Ethyl acetate fraction of Thesium chinense Turcz. alleviates chronic obstructive pulmonary disease through inhibition of ferroptosis mediated by activating Nrf2/SLC7A11/GPX4 axis

Article

Author: Wang, Ying-Yue ; Guan, Yue-Qin ; Liu, Ming-Jie ; Wang, Xiao-Ning ; Wen, Xue-Sen ; Shen, Tao ; Li, Guo-Hui ; Xu, Zhen-Peng

ETHNOPHARMACOLOGICAL RELEVANCEThesium chinense Turcz., a traditional Chinese herbal medicine, displays good therapeutic efficiency against respiratory diseases (e.g. pneumonia, pharyngitis) in clinical applications, however, its effects on COPD and the mechanism of action are still unclear.AIM OF THE STUDYThis study aims to investigate the therapeutic effect of the ethyl acetate fraction of Thesium chinense Turcz. (TCEA) on COPD and reveal the underlying mechanism.MATERIALS AND METHODSA cigarette smoke (CS)-induced mouse COPD model was established, and the efficacy of TCEA was evaluated using peripheral blood testing, HE and Masson staining, qRT-PCR and ELISA assays. TCEA was analyzed for chemical composition by LC-MS/MS and HPLC. Prediction of major signaling pathways and potential targets was performed by network pharmacology. The molecular mechanism of TCEA was explored by immunoblotting, immunofluorescence staining, flow cytometry, and ubiquitination assay. Finally, potential active small molecules in TCEA were identified by molecular virtual screening.RESULTSTCEA treatment significantly inhibited the secretion of pro-inflammatory factors and attenuated pathological emphysema. The main chemical constituents of TCEA were identified as flavonoids by UPLC-MS/MS. Network pharmacology analysis enriched the Nrf2 signaling pathway closely related to oxidative stress. Our results suggested that TCEA inhibited ferroptosis by activating Nrf2/SLC7A11/GPX4 axis and inhibiting lipid metabolism-related proteins, ACSL4, ALOX5 and COX2 in vivo and in vitro. Noteworthily, the beneficial impact of TCEA on regulation of SLC7A11 and GPX4 vanished after silencing Nrf2. Moreover, Nrf2 ubiquitination was inhibited by TCEA treatment. Finally, several flavonoids modulating Nrf2 were identified by molecular virtual screening.CONCLUSIONSTCEA significantly alleviated COPD progression by inhibiting ferroptosis primarily through activation of Nrf2/SLC7A11/GPX4 signaling. Flavonoids are the main active components that exert their effects. These findings shed light on the mechanism of action of TCEA and its potential active components, providing a feasible approach for the treatment of COPD.

01 Jan 2025·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Eicosanoid biosynthesizing enzymes in Prototheria

Article

Author: Heydeck, Dagmar ; Kakularam, Kumar R. ; Stehling, Sabine ; Rothe, Michael ; Gündem, Eda ; Kakularam, Kumar R ; Kuhn, Hartmut

Eicosanoids and related compounds are pleiotropic lipid mediators, which play a role in cell differentiation and in the pathogenesis of various diseases. The biosynthesis of these lipids has extensively been studied in highly developed mammals including humans but little is known about the formation of these mediators in more ancient Prototheria. We searched the genomes of two extant prototherian species (platypus, short-beaked echidna) for genes encoding for lipoxygenase- (ALOX) and prostaglandin synthase-isoforms (PTGS) and detected intact single copy genes for ALOX5, ALOX12, ALOX12B, ALOXE3, PTGS1 and PTGS2. Moreover, we identified two copies of ALOX15B genes (ALOX15B-1 and ALOX15B-2) but in echidna the ALOX15B-2 gene was structurally corrupted. Interestingly, in the two genomes ALOX15 genes were lacking. For functional characterization we expressed the prototherian ALOX15B isoforms and compared important enzyme characteristics of the wildtype proteins and of relevant enzyme mutants with those of human and mouse ALOX15B. Here we observed that the prototherian ALOX15B isoforms exhibit the same reaction specificity as their human ortholog. Mutagenesis of the Triad determinants did not alter the reaction specificity of the prototherian enzymes but modification of the Jisaka determinants murinized the catalytic properties. These data indicate that Prototheria exhibit an active eicosanoid metabolism. They express functional ALOX15B orthologs but lack ALOX15 genes. These observations and the previous findings that ALOX15 orthologs rarely occur in non-mammalian vertebrates such as fish and birds suggest that ALOX15 orthologs were introduced during Prototheria-Metatheria transition via an ALOX15B gene duplication and subsequent divergent enzyme evolution.

31 Dec 2024·Journal of Enzyme Inhibition and Medicinal Chemistry

Discovery of new thymol-3,4-disubstituted thiazole hybrids as dual COX-2/5-LOX inhibitors with in vivo proof

Article

Author: El-Miligy, Mostafa M M ; Al-Kubeisi, Ahmed K ; Hazzaa, Aly A ; Nassra, Rasha A ; El-Zemity, Saad R

New thymol-3,4-disubstitutedthiazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 6b, 6d, 6e, and 6f displayed in vitro inhibitory activity against COX-2 (IC₅₀= 0.037, 0.042, 0.046, and 0.039 µM) nearly equal to celecoxib (IC₅₀= 0.045 µM). 6b, 6d, and 6f showed SI (379, 341, and 374, respectively) higher than that of celecoxib (327). 6a-l elicited in vitro 5-LOX inhibitory activity higher than quercetin. 6a-f, 6i-l, 7a, and 7c possessed in vivo inhibition of formalin induced paw edoema higher than celecoxib. 6a, 6b, 6f, 6h-l, and 7b showed gastrointestinal safety profile as celecoxib and diclofenac sodium in the population of fasted rats. Induced fit docking and molecular dynamics simulation predicted good fitting of 6b and 6f without changing the packing and globularity of the apo protein. In conclusion, 6b and 6f achieved the target goal as multitarget inhibitors of inflammation.

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