High glucose induces tau hyperphosphorylation in hippocampal neurons via inhibition of ALKBH5-mediated Dgkh m6A demethylation: a potential mechanism for diabetic cognitive dysfunction DOI Creative Commons

Minli Qu,

L. Zuo,

Mengru Zhang

et al.

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(6)

Published: June 29, 2023

Abstract Tau hyperphosphorylation in hippocampal neurons has an important pathogenetic role the development of diabetic cognitive dysfunction. N 6 -methyladenosine (m A) methylation is most common modification eukaryotic mRNA and involved regulating diverse biological processes. However, m A alteration tau hippocampus not been reported. We found lower ALKBH5 expression rats HN-h cells with high-glucose intervention, accompanied by hyperphosphorylation. overexpression significantly reversed high-glucose-stimulated cells. Furthermore, we confirmed A–mRNA epitope transcriptome microarray RNA sequencing coupled methylated immunoprecipitation that regulates Dgkh mRNA. High glucose inhibited demethylation ALKBH5, resulting decreases protein levels. Overexpression after stimulation. adenovirus suspension injection into bilateral ameliorated In addition, targeted to activate PKC-α, leading under conditions. The results this study reveal high suppresses which downregulates leads through activation PKC-α neurons. These findings may indicate a new mechanism novel therapeutic target for

Language: Английский

Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation DOI Creative Commons
Shengnan Chen, Bo Li, Lei Chen

et al.

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: June 12, 2023

Abstract Background Diabetic kidney disease (DKD) has been the leading cause of chronic in developed countries. Evidence benefits resveratrol (RES) for treatment DKD is accumulating. However, comprehensive therapeutic targets and underlying mechanisms through which RES exerts its effects against are limited. Methods Drug were obtained from Drugbank SwissTargetPrediction Databases. Disease DisGeNET, Genecards, Therapeutic Target Database. identified by intersecting drug targets. GO functional enrichment analysis, KEGG pathway association analysis performed using DAVID database visualized Cytoscape software. Molecular docking validation binding capacity between was UCSF Chimera software SwissDock webserver. The high glucose (HG)-induced podocyte injury model, RT-qPCR, western blot used to verify reliability on target proteins. Results After intersection 86 566 targets, 25 obtained. And proteins classified into 6 categories. A total 11 cellular components terms 27 diseases, top 20 enriched biological processes, molecular functions, pathways potentially involved action recorded. studies showed that had a strong affinity toward PPARA, ESR1, SLC2A1, SHBG, AR, AKR1B1, PPARG, IGF1R, RELA, PIK3CA, MMP9, AKT1, INSR, MMP2, TTR, CYP2C9 domains. HG-induced model successfully constructed validated RT-qPCR blot. able reverse abnormal gene expression INSR. Conclusions may INSR domains act as agent DKD. These findings comprehensively reveal potential provide theoretical bases clinical application

Language: Английский

Citations

53
STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease DOI Creative Commons
Li Gao, Jun‐Sheng Zhang, Tingting Yang

et al.

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(10), P. 3084 - 3103

Published: Aug. 2, 2023

Hypertension is a primary modifiable risk factor for cardiovascular diseases, which often induces renal end-organ damage and complicates chronic kidney disease (CKD). In the present study, histological analysis of human samples revealed that hypertension induced mtDNA leakage promoted expression stimulator interferon genes (STING) in epithelial cells. We used angiotensin II (AngII)- 2K1C-treated mouse kidneys to elucidate underlying mechanisms. Abnormal packing caused by AngII STING-dependent production inflammatory cytokines, macrophage infiltration, fibrogenic response. STING knockout significantly decreased nuclear factor-κB activation immune cell attenuating tubule atrophy extracellular matrix accumulation vivo vitro. These effects delayed CKD progression. Immunoprecipitation assays liquid chromatography-tandem mass spectrometry showed ACSL4 were directly combined at D53 K412 amino acids ACSL4. Furthermore, response fibrosis through ACSL4-dependent ferroptosis. Last, inhibition using small interfering RNA, rosiglitazone, or Fer-1 downregulated AngII-induced mtDNA-STING-dependent inflammation. results suggest targeting STING/ACSL4 axis might represent potential strategy treating hypertension-associated CKD.

Language: Английский

Citations

49
m6A demethylase Fto inhibited macrophage activation and glycolysis in diabetic nephropathy via m6A/Npas2/Hif‐1α axis DOI Creative Commons
Sai Zhu, Ling Jiang, Xinran Liu

et al.

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(2)

Published: Jan. 20, 2025

Abstract Macrophage infiltration and activation is a key factor in the progression of diabetic nephropathy (DN). However, aerobic glycolysis induced by m6A methylation modification plays role M1‐type macrophages, but specific mechanism remains unclear DN. In this study, expression demethylase Fto bone marrow derived macrophages primary kidney from db/db mice. Loss gain‐of‐function analysis were performed to assess Transcriptome MeRIP‐seq association was identified target gene Npas2. we found that exhibits low type 2 DN Npas2 mediated regulates glucose metabolism reprogramming participate process Furthermore, reduces level through Prrc2a‐dependent mechanism, decreasing its stability. This mediates inflammation M1 regulating Hif‐1α signaling pathway. may act as suppressor m6A/Npas2/Hif‐1α axis. findings providing new basis for prevention treatment

Language: Английский

Citations

2
METTL3: a multifunctional regulator in diseases DOI
Na Li, Wei Xiang,

J.J. Dai

et al.

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Language: Английский

Citations

2
Inhibition of IGF2BP1 attenuates renal injury and inflammation by alleviating m6A modifications and E2F1/MIF pathway DOI Creative Commons
Yan Mao, Feng Jiang,

Xue-Jiao Xu

et al.

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(2), P. 593 - 609

Published: Jan. 1, 2023

Septic acute kidney injury (AKI) is characterized by inflammation. Pyroptosis often occurs during AKI and associated with the development of septic AKI. This study found that induction insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to a higher level can induce pyroptosis in renal tubular cells. Meanwhile, macrophage migration inhibitory (MIF), subunit NLRP3 inflammasomes, was essential for IGF2BP1-induced pyroptosis. A putative m6A recognition site identified at 3'-UTR region E2F transcription (E2F1) via bioinformatics analyses validated using mutation luciferase experiments. Further actinomycin D (Act D) chase experiments showed IGF2BP1 stabilized E2F1 dependent on m6A. Electrophoretic mobility shift assay (EMSA) chromatin immunoprecipitation (ChIP) indicated acted as promote MIF expression. Thus, upregulated through directly upregulating expression modification. Experiments mice cecum ligation puncture (CLP) surgery verified relationships between IGF2BP1, E2F1, demonstrated significance MIF-associated vivo. In conclusion, potent inducer targeting component inflammasomes. Inhibiting could be an alternate pyroptosis-based treatment

Language: Английский

Citations

27
Emerging role of METTL3 in inflammatory diseases: mechanisms and therapeutic applications DOI Creative Commons

Bimei Song,

Yue Zeng,

Yanqing Cao

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 21, 2023

Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney and autoimmune diseases have high incidence rates, still threaten human health, represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis various diseases. As most widely discussed m6A methyltransferase, pathogenic role METTL3 has become research hotspot, but there been no comprehensive review topic. Here, we summarize expression changes, modified target genes, related cardiovascular, metabolic, degenerative, immune, infectious well tumors. In addition epithelial cells, endothelial fibroblasts, also regulates function inflammation-related immune including macrophages, neutrophils, dendritic Th17 NK cells. Regarding therapeutic applications, serves for treatment with natural plant drug components, emodin, cinnamaldehyde, total flavonoids Abelmoschus manihot , resveratrol. This focuses on recent advances initiation, development, application Knowledge specific regulatory mechanisms involving can help deepen understanding lay foundation development precisely targeted drugs address processes.

Language: Английский

Citations

25
METTL3-Mediated N6-Methyladenosine mRNA Modification and cGAS-STING Pathway Activity in Kidney Fibrosis DOI

Yu-Cheng Tsai,

Tsung‐Han Hsieh, Yuan‐Ru Liao

et al.

Journal of the American Society of Nephrology, Journal Year: 2024, Volume and Issue: 35(10), P. 1312 - 1329

Published: June 10, 2024

Chemical modifications on RNA profoundly affect function and regulation. m6A, the most abundant modification in eukaryotes, plays a pivotal role diverse cellular processes disease mechanisms. However, its importance is understudied human CKD samples regarding influence pathological

Language: Английский

Citations

13
N6-methyladenosine RNA methylation in diabetic kidney disease DOI Creative Commons

Jiaan Huang,

Fan Yang,

Yan Liu

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 171, P. 116185 - 116185

Published: Jan. 18, 2024

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, and hyperglycemic memory associated with diabetes carries the risk occurrence, even after termination blood glucose injury. The existence supports concept an epigenetic mechanism involving n6-methyladenosine (m6A) modification. Several studies have shown that m6A plays key role in pathogenesis DKD. This review addresses RNA modification progression DKD, including regulatory pathological processes, such as inflammation, oxidative stress, fibrosis, non-coding (nc) RNA. reveals importance occurrence development suggesting may play phenomenon. also discusses how some gray areas, modified multiple enzymes, interact to affect DKD provides countermeasures. In conclusion, this enhances our understanding from perspective modifications new targets for future therapeutic strategies. addition, insights discussed here support effects which far-reaching implications novel treatments. We hypothesize modification, factor regulating in-depth exploration option clinical management patients

Language: Английский

Citations

11
Silencing of METTL3 prevents the proliferation, migration, epithelial-mesenchymal transition, and renal fibrosis of high glucose-induced HK2 cells by mediating WISP1 in m6A-dependent manner DOI Creative Commons
Yuanzhen Chen, Ping Li,

Mei Lin

et al.

Aging, Journal Year: 2024, Volume and Issue: 16(2), P. 1237 - 1248

Published: Jan. 29, 2024

Diabetic nephropathy (DN) is one of the most serious complications in diabetic patients. And m6A modifications mediated by METTL3 are involved multiple biological processes. However, specific function and mechanism DN remains unclear. model mice were first established with streptozotocin, WISP1 expression was confirmed qRT-PCR. Then influences or/and on proliferation, migration, epithelial-mesenchymal transition (EMT) fibrosis-related proteins high glucose (HG)-induced HK2 cells or tested through CCK-8, wound healing, western blot. We revealed that highly expressed renal tissues HG-induced cells. Functionally, silencing could weaken EMT, fibrosis HG-treated cells, overexpression induce Additionally, decrease modification, also notably suppress functions downregulating WISP1. Silencing prevents development process decreasing modification pattern. Therefore, we suggest METTL3/WISP1 axis might be a novel therapeutic target for DN.

Language: Английский

Citations

9
Seabuckthorn polysaccharide alleviates renal fibrosis in a mouse model of diabetic nephropathy via p311/TGFβ1/Fstl1 signaling pathway DOI
Qian Huang,

Zilu Shi,

Dandan Zheng

et al.

Pathology - Research and Practice, Journal Year: 2025, Volume and Issue: 267, P. 155808 - 155808

Published: Jan. 1, 2025

Language: Английский

Citations

1