Investigating the Hypolipidemic Mechanism of Anthocyanins Combined with Allicin in Rats Using Network Pharmacology

Objectives: Using network pharmacology methods, investigate the potential lipid-lowering mechanism of the combination of anthocyanins and allicin in hyperlipidemic rats. Methods: Apply databases such as Pubchem, SwissTargetPrediction, TCMSP, DrugBank and BATMAN-TCM to predict potential targets for anthocyanins and allicin. Additionally, targets connected to hyperlipidemia were found in multiple databases (GeneCards, OMIM, Drugbank, and TTD). Upload the discovered drug-disease intersection targets into the database of STRING in order to construct a common target protein-protein interactions network (PPI). To find important targets, a PPI network analysis was built using Cytoscape 3.9.1. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enriched and analyzed these common drug-disease targets. In order to further confirm the key targets of anthocyanins combined with allicin in hyperlipidemia, animal experiments were conducted. Results: There are 63 potential targets for the combined effect of anthocyanins and allicin on hyperlipidemia. The PPI topology analysis results found that TNF, IL-6, AKT1, PTGS2, GSK3B, EGFR, etc. are the main key targets. The main pathways included PI3K-Akt, JAK-STAT, Fluid shear stress and atherosclerosis, HIF-1and MAPK signaling pathway. The animal experiments results revealed that anthocyanins combined with allicin can improve blood lipid levels in hyperlipidemic rats and decrease the serum levels of inflammatory factors. Conclusion: Anthocyanins combined with allicin can intervene in hyperlipidemia through a variety of targets and pathways. This research offers a theoretical reference for the investigation of the pathogenesis of hyperlipidemia and the production of functional foods

Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a \u3cem\u3eDrosophila\u3c/em\u3e model of Fus-mediated ALS

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a Drosophila model to examine the toxicity of Fus, its Drosophila orthologue Cabeza (Caz), and the ALS-related Fus mutants. RESULTS: Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the transgenic flies in a dose- and age-dependent manner. The expression of Fus, Caz, or FusR521G in motor neurons significantly impaired the locomotive ability of fly larvae and adults. The presynaptic structures in neuromuscular junctions were disrupted and motor neurons in the ventral nerve cord (VNC) were disorganized and underwent apoptosis. Surprisingly, the interruption of Fus nuclear localization by either deleting its nuclear localization sequence (NLS) or adding a nuclear export signal (NES) blocked Fus toxicity. Moreover, we discovered that the loss of caz in Drosophila led to severe growth defects in the eyes and VNCs, caused locomotive disability and NMJ disruption, but did not induce apoptotic cell death. CONCLUSIONS: These data demonstrate that the overexpression of Fus/Caz causes in vivo toxicity by disrupting neuromuscular junctions (NMJs) and inducing apoptosis in motor neurons. In addition, the nuclear localization of Fus is essential for Fus to induce toxicity. Our findings also suggest that Fus overexpression and gene deletion can cause similar degenerative phenotypes but the underlying mechanisms are likely different

Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS

<p>Abstract</p> <p>Backgound</p> <p>Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a <it>Drosophila </it>model to examine the toxicity of Fus, its <it>Drosophila </it>orthologue Cabeza (Caz), and the ALS-related Fus mutants.</p> <p>Results</p> <p>Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the transgenic flies in a dose- and age-dependent manner. The expression of Fus, Caz, or FusR521G in motor neurons significantly impaired the locomotive ability of fly larvae and adults. The presynaptic structures in neuromuscular junctions were disrupted and motor neurons in the ventral nerve cord (VNC) were disorganized and underwent apoptosis. Surprisingly, the interruption of Fus nuclear localization by either deleting its nuclear localization sequence (NLS) or adding a nuclear export signal (NES) blocked Fus toxicity. Moreover, we discovered that the loss of <it>caz </it>in <it>Drosophila </it>led to severe growth defects in the eyes and VNCs, caused locomotive disability and NMJ disruption, but did not induce apoptotic cell death.</p> <p>Conclusions</p> <p>These data demonstrate that the overexpression of Fus/Caz causes <it>in vivo </it>toxicity by disrupting neuromuscular junctions (NMJs) and inducing apoptosis in motor neurons. In addition, the nuclear localization of Fus is essential for Fus to induce toxicity. Our findings also suggest that Fus overexpression and gene deletion can cause similar degenerative phenotypes but the underlying mechanisms are likely different.</p

Production of Glycopeptide Derivatives for Exploring Substrate Specificity of Human OGA Toward Sugar Moiety.

O-GlcNAcase (OGA) is the only enzyme responsible for removing N-acetyl glucosamine (GlcNAc) attached to serine and threonine residues on proteins. This enzyme plays a key role in O-GlcNAc metabolism. However, the structural features of the sugar moiety recognized by human OGA (hOGA) remain unclear. In this study, a set of glycopeptides with modifications on the GlcNAc residue, were prepared in a recombinant full-length human OGT-catalyzed reaction, using chemoenzymatically synthesized UDP-GlcNAc derivatives. The resulting glycopeptides were used to evaluate the substrate specificity of hOGA toward the sugar moiety. This study will provide insights into the exploration of probes for O-GlcNAc modification, as well as a better understanding of the roles of O-GlcNAc in cellular physiology

FUS-NLS/Transportin 1 complex structure provides insights into the nuclear targeting mechanism of FUS and the implications in ALS

The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1). Familial amyotrophic lateral sclerosis (ALS) related mutations are clustered in FUS-NLS. We report here the structural, biochemical and cell biological characterization of the FUS-NLS and its clinical implications. The crystal structure of the FUS-NLS/Trn1 complex shows extensive contacts between the two proteins and a unique α-helical structure in the FUS-NLS. The binding affinity between Trn1 and FUS-NLS (wide-type and 12 ALS-associated mutants) was determined. As compared to the wide-type FUS-NLS (K(D) = 1.7 nM), each ALS-associated mutation caused a decreased affinity and the range of this reduction varied widely from 1.4-fold over 700-fold. The affinity of the mutants correlated with the extent of impaired nuclear localization, and more importantly, with the duration of disease progression in ALS patients. This study provides a comprehensive understanding of the nuclear targeting mechanism of FUS and illustrates the significance of FUS-NLS in ALS

Single-nucleotide polymorphisms are associated with cognitive decline at Alzheimer's disease conversion within mild cognitive impairment patients

INTRODUCTION: The growing public threat of Alzheimer's disease (AD) has raised the urgency to quantify the degree of cognitive decline during the conversion process of mild cognitive impairment (MCI) to AD and its underlying genetic pathway. The aim of this article was to test genetic common variants associated with accelerated cognitive decline after the conversion of MCI to AD. METHODS: In 583 subjects with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI; ADNI-1, ADNI-Go, and ADNI-2), 245 MCI participants converted to AD at follow-up. We tested the interaction effects between individual single-nucleotide polymorphisms and AD diagnosis trajectory on the longitudinal Alzheimer's Disease Assessment Scale-Cognition scores. RESULTS: Our findings reveal six genes, including BDH1, ST6GAL1, RAB20, PDS5B, ADARB2, and SPSB1, which are directly or indirectly related to MCI conversion to AD. DISCUSSION: This genome-wide association study sheds light on a genetic mechanism of longitudinal cognitive changes during the transition period from MCI to AD

Biocontrol potential and action mechanism of Bacillus amyloliquefaciens DB2 on Bipolaris sorokiniana

IntroductionBipolaris sorokiniana is the popular pathogenic fungi fungus which lead to common root rot and leaf spot on wheat. Generally, chemical fungicides are used to control diseases. However, the environmental pollution resulting from fungicides should not be ignored. It is important to study the mode of antagonistic action between biocontrol microbes and plant pathogens to design efficient biocontrol strategies.ResultsAn antagonistic bacterium DB2 was isolated and identified as Bacillus amyloliquefaciens. The inhibition rate of cell-free culture filtrate (CF, 20%, v/v) of DB2 against B. sorokiniana reached 92.67%. Light microscopy and scanning electron microscopy (SEM) showed that the CF significantly altered the mycelial morphology of B. sorokiniana and disrupted cellular integrity. Fluorescence microscopy showed that culture filtrate destroyed mycelial cell membrane integrity, decreased the mitochondrial transmembrane potential, induced reactive oxygen species (ROS) accumulation, and nuclear damage which caused cell death in B. sorokiniana. Moreover, the strain exhibited considerable production of protease and amylase, and showed a significant siderophore and indole-3-acetic acid (IAA) production. In the detached leaves and potted plants control assay, B. amyloliquefacien DB2 had remarkable inhibition activity against B. sorokiniana and the pot control efficacy was 75.22%. Furthermore, DB2 suspension had a significant promotion for wheat seedlings growth.ConclusionB. amyloliquefaciens DB2 can be taken as a potential biocontrol agent to inhibit B. sorokiniana on wheat and promote wheat growth

Case Report: Mycobacterium kansasii causing infective endocarditis explored by metagenomic next-generation sequencing

In this report, we describe the first case of infective endocarditis caused by Mycobacterium kansasii in a 45-year-old male patient who presented with a 10-day fever and decompensated cirrhosis. Despite negative results in blood culture and pathology, we employed metagenomic next-generation sequencing (mNGS) to analyze the genome sequences of both the host and microbe. The copy number variation (CNV) indicated a high risk of liver disease in the patient, which correlated with biochemical examination findings. Notably, M. kansasii sequences were detected in peripheral blood samples and confirmed through Sanger sequencing. Unfortunately, the patient’s condition deteriorated, leading to his demise prior to heart surgery. Nevertheless, we propose that mNGS could be a novel approach for diagnosing M. kansasii infection, particularly in cases where blood culture and pathology results are unavailable. It is important to consider M. kansasii infection as a potential cause of endocarditis and initiate appropriate anti-infection treatment

Production of Glycopeptide Derivatives for Exploring Substrate Specificity of Human OGA Toward Sugar Moiety

O-GlcNAcase (OGA) is the only enzyme responsible for removing N-acetyl glucosamine (GlcNAc) attached to serine and threonine residues on proteins. This enzyme plays a key role in O-GlcNAc metabolism. However, the structural features of the sugar moiety recognized by human OGA (hOGA) remain unclear. In this study, a set of glycopeptides with modifications on the GlcNAc residue, were prepared in a recombinant full-length human OGT-catalyzed reaction, using chemoenzymatically synthesized UDP-GlcNAc derivatives. The resulting glycopeptides were used to evaluate the substrate specificity of hOGA toward the sugar moiety. This study will provide insights into the exploration of probes for O-GlcNAc modification, as well as a better understanding of the roles of O-GlcNAc in cellular physiology