MaiJiTong granule attenuates atherosclerosis by reducing ferroptosis via activating STAT6-mediated inhibition of DMT1 and SOCS1/p53 pathways in LDLR-/- mice.

BACKGROUND AND PURPOSE: Atherosclerosis is the primary pathological basis of cardiovascular disease. Ferroptosis is a regulated form of cell death, a process of lipid peroxidation driven by iron, which can initiate and promote atherosclerosis. STAT6 is a signal transducer that shows a potential role in regulating ferroptosis, but, the exact role in ferroptosis during atherogenesis remains unclear. The Traditional Chinese Medicine Maijitong granule (MJT) is used for treating cardiovascular disease and shows a potential inhibitory effect on ferroptosis. However, the antiatherogenic effect and the underlying mechanism remain unclear. In this study, we determined the role of STAT6 in ferroptosis during atherogenesis, investigated the antiatherogenic effect of MJT, and determined whether its antiatherogenic effect was dependent on the inhibition of ferroptosis. METHODS: 8-week-old male LDLR-/- mice were fed a high-fat diet (HFD) at 1st and 10th week, respectively, to assess the preventive and therapeutic effects of MJT on atherosclerosis and ferroptosis. Simultaneously, the anti-ferroptotic effects and mechanism of MJT were determined by evaluating the expression of genes responsible for lipid peroxidation and iron metabolism. Subsequently, we reanalyzed microarray data in the GSE28117 obtained from cells after STAT6 knockdown or overexpression and analyzed the correlation between STAT6 and ferroptosis. Finally, the STAT6-/- mice were fed HFD and injected with AAV-PCSK9 to validate the role of STAT6 in ferroptosis during atherogenesis and revealed the antiatherogenic and anti-ferroptotic effect of MJT. RESULTS: MJT attenuated atherosclerosis by reducing plaque lesion area and enhancing plaque stability in both preventive and therapeutic groups. MJT reduced inflammation via suppressing inflammatory cytokines and inhibited foam cell formation by lowering the LDL level and promoting ABCA1/G1-mediated lipid efflux. MJT ameliorated the ferroptosis by reducing lipid peroxidation and iron dysregulation during atherogenesis. Mechanistically, STAT6 negatively regulated ferroptosis by transcriptionally suppressing SOCS1/p53 and DMT1 pathways. MJT suppressed the DMT1 and SOCS1/p53 via stimulating STAT6 phosphorylation. In addition, STAT6 knockout exacerbated atherosclerosis and ferroptosis, which abolished the antiatherogenic and anti-ferroptotic effects of MJT. CONCLUSION: STAT6 acts as a negative regulator of ferroptosis and atherosclerosis via transcriptionally suppressing DMT1 and SOCS1 expression and MJT attenuates atherosclerosis and ferroptosis by activating the STAT6-mediated inhibition of DMT1 and SOCS1/p53 pathways, which indicated that STAT6 acts a novel promising therapeutic target to ameliorate atherosclerosis by inhibiting ferroptosis and MJT can serve as a new therapy for atherosclerosis treatment.

Shegan Mahuang Decoction May Reduce Airway Inflammation in Neutrophilic Asthmatic Mice by Improving the Mitochondrial Function of Bronchoalveolar Lavage Fluid Exosomes.

Asthma is a common pulmonary disease mainly caused by the infiltration of neutrophils. There is a limit to the therapeutic effects of the available asthma drugs on neutrophilic asthma. Shegan Mahuang Decoction (SMD) is one of the representative traditional Chinese medicine (TCM) prescriptions for asthma, and it can effectively relieve the clinical symptoms of patients. However, the effect of SMD on the treatment of neutrophilic asthma remains unknown. In this study, a mouse model of neutrophilic asthma induced by lipopolysaccharide (LPS)/ovalbumin (OVA) was established, and the effect of a modified SMD prescription on the model was evaluated. After treatment, SMD was demonstrated to be therapeutically effective on asthmatic mice via airway resistance detection and lung pathology and was able to affect cytokine levels in vivo. Further experiments verified that SMD regulated the expression of mitochondrial function proteins in bronchoalveolar lavage fluid (BALF) exosomes. The results demonstrate that SMD confers a therapeutic effect on a neutrophilic asthma mouse model, and it may reduce neutrophil airway inflammation by regulating myeloid-derived regulatory cell (MDRC) function and airway exosome mitochondrial function.

[Flavonoids of Erigeron canadensis].

OBJECTIVE: To study the flavonoids of Erigeron canadensis. METHOD: The constituents of EtOH extraction from the whole plant of E. canadensis were isolated and purified by repeated column chromatography. These compounds were identified by their physical and spectral data. RESULT: Twelve flavonoids were isolated and identified as quercetin-7-O-beta-D-galactopyranoside(1),quercetin(2), luteolin(3), apigenin(4),5,7,4'-trihydroxy-3'-methoxy flavone(5), quercetin-3-alpha-rhamnopyranoside(6), quercetin-3-O-beta-D-glucopyranoside(7), apigenin-7-O-beta-D-glucopyranoside(8), luteolin-7-O-beta-D-glucuronide methyl ester(9),4'-hydroxy baicalein-7-O-beta-D-glucopyranoside(10),baicalein(11),rutin(12). CONCLUSION: Compound 1 was isolated from the Compositae family for the first time. Compound 5 and 9 were firstly isolated from the genus Erigeron. Compound 3,4,7,8 and 11 were isolated from E. canadensis for the first time.

Construction of recombinant Bacillus subtilis strains for efficient pimelic acid synthesis

As a precursor, pimelic acid plays an important role in biotin biosynthesis pathway of Bacillus subtilis. Fermentations supplemented with pimelic acid could improve the production of biotin, however, with a disadvantage-high cost. So it is necessary to improve the biosynthesis of pimelic acid via genetic engineering in B. subtilis. In this study, we constructed a recombinant B. subtilis strain for improving the synthesis of pimelic acid, in which a maltose-inducible Pglv promoter was inserted into the upstream of the cistron bioI-orf2-orf3 and, meanwhile, flanked by the tandem cistrons via a single crossover event. The copy number of the integrant was amplified by high-concentration resistance screen and increased to 4-5 copies. The production of pimelic acid from multiple copies integrant was about 4 times higher than that from single copy (1017.13 ug/ml VS. 198.89 μg/ml). And when induced by maltose the production of pimelic acid was about 2 times of that under non-induction conditions (2360.73 μg/ml VS. 991.59 ug/ml). Thus, these results demonstrated that the production of pimelic acid was improved obviously through reconstructed B. subtilis. It also suggested that our expression system provided a convenient source of pimelic acid that would potentially lower the cost of production of biotin from engineered B. subtilis.