A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis

Acute pancreatitis (AP), a common abdominal inflammatory disorder, is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. Although the mechanism remains to be fully understood, inflammation is the main cause of pancreatic damage in AP. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2-ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)], derived from danshensu, exhibits anti-inflammatory and anti-apoptotic properties in vitro. However, its potential beneficial effect in AP has not been demonstrated. This study aimed to investigate the effects and underlying mechanisms of DSC in experimental AP in mice. We found that DSC suppressed inflammatory responses in AP by inhibiting the activation of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3) and nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome. Furthermore, treatment with DSC modulated the infiltration of neutrophils and the phenotypes of macrophages in mice induced with AP. Interestingly, we found that the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) and its regulated antioxidant enzyme heme oxygenase-1 (HO-1), which modulate inflammatory activities, was significantly increased in DSC-treated groups. Together, our findings demonstrate that DSC alleviates pancreatic inflammation and damage in AP by inhibiting the activation of NF-κB, STAT3, and NLRP3 inflammasome and modulating immune cell responses

PRMT2 promotes dextran sulfate sodium-induced colitis by inhibiting SOCS3 via histone H3R8 asymmetric dimethylation

BACKGROUND AND PURPOSE: There is emerging evidence for critical roles of epigenetic modifiers in development of inflammatory bowel disease (IBD). Protein arginine methyltransferase 2 (PRMT2) is responsible for methylation of arginine residues on histones and targets transcription factors critically involved in many cellular processes, including gene transcription, mRNA splicing, cell proliferation and differentiation. However, its role in colitis remains unknown. In this study, the role and underlying mechanisms of PRMT2 in colitis was studied. EXPERIMENTAL APPROACH: A mouse dextran sulfate sodium (DSS)-induced experimental colitis model was applied to study PRMT2 in colitis. Lentivirus induced PRMT2 silencing or overexpression in vivo was applied to address the role of PRMT2 in colitis. Detailed western blot and expression analysis was done to understand epigenetic changes induced by PRMT2 in colitis. KEY RESULTS: PRMT2 is highly expressed in patients with IBD, inflamed colon of mice and TNF-α stimulated mice gut epithelial cells. PRMT2 overexpression aggravates while knockdown alleviates DSS-induced colitis in mice, suggesting that PRMT2 is a pivotal mediator of colitis development. Mechanistically, PRMT2 mediates colitis by increasing repressive histone mark H3R8 asymmetric methylation (H3R8me2a) at the promoter region of the suppressor of cytokine signaling 3 (SOCS3) promoter. Resultant inhibition of SOCS3 expression and SOCS3-mediated degradation of TNF receptor associated factor 5 (TRAF5) via ubiquitination led to elevated TRAF5 expression and TRAF5-mediated downstream NF-κB/MAPK activation. CONCLUSION AND IMPLICATIONS: Our study demonstrates that PRMT2 acts as a transcriptional co-activator for proinflammatory genes during colitis. Hence targeting PRMT2 may provide a novel therapeutic approach for colitis

Study on Accuracy Evaluation of MCD19A2 and Spatiotemporal Distribution of AOD in Arid Zones of Central Asia

The Central Asian arid zone is the largest non-territorial arid zone in the world, so it is particularly important to understand the optical properties of aerosols in this region. In this paper, we validate the MCD19A2 atmospheric aerosol optical depth (AOD) remote sensing data by using ground-based data and measured data. To explore the spatial and temporal changes in aerosols in the Central Asian arid zone as well as the interannual variations and seasonal variations, we characterize the spatial and temporal distributions of the AOD over 20 years. Finally, we analyze the spatial and temporal variations of the AOD in the Central Asian arid zone by using three methods, namely, the Theil–Sen median trend analysis combined with the Mann–Kendall test, coefficient of variation, and Hurst index; analyze the characteristics of the spatial and temporal variations of the AOD in the Central Asian arid zone; and explore the relationships among the AOD, wind speed, and NDVI. This study reveals the characteristics of the long-term changes in the aerosol optical properties in the Central Asian arid zone and provides a scientific basis for estimating the factors affecting climate change

G protein coupled receptor 41 regulates fibroblast activation in pulmonary fibrosis via Gαi/o and downstream Smad2/3 and ERK1/2 phosphorylation

Pulmonary fibrosis is a progressive and fatal fibrotic lung disease with mysterious pathogenesis and limited effective therapies. G protein-coupled receptors (GPRs) participate in a variety of physiologic functions, and several GPRs have critical fibrosis-promoting or -inhibiting roles in pulmonary fibrosis. Here, we explored the role of GPR41 in the pathobiology of pulmonary fibrosis. We found that GPR41 expression was elevated in lung tissues of mice with bleomycin-induced pulmonary fibrosis and lung fibroblasts treated with transforming growth factor-β1 (TGF-β1). Knockout of GPR41 attenuated pulmonary fibrosis in mice, as evidenced by improved lung morphology, decreased lung weight and collagen secretion, and down-regulated α-SMA, collagen type I alpha and fibronectin expression in lungs. Additionally, GPR41 knockout inhibited the differentiation of fibroblasts to myofibroblasts, and decreased myofibroblast migration. By further mechanistic analysis, we demonstrated that GPR41 regulated TGF-β1-induced fibroblast-to-myofibroblast differentiation and Smad2/3 and ERK1/2 phosphorylation via its Gαi/o subunit but not Gβγ subunit. Together, our data indicate that GPR41 is involved in pulmonary fibroblast activation and fibrosis, and GPR41 represents a potential therapeutic target for pulmonary fibrosis

Gut microbiota‐CRAMP axis shapes intestinal barrier function and immune responses in dietary gluten‐induced enteropathy

Abstract In the gut, cathelicidin‐related antimicrobial peptide (CRAMP) has been largely described for its anti‐infective activities. With an increasing recognition of its immune regulatory effects in extra‐intestinal diseases, the role of CRAMP in gluten‐induced small intestinal enteropathy celiac disease remains unknown. This study aimed to investigate the unexplored role of CRAMP in celiac disease. By applying a mouse model of gluten‐induced enteropathy (GIE) recapitulating small intestinal enteropathy of celiac disease, we observed defective CRAMP production in duodenal epithelium during GIE. CRAMP‐deficient mice were susceptible to the development of GIE. Exogenous CRAMP corrected gliadin‐triggered epithelial dysfunction and promoted regulatory immune responses at the intestinal mucosa. Additionally, GIE‐associated gut dysbiosis with enriched Pseudomonas aeruginosa and production of the protease LasB contributed to defective intestinal CRAMP production. These results highlight microbiota‐CRAMP axis in the modulation of barrier function and immune responses in GIE. Hence, modulating CRAMP may represent a therapeutic strategy for celiac disease