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Nine major cell populations among 46,716 cells were identified in mouse intestinal ischemia-reperfusion(Ⅱ/R)injury by single-cell RNA sequencing.For enterocyte cells,11 subclusters were found,in which enterocyte cluster 1(EC1),enterocyte cluster 3(EC3),and enterocyte cluster 8(EC8)were newly discovered cells in ischemia 45 min/reperfusion 720 min(I 45 min/R 720 min)group.EC1 and EC3 played roles in digestion and absorption,and EC8 played a role in cell junctions.For TA cells,after ischemia 45 min/reperfusion 90 min(I 45 min/R 90 min),many TA cells at the stage of proliferation were identified.For Paneth cells,Paneth cluster 3 was observed in the resting state of normal jejunum.After I45 min/R 90 min,three new subsets were found,in which Paneth cluster 1 had good antigen presentation activity.The main functions of goblet cells were to synthesize and secrete mucus,and a novel subcluster(goblet cluster 5)with highly proliferative ability was discovered in I 45 min/R 90 min group.As a major part of immune system,the changes in T cells with important roles were clarified.Notably,enterocyte cells secreted Guca2b to interact with Gucy2c receptor on the membranes of stem cells,TA cells,Paneth cells,and goblet cells to elicit intercellular communication.One marker known as glutathione S-transferase mu 3(GSTM3)affected intestinal mucosal barrier function by adjusting mitogen-activated protein kinases(MAPK)signaling during Ⅱ/R injury.The data on the heterogeneity of intestinal cells,cellular communication and the mechanism of GSTM3 provide a cellular basis for treating Ⅱ/R injury.
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It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease(PD).Dioscin,a bioactive steroidal saponin,shows various activities.How-ever,its effects and mechanisms against PD are limited.In this study,dioscin dramatically alleviated neuroinflammation and oxidative stress,and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).16 S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes-to-Bacteroidetes ratio and the abundances of Enterococcus,Streptococcus,Bacteroides and Lactobacillus genera,which further inhibited bile salt hy-drolase(BSH)activity and blocked bile acid(BA)deconjugation.Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent.In addition,non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and pri-mary bile acid biosynthesis.Moreover,targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid,tauroursodeoxycholic acid,taurodeoxycholic acid and β-muricholic acid in feces and serum.In addition,ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice.Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5(TGR5),glucagon-like peptide-1 receptor(GLP-1R),GLP-1,superoxide dismutase(SOD),and down-regulated NADPH oxidases 2(NOX2)and nu-clear factor-kappaB(NF-κB)levels.Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice,suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.
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The three-dimensional (3D) conformation of chromatin is integral to the precise regulation of gene expression. The 3D genome and genomic variations in non-alcoholic fatty liver disease (NAFLD) are largely unknown, despite their key roles in cellular function and physiological processes. High-throughput chromosome conformation capture (Hi-C), Nanopore sequencing, and RNA-sequencing (RNA-seq) assays were performed on the liver of normal and NAFLD mice. A high-resolution 3D chromatin interaction map was generated to examine different 3D genome hierarchies including A/B compartments, topologically associated domains (TADs), and chromatin loops by Hi-C, and whole genome sequencing identifying structural variations (SVs) and copy number variations (CNVs) by Nanopore sequencing. We identified variations in thousands of regions across the genome with respect to 3D chromatin organization and genomic rearrangements, between normal and NAFLD mice, and revealed gene dysregulation frequently accompanied by these variations. Candidate target genes were identified in NAFLD, impacted by genetic rearrangements and spatial organization disruption. Our data provide a high-resolution 3D genome interaction resource for NAFLD investigations, revealed the relationship among genetic rearrangements, spatial organization disruption, and gene regulation, and identified candidate genes associated with these variations implicated in the pathogenesis of NAFLD. The newly findings offer insights into novel mechanisms of NAFLD pathogenesis and can provide a new conceptual framework for NAFLD therapy.
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Objective To investigate the effect of the aqueous extracts from Dioscorea nipponica Makino (AEDN) against the carbon tetrachloride (CCl4)-induced mice acute liver injury by regulating TLR4/MyD88 signal pathway.Methods 60 mice were randomly divided into control group, model group, low, medium and high dose AEDN groups according to radom number table with 10 mice in each group. Mice in low, medium and high dose AEDN groups were adiminstrated with 50, 100 and 200 mg/kg AEDN, in control and model groups were adiminstrated with solvent once a day for 7 consecutive days. Two hours after the last administration, mice were intraperitoneal injected with with 0.3% CCl4 olive oil solution to induce acute liver injury model, except for the mice in control group. Twenty-four hours after injection, the expressions of TLR4, MyD88 and NF-κB in liver tissue were evaluated by Western blot, mRNA levels were evaluated by PCR, and the AST and ALT levels in serum were also detected.Results Compared with model group, the serum AST (98.00 ± 17.75 U/L, 57.49 ± 9.66 U/L, 39.60 ± 9.49 U/Lvs. 113.40 ± 9.71 U/L) and ALT levels (76.00 ± 14.73 U/L, 50.70 ± 9.35 U/L, 35.25 ± 9.93 U/Lvs. 95.42 ± 11.64 U/L) were significantly decreased in low, medium and high dose AEDN groups (P<0.01); MyD88 (0.67 ± 0.21vs. 1.74 ± 0.42), NF-κB p65 (0.51 ± 0.09vs. 1.76 ± 0.31) and TLR4 (0.97 ± 0.25vs. 2.99 ± 0.72) levels were down-regulated in high dose AEDN group (P<0.01); the mRNA levels of IL-6 (2.22 ± 0.25, 1.76 ± 0.31vs. 5.20 ± 0.60), IL-1β (1.96 ± 0.35, 1.47 ± 0.23vs. 7.37 ± 0.99)、TNF-α (2.06 ± 0.25, 1.34 ± 0.33vs. 2.98 ± 0.50) in medium and high dose AEDN groups significantly decresed (P<0.01).Conclusions The AEDN has protective effect against CCl4-induced acute liver injury in mice via adjusting TLR4/MyD88 signal pathway.
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Acute kidney injury (AKI), a common clinical dis-ease, is one complex pathophysiological process. In this review paper, the relationship and the molecular mechanisms of ische-mia-reperfusion, major surgery, rhabdomyolysis, pus sepsis and drug-induced renal toxicity associated with AKI were comprehen-sively reviewed. In addition, the prevention and treatment of AKI by Chinese medicine and the effective components were also reviewed. Therefore, our review aims to provide valuable infor-mation for treatment of AKI, and also for exploration of innova-tive new drugs.