Ramelteon protects against human pulmonary microvascular endothelial cell injury induced by lipopolysaccharide (LPS) via activating nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway

Abstract

Acute lung injury (ALI) is classified as a moderate or mild acute respiratory distress syndrome and is a prominent cause of morbidity and mortality among the critically ill population. Ramelteon is a melatonin receptor agonist with anti-inflammatory and antioxidant effects. The current study investigated the role of ramelteon in lipopolysaccharide (LPS)-induced human pulmonary microvascular endothelial cells (HPMECs) and its potential regulatory mechanisms. A CCK-8 assay was used to examine the effect of ramelteon on the viability of LPS-induced HPMECs, HPMECs treated with ML385 [a Nrf2 inhibitor] and HPMECs treated with SnPP [a HO-1 inhibitor]. The Nrf2/HO-1 signaling pathway was additionally assessed by performing Western blotting. The levels of oxidative stress and inflammatory cytokines in HPMECs were detected using kits and reverse transcription-quantitative PCR. Cell apoptosis was evaluated via TUNEL staining. Furthermore, cell permeability was assessed using a FITC-dextran fluorescent probe, ZO-1 and occludin expression was determined via Western blotting. The results demonstrated that ramelteon elevated HPMEC viability after LPS stimulation. Additionally, ramelteon markedly reduced LPS-induced oxidative stress, inflammation and apoptosis. Moreover, cell permeability was notably decreased in ramelteon-treated groups and was accompanied by upregulated ZO-1 and occludin expression. Ramelteon treatment also activated the Nrf2/HO-1 signaling pathway in LPS-induced HPMECs. Furthermore, the addition of ML385 or SnPP reversed the protective effects of ramelteon on LPS-induced oxidative stress, inflammation, apoptosis and cell dysfunction in HPMECs. Collectively, the results suggested that ramelteon alleviated LPS-induced HPMEC damage by activating the Nrf2/HO-1 signaling pathway, making it an effective treatment for ALI.

[Retracted] Ginkgolide A Participates in LPS‐Induced PMVEC Injury by Regulating miR‐224 and Inhibiting p21 in a Targeted Manner

“…Leng et al [ 5 ] found that the abnormal apoptosis of PMVECs was the primary cause of pulmonary vascular dysfunction and pivotal for the onset and development of ALI. Therefore, deeply investigating the mechanism of PMVEC apoptosis in disease progression and seeking for new antiapoptotic drugs or therapeutic methods are highly constructive for potentiating the pulmonary function and relieving the clinical symptoms of patients [ 6 ]. Wu et al [ 7 ] reported that large quantities of regulatory genes (microribonucleic acid (miR)-339-3p, miR-4262, and so on.)…”

The Extracts Derived from Artemisia japonica Thunb. Leaves Mitigate Oxidative Stress and Inflammatory Response Induced by LPS in RAW264.7 Cells through Modulation of the Nrf2/HO-1 Signaling Pathway

“…Similarly, the Nrf2/HO-1 pathway not only eliminates ROS but also effectively regulates inflammatory responses [ 35 ]. Those compounds that promote HO-1 expression, such as notopterol, nepetoidin B, and ramelteon, can inhibit inflammation, but their effects can be weakened by HO-1 inhibitors [ 38 , 39 , 40 ]. Therefore, we tested whether EAF exerts antioxidant effects and alleviates inflammation by upregulating the Nrf2/HO-1 pathway.…”

Ramelteon attenuates renal ischemia and reperfusion injury through reducing mitochondrial fission and fusion and inflammation

“…Ramelteon is a selective MT1/2 receptor agonist and is predominantly used to treat difficulty falling asleep ( 24 ). In recent years, numerous studies have suggested that ramelteon protects against injury on human tissues induced by oxidative stress and LPS ( 17 , 25 , 26 ). The current study specified that ramelteon attenuates renal IRI and H/R-induced apoptosis by mitigating ROS generation, mitochondrial injury, and inflammatory response.…”

“…HK-2 cells were randomly divided into five groups: (I) control; (II) H/R; (III) H/R + ramelteon (10 nM); (IV) H/R + ramelteon (30 nM); and (V) H/R + ramelteon (60 nM). Ramelteon concentrations were determined based on previous studies ( 16 , 17 ). HK-2 cells were prophylactically treated with ramelteon and then exposed to H/R.…”