ABSTRACT
Three-dimensional (3D) printing, as an emerging digital production technology, has recently been receiving increasing attention in food processing. It is important to understand the effect of key ingredients of food materials on the printing, which makes it possible to achieve a wider range of structures using few nozzles and to provide tailored nutrition and personalization. This comprehensive review delves into the latest research on 3D-printed lipid-based foods, encompassing a variety of products such as chocolate, processed cheese, as well as meat. It also explores the development and application of food bioinks that incorporate lipids as a pivotal component, including those based on starch, protein, oleogels, bigels, and emulsions, as well as emulsion gels. Moreover, this review identifies the current challenges and presents an outlook on future research directions in the field of 3D food printing, especially the research and application of lipids in food 3D printing.
Subject(s)
Lipids , Printing, Three-Dimensional , Lipids/chemistry , Animals , Food Handling , InkABSTRACT
OBJECTIVE: This study was conducted to characterize the antioxidant and anti-inflammatory properties of Rubber Seed Oil (RSO) against atherosclerosis (AS) through the study of the protective effects and mechanisms on human umbilical vein endothelial cells (HUVECs) injury induced by oxidized low-density lipoprotein (ox-LDL). METHODS: HUVECs were treated with RSO, ox-LDL, RSO + ox-LDL, respectively, followed by cell activity testing, levels of IL-1ß, IL-6, IL-10, TNF-α, ROS, NO, the mRNA expression of eNOS and protein expression of MCP-1, VCAM-1, eNOS, TLR4, NF-κB p65ãp-NF-κB p65. RESULTS: Compared with the ox-LDL group, cell viability, NO level and the expression of eNOS mRNA significantly increased. and the levels of pro-inflammatory factors such as IL-1ß, IL-6, TNF-α, IL-10, ROS were significantly decreased, which was accompanied by decreases in TLR4 mRNA, TLR4, MCP-1, VCAM-1 protein expression, as well as the ratio of NF-κB p-p65/p65 in the group treated with 250 µg/ml ox-LDL + 50 µg/ml RSO, 250 µg/ml ox-LDL + 100 µg/ml RSO, 250 µg/ml ox-LDL + 150 µg/ml RSO. CONCLUSIONS: RSO can reduce the expression of pro-inflammatory mediators, oxidative factors involved in injured vascular endothelial cells, exhibiting anti-inflammatory and antioxidant properties HUVECs exposed to ox-LDL. In addition, it may alleviate endothelial cell damage by inhibiting the TLR4/NF-κB signaling pathway.
Subject(s)
Human Umbilical Vein Endothelial Cells , Lipoproteins, LDL , Humans , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/drug effects , Lipoproteins, LDL/pharmacology , Plant Oils/pharmacology , Cell Survival/drug effects , Antioxidants/pharmacology , Reactive Oxygen Species/metabolism , Toll-Like Receptor 4/metabolism , Cytokines/metabolism , Nitric Oxide/metabolism , NF-kappa B/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Vascular Cell Adhesion Molecule-1/genetics , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Nitric Oxide Synthase Type III/metabolism , Anti-Inflammatory Agents/pharmacology , Seeds/chemistry , Signal Transduction/drug effectsABSTRACT
Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents1,2. TAS2R14 is also widely expressed in extragustatory tissues, suggesting its extra roles in diverse physiological processes and potential therapeutic applications3. Here we present cryogenic electron microscopy structures of TAS2R14 in complex with aristolochic acid, flufenamic acid and compound 28.1, coupling with different G-protein subtypes. Uniquely, a cholesterol molecule is observed occupying what is typically an orthosteric site in class A G-protein-coupled receptors. The three potent agonists bind, individually, to the intracellular pockets, suggesting a distinct activation mechanism for this receptor. Comprehensive structural analysis, combined with mutagenesis and molecular dynamic simulation studies, elucidate the broad-spectrum ligand recognition and activation of the receptor by means of intricate multiple ligand-binding sites. Our study also uncovers the specific coupling modes of TAS2R14 with gustducin and Gi1 proteins. These findings should be instrumental in advancing knowledge of bitter taste perception and its broader implications in sensory biology and drug discovery.
Subject(s)
Aristolochic Acids , Cholesterol , Flufenamic Acid , Receptors, G-Protein-Coupled , Taste , Humans , Aristolochic Acids/metabolism , Aristolochic Acids/chemistry , Aristolochic Acids/pharmacology , Binding Sites/drug effects , Cholesterol/chemistry , Cholesterol/metabolism , Cholesterol/pharmacology , Cryoelectron Microscopy , Flufenamic Acid/chemistry , Flufenamic Acid/metabolism , Flufenamic Acid/pharmacology , GTP-Binding Protein alpha Subunits, Gi-Go/chemistry , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , Ligands , Models, Molecular , Molecular Dynamics Simulation , Mutation , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/ultrastructure , Taste/drug effects , Taste/physiology , Transducin/chemistry , Transducin/metabolismABSTRACT
Glycans, along with proteins, nucleic acids, and lipids, constitute the four fundamental classes of biomacromolecules found in living organisms. Generally, glycans are attached to proteins or lipids to form glycoconjugates that perform critical roles in various biological processes. Automatic synthesis of glycans is essential for investigation into structure-function relationships of glycans. In this study, we presented a method that integrated magnetic bead-based manipulation and modular chemoenzymatic synthesis of human milk oligosaccharides (HMOs), on a DMF (Digital Microfluidics) platform. On the DMF platform, enzymatic modular reactions were conducted in solution, and purification of products or intermediates was achieved by using DEAE magnetic beads, circumventing the intricate steps required for traditional solid-phase synthesis. With this approach, we have successfully synthesized eleven HMOs with highest yields of up to >90% on the DMF platform. This study would not only lay the foundation for OPME synthesis of glycans on the DMF platform, but also set the stage for developing automated enzymatic glycan synthesizers based on the DMF platform.
ABSTRACT
Exposure to environmental cadmium (Cd) is known to cause neuronal death and cognitive decline in humans. Ferroptosis, a novel iron-dependent type of regulated cell death, is involved in various neurological disorders. In the present study, Cd exposure triggered ferroptosis in the mouse hippocampus and in the HT22 murine hippocampal neuronal cell line, as indicated by significant increases in ferroptotic marker expression, intracellular iron levels, and lipid peroxidation. Interestingly, ferroptosis of hippocampal neurons in response to Cd exposure relied on the induction of autophagy since the suppression of autophagy by 3-methyladenine (3-MA) and chloroquine (CQ) substantially ameliorated Cd-induced ferroptosis. Furthermore, nuclear receptor coactivator 4 (NCOA4)-mediated degradation of ferritin was required for the Cd-induced ferroptosis of hippocampal neurons, demonstrating that NCOA4 knockdown decreased intracellular iron levels and lipid peroxidation and increased cell survival, following Cd exposure. Moreover, Cd-induced mitochondrial reactive oxygen species (mtROS) generation was essential for the ferritinophagy-mediated ferroptosis of hippocampal neurons. Importantly, pretreatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated Cd-induced hippocampal neuronal death and cognitive impairment in mice. Taken together, these findings indicate that ferroptosis is a novel mechanism underlying Cd-induced neurotoxicity and cognitive impairment and that the mtROS-ferritinophagy axis modulates Cd-induced neuronal ferroptosis.
Subject(s)
Cadmium , Cognitive Dysfunction , Ferroptosis , Hippocampus , Neurons , Nuclear Receptor Coactivators , Reactive Oxygen Species , Ferroptosis/drug effects , Animals , Mice , Cadmium/toxicity , Neurons/drug effects , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Reactive Oxygen Species/metabolism , Nuclear Receptor Coactivators/metabolism , Nuclear Receptor Coactivators/genetics , Ferritins/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Male , Autophagy/drug effects , Iron/metabolism , Lipid Peroxidation/drug effects , Cell Line , Mice, Inbred C57BLABSTRACT
The natural pesticide phenazine-1-carboxylic acid (PCA) is known to lack phloem mobility, whereas Metalaxyl is a representative phloem systemic fungicide. In order to endow PCA with phloem mobility and also enhance its antifungal activity, thirty-two phenazine-1-carboxylic acid-N-phenylalanine esters conjugates were designed and synthesized by conjugating PCA with the active structure N-acylalanine methyl ester of Metalaxyl. All target compounds were characterized by 1H NMR, 13C NMR and HRMS. The antifungal evaluation results revealed that several target compounds exhibited moderate to potent antifungal activities against Sclerotinia sclerotiorum, Bipolaris sorokiniana, Phytophthora parasitica, Phytophthora citrophthora. In particular, compound F7 displayed excellent antifungal activity against S. sclerotiorum with an EC50 value of 6.57 µg/mL, which was superior to that of Metalaxyl. Phloem mobility study in castor bean system indicated good phloem mobility for the target compounds F1-F16. Particularly, compound F2 exhibited excellent phloem mobility; the content of compound F2 in the phloem sap of castor bean was 19.12 µmol/L, which was six times higher than Metalaxyl (3.56 µmol/L). The phloem mobility tests under different pH culture solutions verified the phloem translocation of compounds related to the "ion trap" effect. The distribution of the compound F2 in tobacco plants further suggested its ambimobility in the phloem, exhibiting directional accumulation towards the apical growth point and the root. These results provide valuable insights for developing phloem mobility fungicides mediated by exogenous compounds.
Subject(s)
Alanine , Alanine/analogs & derivatives , Phenazines , Phenazines/chemistry , Phenazines/pharmacology , Phenazines/chemical synthesis , Alanine/chemistry , Alanine/pharmacology , Phytophthora/drug effects , Antifungal Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Phloem/metabolism , Phloem/drug effects , Ascomycota/drug effects , Ascomycota/metabolism , Fungicides, Industrial/pharmacology , Fungicides, Industrial/chemical synthesis , Fungicides, Industrial/chemistry , Drug Design , Esters/chemistry , Esters/pharmacology , Esters/chemical synthesisABSTRACT
Eukaryotic sialyltransferases play key roles in many physiological and pathological events. The expression of active human recombinant sialyltransferases in bacteria is still challenging. In the current study, the genes encoding human N-acetylgalactosaminide α2,6-sialyltransferase V (hST6GalNAc V) and N-acetylgalactosaminide α2,6-sialyltransferase VI (hST6GalNAc VI) lacking the N-terminal transmembrane domains were cloned into the expression vectors, pET-32a and pET-22b, respectively. Soluble and active forms of recombinant hST6GalNAc V and hST6GalNAc VI when coexpressed with the chaperone plasmid pGro7 were successfully achieved in Escherichia coli. Further, lactose (Lac), Lacto-N-triose II (LNT II), lacto-N-tetraose (LNT), and sialyllacto-N-tetraose a (LSTa) were used as acceptor substrates to investigate their activities and substrate specificities. Unexpectedly, both can transfer sialic acid onto all those substrates. Compared with hST6GalNAc V expressed in the mammalian cells, the recombinant two α2,6-sialyltransferases in bacteria displayed flexible substrate specificities and lower enzymatic efficiency. In addition, an important human milk oligosaccharide disialyllacto-N-tetraose (DSLNT) can be synthesized by both human α2,6-sialyltransferases expressed in E. coli using LSTa as an acceptor substrate. To the best of our knowledge, these two active human α2,6-sialyltransferases enzymes were expressed in bacteria for the first time. They showed a high potential to be applied in biotechnology and investigating the molecular mechanisms of biological and pathological interactions related to sialylated glycoconjugates.
Subject(s)
Escherichia coli , Recombinant Proteins , Sialyltransferases , Humans , Cloning, Molecular , Escherichia coli/genetics , Escherichia coli/metabolism , Lactose/metabolism , Oligosaccharides/metabolism , Recombinant Proteins/metabolism , Recombinant Proteins/genetics , Sialyltransferases/genetics , Sialyltransferases/metabolism , Substrate SpecificityABSTRACT
Melanocortin 4 receptor (MC4-R) antagonists are actively sought for treating cancer cachexia. We determined the structures of complexes with PG-934 and SBL-MC-31. These peptides differ from SHU9119 by substituting His6 with Pro6 and inserting Gly10 or Arg10. The structures revealed two subpockets at the TM7-TM1-TM2 domains, separated by N2857.36. Two peptide series based on the complexed peptides led to an antagonist activity and selectivity SAR study. Most ligands retained the SHU9119 potency, but several SBL-MC-31-derived peptides significantly enhanced MC4-R selectivity over MC1-R by 60- to 132-fold. We also investigated MC4-R coupling to the K+ channel, Kir7.1. Some peptides activated the channel, whereas others induced channel closure independently of G protein coupling. In cell culture studies, channel activation correlated with increased feeding, while a peptide with Kir7.1 inhibitory activity reduced eating. These results highlight the potential for targeting the MC4-R:Kir7.1 complex for treating positive and restrictive eating disorders.
Subject(s)
Peptides , Receptor, Melanocortin, Type 4 , Humans , Peptides/pharmacology , Ligands , Drug Design , Receptor, Melanocortin, Type 3 , Receptors, MelanocortinABSTRACT
The human CC chemokine receptor 8 (CCR8) is an emerging therapeutic target for cancer immunotherapy and autoimmune diseases. Understanding the molecular recognition of CCR8, particularly with nonpeptide ligands, is valuable for drug development. Here, we report three cryo-electron microscopy structures of human CCR8 complexed with Gi trimers in the ligand-free state or activated by nonpeptide agonists LMD-009 and ZK 756326. A conserved Y1.39Y3.32E7.39 motif in the orthosteric binding pocket is shown to play a crucial role in the chemokine and nonpeptide ligand recognition. Structural and functional analyses indicate that the lack of conservation in Y1143.33 and Y1724.64 among the CC chemokine receptors could potentially contribute to the selectivity of the nonpeptide ligand binding to CCR8. These findings present the characterization of the molecular interaction between a nonpeptide agonist and a chemokine receptor, aiding the development of therapeutics targeting related diseases through a structure-based approach.
Subject(s)
Chemokines, CC , Receptors, CCR8 , Humans , Cryoelectron Microscopy , Ligands , Receptors, CCR8/chemistry , Receptors, CCR8/metabolism , Receptors, Chemokine/metabolismABSTRACT
To effectively control the infection of plant pathogens, we designed and synthesized a series of phenylthiazole derivatives containing a 1,3,4-thiadiazole thione moiety and screened for their antibacterial potencies against Ralstonia solanacearum, Xanthomonas oryzae pv. oryzae, as well as their antifungal potencies against Sclerotinia sclerotiorum, Rhizoctonia solani, Magnaporthe oryzae and Colletotrichum gloeosporioides. The chemical structures of the target compounds were characterized by 1H NMR, 13C NMR and HRMS. The bioassay results revealed that all the tested compounds exhibited moderate-to-excellent antibacterial and antifungal activities against six plant pathogens. Especially, compound 5k possessed the most remarkable antibacterial activity against R. solanacearum (EC50 = 2.23 µg/mL), which was significantly superior to that of compound E1 (EC50 = 69.87 µg/mL) and the commercial agent Thiodiazole copper (EC50 = 52.01 µg/mL). Meanwhile, compound 5b displayed the most excellent antifungal activity against S. sclerotiorum (EC50 = 0.51 µg/mL), which was equivalent to that of the commercial fungicide Carbendazim (EC50 = 0.57 µg/mL). The preliminary structure-activity relationship (SAR) results suggested that introducing an electron-withdrawing group at the meta-position and ortho-position of the benzene ring could endow the final structure with remarkable antibacterial and antifungal activity, respectively. The current results indicated that these compounds were capable of serving as promising lead compounds.
Subject(s)
Antifungal Agents , Fungicides, Industrial , Thiadiazoles , Antifungal Agents/pharmacology , Thiones , Fungicides, Industrial/pharmacology , Anti-Bacterial Agents/pharmacologyABSTRACT
The ten Frizzled receptors (FZDs) are essential in Wnt signaling and play important roles in embryonic development and tumorigenesis. Among these, FZD6 is closely associated with lens development. Understanding FZD activation mechanism is key to unlock these emerging targets. Here we present the cryo-EM structures of FZD6 and FZD3 which are known to relay non-canonical planar cell polarity (PCP) signaling pathways as well as FZD1 in their G protein-coupled states and in the apo inactive states, respectively. Comparison of the three inactive/active pairs unveiled a shared activation framework among all ten FZDs. Mutagenesis along with imaging and functional analysis on the human lens epithelial tissues suggested potential crosstalk between the G-protein coupling of FZD6 and the PCP signaling pathways. Together, this study provides an integrated understanding of FZD structure and function, and lays the foundation for developing therapeutic modulators to activate or inhibit FZD signaling for a range of disorders including cancers and cataracts.
ABSTRACT
Based on the importance of chronic inflammation in the pathogenesis of periodontitis and diabetes, the bidirectional relationship between these 2 diseases has been widely confirmed. However, the molecular mechanisms of bidirectional relationship still need to be studied further. In this study, gene expression profile data for diabetes and periodontitis were obtained from Gene Expression Omnibus (GEO) database. Integrative analytical platform were constructed, including common differentially expressed genes (cDEGs), Gene Ontology-Kyoto Encyclopedia of Genes and Genomes (GO-KEGG), and protein-protein interaction. Hub genes and essential modules were detected via Cytoscape. Key hub genes and signaling pathway that mediate chronic inflammation were validated by qPCR and Western blot. Eleven cDEGs were identified. Function analysis showed that cDEGs plays an important role in inflammatory response, cytokine receptor binding, TNF signaling pathway. As hub genes, CXCR4, IL1B, IL6, CXCL2, and MMP9 were detected based on the protein-protein interactions network. IL1B, CXCR4 mRNA were up-regulated in gingivitis samples compared with normal tissues (P < .05). Western blot indicated that the levels of TNF were enhanced in gingivitis of type 2 diabetes compared with normal tissues (P < .01). Hub gene and TNF signaling pathway are helpful to elucidate the molecular mechanism of the bidirectional relationship between periodontitis and diabetes.
Subject(s)
Diabetes Mellitus, Type 2 , Gingivitis , Periodontitis , Humans , Gene Expression Profiling , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Biomarkers , Periodontitis/genetics , Inflammation , Computational BiologyABSTRACT
Aflatoxin B1 (AFB1), a potent mycotoxin, is one of the two primary risk factors that cause liver cancer. In the liver, the bioactivated AFB1 intercalates into the DNA double helix to form a bulky DNA adduct which will lead to mutation if left unrepaired. We have adapted the tXR-seq method to measure the nucleotide excision repair of AFB1-induced DNA adducts. We have found that transcription-coupled repair plays a major role in the damage removal process and the released excision products have a distinctive length distribution pattern. We further analyzed the impact of 3D genome organization on the repair of AFB1-induced DNA adducts. We have revealed that chromosomes close to the nuclear center and A compartments undergo expedited repair processes. Notably, we observed an accelerated repair around both TAD boundaries and loop anchors. These findings provide insights into the complex interplay between repair, transcription, and 3D genome organization, shedding light on the mechanisms underlying AFB1-induced liver cancer.
ABSTRACT
When designing nano-structured metamaterials with an iterative optimization method, a fast deep learning solver is desirable to replace a time-consuming numerical solver, and the related issue of data shift is a subtle yet easily overlooked challenge. In this work, we explore the data shift challenge in an AI-based electromagnetic solver and present innovative solutions. Using a one-dimensional grating coupler as a case study, we demonstrate the presence of data shift through the probability density method and principal component analysis, and show the degradation of neural network performance through experiments dealing with data affected by data shift. We propose three effective strategies to mitigate the effects of data shift: mixed training, adding multi-head attention, and a comprehensive approach that combines both. The experimental results validate the efficacy of these approaches in addressing data shift. Specifically, the combination of mixed training and multi-head attention significantly reduces the mean absolute error, by approximately 36%, when applied to data affected by data shift. Our work provides crucial insights and guidance for AI-based electromagnetic solvers in the optimal design of nano-structured metamaterials.
ABSTRACT
Metastasis is the leading cause of high ovarian-cancer-related mortality worldwide. Three major processes constitute the whole metastatic cascade: invasion, intravasation, and extravasation. Tumor cells often reprogram their metabolism to gain advantages in proliferation and survival. However, whether and how those metabolic alterations contribute to the invasiveness of tumor cells has yet to be fully understood. Here we performed a genome-wide CRISPR-Cas9 screening to identify genes participating in tumor cell dissemination and revealed that PTGES3 acts as an invasion suppressor in ovarian cancer. Mechanistically, PTGES3 binds to phosphofructokinase, liver type (PFKL) and generates a local source of prostaglandin E2 (PGE2) to allosterically inhibit the enzymatic activity of PFKL. Repressed PFKL leads to downgraded glycolysis and the subsequent TCA cycle for glucose metabolism. However, ovarian cancer suppresses the expression of PTGES3 and disrupts the PTGES3-PGE2-PFKL inhibitory axis, leading to hyperactivation of glucose oxidation, eventually facilitating ovarian cancer cell motility and invasiveness.
Subject(s)
Dinoprostone , Ovarian Neoplasms , Humans , Female , Phosphofructokinases , Phosphofructokinase-1/genetics , Liver/metabolism , Glucose/metabolism , Ovarian Neoplasms/pathology , Cell Proliferation , Cell Line, Tumor , Neoplasm InvasivenessABSTRACT
Despite the essential roles of Frizzled receptors (FZDs) in mediating Wnt signaling in embryonic development and tissue homeostasis, ligands targeting FZDs are rare. A few antibodies and peptide modulators have been developed that mainly bind to the family-conserved extracellular cysteine-rich domain of FZDs, while the canonical binding sites in the transmembrane domain (TMD) are far from sufficiently addressed. Based on the recent structures of FZDs, we explored small-molecule ligand discovery by targeting TMD. From the ChemDiv library with â¼1.6 million compounds, we identified compound F7H as an antagonist of FZD7 with an IC50 at 1.25 ± 0.38 µM. Focusing on this hit, the structural dissection study, together with computing studies such as molecular docking, molecular dynamics simulation, and free energy perturbation calculations, defined the binding pocket with key residue recognition. Our results revealed the structural basis of ligand recognition and demonstrated the feasibility of structure-guided ligand discovery for FZD7-TMD.
Subject(s)
Antibodies , Frizzled Receptors , Female , Pregnancy , Humans , Ligands , Molecular Docking Simulation , Binding SitesABSTRACT
Cadmium (Cd), a toxic heavy metal, exerts deleterious effects on neuronal survival and cognitive function. NOD-like receptor 3 (NLRP3) inflammasome-dependent pyroptosis has been linked to Cd-induced cytotoxicity. The current research intended to elucidate the role of NLRP3 inflammasome-mediated pyroptosis in Cd-evoked neuronal death and cognitive impairments and the underlying mechanisms. Exposure to 1 mg/kg Cd for 8 weeks led to hippocampal-dependent cognitive deficits and neural/synaptic damage in mice. NLRP3 inflammasome-related protein expression (NLRP3, ASC, and caspase1 p20) and neuronal pyroptosis were significantly upregulated in Cd-treated hippocampi and SH-SY5Y cells. Moreover, pretreatment with the NLRP3 inhibitor MCC950 mitigated Cd-elicited NLRP3 inflammasome activation and subsequent neuronal pyroptosis in SH-SY5Y cells. Furthermore, exposure to Cd downregulated Sirt3 expression, suppressed SOD2 activity by hyperacetylation, and enhanced mtROS accumulation in vivo and in vitro. Notably, Cd-induced NLRP3 inflammasome-dependent neuronal pyroptosis was attenuated by a mtROS scavenger or Sirt3 overexpression in SH-SY5Y cells. In addition, Cd failed to further suppress SOD activity and activate NLRP3 inflammasome-dependent neuronal pyroptosis in Sirt3 shRNA-treated SH-SY5Y cells. Collectively, our findings indicate that Cd exposure induces neuronal injury and cognitive deficits by activating NLRP3 inflammasome-dependent neuronal pyroptosis and that activation of the NLRP3 inflammasome is partially mediated by the Sirt3-mtROS axis.
ABSTRACT
Glycans are an important group of natural biopolymers, which not only play the role of a major biological energy resource but also as signaling molecules. As a result, structural characterization or sequencing of glycans, as well as targeted synthesis of glycans, is of great interest for understanding their structure-function relationship. However, this generally involves tedious manual operations and high reagent consumptions, which are the main technical bottlenecks retarding the advances of both automatic glycan sequencing and synthesis. Until now, automated enzymatic glycan sequencers or synthesizers are still not available on the market. In this study, to promote the development of automation in glycan sequencing or synthesis, first, programmed degradation and synthesis of glycans catalyzed by enzymes were successfully conducted on a digital microfluidic (DMF) device by using microdroplets as microreactors. In order to develop automatic glycan synthesizers and sequencers, a strategy integrating enzymatic oligosaccharide degradation or synthesis and magnetic manipulation to realize the separation and purification process after enzymatic reactions was designed and performed on DMF. An automatic process for enzymatic degradation of tetra-N-acetyl chitotetraose was achieved. Furthermore, the two-step enzymatic synthesis of lacto-N-tetraose was successfully and efficiently completed on the DMF platform. This work demonstrated here would open the door to further develop automatic enzymatic glycan synthesizers or sequencers based on DMF.
ABSTRACT
The effect of vitamin D supplementation on individuals with autism spectrum disorder (ASD) is inconclusive. We aimed to conduct a meta-analysis of the available randomized controlled trials (RCTs) to explore whether vitamin D supplementation can improve core symptoms and coexisting conditions in children with ASD. Data were obtained by searching the PubMed, Embase, Web of Science, CINAHL and Cochrane Library databases up to February 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using a random-effects model, mean differences with 95% confidence intervals (CIs) were calculated through a meta-analysis. There were eight RCTs with 266 children with ASD in the present review, among which six RCTs were included in the meta-analysis. Children who received vitamin D supplementation showed a significant improvement in stereotypical behavior scores (pooled mean difference (MD): -1.39; 95% CI: -2.7, -0.07; P = 0.04) with low heterogeneity (I2 = 34%), and there was a trend toward decreased total scores on the Social Responsiveness Scale (SRS) and Childhood Autism Rating Scale (CARS, P = 0.05); however, there were no other significant differences in the core symptoms of ASD and coexisting conditions between groups as measured by the Aberrant Behavior Checklist (ABC). Vitamin D supplementation appears to improve stereotypical behaviors but does not improve other core symptoms and coexisting conditions. Further randomized controlled trials with large sample sizes and individualized doses are needed.
ABSTRACT
The hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. Extensive efforts have been made to identify HCA2 targeting lipid lowering agents with fewer adverse effects, despite little being known about the molecular basis of HCA2 mediated signalling. Here, we report the cryo-electron microscopy structure of the HCA2-Gi signalling complex with the potent agonist MK-6892, along with crystal structures of HCA2 in inactive state. These structures, together with comprehensive pharmacological analysis, reveal the ligand binding mode and activation and signalling mechanisms of HCA2. This study elucidates the structural determinants essential for HCA2 mediated signalling and provides insights into ligand discovery for HCA2 and related receptors.