Metformin intervention ameliorates AS in ApoE-/- mice through restoring gut dysbiosis and anti-inflammation

Ning, Yan; Wang, Limin; Li, Yiwei; Wang, Ting; Yang, Libo; Yan, Rong; Wang, Hao; Jia, Shanshan

doi:10.1371/journal.pone.0254321

Cited by 18 publications

(20 citation statements)

References 85 publications

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“…We also found a marked alteration in levels of Romboutsia, with WTD-fed mice showing an increase vs. chow-fed mice, while mice fed with WTD + Miltefosine showed marked reduction in Romboutsia levels vs. WTD-fed mice. Previous studies have shown a differential abundance of Enterobacteriaceae, Bacteroides, and Romboutsia in atherosclerosis [51][52][53][54] . One of the mechanisms by which Miltefosine can alter gut microbiota is via its antibacterial properties 8 .…”

Section: Discussionmentioning

confidence: 87%

“…Given that Miltefosine had been used in humans for decades, it can be potentially used in lower doses as a stand-alone or as an adjuvant to LDL lowering therapies to treat inflammatory diseases such as atherosclerosis. In support of Miltefosine as a potential anti-atherosclerotic molecule, previous studies have shown that alterations in gut microbial species, either via dietary interventions with chemical compounds such as Metformin and resveratrol or via gavage inoculation, can impact the progression of atherosclerosis 51,54,56,57 .…”

Section: Discussionmentioning

confidence: 99%

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Miltefosine attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice

Traughber

Iacano

Khan

et al. 2022

Preprint

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Excess cholesterol induces foam cell formation, NLRP3 inflammasome activation, and IL-1β release in atherosclerotic plaques. We have shown previously that Miltefosine increased cholesterol release and dampened NLRP3 inflammasome assembly in macrophages. Here, we show that Miltefosine reduced LPS-induced choline uptake by macrophages and attenuated NLRP3 inflammasome assembly in mice. Miltefosine-fed mice showed reduced plasma IL-1β in a polymicrobial cecal slurry injection model of systemic inflammation. Miltefosine-fed mice showed increased reverse cholesterol transport from macrophages to plasma, liver, and feces. Hyperlipidemic apoE-/- mice fed with Miltefosine showed significantly reduced weight gain and markedly reduced atherosclerotic lesions vs. control mice. 16S rDNA sequencing and analysis showed alterations in the gut microbiota profile of Miltefosine-fed hyperlipidemic apoE-/- vs. control mice, with the most notable changes in Romboutsia and Bacteroidetes species. Taken together, these data indicate that Miltefosine causes pleiotropic effects on lipid metabolism, inflammasome activity, atherosclerosis, and the gut microbiota.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Miltefosine attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice

Traughber

Iacano

Khan

et al. 2022

Preprint

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“…In this study, we found that phyla Bacteriodetes and Firmicutes were kept predominantly in diverse groups, which are paralleled with previous studies ( 18 , 23 , 32 ). An increase in Firmicutes / Bacteriodetes ratio is closely related to chronic metabolic diseases [( 24 , 25 , 41 )]. In this study, the increased ratio of Firmicutes / Bacteriodetes in AS was rectified by the dietary FO administration, suggesting that FO could markedly modulate the gut microbiota by decreasing the predominant Firmicutes / Bacteriodetes in phylum level ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

Dietary α-Linolenic Acid-Rich Flaxseed Oil Ameliorates High-Fat Diet-Induced Atherosclerosis via Gut Microbiota-Inflammation-Artery Axis in ApoE−/− Mice

Liu

et al. 2022

Front. Cardiovasc. Med.

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Atherosclerosis (AS) is closely associated with abnormally chronic low-grade inflammation and gut dysbiosis. Flaxseed oil (FO) rich in omega-3 polyunsaturated fatty acids (PUFAs), which are mainly composed of alpha-linolenic acid (ALA, 18:3 omega-3), has been demonstrated to exhibit pleiotropic benefits in chronic metabolic diseases. However, the impact of dietary ALA-rich FO on AS and its associated underlying mechanisms remain poorly understood. Thus, the present study was designed as two phases to investigate the effects in atherosclerotic Apolipoprotein E (ApoE)−/− mice. In the initial portion, the ApoE−/− mice were randomly allocated to three groups: control group (CON), model group (MOD), and FO-fed model group (MOD/FO) and were treated for 12 weeks. The second phase used antibiotic (AB)-treated ApoE−/− mice were divided into two groups: AB-treated model group (AB/MOD) and FO-fed AB-treated model group (AB/FO). In the results, the dietary ALA-rich FO administration ameliorated atherosclerotic lesion, as well as the parameters of AS (body weights (BWs) and the total bile acids (TBA). Chronic systemic/vascular inflammatory cytokines and in situ macrophages (Mψs) were reduced with FO intervention. In addition, the FO improved the gut integrity and permeability by decreasing the plasma lipopolysaccharide (LPS). Moreover, gut dysbiosis and metabolites [short-chain fatty acids (SCFAs) and bile acids (BAs)] in AS were modulated after FO treatment. Intriguingly, during an AB-treated condition, a significantly weakened amelioration of FO-treated on AS proposed that the intestinal microbiota contributed to the FO effects. A correlation analysis showed close relationships among gut bacteria, metabolites, and inflammation. Collectively, these results suggested that the dietary ALA-rich FO ameliorated the AS in ApoE−/− mice via the gut microbiota-inflammation-artery axis.

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“…It is extremely necessary to investigate the mechanism of RILI, and develop new drugs. NaB has been reported, by a large number of studies, that exerts potential activities of anti-radiation toxicity ( 11 , 12 ), anti-inflammation ( 45 – 47 ), immunomodulation ( 48 , 49 ), and anti-tumor ( 50 – 52 ). The anti-lung cancer effect of NaB has been proved in our preliminary study ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations

et al. 2022

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BackgroundRadiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC) ,and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiation toxicity. However, the mechanism of the protective effect of NaB against RILI has not yet been clarified. This study aimed to explore the underlying protective mechanisms of NaB against RILI in NSCLC through network pharmacology, molecular docking, molecular dynamic simulations and in vivo experiments.MethodsThe predictive target genes of NaB were obtained from the PharmMapper database and the literature review. The involved genes of RILI and NSCLC were predicted using OMIM and GeneCards database. The intersectional genes of drug and disease were identified using the Venny tool and uploaded to the Cytoscape software to identify 5 core target genes of NaB associated with RILI. The correlations between the 5 core target genes and EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors were analyzed using TIMER 2.0, TIMER and TISIDB databases. We constructed the mechanism maps of the 3 key signaling pathways using the KEGG database based on the results of GO and KEGG analyses from Metascape database. The 5 core target genes and drug were docked using the AutoDock Vina tool and visualized using PyMOL software. GROMACS software was used to perform 100 ns molecular dynamics simulation. Irradiation-induced lung injury model in mice were established to assess the therapeutic effects of NaB.ResultsA total of 51 intersectional genes involved in NaB against RILI in NSCLC were identified. The 5 core target genes were AKT1, TP53, NOTCH1, SIRT1, and PTEN. The expressions of the 5 core target genes were significantly associated with EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors, respectively. The results from GO analysis of the 51 intersectional genes revealed that the biological processes were focused on the regulation of smooth muscle cell proliferation, oxidative stress and cell death, while the three key KEGG pathways were enriched in PI3K-Akt signal pathway, p53 signal pathway, and FOXO signal pathway. The docking of NaB with the 5 core target genes showed affinity and stability, especially AKT1. In vivo experiments showed that NaB treatment significantly protected mice from RILI, with reduced lung histological damage. In addition, NaB treatment significantly inhibited the PI3K/Akt signaling pathway.ConclusionsNaB may protect patients from RILI in NSCLC through multiple target genes including AKT1, TP53, NOTCH1, SIRT1 and PTEN, with multiple signaling pathways involving, including PI3K-Akt pathway, p53 pathway, and FOXO pathways. Our findings effectively provide a feasible theoretical basis to further elucidate the mechanism of NaB in the treatment of RILI.

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Metformin intervention ameliorates AS in ApoE-/- mice through restoring gut dysbiosis and anti-inflammation

Cited by 18 publications

References 85 publications

Miltefosine attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice

Miltefosine attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice

Dietary α-Linolenic Acid-Rich Flaxseed Oil Ameliorates High-Fat Diet-Induced Atherosclerosis via Gut Microbiota-Inflammation-Artery Axis in ApoE−/− Mice

Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations

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