Protostemonine effectively attenuates lipopolysaccharide-induced acute lung injury in mice

Abstract

Protostemonine (PSN) is the main anti-inflammatory alkaloid extracted from the roots of Stemona sessilifolia (known as "Baibu" in traditional Chinese medicine). Here, we reported the inhibitory effects of PSN on lipopolysaccharide (LPS)-induced macrophage activation in vitro and LPS-induced acute lung injury in mice. Macrophage cell line RAW264.7 cells and mouse bone marrow-derived macrophages (BMDMs) were treated with PSN (1, 3, 10, 30 and 100 μmol/L) for 0.5 h and then challenged with LPS (0.1 μg/mL) for 24 h. Pretreatment with PSN significantly inhibited LPS-induced phosphorylation of MAPKs and AKT, iNOS expression and NO production in the macrophages. C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) to induce acute lung injury (ALI). The mice were subsequently treated with PSN (10 mg/kg, ip) at 4 and 24 h after LPS challenge. PSN administration significantly attenuated LPS-induced inflammatory cell infiltration, reduced pro-inflammatory cytokine (TNF-α, IL-1β and IL-6) production and eliminated LPS-mediated lung edema. Furthermore, PSN administration significantly inhibited LPS-induced pulmonary MPO activity. Meanwhile, LPS-induced phosphorylation of p38 MAPK, iNOS expression and NO production in the lungs were also suppressed. The results demonstrate that PSN effectively attenuates LPS-induced inflammatory responses in vitro and in vivo; the beneficial effects are associated with the decreased phosphorylation of MAPK and AKT and the reduced expression of pro-inflammatory mediators, such as iNOS, NO and cytokines. These data suggest that PSN may be a potential therapeutic agent in the treatment of ALI.

Structural classification and biological activities of Stemona alkaloids

“…The effects were shown to be associated with the decreased phosphorylation of MAP (mitogen-activated protein) kinase and proteinkinase B and the reduced expression of pro-inflammatory mediators. The results suggested that 137 may be a potential therapeutic agent in the treatment of acute lung injury (Wu et al 2018).…”

“…Following the first report on multidrug resistance properties of an ethanolic extract of Stemona aphylla (Limtrakul et al 2007), a series of studies evaluated the synergistic growth inhibitory effect of Stemona alkaloids with cancer chemotherapeutic agents (Chanmahasathien et al 2011a, b;Umsumarng et al 2013Umsumarng et al , 2015Umsumarng et al , 2017Umsumarng et al , 2018. Furthermore, their anti- inflammatory activity was investigated and regarded as an inhibition of the expression of diverse inflammatory mediators (Hosoya et al 2011;Lim et al 2015;Jung et al 2016;Lee et al 2016;Wu et al 2018). The present review also reports on the nematicidal activity (Huang et al 2016;Chen et al 2018) and other miscellaneous properties as well as on the pharmacokinetics of that class of alkaloids (Dong et al 2012;Sun et al 2012;Han et al 2016).…”

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

“… Compounds Structure In vitro/in vivo Model (effective dose) Cells (effective concentration) Related pharmacological indicators Related molecular mechanisms Refs. Berberine 40 LPS/Cigarette smoke (10 mg/kg) 16HBE (10 μM) MPO↓ TNF-α↓ IL-6↓ IL8↓ KC↓ MIP-2↓ cPLA-2↓ MCP-1↓ Regulation of PERK‐mediated Nrf2/HO‐1 signaling pathway Inhibition of NF-κB signaling pathway [ [191] , [192] , [193] ] Tetrahydroberberrubine 41 LPS (10 mg/kg) THP-1 (10 μM) TNF-α↓ NO↓ Inactivation of MAPK, AKT and NF-κB signaling pathways [ 194 ] Cavidine 42 LPS (3 mg/kg) A549 (10 μg/mL) TNF-α↓ IL-6↓ Inhibition of NF-κB signaling pathway [ 195 ] Corynoline 43 LPS (15 mg/kg) MPO↓ TNF-α↓ IL-1β↓ IL-6↓ Up-regulation of Nrf2 signaling pathway Inactivation of NF-κB signaling pathway [ 196 ] Ukrain 44 I/R (70 mg/kg) TAS↓ TOS↓ OSI↓ None [ 197 ] Tetrahydhydrocoptisine 45 LPS (10 mg/kg) MPO↓ TNF-α↓ IL-6↓ Inhibition of NF-κB signaling pathway [ 198 ] Protostemonine 46 LPS (10 mg/kg) RAW264.7/BMDMs (30 μM) MPO↓ TNF-α↓ IL1-β↓ IL-6↓ iNOS↓ NO↓ Inactivation of MAPK and AKT signaling pathway [ 199 , ...…”

“…This may be related to its inhibition of inflammatory responses via reducing expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, iNOS and NO) in RAW264.7, bone marrow-derived macrophages and ALI mice. Of note, the protective effects of protostemonine were related to inactivation of the MAPK and Akt signaling pathways [ 199 , 200 ].…”

Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury

“…K63 polyubiquitination has an essential role in kinase activation in TLR pathways [20]. MAPKs are a superfamily composed of extracellular signal regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAPK, which are critical in the regulation of inflammation and apoptosis [21,22]. With LPS stimulation, NF-κB is translocated from the cytoplasm to the nucleus and is activated to cause the transcription of pro-inflammatory genes [23].…”