Diazepam inhibited lipopolysaccharide (LPS)-induced pyroptotic cell death and alleviated pulmonary fibrosis in mice by specifically activating GABAA receptor α4-subunit

Li, Yun; Song, Duanyi; Bo, Fanyan; Deng, Min; Tang, Xuefang

doi:10.1016/j.biopha.2019.109239

Cited by 23 publications

(11 citation statements)

References 38 publications

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“…LPS, the outer membrane of Gram‐negative, can activate the inflammatory response, and it has been widely used to construct the pneumonia in vitro model . In the present work, our data validated that LPS induced inflammatory injury in 16HBE cells, as evidenced by a repression in cell viability and an enhancement in cell apoptosis, as well as the augment in proinflammatory cytokines (IL‐6, IL‐8 and IL‐1β) levels, in agreement with recent work . The current study had led to the identification of circ_0038467 silencing that alleviated LPS‐induced inflammatory injury in 16HBE cells through regulating miR‐338‐3p/JAK/STAT3 pathway.…”

Section: Discussionsupporting

confidence: 90%

Circ_0038467 regulates lipopolysaccharide‐induced inflammatory injury in human bronchial epithelial cells through sponging miR‐338‐3p

Liu

Wan

et al. 2020

Thoracic Cancer

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Background: Pneumonia is a common acute lower respiratory infection in children and elders. Circular RNAs (circRNAs) have recently been uncovered to play important roles in pneumonia. However, the function and mechanism of circ_0038467 in pneumonia remain elusive. Methods: Cell viability and apoptosis were determined using the Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. The levels of interleukin 6 (IL-6), IL-8 and IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). Western blot analysis was performed to assess the expression of related proteins. Circ_0038467 was characterized by Ribonuclease R (RNase) digestion and subcellular localization assays. The levels of circ_0038467 and miR-338-3p were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The direct interaction between circ_0038467 and miR-338-3p was validated by the dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Results: Our data indicated that lipopolysaccharide (LPS) induced an inflammatory injury in 16HBE cells by repressing cell viability and enhancing cell apoptosis and proinflammatory cytokines production. Circ_0038467 was upregulated and miR-338-3p was downregulated in LPS-treated 16HBE cells. Circ_0038467 knockdown or miR-338-3p overexpression attenuated LPS-induced 16HBE cell inflammatory injury. Moreover, circ_0038467 acted as a sponge of miR-338-3p in 16HBE cells. MiR-338-3p mediated the alleviated effect of circ_0038467 knockdown on LPS-induced 16HBE cell inflammatory injury. Additionally, the Janus kinase/ signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway was involved in the circ_0038467/miR-338-3p axis-mediated regulation in LPS-induced 16HBE cell inflammatory injury. Conclusions: The current work had led to the identification of circ_0038467 knockdown that alleviated LPS-induced inflammatory injury in 16HBE cells at least partly through sponging miR-338-3p and regulating JAK/STAT3 pathway, highlighting novel molecular targets for the treatment of pneumonia.

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Section: Discussionsupporting

confidence: 90%

Circ_0038467 regulates lipopolysaccharide‐induced inflammatory injury in human bronchial epithelial cells through sponging miR‐338‐3p

Liu

Wan

et al. 2020

Thoracic Cancer

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“…Our experiments uncovered a difference in the mechanisms of action of diazepam on mouse and human immune cells. These differences may explain the discrepancies in diazepam data interpretation reported by previous researchers [39,40].…”

Section: Discussionmentioning

confidence: 75%

Activation of GABA(A) receptors inhibits T cell proliferation

et al. 2021

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Background The major sites for fast synaptic inhibition in the central nervous system (CNS) are ion channels activated by γ-aminobutyric acid (GABA). These receptors are referred as GABA(A) receptors (GABA(A)R). Recent evidence indicates a role of GABA(A)R in modulating the immune response. This work aimed to discern the role of GABA and GABA(A)Rs in human and mouse T cell activity. Methods Mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) were activated with anti-CD3 antibodies and the proliferation of both CD8+ and CD4+ T cells assessed through flow cytometry. Subsequently, the effects on T cell proliferation of either GABA(A)R modulation by diazepam that is also capable of activating mitochondrial based translocator protein (TSPO), alprazolam and allopregnanolone or inhibition by bicucculine methiodide (BMI) and (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) were assessed. Results Positive modulation of GABA(A)Rs either by benzodiazepines or the neurosteroid allopregnanolone inhibits both mouse and human T cell proliferation. GABAergic inhibition of T cell proliferation by benzodiazepines could be rescued by GABA(A)R blocking. Our data suggest that benzodiazepines influence T cell proliferation through both TSPO and GABA(A)Rs activation. Conclusions We conclude that activation of GABA(A)Rs provides immunosuppression by inhibiting T cell proliferation.

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“…Previous studies have reported that LPS could induce pyroptosis in various epithelial cells 26,27 . Thus, in the present study, HBE‐135 cells were stimulated with LPS to establish a pyroptotic HBEC model, which was then used to examine the role of GAS5 in HBEC pyroptosis.…”

Section: Discussionmentioning

confidence: 93%

Knockdown of long noncoding RNA growth arrest‐specific transcript 5 regulates forkhead box O3 to inhibit lipopolysaccharide‐induced human bronchial epithelial cell pyroptosis

Wen

et al. 2021

The Kaohsiung J of Med Scie

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Pyroptosis is a novel proinflammatory programmed cell death process. This study was designed to investigate the functional mechanisms of long noncoding RNA growth arrest‐specific transcript 5 (lncRNA GAS5) on lipopolysaccharide (LPS)‐induced human bronchial epithelial cell (HBEC) pyroptosis. LPS was used to induce pyroptosis in HBECs, followed by the detection of the expression of GAS5, forkhead box O3 (FOXO3), and nuclear factor E2‐related factor 2/heme oxygenase 1 (Nrf2/HO‐1) signaling pathway‐related factors. Cell viability was evaluated using CCK‐8 assay, lactate dehydrogenase (LDH) release was assessed by LDH assay kit and caspase‐1 activity by flow cytometry. Furthermore, expression of NOD‐like receptor family pyrin domain containing 3 and pyroptosis‐related proteins was evaluated using Western blot analysis, while enzyme‐linked immunosorbent assay was used to determine the levels of inflammatory factors. The interaction between GAS5 and FOXO3 was confirmed using bioinformatic prediction, RNA immunoprecipitation assay, RNA pull‐down, and dual‐luciferase reporter gene assay. Treatment of HBECs with LPS upregulated the expression of GAS5 and FOXO3, resulting in the inactivation of the Nrf2/HO‐1 signaling pathway. On the other hand, inhibition of both GAS5 and FOXO3 promoted cell viability, reduced LDH release, pyroptosis, and inflammatory response in LPS‐induced HBECs. Furthermore, FOXO3 could interact with GAS5, while FOXO3 overexpression reversed the inhibitory effect of GAS5 knockdown on cell pyroptosis. Thus, mechanistically, inhibition of FOXO3 activates the Nrf2/HO‐1 pathway to suppress LPS‐induced pyroptosis in HBECs. This study revealed that GAS5 knockdown attenuates FOXO3 expression thereby activating the Nrf2/HO‐1 pathway to inhibit LPS‐induced pyroptosis in HBECs. These findings may contribute to identifying novel targets that inhibit pyroptosis in HBECs.

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Diazepam inhibited lipopolysaccharide (LPS)-induced pyroptotic cell death and alleviated pulmonary fibrosis in mice by specifically activating GABAA receptor α4-subunit

Cited by 23 publications

References 38 publications

Circ_0038467 regulates lipopolysaccharide‐induced inflammatory injury in human bronchial epithelial cells through sponging miR‐338‐3p

Circ_0038467 regulates lipopolysaccharide‐induced inflammatory injury in human bronchial epithelial cells through sponging miR‐338‐3p

Activation of GABA(A) receptors inhibits T cell proliferation

Knockdown of long noncoding RNA growth arrest‐specific transcript 5 regulates forkhead box O3 to inhibit lipopolysaccharide‐induced human bronchial epithelial cell pyroptosis

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