Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway

Li, Lifu; Lee, Chung-Shu; Lin, Changwei; Chen, Ning‐Hung; Chuang, Li‐Pang; Hung, Cheng‐Chieh; Liu, Yung-Yang

doi:10.1371/journal.pone.0172571

Cited by 18 publications

(12 citation statements)

References 51 publications

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“…MMP-9) [ 48 ]. In addition, HDAC4 inhibition has been shown to prevent increases in MMP-9 and hence EMT in a mouse model of bleomycin-induced acute lung injury [ 50 ]. MMP-9 was reported to be increased in the airways of asthmatics and to play important multiple roles in tissue remodeling by degrading the extracellular matrix, and inducing inflammation [ 51 , 52 ].…”

Section: Resultsmentioning

confidence: 99%

“…Blocking HDAC4 reported to suppress TGF-ß1 associated inductions of α-smooth muscle actin, fibronectin and vimentin while restore TGF-ß1 related suppression of E-cadherin and TGF-ß1 induced migration of lung epithelial cells [ 49 ]. In addition, inhibiting HDAC4 suppressed MMP-9 elevation and hence EMT in a mouse model of bleomycin-induced acute lung injury [ 50 ]. Hence, MMP-9 is an important downstream factor of both CD147 and HDAC4 activity that is associated with tissue remodeling directly and via EMT processes.…”

Section: Discussionmentioning

confidence: 99%

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Influenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics

et al. 2018

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BackgroundSpecific microRNAs (miRNAs) play essential roles in airway remodeling in asthma. Infection with influenza A virus (IAV) may also magnify pre-existing airway remodeling leading to asthma exacerbation. However, these events remain to be fully defined. We investigated the expression of miRNAs with diverse functions including proliferation (miR-20a), differentiation (miR-22) or innate/adaptive immune responses (miR-132) in primary bronchial epithelial cells (pBECs) of asthmatics following infection with the H1N1 strain of IAV.MethodspBECs from subjects (n = 5) with severe asthma and non-asthmatics were cultured as submerged monolayers or at the air-liquid-interface (ALI) conditions and incubated with IAV H1N1 (MOI 5) for up to 24 h. Isolated miRNAs were subjected to Taqman miRNAs assays. We confirmed miRNA targets using a specific mimic and antagomir. Taqman mRNAs assays and immunoblotting were used to assess expression of target genes and proteins, respectively.ResultsAt baseline, these miRNAs were expressed at the same level in pBECs of asthmatics and non-asthmatics. After 24 h of infection, miR-22 expression increased significantly which was associated with the suppression of CD147 mRNA and HDAC4 mRNA and protein expression in pBECs from non-asthmatics, cultured in ALI. In contrast, miR-22 remained unchanged while CD147 expression increased and HDAC4 remained unaffected in cells from asthmatics. IAV H1N1 mediated increases in SP1 and c-Myc transcription factors may underpin the induction of CD147 in asthmatics.ConclusionThe different profile of miR-22 expression in differentiated epithelial cells from non-asthmatics may indicate a self-defense mechanism against aberrant epithelial responses through suppressing CD147 and HDAC4, which is compromised in epithelial cells of asthmatics.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0851-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Influenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics

et al. 2018

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“…Trichostatin A, a histone deacetylase inhibitor, is an antifungal antibiotic. In addition to its antibiotic properties, trichostatin A alleviated EMT in bleomycin‐induced lung injury in mice via inhibiting the Akt signaling pathway …”

Section: Small Molecules Against Emtmentioning

confidence: 97%

“…In addition to its antibiotic properties, trichostatin A alleviated EMT in bleomycininduced lung injury in mice via inhibiting the Akt signaling pathway. 60 Ubenimex inhibits multiple proteases, including arginyl aminopeptidase, leukotriene A 4 hydrolase, alanyl aminopeptidase, and leucyl/cysteinyl aminopeptidase, a membrane dipeptidase used to treat acute myelocytic leukemia and lymphedema. Ubenimex alleviated acquired sorafenib (a first-line anticancer drug) resistance in renal cell carcinoma via suppressing the Akt pathway.…”

Section: Akt Signaling Pathwaymentioning

confidence: 99%

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Feng

Chen

Vaziri

et al. 2019

Medicinal Research Reviews

109

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Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial‐mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc‐finger E‐box‐binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor‐β1, RAC‐α serine/threonine‐protein kinase, Wnt, nuclear factor‐kappa B, peroxisome proliferator‐activated receptor, Notch, and RAS), RNA‐binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

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“…Since Nrf2 and NF-κB are transcription factors, these data would suggest that myricitrin regulates cardiac gene expression through the regulation of intracellular signaling cascades. HDAC inhibitors have previously been shown to regulate Akt [ 162 ], MAPK phosphorylation [ 50 , 51 ] and NF-κB [ 131 ]. Only one report to date, however, has shown myricetin and myricitrin regulated lysine acetylation through HDAC inhibition [ 119 ].…”

Section: Phytochemicalsmentioning

confidence: 99%

Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure

Evans

Ferguson

2018

Nutrients

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Approximately 5.7 million U.S. adults have been diagnosed with heart failure (HF). More concerning is that one in nine U.S. deaths included HF as a contributing cause. Current HF drugs (e.g., β-blockers, ACEi) target intracellular signaling cascades downstream of cell surface receptors to prevent cardiac pump dysfunction. However, these drugs fail to target other redundant intracellular signaling pathways and, therefore, limit drug efficacy. As such, it has been postulated that compounds designed to target shared downstream mediators of these signaling pathways would be more efficacious for the treatment of HF. Histone deacetylation has been linked as a key pathogenetic element for the development of HF. Lysine residues undergo diverse and reversible post-translational modifications that include acetylation and have historically been studied as epigenetic modifiers of histone tails within chromatin that provide an important mechanism for regulating gene expression. Of recent, bioactive compounds within our diet have been linked to the regulation of gene expression, in part, through regulation of the epi-genome. It has been reported that food bioactives regulate histone acetylation via direct regulation of writer (histone acetyl transferases, HATs) and eraser (histone deacetylases, HDACs) proteins. Therefore, bioactive food compounds offer unique therapeutic strategies as epigenetic modifiers of heart failure. This review will highlight food bio-actives as modifiers of histone deacetylase activity in the heart.

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Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway

Cited by 18 publications

References 51 publications

Influenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics

Influenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure

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