Impact of intestinal microbiota on metabolic toxicity and potential detoxification of amygdalin

Amygdalin (Amy) is metabolized into cyanide in vivo, which may lead to fatal poisoning after oral administration. The defense mechanisms against toxic cyanide have not yet been adequately studied. In this study, comparative toxicokinetics study of Amy was performed in normal and pseudo germ-free rats. The efficiency of cyanide release was significant higher in normal group when given a single oral dose of 440 mg/kg (50% median lethal dose). Thiocyanate, the detoxification metabolite, was firstly detected in feces, caecum, and intestinal microbiota incubation enzymic system. The results suggest intestinal microbiota is involved in bidirectional regulation of toxicity and detoxification of Amy. We further identified the species related to cyanogenesis of Amy with metagenomic sequencing, such as Bifidobacterium pseudolongum, Marvinbryantia formatexigens, and Bacteroides fragilis. Functional analysis of microbiota reveals the detoxification potential of intestinal microbiota for cyanide. Sulfurtransferase superfamily, such as rhodanese, considered as main detoxification enzymes for cyanide, are largely found in Coriobacteriaceae bacterium, Butyricicoccus porcorum, Akkermansia muciniphila, etc. Besides, cyanoamino acid metabolism pathway dominated by Escherichia coli may contribute to the detoxification metabolism of cyanide. In summary, intestinal microbiota may be the first line of defense against the toxicity induced by Amy

Robust strategies in nuclear-targeted cancer therapy based on functional nanomaterials

Nucleus, as the machinery for genome transcription, play prominent roles to support the fundamental cel-lular functions, the destruction of any of these specific parts would significantly modulate the cell function. Therefore, troumendous drug delivery systems with enhanced nucleus targeting ability have been studied for nucleus-related disease regulation. The purpose of this review is to sort out the fundamental nuclear tar-geting strategy, especially the active mechanism of various nuclear targeting ligands and their extensive applications based on cancer targeting therapy. Various nuclear targeting ligands are first introduced to understand their nuclear entry mechanism. Next, to overcome biological barriers and avoid the serum pro-tein absorption, diverse robust delivery strategies based on different nuclear targeting ligands are dis-cussed. Moreover, other sophisticated carrier systems with enhanced nuclear entry, while without nuclear targeting ligands are also assembled. At the end the challenges and future opportunities in the field of nuclear targeting nanotherapeutics are tentatively proposed, to speed up their clinical translation. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/)

Structural and mechanistic insights into the biosynthesis of CDP-archaeol in membranes

The divergence of archaea, bacteria and eukaryotes was a fundamental step in evolution. One marker of this event is a major difference in membrane lipid chemistry between these kingdoms. Whereas the membranes of bacteria and eukaryotes primarily consist of straight fatty acids ester-bonded to glycerol-3-phosphate, archaeal phospholipids consist of isoprenoid chains ether-bonded to glycerol-1-phosphate. Notably, the mechanisms underlying the biosynthesis of these lipids remain elusive. Here, we report the structure of the CDP-archaeol synthase (CarS) of Aeropyrum pernix (ApCarS) in the CTP- and Mg(2+)-bound state at a resolution of 2.4 Å. The enzyme comprises a transmembrane domain with five helices and cytoplasmic loops that together form a large charged cavity providing a binding site for CTP. Identification of the binding location of CTP and Mg(2+) enabled modeling of the specific lipophilic substrate-binding site, which was supported by site-directed mutagenesis, substrate-binding affinity analyses, and enzyme assays. We propose that archaeol binds within two hydrophobic membrane-embedded grooves formed by the flexible transmembrane helix 5 (TM5), together with TM1 and TM4. Collectively, structural comparisons and analyses, combined with functional studies, not only elucidated the mechanism governing the biosynthesis of phospholipids with ether-bonded isoprenoid chains by CTP transferase, but also provided insights into the evolution of this enzyme superfamily from archaea to bacteria and eukaryotes.Cell Research advance online publication 29 September 2017; doi:10.1038/cr.2017.122

Landslide Dynamic Susceptibility Mapping Base on Machine Learning and the PS-InSAR Coupling Model

Complex and fragile geological conditions combined with periodic fluctuations in reservoir water levels have led to frequent landslide disasters in the Three Gorges Reservoir area. With the development of remote sensing technology, many scholars have applied it to landslide susceptibility assessment to improve model accuracy; however, how to couple these two to obtain the optimal susceptibility assessment model remains to be studied. Based on Sentinel-1 data, relevant data, and existing research results, the information value method (IV), random forest (RF), support vector machine (SVM), and convolutional neural network (CNN) models were selected to analyze landslide susceptibility in the urban area of Wanzhou. Models with superior performance will be coupled with PS-InSAR deformation data using two methods: joint training and weighted overlay. The accuracy of different models was assessed and compared with the aim of determining the optimal coupling model and the role of InSAR in the model. The results indicate that the accuracy of different landslide susceptibility prediction models is ranked as RF > SVM > CNN > IV. Among the coupled dynamic models, the performance ranking was as follows: InSAR jointly trained RF (IJRF) > InSAR weighted overlay RF (IWRF) > InSAR jointly trained SVM (IJSVM) > InSAR weighted overlay SVM (IWSVM). Notably, the IJRF model, which combines InSAR deformation data through joint training, exhibited the highest accuracy, with an AUC value of 0.995. In the factor importance analysis within the IJRF model, InSAR deformation data ranked third after hydrological distance (0.210) and elevation (0.163), with a value of 0.154. A comparison between landslide dynamic susceptibility mapping (LDSM) and landslide susceptibility mapping (LSM) revealed that the inclusion of InSAR deformation data effectively reduced false positives around the landslide areas. The results suggest that joint training is the most suitable coupling method, allowing for the optimal expression of InSAR deformation data and enhancing the predictive accuracy of the model. This study serves as a reference for future research and provides a foundation for landslide risk management

Amphiphilic Polymer Capped Perovskite Compositing with Nano Zr‐MOF for Nanozyme‐Involved Biomimetic Cascade Catalysis

Abstract CsPbX3 perovskite nanocrystal (NC) is considered as an excellent optical material and is widely applied in optoelectronics. However, its poor water stability impedes its study in enzyme‐like activity, and further inhibits its application in biomimetic cascade catalysis. Herein, for the first time, the oxidase‐like and ascorbate oxidase‐like activities of an amphiphilic polymer capped CsPbX3 are demonstrated, and its catalytic mechanism is further explored. Furthermore, an all‐nanozyme cascade system (multifunctional CsPbBr3@Zr‐metal organic framework (Zr‐MOF) and Prussian blue as oxidase‐like and peroxidase‐like nanozyme) is constructed with a portable paper‐based device for realizing the dual‐mode (ratiometric fluorescence and colorimetric) detection of ascorbic acid in a point‐of‐care (POC) fashion. This is the first report on the utilization of all‐inorganic CsPbX3 perovskite NC in biomimetic cascade catalysis, which opens a new avenue for POC clinical disease diagnosis

Internal standard fluorogenic probe based on vibration-induced emission for visualizing PTP1B in living cells†

10.1039/C9CC07680HChemical Communications56158-6

Sodium Butyrate Induces CRC Cell Ferroptosis via the CD44/SLC7A11 Pathway and Exhibits a Synergistic Therapeutic Effect with Erastin

Colorectal cancer (CRC) is one of the most common malignancies, and effective treatment and prevention methods are lacking. Sodium butyrate (NaB) is a short-chain fatty acid produced by intestinal microbial fermentation of dietary fiber. It has been shown to be effective in inhibiting CRC, but the mechanism is not known. Methods: Human normal intestinal epithelial cell line FHT and colorectal tumor cell line HCT-116 were treated with NaB alone or in combination with different programmed cell death inhibitors. Cell activity was then assessed with MTT assays and PI staining; ferroptosis with Fe2+, glutathione (GSH), and lipid peroxidation assays; signaling pathway screening with PCR arrays; and CD44, SCL7A11, and GPX4 expression with Western blotting. A CD44-overexpressing HCT-116 cell line was constructed to determine the effect of the overexpression of CD44 on NaB-induced ferroptosis. The synergistic effect of co-treatment with NaB and Erastin was assessed by isobolographic analysis. Results: NaB induced apoptosis and ferroptosis in HCT-116 cells but only induced low-level apoptosis in FHC cells. Moreover, NaB significantly increased intracellular Fe2+ and promoted GSH depletion and lipid peroxidation in HCT-116 cells. Ferroptosis-related qPCR array analysis identified CD44/SLC7A11 as a potential effector molecular of NaB-induced ferroptosis. NaB significantly inhibited the expression of CD44 and SLC7A11 in mouse CRC tissues. A CD44 overexpressed HCT-116 cell line was used to verify that CD44/SLC7A11 was a key signaling pathway that NaB-induced GSH depletion, lipid peroxidation accumulation, and ferroptosis in HCT-116 cells. Examination of whether NaB can increase the effect of ferroptosis agents showed that NaB, in combination with Erastin, a ferroptosis inducer, further promoted HCT-116 cell death and increased changes of ferroptosis markers. Conclusions: Our results suggest that NaB induces ferroptosis in CRC cells through the CD44/SLC7A11 signaling pathway and has synergistic effects with Erastin. These results may provide new insights into CRC prevention and the combined use of NaB and ferroptosis-inducing agents

Effect of Soybean Soluble Polysaccharide on the Formation of Glucono-δ-Lactone-Induced Soybean Protein Isolate Gel

The effect of soybean soluble polysaccharide (SSPS) on the formation of glucono-δ-lactone (GDL)-induced soybean protein isolate (SPI) gel was investigated. Electrophoretic analysis showed the SSPS did not change the electrophoretic behavior of SPI during the formation of SPI gel. However, infrared analysis indicated the β-sheet content increased, and the contents of random coil and α-helix decreased in both cooked SPI and SPI gel. The SSPS and SPI might conjugate via the Maillard reaction according to the results of grafting degree, color change, and infrared analyses. The main interactions during the formation of SPI gel changed from non-covalent to electrostatic interaction after adding SSPS. Sulfhydryl group content also increased in both cooked SPI and SPI gel. The water-holding capacity and gel strength of SPI gel decreased as the SSPS concentration increased. Larger aggregate holes were observed in the microstructure of SPI gel at higher SSPS concentration. Thus, SSPS could covalently conjugate with SPI and influence the formation of hydrogen bonds, disulfide bonds, and electrostatic interaction among SPI molecules to eventually form a loose gel network