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A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the ...treatment of Alzheimer’s disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20μM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
As an analog of clopidogrel and prasugrel, vicagrel is completely hydrolyzed to intermediate thiolactone metabolite 2‐oxo‐clopidogrel (also the precursor of active thiol metabolite H4) in human ...intestine, predominantly by AADAC and CES2; however, other unknown vicagrel hydrolases remain to be identified. In this study, recombinant human Raf kinase inhibitor protein (rhRKIP) and pooled human intestinal S9 (HIS9) fractions and microsome (HIM) preparations were used as the different enzyme sources; prasugrel as a probe drug for RKIP (a positive control), vicagrel as a substrate drug of interest, and the rate of the formation of thiolactone metabolites 2‐oxo‐clopidogrel and R95913 as metrics of hydrolase activity examined, respectively. In addition, an IC50 value of inhibition of rhRKIP‐catalyzed vicagrel hydrolysis by locostatin was measured, and five classical esterase inhibitors with distinct esterase selectivity were used to dissect the involvement of multiple hydrolases in vicagrel hydrolysis. The results showed that rhRKIP hydrolyzed vicagrel in vitro, with the values of Km, Vmax, and CLint measured as 20.04 ± 1.99 μM, 434.60 ± 12.46 nM/min/mg protein, and 21.69 ± 0.28 ml/min/mg protein, respectively, and that an IC50 value of locostatin was estimated as 1.24 ± 0.04 mM for rhRKIP. In addition to locostatin, eserine and vinblastine strongly suppressed vicagrel hydrolysis in HIM. It is concluded that RKIP can catalyze the hydrolysis of vicagrel in the human intestine, and that vicagrel can be hydrolyzed by multiple hydrolases, such as RKIP, AADAC, and CES2, concomitantly.
As a promising novel antiplatelet drug and an analog of clopidogrel and prasugrel, vicagrel is hydrolyzed to its thiolactone metabolite 2‐oxo‐clopidogrel by esterases AADAC and CES2 in human intestine. In this study, vicagrel was hydrolyzed to 2‐oxo‐clopidogrel by RKIP (Raf kinase inhibitor protein) as measured with recombinant human RKIP and human intestine S9 and microsome preparations, respectively, showing that vicagrel is the second substrate drug of RKIP in humans, next to prasugrel.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Genes involved in cellular processes undergo environment-dependent co-regulation, but the co-expression patterns of fungal cellulase and xylanase-encoding genes remain unclear. Here, we identified ...two novel carbon sources, methylcellulose and 2-hydroxyethyl cellulose, which efficiently induced the secretion of cellulases and xylanases in
. Comparative transcriptomic analyses identified carbon source-specific transcriptional patterns, mainly including major cellulase and xylanase-encoding genes, genes involved in glycolysis/gluconeogenesis and the tricarboxylic acid cycle, and genes encoding transcription factors, transporters and G protein-coupled receptors. Moreover, the weighted correlation network analysis of time-course transcriptomes, generated 17 highly connected modules. Module MEivory, comprising 120 members, included major cellulase and xylanase-encoding genes, genes encoding the key regulators PoxClrB and PoxXlnR, and a cellodextrin transporter POX06051/CdtC, which were tightly correlated with the filter-paper cellulase, carboxymethylcellulase and xylanase activities in
. An expression kinetic analysis indicated that members in MEivory were activated integrally by carbon sources, but their expressional levels were carbon source- and/or induction duration-dependent. Three uncharacterized regulatory genes in MEivory were identified, which regulate the production of cellulases and xylanases in
. These findings provide insights into the mechanisms associated with the synthesis and secretion of fungal cellulases and xylanases, and a guide for
application in biotechnology.
Indole alkaloids have attracted widespread attention of chemists and biologists. Therefore, the aim of this study is to screen more bioactivities indole alkaloids from the microorganisms. In this ...study, five undescribed CPA-type indole alkaloids, aspergillines F–J, and three known CPA-type indole alkaloids, aspergilline A, aspergilline C, and cyclopiamide E, were obtained from the Nicotiana tabacum-derived fungus Aspergillus versicolor. Notably, aspergillines F and G represent the first examples of indole alkaloids with a benzocdindol-2(1H)-one skeleton, and aspergilline J is also the firstly obtained indole alkaloids bearing a N-1-(2-(1H-imidazole-5-yl)ethyl) moiety. Aspergillines F–J and cyclopiamide E were tested for their anti-TMV activities, and the results revealed that aspergillines G and J exhibited obvious anti-TMV activities with inhibition rates of 41.2 and 56.8% at the concentration of 20 μM, respectively. These rates are high than that of positive control (with inhibition rate of 32.5%). In addition, the molecular docking studies for the isolated CPA-type indole alkaloids may also reveal that the benzocdindol-2(1H)-one substructure is the fundamental for anti-TMV activity and the oxygen-containing substituent groups at C-19 also increases the inhibitory activity. This study of structure-activity relationship is helpful to find new anti-TMV activity inhibitors.
Five undescribed CPA-type indole alkaloids were obtained from N. tabacum-derived fungus A. versicolor. Aspergillines G and J exhibited obvious anti-TMV activities. Display omitted
•Five undescribed CPA-type alkaloids were obtained from fungus A. versicolor.•Aspergillines F and G represent the examples of benzocdindol-2(1H)-one skeleton.•Aspergilline J is the CPA alkaloids bearing a N-1-(2-(1H-imidazole-5-yl)ethyl) moiety.•Aspergillines G and J exhibited obvious anti-TMV activities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Diabetic nephropathy (DN), the primary cause of end-stage renal disease (ESRD), is often accompanied by dyslipidemia, which is closely related to the occurrence and development of DN and even the ...progression to ESRD. Mitophagy, the selective degradation of damaged and dysfunctional mitochondria by autophagy, is a crucial mitochondrial quality control mechanism, and largely regulated by PINK1 (PTEN-induced putative kinase 1)/Parkin signaling pathway. In the present study, we demonstrated that PA induced mitochondrial damage and excessive mitoROS generation in podocytes. We also found PA treatment resulted in the activation of mitophagy by increasing co-localization of GFP-LC3 with mitochondria and enhancing the formation of mitophagosome, stabilization of PINK1 and mitochondrial translocation of Parkin, which indicated that PINK1/Parkin pathway was involved in PA-induced mitophagy in podocytes. Furthermore, inhibition of mitophagy by silencing Parkin dramatically aggravated PA-induced mitochondrial dysfunction, mitoROS production, and further enhanced PA-induced apoptosis of podocytes. Finally, we showed that PINK1/Parkin pathway were up-regulated in kidney of high fat diet (HFD)-induced obese rats. Taken together, our results suggest that PINK1/Parkin mediated mitophagy plays a protective role in PA-induced podocytes apoptosis through reducing mitochondrial ROS production and that enhancing mitophagy provides a potential therapeutic strategy for kidney diseases with hyperlipidemia, such as DN.
•PA induced lipotoxicity promoted podocytes injury and apoptosis.•PA induced mitochondrial injury, a decreased ΔΨm and excessive mitoROS generation in podocytes.•PINK1/Parkin pathway was involved in PA-induced mitophagy in podocytes.•PINK1/Parkin mediated mitophagy play a protective role in PA-induced apoptosis of podocytes by reducing mitoROS production.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Qilian Mountains (QM) is an important ecological security barrier in China and has been significantly affected by climate change, it is therefore of great importance and necessity to project its ...future climate change using high-resolution climate models because of mountainous areas in the QM and relatively few targeted simulation analyses. In this study, we used the simulations of the regional climate model REMO with 25 km spatial resolution, driven by three different global climate models (MPI-ESM-MR, NorESM1-M, and HadGEM2-ES), to evaluate how annual and seasonal mean surface air temperature and precipitation in the QM are likely to change for three future periods (2011–2040, 2041–2070, and 2071–2100) under two representative concentration pathways (RCP2.6 and RCP8.5). The REMO model, shows noticeable cold and wet biases compared to observations for the reference period (1971–2000) and air temperature simulation outperforms precipitation simulation. The REMO simulations exhibit a warm and wet centre around lake, indicating that the simulation are likely influenced by lake. Projections under RCP2.6 show regional warming reaching 1.74 °C during 2011–2100, characterized by an initial increase and a decrease afterwards. Under RCP8.5, air temperatures increase monotonously from 2011 to 2100, with a warming magnitude of 5.36 °C for 2071–2100 relative to 1971–2000. The overall change in regional-average annual precipitation is not evident during 2011–2100, with some increases or decreases in certain time periods. In the 2071–2100 both the strongest warming and precipitation increase are projected to occur in winter under both scenarios, while precipitation in summer and autumn is projected to decrease in the east of the QM for the three future periods. The results suggest that the QM is likely to experience drought conditions in warm seasons in the future, which could impact agricultural and livestock production.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thermally activated delayed fluorescence (TADF) emitters have attracted much interest for their great applications in organic light-emitting diodes (OLEDs), but the TADF OLEDs are limited by large ...efficiency roll-offs. In this study, we report two coumarin-based TADF emitters, 3-methyl-6-(10H-phenoxazin-10-yl)-1H-isochromen-1-one (PHzMCO) and 9-(10H-phenoxazin-10-yl)-6H-benzocchromen-6-one (PHzBCO), with relatively high photoluminescence quantum yields (PLQYs) and extremely small singlet–triplet splittings. OLEDs using these two TADF compounds as the emitters respectively demonstrate high external quantum efficiencies of 17.8% for PHzMCO and 19.6% for PHzBCO, which are the highest among the reported coumarin-derivative-based OLEDs. More importantly, these devices based on PHzMCO and PHzBCO remained 10.3% and 12.9% at 10000 cd m–2, respectively, showing relatively low efficiency roll-offs at high brightness. These results reveal that the TADF emitters with high PLQYs can effectively reduce the efficiency roll-off in the devices.
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IJS, KILJ, NUK, PNG, UL, UM
Heterotrimeric-G-protein-mediated signaling pathways modulate the expression of the essential genes in many fundamental cellular processes in fungi at the transcription level. However, these ...processes remain unclear in
Penicillium oxalicum
. In this study, we generated knockout and knockout-complemented strains of
gng
-
1
(
POX07071
) encoding the Gγ protein and found that GNG-1 modulated the expression of genes encoding plant-biomass-degrading enzymes (PBDEs) and sporulation-related activators. Interestingly, GNG-1 affected expression of the
cxrB
that encodes a known transcription factor required for the expression of major cellulase and xylanase genes. Constitutive overexpression of
cxrB
in ∆
gng
-
1
circumvented the dependence of PBDE production on GNG-1. Further evidence indicated that CxrB indirectly regulated the transcription levels of key amylase genes by controlling the expression of the regulatory gene
amyR
. These data extended the diversity of Gγ protein functions and provided new insight into the signal transduction and regulation of PBDE gene expression in filamentous fungi.
Key points
•
GNG-1 modulates the expression of PBDE genes and sporulation-related genes.
•
GNG-1 controls expression of the key regulatory gene cxrB.
•
Overexpression of cxrB circumvents dependence of PBDE production on GNG-1.
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CEKLJ, DOBA, EMUNI, FZAB, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Based on the combination of gas engine cogeneration of heat and power (GECHP) technology and temperature and humidity independent control air-conditioning technology, an air-conditioning system ...combined with desiccant wheel driven by GECHP was proposed to decrease cooling energy consumption and utilize the waste heat of gas engine. In this study, Dymola software was adopted to model the hybrid system and conduct hourly simulation throughout the cooling and heating season for two types of large public buildings: the supermarket building and the office building. Results show that the hybrid system applied to target buildings can meet the requirements of each index of air-conditioning energy supply. Comparing two types of application scenarios, the system primary energy conversion ratio of the supermarket building reaches 112%, 19% higher than that of the office building. And the system CO2 emission reduction rate per unit of capacity of the supermarket building is 0.18 kg/kWh, lower than the 0.22 kg/kWh of the office building. Therefore, the hybrid system has superior energy-saving and environmental performance and is especially suitable for high-temperature and high-humidity areas in summer as well as building application scenarios with high indoor moisture gain and fresh air demand.
•Dynamic simulation for desiccant wheel air-conditioning systems applied in different types of large public buildings.•Desiccant wheels can significantly reduce air-conditioning cooling demand by converting latent load to regenerative heat demand.•Desiccant wheel air-conditioning system driven by gas engine cogeneration of heat and power (GEDWS) has superior energy-saving and environmental performance.•GEDWS is especially suitable for high-temperature and high-humidity areas as well as building application scenarios with high indoor moisture gain and fresh air demand.•System performance will be further improved for buildings with sanitary hot water demand.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Based on the theory of rack-gear common-tangential conjugate generating, the constructing of ease-off surface has been done by means of the topology modification of polynomial surface. By analyzing ...topological structure characteristics of ease-off surface, the meshing characteristics such as the contact area, the contact line, and transmission error are determined. By using the geometric analysis of ease-off surface and the potential energy method, the calculation methods of gear tooth stiffness and loaded transmission error are given, and a series of results for the tooth meshing stiffness, loaded transmission error, and load distribution map under varied loads are obtained. In order to solve the stress problem of tooth surface edge contact, the calculation method of quasi-Hertz contact is proposed by subdividing finite contact elements. Taking the second-order parabolic topological modification as an example, the time-varying history characteristics of tooth surface meshing are analyzed. The simulation results of the maximum contact stress and contact area are in good agreement with those calculated by MASTA software. Based on the integration of the geometric analysis of ease-off surface, the tooth stiffness calculation of potential energy method and the quasi-Hertz contact, it provides a convenient method for loaded tooth contact analysis.
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