N6-methyladenosine modification: Regulatory mechanisms and therapeutic potential in sepsis

Wang, Wei; Wang, Huaili; Sun, Tongwen

doi:10.1016/j.biopha.2023.115719

Cited by 6 publications

(1 citation statement)

References 85 publications

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“…Inhibition of METTL3 may potentially exhibit anti-apoptotic and protective effects against acute lung injury (ALI) by restoring the expression of neprilysin. Conversely, increasing the levels of METTL3 in mouse lungs demonstrated a preventive effect on LPS-induced ALI and decreased the synthesis of pro-inflammatory cytokines [ 31 ]. Previous studies, along with our own findings, propose that modulating m6A modification through adjustments in METTL3 levels could present a promising therapeutic approach for managing ALI.…”

Section: Discussionmentioning

confidence: 99%

METTL3-m6A methylation inhibits the proliferation and viability of type II alveolar epithelial cells in acute lung injury by enhancing the stability and translation efficiency of Pten mRNA

Wang,

Shen,

Luo

et al. 2024

Respir Res

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Background The pathogenesis of acute lung injury (ALI) involves a severe inflammatory response, leading to significant morbidity and mortality. N6-methylation of adenosine (m6A), an abundant mRNA nucleotide modification, plays a crucial role in regulating mRNA metabolism and function. However, the precise impact of m6A modifications on the progression of ALI remains elusive. Methods ALI models were induced by either intraperitoneal injection of lipopolysaccharide (LPS) into C57BL/6 mice or the LPS-treated alveolar type II epithelial cells (AECII) in vitro. The viability and proliferation of AECII were assessed using CCK-8 and EdU assays. The whole-body plethysmography was used to record the general respiratory functions. M6A RNA methylation level of AECII after LPS insults was detected, and then the “writer” of m6A modifications was screened. Afterwards, we successfully identified the targets that underwent m6A methylation mediated by METTL3, a methyltransferase-like enzyme. Last, we evaluated the regulatory role of METTL3-medited m6A methylation at phosphatase and tensin homolog (Pten) in ALI, by assessing the proliferation, viability and inflammation of AECII. Results LPS induced marked damages in respiratory functions and cellular injuries of AECII. The m6A modification level in mRNA and the expression of METTL3, an m6A methyltransferase, exhibited a notable rise in both lung tissues of ALI mice and cultured AECII cells subjected to LPS treatment. METTL3 knockdown or inhibition improved the viability and proliferation of LPS-treated AECII, and also reduced the m6A modification level. In addition, the stability and translation of Pten mRNA were enhanced by METTL3-mediated m6A modification, and over-expression of PTEN reversed the protective effect of METTL3 knockdown in the LPS-treated AECII. Conclusions The progression of ALI can be attributed to the elevated levels of METTL3 in AECII, as it promotes the stability and translation of Pten mRNA through m6A modification. This suggests that targeting METTL3 could offer a novel approach for treating ALI.

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Section: Discussionmentioning

confidence: 99%

METTL3-m6A methylation inhibits the proliferation and viability of type II alveolar epithelial cells in acute lung injury by enhancing the stability and translation efficiency of Pten mRNA

Wang,

Shen,

Luo

et al. 2024

Respir Res

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Molecular mechanism of ALKBH5‐mediated m6A demethylation regulating lipopolysaccharide‐induced epithelial–mesenchymal transition in sepsis‐induced acute kidney injury

Zhao,

Chen,

Chen

et al. 2024

The Kaohsiung J of Med Scie

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This study explored the mechanism by which the m6A demethylase ALKBH5 mediates epithelial–mesenchymal transition (EMT) in sepsis‐associated acute kidney injury (SA‐AKI) and AKI‐chronic kidney disease (CKD) transition. HK‐2 cells were stimulated with lipopolysaccharide (LPS) to establish an in vitro model of SA‐AKI. ALKBH5 expression was reduced through the transfection of si‐ALKBH5. Cell viability, apoptosis, and migration were detected by CCK‐8 assay, TUNEL staining, and Transwell. The levels of TNF‐α, IL‐1β, and IL‐6 were measured by enzyme‐linked immunosorbent assay. Quantitative real‐time polymerase chain reaction or Western blotting was performed to determine the expressions of ALKBH5, miR‐205‐5p, DDX5, E‐cadherin, and α‐SMA. The m6A level was quantitatively analyzed. The expression of pri‐miR‐205 bound to DGCR8 and m6A‐modified pri‐miR‐205 after intervention with ALKBH5 expression was detected by RNA immunoprecipitation. A dual‐luciferase assay confirmed the binding between miR‐205‐5p and DDX5. ALKBH5 was highly expressed in LPS‐induced HK‐2 cells. Inhibition of ALKBH5 increased cell viability, repressed apoptosis, and reduced EMT. Inhibition of ALKBH5 increased the m6A modification level, thereby promoting DGCR8 binding to pri‐miR‐205 to increase miR‐205‐5p expression and eventually targeting DDX5 expression. Low expression of miR‐205‐5p or overexpression of DDX5 partially abolished the inhibitory effect of ALKBH5 silencing on EMT. In conclusion, ALKBH5 represses miR‐205‐5p expression by removing m6A modification to upregulate DDX5 expression, thereby promoting EMT and AKI‐CKD transition after SA‐AKI.

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Curcumin‐induced exosomal FTO from bone marrow stem cells alleviates sepsis‐associated acute kidney injury by modulating the m6A methylation of OXSR1

Yang,

Yu,

Xie

2024

The Kaohsiung J of Med Scie

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Curcumin and bone marrow stem cells (BMSCs)‐derived exosomes are considered to be useful for the treatment of many human diseases, including sepsis‐associated acute kidney injury (SA‐AKI). However, the role and underlying molecular mechanism of curcumin‐loaded BMSCs‐derived exosomes in the progression of SA‐AKI remain unclear. Exosomes (BMSCs‐EXOCurcumin or BMSCs‐EXOControl) were isolated from curcumin or DMSO‐treated BMSCs, and then co‐cultured with LPS‐induced HK2 cells. Cell proliferation and apoptosis were determined by cell counting kit 8 (CCK8) assay, 5‐ethynyl‐2‐deoxyuridine (EdU) assay, and flow cytometry. Enzyme‐linked immunosorbent assay (ELISA) was used for examining inflammatory factors. The levels of SOD, MDA, and ROS were tested to assess oxidative stress. The levels of fat mass and obesity‐associated protein (FTO) and oxidative stress responsive 1 (OXSR1) were detected by quantitative real‐time PCR and western blot. Methylated RNA immunoprecipitation (MeRIP) assay and RNA immunoprecipitation (RIP) assay were used for measuring the interaction between FTO and OXSR1. BMSCs‐EXOCurcumin treatment could inhibit LPS‐induced HK2 cell apoptosis, inflammation, and oxidative stress. FTO was downregulated in SA‐AKI patients and LPS‐induced HK2 cells, while was upregulated in BMSCs‐EXOCurcumin. Exosomal FTO from curcumin‐induced BMSCs suppressed apoptosis, inflammation, and oxidative stress in LPS‐induced HK2 cells. FTO decreased OXSR1 expression through m6A modification, and the inhibitory effect of FTO on LPS‐induced HK2 cell injury could be eliminated by OXSR1 overexpression. In animal experiments, BMSCs‐EXOCurcumin alleviated kidney injury in SA‐AKI mice models by regulating FTO/OXSR1 axis. In conclusion, exosomal FTO from curcumin‐induced BMSCs reduced OXSR1 expression to alleviate LPS‐induced HK2 cell injury and improve kidney function in CLP‐induced mice models, providing a new target for SA‐AKI.

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N6-methyladenosine modification: Regulatory mechanisms and therapeutic potential in sepsis

Cited by 6 publications

References 85 publications

METTL3-m6A methylation inhibits the proliferation and viability of type II alveolar epithelial cells in acute lung injury by enhancing the stability and translation efficiency of Pten mRNA

METTL3-m6A methylation inhibits the proliferation and viability of type II alveolar epithelial cells in acute lung injury by enhancing the stability and translation efficiency of Pten mRNA

Molecular mechanism of ALKBH5‐mediated m6A demethylation regulating lipopolysaccharide‐induced epithelial–mesenchymal transition in sepsis‐induced acute kidney injury

Curcumin‐induced exosomal FTO from bone marrow stem cells alleviates sepsis‐associated acute kidney injury by modulating the m6A methylation of OXSR1

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