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1.
Behav Brain Res ; 391: 112684, 2020 08 05.
Article in English | MEDLINE | ID: mdl-32454054

ABSTRACT

A relatively large number of diabetic patients risk complications of clinical depression that lead to poorer quality of life, however the precise mechanisms for diabetes-associated depression are not fully understood. Links between hyperglycemia-induced oxidative stress and NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation have been reported in the pathogenesis of diabetes. The present study aimed to elucidate the contribution of NLRP3-mediated apoptotic/pyroptotic neuronal cell death to diabetes-associated depression. We found that depressive-like behavior in streptozotocin (STZ)-induced diabetic mice was associated with hippocampal NLRP3 inflammasome activation. Hyperglycemia increased reactive oxygen species (ROS) production, thus leading to NLRP3 inflammasome activation in hippocampal neurons. It was found that STZ treatment induced apoptotic and pyroptotic cell death in the hippocampus as evidenced by increases of cleaved caspase 3 positive hippocampal neurons, TUNEL-positive cells, protein levels of p53, Bax, Puma, and the cleaved GSDMD N-terminal fragment, all of which were decreased in NLRP3 deficient mice. Using murine hippocampal neuronal cell line HT22, we found that high glucose induced apoptotic and pyroptotic cell death in a NLRP3 inflammasome-dependent manner in vitro. In addition, NLRP3 deficiency alleviated depressive-like behavior in STZ-induced diabetic mice. Our results suggest that hyperglycemia results in apoptosis and pyroptosis of hippocampal neuron cells in a NLRP3-dependent manner, which was associated with the depressive phenotypes evoked by STZ-induced diabetes. The study identifies a novel function of NLRP3 activation in high glucose-induced neuronal cell death, which sheds further light on the pathogenesis and new therapeutic targets of diabetes-associated depression.


Subject(s)
Depression/metabolism , Hippocampus/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Animals , Apoptosis/physiology , Cell Line , Depression/physiopathology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Disease Models, Animal , Hippocampus/physiopathology , Inflammasomes/metabolism , Inflammasomes/physiology , Intracellular Signaling Peptides and Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/physiology , Neurons/metabolism , Neurons/physiology , Pyroptosis/physiology , Reactive Oxygen Species/metabolism , Signal Transduction , Streptozocin/pharmacology
2.
Pulm Pharmacol Ther ; 57: 101803, 2019 08.
Article in English | MEDLINE | ID: mdl-31085231

ABSTRACT

Pulmonary fibrosis is a progressive fibrotic lung disease with a paucity of therapeutic options. Here we investigated the potential roles of probucol, a cholesterol-lowering drug with potent anti-oxidation properties, on pulmonary epithelial-mesenchymal transition (EMT) and fibrosis. We found that bleomycin-induced lung fibrosis was associated with increased transforming growth factor (TGF)-ß1, α-smooth muscle actin (α-SMA) and decreased E-cadherin expression in lung tissues, indicating EMT formation. Bleomycin treatment resulted in an induction of oxidative stress in lung tissues. Probucol treatment attenuated bleomycin-induced TGF-ß1 production, EMT and pulmonary fibrosis, meanwhile it suppressed bleomycin-induced oxidative stress. Bleomycin treatment resulted in decreases in protein expressions of Sirtuin 3 (SIRT3) in the lung, which were restored by ROS scavenger NAC and probucol treatment, suggesting that probucol might restore SIRT3 expression by suppressing bleomycin-induced oxidative stress. In the mouse alveolar type II epithelial cell line MLE-12, probucol treatment leads to an increase in SIRT3 expression in bleomycin-treated AT-II cells, which might contribute to the inhibitory effect of probucol on EMT through suppressing hypoxia inducible factor (HIF)-1α/TGF-ß1 pathway. In addition, probucol inhibited bleomycin-induced macrophage infiltration in the lung. Bleomycin decreased SIRT3 protein expression, whereas increased HIF-1α activation and TGF-ß1 release in the mouse macrophage cell line RAW264.7, which were attenuated by probucol treatment. Taken together, the present study suggests that probucol may ameliorate EMT and lung fibrosis through restoration of SIRT3 expression. The data obtained in this study provides proof for the idea that probucol may be a potential therapeutic option for the treatment of pulmonary fibrosis.


Subject(s)
Epithelial-Mesenchymal Transition/drug effects , Probucol/pharmacology , Pulmonary Fibrosis/drug therapy , Sirtuin 3/metabolism , Actins/metabolism , Alveolar Epithelial Cells , Animals , Bleomycin/pharmacology , Cadherins/metabolism , Cell Culture Techniques , Collagen Type I/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mice , Models, Animal , Oxidative Stress/drug effects , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , RAW 264.7 Cells , Signal Transduction/drug effects , Sirtuin 3/biosynthesis , Transforming Growth Factor beta1/metabolism
3.
Acta Physiol (Oxf) ; 225(2): e13177, 2019 02.
Article in English | MEDLINE | ID: mdl-30136377

ABSTRACT

AIMS: Clinical trials have shown the beneficial effects of exercise training against pulmonary fibrosis. This study aimed to investigate whether prophylactic intervention with exercise training attenuates lung fibrosis via modulating endogenous hydrogen sulphde (H2 S) generation. METHODS: First, ICR mice were allocated to Control, Bleomycin, Exercise, and Bleomycin + Exercise groups. Treadmill exercise began on day 1 and continued for 4 weeks. A single intratracheal dose of bleomycin (3 mg/kg) was administered on day 15. Second, ICR mice were allocated to Control, Bleomycin, H2 S, and Bleomycin + H2 S groups. H2 S donor NaHS (28 µmol/kg) was intraperitoneally injected once daily for 2 weeks. RESULTS: Bleomycin-treated mice exhibited increased levels of collagen deposition, hydroxyproline, collagen I, transforming growth factor (TGF)-ß1, Smad2/Smad3/low-density lipoprotein receptor-related proteins (LRP-6)/glycogen synthase kinase-3ß (GSK-3ß) phosphorylation, and Smad4/ß-catenin expression in lung tissues (P < 0.01), which was alleviated by exercise training (P < 0.01 except for Smad4 and phosphorylated GSK-3ß: P < 0.05). Bleomycin-induced lung fibrosis was associated with increased α smooth muscle actin (α-SMA) and decreased E-cadherin expression (P < 0.01). Double immunofluorescence staining showed the co-localization of E-cadherin/α-SMA, indicating epithelial-mesenchymal transition (EMT) formation, which was ameliorated by exercise training. Moreover, exercise training restored bleomycin-induced downregulation of cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) expression, as well as H2 S generation in lung tissue (P < 0.01). NaHS treatment attenuated bleomycin-induced TGF-ß1 production, activation of LRP-6/ß-catenin signalling, EMT and lung fibrosis (P < 0.01 except for ß-catenin: P < 0.05). CONCLUSION: Exercise training restores bleomycin-induced downregulation of pulmonary CBS/CSE expression, thus contributing to the increased H2 S generation and suppression of TGF-ß1/Smad and LRP-6/ß-catenin signalling pathways, EMT and lung fibrosis.


Subject(s)
Epithelial-Mesenchymal Transition , Physical Conditioning, Animal , Pulmonary Fibrosis/prevention & control , Sulfites/metabolism , Animals , Bleomycin , Low Density Lipoprotein Receptor-Related Protein-6/metabolism , Male , Mice , Mice, Inbred ICR , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Signal Transduction , Transforming Growth Factor beta1/metabolism , beta Catenin/metabolism
4.
J Appl Physiol (1985) ; 123(4): 717-727, 2017 Oct 01.
Article in English | MEDLINE | ID: mdl-28663379

ABSTRACT

Exercise training is advocated for treating chronic inflammation and obesity-related metabolic syndromes. Glucocorticoids (GCs), the anti-inflammatory hormones, are synthesized or metabolized in extra-adrenal organs. This study aims to examine whether exercise training affects obesity-associated pulmonary inflammation by regulating local GC synthesis or metabolism. We found that sedentary obese (ob/ob) mice exhibited increased levels of interleukin (IL)-1ß, IL-18, monocyte chemotactic protein (MCP)-1, and leukocyte infiltration in lung tissues compared with lean mice, which was alleviated by 6 wk of exercise training. Pulmonary corticosterone levels were decreased in ob/ob mice. Exercise training increased pulmonary corticosterone levels in both lean and ob/ob mice. Pulmonary corticosterone levels were negatively correlated with IL-1ß, IL-18, and MCP-1. Immunohistochemical staining of the adult mouse lung sections revealed positive immunoreactivities for the steroidogenic acute regulatory protein, the cholesterol side-chain cleavage enzyme (CYP11A1), the steroid 21-hydroxylase (CYP21), 3ß-hydroxysteroid dehydrogenase (3ß-HSD), and type 1 and type 2 11ß-hydroxysteroid dehydrogenase (11ß-HSD) but not for 11ß-hydroxylase (CYP11B1). Exercise training significantly increased pulmonary 11ß-HSD1 expression in both lean and ob/ob mice. In contrast, exercise training per se had no effect on pulmonary 11ß-HSD2 expression, although pulmonary 11ß-HSD2 levels in ob/ob mice were significantly higher than in lean mice. RU486, a glucocorticoid receptor antagonist, blocked the anti-inflammatory effects of exercise training in lung tissues of obese mice and increased inflammatory cytokines in lean exercised mice. These findings indicate that exercise training increases pulmonary expression of 11ß-HSD1, thus contributing to local GC activation and suppression of pulmonary inflammation in obese mice.NEW & NOTEWORTHY Treadmill training leads to a significant increase in pulmonary corticosterone levels in ob/ob mice, which is in parallel with the favorable effects of exercise on obesity-associated pulmonary inflammation. Exercise training increases pulmonary 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression but has no significant effect on 11ß-HSD2 expression in both lean and ob/ob mice. These findings indicate that exercise training increases pulmonary expression of 11ß-HSD1, thus contributing to local glucocorticoid activation and suppression of pulmonary inflammation in obese mice.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Glucocorticoids/metabolism , Obesity/metabolism , Physical Conditioning, Animal , Pneumonia/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , 3-Hydroxysteroid Dehydrogenases/metabolism , Animals , Chemokine CCL2/metabolism , Cholesterol Side-Chain Cleavage Enzyme/metabolism , Cytochrome P450 Family 21/metabolism , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Lung/metabolism , Mice, Obese , Mifepristone/pharmacology , Steroid 11-beta-Hydroxylase/metabolism
5.
Mar Biotechnol (NY) ; 18(3): 418-35, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27255337

ABSTRACT

The inclusion of plant meals in diets of farmed Atlantic salmon can elicit inflammatory responses in the distal intestine (DI). For the present work, fish were fed a standard fish meal (FM) diet or a diet with partial replacement of FM with solvent-extracted camelina meal (CM) (8, 16, or 24 % CM inclusion) during a 16-week feeding trial. A significant decrease in growth performance was seen in fish fed all CM inclusion diets (Hixson et al. in Aquacult Nutr 22:615-630, 2016). A 4x44K oligonucleotide microarray experiment was carried out and significance analysis of microarrays (SAM) and rank products (RP) methods were used to identify differentially expressed genes between the DIs of fish fed the 24 % CM diet and those fed the FM diet. Twelve features representing six known transcripts and two unknowns were identified as CM responsive by both SAM and RP. The six known transcripts (including thioredoxin and ependymin), in addition to tgfb, mmp13, and GILT, were studied using qPCR with RNA templates from all four experimental diet groups. All six microarray-identified genes were confirmed to be CM responsive, as was tgfb and mmp13. Histopathological analyses identified signs of inflammation in the DI of salmon fed CM-containing diets, including lamina propria and sub-epithelial mucosa thickening, infiltration of eosinophilic granule cells, increased goblet cells and decreased enterocyte vacuolization. All of these were significantly altered in 24 % CM compared to all other diets, with the latter two also altered in 16 % CM compared with 8 % CM and control diet groups. Significant correlation was seen between histological parameters as well as between five of the qPCR analyzed genes and histological parameters. These molecular biomarkers of inflammation arising from long-term dietary CM exposure will be useful in the development of CM-containing diets that do not have deleterious effects on salmon growth or physiology.


Subject(s)
Animal Feed/adverse effects , Brassicaceae/adverse effects , Fish Proteins/genetics , Intestines/immunology , RNA, Messenger/genetics , Salmo salar/genetics , Animals , Brassicaceae/chemistry , Diet/adverse effects , Fish Proteins/immunology , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Inflammation/etiology , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Intestines/pathology , Matrix Metalloproteinase 13/genetics , Matrix Metalloproteinase 13/immunology , Molecular Sequence Annotation , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/immunology , Oligonucleotide Array Sequence Analysis , Oxidoreductases Acting on Sulfur Group Donors/genetics , Oxidoreductases Acting on Sulfur Group Donors/immunology , RNA, Messenger/immunology , Salmo salar/growth & development , Salmo salar/immunology , Thioredoxins/genetics , Thioredoxins/immunology , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology
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