Activated AMPK by metformin protects against fibroblast proliferation during pulmonary fibrosis by suppressing FOXM1

Gu, Xuan; Han, Yong-Yue; Yang, Chong-Yang; Ji, Hui-min; Lan, Yue-Jiao; Bi, Yu-Qian; Cheng, Zheng; Qu, Jiao; Cheng, Ming; Gao, Jian

doi:10.1016/j.phrs.2021.105844

Cited by 32 publications

(29 citation statements)

References 40 publications

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“…After removing duplicate studies, 285 articles remained, and we performed title and abstract readings to exclude 265 articles, including 238 irrelevant studies, 16 studies whose interventions did not meet inclusion requirements, five literature reviews, three conference abstracts, and three articles for which the full text was not available. The complete manuscripts of the 20 screened studies were then read, and one manuscript with an outcome that did not meet the requirements was excluded ( Kheirollahi et al, 2019 ), resulting in 19 remaining studies ( Huang, 2015 ; Choi et al, 2016 ; Jiang 2016 ; Jian 2017 ; Wang J. et al, 2017 ; Wang Y. et al, 2017 ; Gamad et al, 2018 ; Rangarajan et al, 2018 ; Wu 2018 ; Xiao et al, 2018 ; Farhood et al, 2019 ; Hao et al, 2019 ; Yahyapour et al, 2019 ; Wang et al, 2020 ; Xiao et al, 2020 ; Li et al, 2021a ; Li et al, 2021b ; Cheng et al, 2021 ; Gu et al, 2021 ). Six studies included multiple dose groups.…”

Section: Resultsmentioning

confidence: 99%

Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis

Xiao

Chen

et al. 2022

Front. Pharmacol.

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Background: Pulmonary fibrosis (PF) is a lung disease with no curative drug, characterized by a progressive decrease in lung function. Metformin (MET) is a hypoglycemic agent with the advantages of high safety and low cost and has been used in several in vivo trials to treat fibrotic diseases.Objective: This study aimed to explore the efficacy and safety of MET in treating PF and elaborate on its mechanism.Methods: Eight databases were searched for in vivo animal trials of MET for PF from the time of database creation until 1 March 2022. The risk of bias quality assessment of the included studies was conducted using SYRCLE’s risk of bias assessment. Pulmonary inflammation and fibrosis scores were the primary outcomes of this study. Hydroxyproline (HYP), type I collagen (collagen I), α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), Smad, AMP-activated protein kinase (AMPK), and extracellular signal–regulated kinase (ERK) protein expression in lung tissues and animal mortality were secondary outcomes. Effect magnitudes were combined and calculated using Revman 5.3 and Stata 16.0 to assess the efficacy and safety of MET in animal models of PF. Inter-study heterogeneity was examined using the I2 or Q test, and publication bias was assessed using funnel plots and Egger’s test.Results: A total of 19 studies involving 368 animals were included, with a mean risk of bias of 5.9. The meta-analysis showed that MET significantly suppressed the level of inflammation and degree of PF in the lung tissue of the PF animal model. MET also reduced the content of HYP, collagen I, α-SMA, and TGF-β and phosphorylation levels of Smad2, Smad3, p-smad2/3/smad2/3, ERK1/2, and p-ERK1/2/ERK1/2 in lung tissues. MET also elevated AMPK/p-AMPK levels in lung tissues and significantly reduced animal mortality.Conclusion: The results of this study suggest that MET has a protective effect on lung tissues in PF animal models and may be a potential therapeutic candidate for PF treatment.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=327285, identifier CRD42022327285.

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Section: Resultsmentioning

confidence: 99%

Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis

Xiao

Chen

et al. 2022

Front. Pharmacol.

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“…This finding suggests that AC125807.2-201 could be acting as a topological anchor point RNA (tapRNA), a recently proposed class of lncRNAs which are located at chromatin anchor points and on the border of TADs, regulating their activity [ 43 ]. Interestingly, FOXM1 previously was found to be downregulated in metformin-treated cells [ 46 , 47 , 48 ]. Our results suggest that AC125807.2-201 may act as a regulator for FOXM1-202 expression in a cis-acting manner.…”

Section: Resultsmentioning

confidence: 99%

Metformin Treatment Modulates Long Non-Coding RNA Isoforms Expression in Human Cells

Conceição

Dias

Queiroz

et al. 2022

ncRNA

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Long noncoding RNAs (lncRNAs) undergo splicing and have multiple transcribed isoforms. Nevertheless, for lncRNAs, as well as for mRNA, measurements of expression are routinely performed only at the gene level. Metformin is the first-line oral therapy for type 2 diabetes mellitus and other metabolic diseases. However, its mechanism of action remains not thoroughly explained. Transcriptomic analyses using metformin in different cell types reveal that only protein-coding genes are considered. We aimed to characterize lncRNA isoforms that were differentially affected by metformin treatment on multiple human cell types (three cancer, two non-cancer) and to provide insights into the lncRNA regulation by this drug. We selected six series to perform a differential expression (DE) isoform analysis. We also inferred the biological roles for lncRNA DE isoforms using in silico tools. We found the same isoform of an lncRNA (AC016831.6-205) highly expressed in all six metformin series, which has a second exon putatively coding for a peptide with relevance to the drug action. Moreover, the other two lncRNA isoforms (ZBED5-AS1-207 and AC125807.2-201) may also behave as cis-regulatory elements to the expression of transcripts in their vicinity. Our results strongly reinforce the importance of considering DE isoforms of lncRNA for understanding metformin mechanisms at the molecular level.

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“…PF animal model was established by intratracheal injection of 4.5 mg/kg BLM (Anhui Pharmaceutical Co, Anhui, China) as described previously, and the control group was injected with equal volume of normal saline [ 21 , 22 ]. For drug treatment, MT (5 mg·kg −1 ·d −1 ) was administered every day by intraperitoneal injection (ip).…”

Section: Methodsmentioning

confidence: 99%

Melatonin ameliorates bleomycin-induced pulmonary fibrosis via activating NRF2 and inhibiting galectin-3 expression

Lan

Cheng

et al. 2022

Acta Pharmacol Sin

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Pulmonary fibrosis (PF) is a chronic interstitial lung disease with no effective therapies. Galectin-3 (Gal-3), a marker of oxidative stress, plays a key role in the pathogenesis of PF. Fibroblast-myofibroblast differentiation (FMD) is an important source of fibrotic cells in PF. Previous studies showed that melatonin (MT) exerted anti-fibrotic effect in many diseases including PF through its antioxidant activity. In the present study we investigated the relationships among Gal-3, NRF2, ROS in FMD and their regulation by MT. We established an in vitro model of FMD in TGF-β1-treated human fetal lung fibroblast1 (HFL1) cells and a PF mouse model via bleomycin (BLM) intratracheal instillation. We found that Gal-3 expression was significantly increased both in vitro and in vivo. Knockdown of Gal-3 in HFL1 cells markedly attenuated TGF-β1-induced FMD process and ROS accumulation. In TGF-β1-treated HFL1 cells, pretreatment with NRF2-specific inhibitor ML385 (5 μM) significantly increased the levels of Gal-3, α-SMA and ROS, suggesting that the expression of Gal-3 was regulated by NRF2. Treatment with NRF2-activator MT (250 μM) blocked α-SMA and ROS accumulation accompanied by reduced Gal-3 expression. In BLM-induced PF model, administration of MT (5 mg·kg −1 ·d −1 , ip for 14 or 28 days) significantly attenuated the progression of lung fibrosis through up-regulating NRF2 and down-regulating Gal-3 expression in lung tissues. These results suggest that Gal-3 regulates TGF-β1-induced pro-fibrogenic responses and ROS production in FMD, and MT activates NRF2 to block FMD process by down-regulating Gal-3 expression. This study provides a useful clue for a clinical strategy to prevent PF. Graphic abstract of the mechanisms. MT attenuated BLM-induced PF via activating NRF2 and inhibiting Gal-3 expression.

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Activated AMPK by metformin protects against fibroblast proliferation during pulmonary fibrosis by suppressing FOXM1

Cited by 32 publications

References 40 publications

Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis

Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis

Metformin Treatment Modulates Long Non-Coding RNA Isoforms Expression in Human Cells

Melatonin ameliorates bleomycin-induced pulmonary fibrosis via activating NRF2 and inhibiting galectin-3 expression

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