and stability of the proposed method through simulations and experiments. • An environment-aware motion planning system based on Robot Operating System (ROS) is developed. • A hand–eye calibration method for RGB-D cameras using a calibration sphere is proposed. • Simulations are carried out in a virtual scene based on the real size of the vacuum vessel of EAST and the installation position of the robotic arm. • Experiments using an eye-in-hand system consisting of a UR5 robotic arm and a RealSense D435 validate the feasibility of the proposed method. [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]

This paper reports metal oxide (MOx)-decorated graphene-based sensor array combining with back-propagation (BP) neural network toward the detection of indoor air pollutant exposure. Tin dioxide (SnO 2 ) nanospheres and copper oxide (CuO) nanoflowers-decorated graphene were used as candidates for formaldehyde and ammonia gas sensing, respectively. The as-synthesized sensing materials were characterized in terms of their nanostructural, morphological and compositional features by SEM, Raman spectra, and XRD. The sensor array was fabricated via one-step hydrothermal route and layer-by-layer (LbL) self-assembly technique on the substrate with interdigital microelectrodes. The sensing properties of MOx/graphene composite toward the mixture gas of ammonia and formaldehyde, such as dynamic response, sensitivity, response/recovery time, and stability, were investigated at room temperature. And furthermore, this work successfully achieved the recognition and quantitative prediction of components in the gas mixture of formaldehyde and ammonia through the combination of MOx/graphene-based sensor array and neural network-based signal processing technologies. [ABSTRACT FROM AUTHOR]

While gemfibrozil and fenofibrate are prescribed for anti-dyslipidemia treatment, a rational basis for the use of these drugs for treatment of dyslipidemia with concurrent metabolic syndrome has not been established. In this study, wild-type and Pparα-null mice were fed gemfibrozil- or fenofibrate-containing diets for 14 days. Urine output (24 h) was monitored, and urine, serum, and liver and kidney tissues were subjected to toxicity assessment. A 2-month challenge followed by a 2-week wash-out was performed for gemfibrozil to determine urine output and the potential toxicity. A therapeutically equivalent dose of gemfibrozil was more effective than fenofibrate in increasing urine output. This regulatory effect was not observed in Pparα-null mice. In contrast, hepatomegaly induced by fenofibrate was more pronounced than that of gemfibrozil. No significant toxicity was observed in liver or kidney in the 2-month treatment with gemfibrozil. These data demonstrated PPARα mediates the increased urine output by fibrates. Considering the relative action on hepatomegaly and the regulatory effect on urine output, gemfibrozil may be the preferable drug to increase urine output. These results revealed a new pharmacodynamic effect of clinically prescribed PPARα agonists and suggested the potential value of gemfibrozil in modification of blood pressure. [ABSTRACT FROM AUTHOR]

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]

TiO 2 nano-particle (TiO 2 NP) is widely used in industrial, household necessities, as well as medicinal products. However, the effect of TiO 2 NP on liver metabolic function has not been reported. In this study, after mice were orally administered TiO 2 NP (21 nm) for 14 days, the serum and liver tissues were assayed by biochemical analysis, real time quantitative polymerase chain reaction, western blot and transmission electron microscopy. The serum bilirubin was increased in a dose dependent manner. Deposition of TiO 2 NP in hepatocytes and the abnormality of microstructures was observed. Expression of metabolic genes involved in the endogenous and exogenous metabolism was modified, supporting the toxic phenotype. Collectively, oral administration of TiO 2 NP (21 nm) led to deposition of particles in hepatocytes, mitochondrial edema, and the disturbance of liver metabolism function. These data suggested oral administration disrupts liver metabolic functions, which was more sensitive than regular approaches to detect material hepatotoxicity. This study provided useful information for risk analysis and regulation of TiO 2 NPs by administration agencies. [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]

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]

• A modified RepVGG based visual servo method for quick-change tool alignment is investigated. • The robot is controlled by the position-based visual servo control law. • Experiments in real world are conducted to validate the effectiveness of the proposed visual servo method. The remote maintenance process for fusion reactor is complex, which can be very time-consuming and labor-consuming. This paper proposes a modified neural network based visual servo method to align a quick-change device with robot camera system. A classical position-based visual servo control law is used to guide the robot to reach the desired position. The key target for the above visual servo controller is to obtain a robust pose estimator to calculate the quick-change device pose with respect to the camera. This pose estimator is trained using RepVGG model with a self built image samples. An attention mechanism is added to the neural network to enhance the stability of pose prediction for reflective metal objects. The robot joint speed is also smoothed to reduce the image motion blur effect and make the visual servo process stable. The performance of the proposed visual servo controller was verified on an UR5 robot, and the results show that the stable and rough alignment of the quick-change device can be realized. [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]

Highlights: [•] Phosphodiesterase-5 (PDE5) inhibitor sildenafil ameliorates cognitive performance. [•] Sildenafil significantly rescues CREB phosphorylation and lowers Aβ levels. [•] Sildenafil may be as a potential therapeutic agent in long-term AD therapy. [ABSTRACT FROM AUTHOR]

Abstract: A chiral liquid chromatography–tandem mass spectrometry (LC–MS/MS) simultaneous stereoselective analysis of bambuterol and its active metabolite terbutaline enantiomers in Wistar rat plasma has been developed and validated. All analytes and the internal standard were extracted from rat plasma samples by liquid–liquid extraction, separated on macrocyclic glycopeptide teicoplanin column with mobile phase constituted of 20mM ammonium acetate solution–methanol (10:90, v/v) at a flow-rate of 0.4mL/min. Detection was performed on an API 3000 tandem mass spectrometer with positive electrospray ionization in multiple reaction monitoring mode. The calibration curves in the range 1–800ng/mL were linear and the accuracy for each analyte was within 8.0%. The intra- and inter-day precision as determined from quality control samples was less than 10.1%. The validated assay was successfully used to determine the enantiomers of bambuterol and terbutaline in rat plasma samples in the pharmacokinetic studies of rac-bambuterol. [Copyright &y& Elsevier]

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]

• This multi-center RCT will provide evidence for the rational application of PPI in ESD. • Low-dose PPIs were sufficient for prevention post-ESD bleeding and its efficacy level was equivalent to high dose PPIs. • Artificial ulcer healing after ESD in low-dose PPIs was similar to high dose PPIs. Although proton pump inhibitors (PPIs) are widely used in the prevention of gastric bleeding caused by endoscopic submucosal dissection (ESD), there is no consensus on the optimal regimen for these patients. Therefore, we aim to investigate whether intermittent use of low-dose PPI is sufficient to prevent post-ESD bleeding. This multicenter, non-inferiority, randomized controlled trial was conducted at 9 hospitals in China. Consecutive eligible patients with a diagnosis of gastric mucosal lesions after ESD treatment were randomly assigned (1:1) to receive either intermittent low-dose or continuous high-dose PPIs treatment. After three days, all patients administered orally esomeprazole 40 mg once a day for 8 weeks. The primary endpoint was post-ESD bleeding within 7 days. Analysis was done according to the intention-to-treat principle with the non-inferiority margin (Δ) of 5%. 526 consecutive patients were assessed for eligibility from 30 September 2017 to 30 July 2019, of whom 414 were randomly assigned to low-dose (n = 209) or high-dose (n = 205) esomeprazole treatment group without dropouts within7 days. The total post-ESD bleeding is occurred in 13 (6.2 %, 95 % CI 3.3–9.6) of 209 within 7 days in the intermittent low-dose group, and 12 (5.9 %, 95 % CI 2.9–9.3) of 205 in the continuous high-dose group. The absolute risk reduction (ARR) was 0.4 % (−4.2, 4.9). One month after ESD, There are 44 patients (21.1 %, 95 % CI 15.8, 26.8) and 39 patients (19.0 % 95 % CI 13.7, 24.4) in scar stage respectively in low-dose group and high-dose group (P = 0.875).The hospital costs in the low-dose PPI group was lower than high -dose group (P = 0.005). The intermittent use of low-dose PPIs is sufficient to prevent post-ESD bleeding. It might be applied in clinical practice to prevent post-ESD bleeding and reduce the costs related to PPIs. [ABSTRACT FROM AUTHOR]