Lipids were described by the Slipids force field (Jämbeck and Lyubartsev 2012a, b) which is well established force field for simulations of lipid bilayers (Lyubartsev and Rabinovich 2016) including also polyunsaturated lipids (Ermilova and Lyubartsev 2016). The force field parameters, as well as molecular topology files in the Gromacs format (Hess et al. 2008), are available from Slipids v.2.0 archive at Zenodo repository (Jämbeck et al. 2016). The peptides were presented by the General Amber Force Field (GAFF) (Wang et al. 2004). Recently, several comparative studies of different force fields to describe peptide structure have been carried out (Gerben et al. 2014; Somavarapu and Kepp 2016; Carballo-Pacheco and Strodel 2017; Robustelli et al. 2018) but their results on the force field performance were not unambiguous. GAFF, derived on the basis of Amber99 parameter set, was designed to provide better transferability of parameters over a wide range of organic molecules, which can be an advantage for description of intrinsically disordered peptides such as A\(\beta \). Furthermore, GAFF showed the best performance to describe partitioning of solute molecules across bilayer with lipids described by the Slipids force field (Paloncýová et al. 2014). Previously, GAFF was used in simulations of peptides in a number of works (Tan et al. 2010; Zhu et al. 2016; Xu et al. 2016; Kang et al. 2016).
Since in all considered cases the peptides interact with the bilayers, either by clustering at the surface or entering inside the membrane, it is instructive to investigate which effect the peptides exert on the bilayer structure. For this purpose, we have computed average area per lipid in the simulated systems and NMR order parameters, and compared with results of simulations of the corresponding bilayers without peptides. For pure monocomponent 14:0-14:0 PC and 18:0-22:6 PC bilayers we used data from previous works (Jämbeck and Lyubartsev 2012a; Ermilova and Lyubartsev 2016), while for the mixed bilayers the areas and order parameters were determined from additional 100 ns simulations of the pre-equilibrated bilayers without peptides (see section Model and Methods).
Force Effect For Pc 18l
(a) Any person who deprives or violates the personal liberty of another with the intent to effect or maintain a felony violation of Section 266, 266h, 266i, 267, 311.4, or 518, or to obtain forced labor or services, is guilty of human trafficking.
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The application of titanium dioxide nanoparticles (TiO2 NPs) as food additives poses a risk of oral exposure that may lead to adverse health effects. Even though the substantial evidence supported liver as the target organ of TiO2 NPs via oral exposure, the mechanism of liver toxicity remains largely unknown. Since the liver is a key organ for lipid metabolism, this study focused on the landscape of lipidomic metabolites in gut-liver axis of Sprague Dawley (SD) rats exposed to TiO2 NPs at 0, 2, 10, 50 mg/kg body weight per day for 90 days.
Liver is the main metabolic organ of human body. Metabolic disorders are very sensitive to liver damage. Previous animal studies found that dietary intake of TiO2 NPs could induce glucose homeostasis imbalance [36, 37], including the disorder of glucose metabolism in liver. Meanwhile, pathological change of fatty degeneration in hepatocytes was found in rats after oral exposure to TiO2 NPs [38]. Other studies also indicated that lipid metabolism disorder may be one of the obvious toxic effects of TiO2 NPs [39,40,41]. The link between the gut microbiota and adipose tissue has been recently identified. It has been shown that bacterial product such as lipopolysaccharide (LPS) acts as a master switch to control adipose tissue metabolism [42]. Therefore, the changes of lipid metabolism in the gut-liver axis may be closely related to the hepatotoxicity induced by TiO2 NPs. In recent years, lipidomics provides a highly sensitive and high-resolution method for analyzing the structure and function of the complete set of lipids as well as their interactions [43]. It is sensitive enough to detect the subtle metabolomic changes when functional cellular assays showed no significant difference [40]. Research on lipid metabolism using lipidomics will contribute to the safety assessment of nanomaterials.
Further collation of mass spectrometry (MS) data found that the total amount of PCs (all identified) did not change significantly, but the content of some PC subtypes with different MS parameters changed (Fig. 4). In feces, liver and serum, there was one kind, five kinds and twenty-seven kinds of PCs subtypes expressed differently between the TiO2 NPs treated group and the control group, respectively (Detailed information of differential metabolites was shown in Additional file 1: Table S4). The results suggested that we need to pay attention to the subtypes of PC, not just the total content of PCs, which may play a key role in the biological effects of oral exposure to TiO2 NPs. The total amount of differentially expressed PCs in liver decreased significantly, but in feces increased significantly (Fig. 4B). Among all differentially expressed PC subtypes, most of them increased in serum samples after treatment of TiO2 NPs, including the three kinds of PCs that had the most significant correlation with other metabolites (Fig. 4C). One subtype labelled as PC(20:3(8Z,11Z,14Z)/0:0) overlapped in serum and liver, and its content decreased both in serum and liver. In addition, we used absolute quantitative lipidomics to verify the changes of the concentrations of 48 kinds of PCs. It was found that the concentration of PC(16:0/20:1) increased significantly and the concentrations of PC(18:0/18:0) and PC(18:2/20:2) decreased significantly in the serum samples after treatment of TiO2 NPs (50 mg/kg) (Fig. 5).
In the present study, we focused on the effect of dietary intake of TiO2 NPs on lipid metabolism in gut-liver axis for the first time. Although there were still some inconsistent results from previous studies, liver was considered as the target organ for oral toxicity of TiO2 NPs [20]. Considering that the gut microbiota could be significantly affected by the ingestion of TiO2 NPs [29,30,31,32], the gut-liver axis, linking the intestine and liver, may be the key to inducing hepatotoxicity [28]. Furthermore, the effect of TiO2 NPs on lipid metabolism has been proposed and concerned recently. Both in vitro and in vivo metabolomics studies found that TiO2 NPs significantly affected the metabolic pathway of lipid metabolism [39, 40], which arose even in other metal oxide nanoparticles such as SiO2 and CeO2 nanoparticles. In this study, we used lipidomics to comprehensively understand the changes of lipid metabolism in the gut-liver axis induced by TiO2 NPs (Additional file 1: Figure S2). It was found that altered lipidomic signatures of main organs or systems in the gut-liver axis including liver, serum and gut were closely related, as the key metabolic pathway and lipophilic metabolites were the same. Glycerophospholipid metabolism pathway and PCs played an important role in the altered lipid metabolism of gut-liver axis induced by TiO2 NPs.
Glycerophospholipids are the main lipid constituents of cell membranes, which can directly affect the physiological functions of cells [44]. Changes in the glycerophospholipid metabolism pathway first prompted the transformations of cell membrane composition and permeability. Using a combination of fluorescent probes, Sohm et al. found that ingested TiO2 NPs could induce oxidative stress under dark conditions and cause intestinal bacteria membrane depolarization such as Escherichia coli and loss of integrity, leading to higher cell permeability [33]. In the present study, we found differentially expressed glycerophospholipids in feces, including phosphatidylcholine (PC) and phosphatidylserine (PS). Specifically, PC(18:3(6Z,9Z,12Z)/16:0) and PS(16:0/16:0) increased significantly in feces, which may be caused by bacterial fragmentation, increasing cell membrane components in feces. Alterations of gut microbiota can contribute to the pathogenesis of liver disease by affecting on host metabolism through intestinal-hepatic circulation and the gut-liver axis [34, 35, 45, 46]. In fact, the present study found four kinds of differentially expressed glycerophospholipids in gut-liver axis, including phosphatidylcholine (PC), LysoPC, GlyceroPC and phosphatidylserine (PS) (Table 2). Among them, PC altered significantly in all three kinds of samples including liver, serum and feces of TiO2 NPs-treated rats. So PCs may be the key metabolites in the effect of TiO2 NPs on the gut-liver axis and hepatotoxicity.
The circulatory system, especially the portal vein, transports intestinal substances through the liver, which is an important place for intermediary metabolism of the gut-liver axis. In the present study, we confirmed the relationship between the changes of serum lipidomics and that in the gut and liver. The same key metabolic pathway (Glycerophospholipid metabolism) and metabolites (PCs) were found in analysis of serum lipidomics. Of course, the characteristics of serum metabolism are also the comprehensive performance of the whole body organ and system health effects. Therefore, we found metabolic changes in serum were more complex than that in liver and feces. For example, more differential metabolites including more subtypes of PCs were observed in serum and the most related three kinds of PCs (PC(24:1(15Z)/18:4(6Z,9Z,12Z,15Z)), PC(24:1(15Z)/22:4(7Z,10Z,13Z,16Z)) and PC(24:0/20:5(5Z,8Z,11Z,14Z,17Z))) were all in serum. In addition, pathway analysis also found that LysoPC and GlyceroPC differentially expressed in serum. Besides PC, LysoPC and GlyceroPC are important glycerophospholipids. Low level of LysoPC in plasma might be a general indicator of severity of malignant disease, such as cancer, and also correlated with weight loss and inflammatory parameters [50]. A prospective metabolomics study also found that higher plasma levels of lysoPCs were consistently related to lower risks of breast, prostate, and colorectal cancer [51]. Moreover, LysoPCs have been suggested to mediate anti-inflammatory effects in the liver as they negatively correlated with intrahepatic C-reactive protein [52, 53] and induced secretion of anti-inflammatory signals in human Tregs that lead to a reduction of macrophage migration [54]. Decreased GlyceroPC was also highly correlated with NAFLD [55]. Thus, we thought that the changes on serum lipidomic signatures induced by oral exposure to TiO2 NPs may be closely related to the hepatotoxicity. The changes of intermediate metabolism further confirmed the important role of gut-liver axis in the hepatotoxicity induced by TiO2 NPs. 2ff7e9595c
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