Dedicator of Cytokinesis 2 (DOCK2) Deficiency Attenuates Lung Injury Associated with Chronic High-Fat and High-Fructose Diet–Induced Obesity

Qian, Guoqing; Adeyanju, O.; Sunil, Christudas; Chen, Shiyou; Tucker, Torry A.; Idell, Steven; Guo, Xia

doi:10.1016/j.ajpath.2021.10.011

Cited by 17 publications

(18 citation statements)

References 64 publications

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“…Our recent work shows that a high-fat and high-fructose (HFHF) diet promotes inflammatory infiltration in the lungs of C56BL/6 mice after 10- and 20-weeks’ treatment. Conversely, collagen deposition in the lung tissues as determined by Masson’s staining and Western blotting analysis was found to be prominent only after 20 weeks but not 10 weeks ( Qian et al, 2021 ).…”

Section: Association Of Obesity With Lung Fibrosismentioning

confidence: 99%

“…Mechanic effects of accumulating fat impairs lung function and induces fibrotic changes in the diaphragm ( Buras et al, 2019 ), which may play a role in the fibrosis of the lung through inflammatory changes. Other factors related with obesity are likely being involved to promote lung fibrosis, such as a potential direct effect through oxidized LDL ( Qian et al, 2021 ), indirect conditions such as insulin resistance ( Park et al, 2019 ) and altered microbiota in the lung ( Chioma et al, 2021 ). Inflamed lung also propagates the secretion of those mediators from diverse cell types locally, further leading to a transition towards profibrotic changes.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

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Obesity and the Development of Lung Fibrosis

2022

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Obesity is an epidemic worldwide and the obese people suffer from a range of respiratory complications including fibrotic changes in the lung. The influence of obesity on the lung is multi-factorial, which is related to both mechanical injury and various inflammatory mediators produced by excessive adipose tissues, and infiltrated immune cells. Adiposity causes increased production of inflammatory mediators, for example, cytokines, chemokines, and adipokines, both locally and in the systemic circulation, thereby rendering susceptibility to respiratory diseases, and altered responses. Lung fibrosis is closely related to chronic inflammation in the lung. Current data suggest a link between lung fibrosis and diet-induced obesity, although the mechanism remains incomplete understood. This review summarizes findings on the association of lung fibrosis with obesity, highlights the role of several critical inflammatory mediators (e.g., TNF-α, TGF-β, and MCP-1) in obesity related lung fibrosis and the implication of obesity in the outcomes of idiopathic pulmonary fibrosis patients.

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Section: Association Of Obesity With Lung Fibrosismentioning

confidence: 99%

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

Obesity and the Development of Lung Fibrosis

2022

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“…Previously reported studies have shown that the expression of LBP (lipopolysaccharide binding protein) [273], MC1R [274], CXCL14 [275], RGN (regucalcin) [276], NPY2R [277], MFAP5 [278], WNT5A [279], EDA (ectodysplasin A) [280], THSD7A [281], NEUROD1 [282], SLIT2 [283], PPARGC1A [219], IGF1 [144], OSR1 [284], TLR3 [285], BMP7 [286], POSTN (periostin) [287], LRP1B [288], THBS1 [289], NOTCH2 [290]. LRP1 [291], CLU (clusterin) [292], SMAD3 [91], TGFB1 [293], APP (amyloid beta precursor protein) [294], ITGB2 [295], IL6R [296], TIMP1 [297], CD47 [298], CD74 [299], RARA (retinoic acid receptor alpha) [300], DOCK2 [301], F13A1 [302], IRF7 [303], STIM1 [304], CXCR4 [305], MGLL (monoglyceride lipase) [306], M6PR [307], USP22 [308] and CASP2 [309] were mainly involved in progression of obesity, but these genes might be novel targets for GDM. Recent studies have shown that GLP1R [310], NEUROD1 [311], PPARGC1A [312], IGF1 [313], LRP1B [314], NOTCH2 [315], BAK1 [316], TLR2 [317], IL6R [318], TIMP1 [319], PIK3CD [320], PRKCA (protein kinase C alpha) [321], CXCR4 [322], RAB8A [323] and M6PR [324] are associated with GDM.…”

Section: Discussionmentioning

confidence: 99%

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

Vastrad¹,

Vastrad²

2021

Preprint

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Gestational diabetes mellitus (GDM) is a metabolic disorder during pregnancy. Numerous biomarkers have been identified that are linked with the occurrence and development of GDM. The aim of this investigation was to identify differentially expressed genes (DEGs) in GDM using a bioinformatics approach to elucidate their molecular pathogenesis. GDM associated expression profiling by high throughput sequencing dataset (GSE154377) was obtained from Gene Expression Omnibus (GEO) database including 28 normal pregnancy samples and 33 GDM samples. DEGs were identified using DESeq2. The gene ontology (GO) and REACTOME pathway enrichments of DEGs were performed by g:Profiler. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into modules using the PEWCC1 algorithm. MiRNA-hub gene regulatory network and TF-hub gene regulatory network were performed with the miRNet database and NetworkAnalyst database. Receiver Operating Characteristic (ROC) analyses was conducted to validate the hub genes. A total of 953 DEGs were identified, of which 478 DEGs were up regulated and 475 DEGs were down regulated. Furthermore, GO and REACTOME pathway enrichment analysis demonstrated that these DEGs were mainly enriched in multicellular organismal process, cell activation, formation of the cornified envelope and hemostasis. TRIM54, ELAVL2, PTN, KIT, BMPR1B, APP, SRC, ITGA4, RPA1 and ACTB were identified as key genes in the PPI network, miRNA-hub gene regulatory network and TF-hub gene regulatory network. TRIM54, ELAVL2, PTN, KIT, BMPR1B, APP, SRC, ITGA4, RPA1 and ACTB in GDM were validated using ROC analysis. This investigation provides further insights into the molecular pathogenesis of GDM, which might facilitate the diagnosis and treatment of GDM.

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“…The involvement of DOCK2 in the transition of lung fibroblast (LF) phenotype affecting lung disease was also confirmed in a bleomycin-induced lung fibrosis model in mice and in IPF patients. In a high-fat and high-fructose (HFHF) diet, often accompanied by the development of pulmonary inflammation and pulmonary fibrosis ( Qian et al, 2022b ). LFs play a key role in lung inflammation.…”

Section: Role Of Dock2 In Diseasesmentioning

confidence: 99%

“…DOCK2 promotes pleural fibrosis by regulating the mesothelial to mesenchymal transition (MesoMT) leading to restrictive lung disease, as well as mediating the transition of fibroblasts to myofibroblasts (FMT) during the development of idiopathic pulmonary fibrosis (IPF) ( Qian et al, 2022a ; Guo et al, 2022 ). The alteration of TNF-α-induced, lung fibroblast (LF) pro-inflammatory phenotype in high-fat and high-fructose (HFHF)-induced pulmonary fibrosis was found to be possibly mediated by DOCK2-regulated PI3K/AKT and NF-κB pathways ( Qian et al, 2022b ). It is evident that DOCK2 plays different roles in different diseases, and the degree of inflammatory response has different effects on disease progression.…”

Section: Introductionmentioning

confidence: 99%

Insights from DOCK2 in cell function and pathophysiology

Luo

et al. 2022

Front. Mol. Biosci.

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Dedicator of cytokinesis 2 (DOCK2) can activate the downstream small G protein Rac and regulate cytoskeletal reorganization. DOCK2 is essential for critical physiological processes such as migration, activation, proliferation, and effects of immune cells, including lymphocytes, neutrophils, macrophages, and dendritic cells. For example, DOCK2 is involved in the development and activation of T and B lymphocytes by affecting synapse formation and inhibiting the development of the Th2 lineage by downregulating IL-4Rα surface expression. Not only that, DOCK2 may be a molecular target for controlling cardiac transplant rejection and Alzheimer’s disease (AD). Patients with defects in the DOCK2 gene also exhibit a variety of impaired cellular functions, such as chemotactic responses of lymphocytes and reactive oxygen species (ROS) production by neutrophils. To date, DOCK2 has been shown to be involved in the development of various diseases, including AD, pneumonia, myocarditis, colitis, tumors, etc. DOCK2 plays different roles in these diseases and the degree of inflammatory response has a different impact on the progression of disease. In this paper, we present a review of recent advances in the function of DOCK2 in various immune cells and its role in various diseases.

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Dedicator of Cytokinesis 2 (DOCK2) Deficiency Attenuates Lung Injury Associated with Chronic High-Fat and High-Fructose Diet–Induced Obesity

Cited by 17 publications

References 64 publications

Obesity and the Development of Lung Fibrosis

Obesity and the Development of Lung Fibrosis

Identification of differentially expressed genes and signaling pathways in gestational diabetes mellitus by integrated bioinformatics analysis

Insights from DOCK2 in cell function and pathophysiology

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