Lias overexpression alleviates pulmonary injury induced by fine particulate matter in mice.

Oxidative stress and inflammation are mechanisms underlying toxicity induced by fine particulate matter (PM2.5). The antioxidant baseline of the human body modulates the intensity of oxidative stress in vivo. This present study aimed to evaluate the role of endogenous antioxidants in alleviating PM2.5-induced pulmonary injury using a novel mouse model (LiasH/H) with an endogenous antioxidant capacity of approximately 150% of its wild-type counterpart (Lias+/+). LiasH/H and wild-type (Lias+/+) mice were randomly divided into control and PM2.5 exposure groups (n = 10), respectively. Mice in the PM2.5 group and the control group were intratracheally instilled with PM2.5 suspension and saline, respectively, once a day for 7 consecutive days. The metal content, major pathological changes in the lung, and levels of oxidative stress and inflammation biomarkers were examined. The results showed that PM2.5 exposure induced oxidative stress in mice. Overexpression of the Lias gene significantly increased the antioxidant levels and decreased inflammatory responses induced by PM2.5. Further study found that LiasH/H mice exerted their antioxidant function by activating the ROS-p38MAPK-Nrf2 pathway. Therefore, the novel mouse model is useful for the elucidation of the mechanisms of pulmonary injury induced by PM2.5.

Abelmoschus Manihot ameliorates the levels of circulating metabolites in diabetic nephropathy by modulating gut microbiota in non-obese diabetes mice.

Huangkui capsule (HKC), a traditional Chinese medicine, has been used for medication of kidney diseases, including diabetic nephropathy (DN). The current study aimed to evaluate the effects of HKC in the modulation of gut microbiota and the amelioration of metabolite levels by using non-obese diabetes (NOD) mice with DN. The microbiota from three parts of intestines (duodenum, ileum and colon) in NOD mice with and without HKC treatment were analysed using 16S rDNA sequencing techniques. Untargeted metabolomics in plasma of NOD mice were analysed with liquid mass spectrometry. Results showed that HKC administration ameliorated DN in NOD mice and the flora in duodenum were more sensitive to HKC intervention, while the flora in colon had more effects on metabolism. The bacterial genera such as Faecalitalea and Muribaculum significantly increased and negatively correlated with most of the altered metabolites after HKC treatment, while Phyllobacterium, Weissella and Akkermansia showed an opposite trend. The plasma metabolites, mainly including amino acids and fatty acids such as methionine sulfoxide, BCAAs and cis-7-Hexadecenoic acid, exhibited a distinct return to normal after HKC treatment. The current study thereby provides experimental evidence suggesting that HKC may modulate gut microbiota and subsequently ameliorate the metabolite levels in DN.

Prediction of cellular targets in diabetic kidney diseases with single-cell transcriptomic analysis of db/db mouse kidneys.

Diabetic kidney disease is the leading cause of impaired kidney function, albuminuria, and renal replacement therapy (dialysis or transplantation), thus placing a large burden on health-care systems. This urgent event requires us to reveal the molecular mechanism of this disease to develop more efficacious treatment. Herein, we reported single-cell RNA sequencing analyses in kidneys of db/db mouse, an animal model for type 2 diabetes and diabetic kidney disease. We first analyzed the hub genes expressed differentially in the single cell resolution transcriptome map of the kidneys. Then we figured out the communication among the renal and immune cells in the kidneys. Data from this report may provide novel information for better understanding the cell-specific targets involved in the aetiologia of type 2 diabetic kidney disease and for cell communication and signaling between renal cells and immune cells of this complex disease.

Interaction between Plasma Metabolomics and Intestinal Microbiome in db/db Mouse, an Animal Model for Study of Type 2 Diabetes and Diabetic Kidney Disease.

Evidence has demonstrated that either metabolites or intestinal microbiota are involved in the pathogenesis of type 2 diabetes (T2D) and diabetic kidney disease (DKD). To explore the interaction between plasma metabolomics and intestinal microbiome in the progress of T2D-DKD, in the current study, we analyzed metabolomics in the plasma of db/db mice with liquid chromatography-mass spectrometry and also examined intestinal prokaryotes and entire gut microbiome dysbiosis at the genus level with both 16S rDNA and metagenomic sequencing techniques. We found that Negativibacillus and Rikenella were upregulated, while Akkermansia, Candidatus, Erysipelatoclostridium and Ileibacterium were downregulated in the colon of db/db mice compared with non-diabetic controls. In parallel, a total of 91 metabolites were upregulated, while 23 were downregulated in the plasma of db/db mice. The top five upregulated metabolites included D-arabinose 5-phosphate, estrone 3-sulfate, L-theanine, 3'-aenylic acid and adenosine 5'-monophosphate, and the five most significantly downregulated metabolites were aurohyocholic acid sodium salt, calcium phosphorylcholine chloride, tauro-alpha-muricholic acid sodium salt, galactinol and phosphocholine. These plasma metabolites were interacted with intestinal microbiomes, which are mainly involved in the pathways related to the biosynthesis of unsaturated fatty acids, fatty acid elongation, steroid biosynthesis, and D-arginine and D-ornithine metabolism. In the differential metabolites, N-acetyl-L-ornithine, ornithine and L-kyn could be metabolized by the correspondingly differential ontology genes in the intestinal metagenome. The current study thereby provides evidence for a gut-metabolism-kidney axis in the metabolism of db/db mice, in which the gut microbiome and circulating metabolomics interact, and suggests that information from this axis may contribute to our understanding of T2D and DKD pathogenesis.

Copper and Photocatalytic Radical Relay Enabling Fluoroalkylphosphorothiolation of Alkenes: Modular Synthesis of Fluorine-Containing S-Alkyl Phosphorothioates and Phosphorodithioates.

A photoredox and copper-catalyzed fluoroalkylphosphorothiolation of activated and unactivated alkenes via a radical relay mechanism is reported. By employing fluoroalkyl halides as radical precursors and P(O)SH or P(S)SH compounds as coupling partners, a wide range of ß-monofluoroalkyl-, -difluoroalkyl-, -trifluoromethyl-, or -perfluoroalkyl-substituted S-alkyl phosphorothioates and phosphorodithioates can be easily constructed under mild conditions with good functional group tolerance. Furthermore, this modular reaction system can be successfully applied to late-stage functionalization of bioactive molecules.

Genome-wide mRNA profiling identifies the NRF2-regulated lymphocyte oxidative stress status in patients with silicosis.

BACKGROUND: The immunomodulatory abnormalities of silicosis are related to the lymphocyte oxidative stress state. The potential effect of antioxidant therapy on silicosis may depend on the variation in nuclear factor erythroid 2-related factor 2 (NRF2)-regulated antioxidant genes in peripheral blood mononuclear cells (PBMCs). As NRF2 is a redox-sensitive transcription factor, its possible roles and underlying mechanism in the treatment of silicosis need to be clarified. METHODS: Ninety-two male patients with silicosis and 87 male healthy volunteers were randomly selected. PBMCs were isolated from fresh blood from patients with silicosis and healthy controls. The lymphocyte oxidative stress state was investigated by evaluating NRF2 expression and NRF2-dependent antioxidative genes in PBMCs from patients with silicosis. Key differentially expressed genes (DEGs) and signaling pathways were identified utilizing RNA sequencing (RNA-Seq) and bioinformatics technology. Gene set enrichment analysis was used to identify the differences in NRF2 signaling networks between patients with silicosis and healthy controls. RESULTS: The number of monocytes was significantly higher in patients with silicosis than that of healthy controls. Furthermore, RNA-Seq findings were confirmed using quantitative polymerase chain reaction and revealed that NRF2-regulated DEGs were associated with glutathione metabolism, transforming growth factor-ß, and the extracellular matrix receptor interaction signaling pathway in PBMCs from patients with silicosis. The top 10 hub genes were identified by PPI analysis: SMAD2, MAPK3, THBS1, SMAD3, ITGB3, integrin alpha-V (ITGAV), von Willebrand factor (VWF), BMP4, CD44, and SMAD7. CONCLUSIONS: These findings suggest that NRF2 signaling regulates the lymphocyte oxidative stress state and may contribute to fibrogenic responses in human PBMCs. Therefore, NRF2 might serve as a novel preventive and therapeutic candidate for silicosis.

Alpha-lipoic acid attenuates silica-induced pulmonary fibrosis by improving mitochondrial function via AMPK/PGC1α pathway activation in C57BL/6J mice.

Silicosis is characterized by pulmonary interstitial fibrosis that arises as a result of chronic exposure to silica. The few available treatments only delay its progression. As α-lipoic acid (ALA) has been shown to have various beneficial effects, including mitoprotective, antioxidant, and anti-inflammatory effects, we hypothesized that it may exhibit therapeutic effects in pulmonary fibrosis. Therefore, in the present study, we used a murine model of silicosis to investigate whether supplementation with exogenous ALA could attenuate silica-induced pulmonary fibrosis by improving mitochondrial function. ALA was administered to the model mice via continuous intragastric administration for 28 days, and then the antioxidant and mitoprotective effects of ALA were evaluated. The results showed that ALA decreased the production of reactive oxygen species, protected mitochondria from silica-induced dysfunction, and inhibited extracellular matrix deposition. ALA also decreased hyperglycemia and hyperlipidemia. Activation of the mitochondrial AMPK/PGC1α pathway might be responsible for these ALA-mediated anti-fibrotic effects. Exogenous ALA blocked oxidative stress by activating NRF2. Taken together, these findings demonstrate that exogenous ALA effectively prevents the progression of silicosis in a murine model, likely by stimulating mitochondrial biogenesis and endogenous antioxidant responses. Therefore, ALA can potentially delay the progression of silica-induced pulmonary fibrosis.