Norisoboldine Attenuates Sepsis-Induced Acute Lung Injury by Modulating Macrophage Polarization <i>via</i> PKM2/HIF-1α/PGC-1α Pathway

Abstract

This study aimed to investigate the effect of norisopoldine (NOR) on acute lung injury in septic mice. Lipopolysaccharide (LPS) was used to establish sepsis induced acute lung injury (ALI) in mice. The dry and wet weight of mice lung was detected, and the pathological changes of lung were observed by hematoxylin and eosin (H&E) staining. Bronchoalveolar lavage fluid (BALF) was detected. Inflammatory factors in BALF were detected by enzyme-linked immunosorbent assay (ELISA). The polarization of macrophages in lung tissue was detected by flow cytometry. The markers of M1 and M2 macrophages were detected by RT-PCR. LPS induced RAW264.7 cells were treated with NOR. Inflammatory response, macrophage polarization, glycolysis, and M2 pyruvate kinase (PKM2)/hypoxia inducible factor-1α (HIF-1α)/peroxisome proliferator activated receptor-γ co-activator 1-α (PGC-1α) signaling pathway were detected. NOR could effectively alleviate sepsis induced ALI, and reduce the number of total cells, total protein concentration, neutrophils, macrophages in BALF. NOR decreased the level of inflammatory factors and promoted macrophages from M1 to M2 type in vivo and vitro. Moreover, NOR could activated PKM2, and inhibited PKM2 from cytoplasm to nuclear, attenuated HIF-1α expression, and increased PGC-1α and peroxisome proliferator-activated receptor (PPAR)-γ expression. In addition, NOR inhibited glycolysis and promoted oxidative phosphorylation in RAW264.7 cells. Furthermore, PKM2 inhibitors could reverse the effect of NOR on PKM2/HIF-1α/PGC-1α signaling pathway in RAW264.7 cells. NOR alleviated sepsis induced AIL in mice, inhibited the inflammatory response, promote M2 polarization of macrophages through regulating PKM2/HIF-1α/PGC-1α signaling pathway.

Unraveling the role of HIF-1α in sepsis: from pathophysiology to potential therapeutics—a narrative review

“…Cynaroside suppresses hepatic inflammation by inhibiting PKM2/HIF-1α interactions, resulting in decreased activation of HIF-1α target genes and facilitating the transition of M1 macrophages to M2 macrophages [ 118 ]. Norisoboldine hinders the translocation of PKM2 from the cytoplasm to the nucleus, reducing HIF-1α expression and mitigating sepsis-induced acute lung injury [ 119 ]. Additionally, resveratrol enhances endothelial nitric oxide synthase (eNOS) expression and lowers HIF-1α levels to enhance vasodilatory function in a septic shock model [ 125 ].…”

A review on the chemical constituents and pharmacological efficacies of Lindera aggregata (Sims) Kosterm

“…For example, NOR could reduce 2,4-dinitrofluorobenzene-induced dermatitis in mice by inhibiting nuclear factor of activated T-cells (NFAT) ( 92 ). It regulates the polarization of macrophages through the M2 pyruvate kinase (PKM2)/hypoxia-inducible factor (HIF-1α)/peroxisome proliferator activated receptor-γ co-activator 1-α (PGC-1α) pathway, thus alleviating sepsis-induced acute lung injury ( 93 ). It can also inhibit the activation of inflammatory bodies of protein 3 associated with nod-like receptor hot protein domain to weaken the colitis induced by 2,4,6-trinitrobenzene sulfonic acid in mice.…”

“…Sesquiterpene dimers are a characteristic class of constituents with C 30 cores in L. aggregata, which are plausibly biosynthesized via the coupling of two identical or different sesquiterpenoid molecules (32). Forty-three dimers have been reported, among which lindenane-type sesquiterpenoid dimers are the most representative structures, such as linderaggrenolides A-N (88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101) and linderanoids H-O (109)(110)(111)(112)(113)(114)(115)(116), where linderaggrenolides A-N have an oxygen bridge (32,33). The remaining dimeric sesquiterpene components, such as linderanoids A-G (102-108), include 3 sesquiterpenoid dimers comprising a lindenane and a noreudesmane unit (102-104); 2 dimers consisting of a lindenane and an eudesmane unit (105)(106), and 2 dimers containing a lindenane and an elemanolide unit (107-108) (33).…”

Cornus iridoid glycoside alleviates sepsis-induced acute lung injury by regulating NF-κB and Nrf2/HO-1 pathways

“…A variety of extracts from traditional Chinese medicine (TCM) have been confirmed to possess protective functions in sepsis-induced ALI, such as steroid ruscogenin extracted from Ophiopogon japonicus (L.f.) Ker-Gawl., 27 artesunate extracted from Artemisia annua L., 28 and norisopoldine (NOR) extracted from Lindera aggregata (Sims) Kosterm. 29 Moreover, loganin, one of the best-known iridoid glycosides extracted from Corni Fructus, has been proven to mitigate the sepsis-induced ALI in CLP-induced mice. 30 Our results revealed that CIG reduced the CLP-induced W/D ratio, which indicated that CIG improved pulmonary edema.…”