YTHDC1 regulates the postnatal development of heart DOI Creative Commons
Lei Shi, Quanwei Wang, Meiwei Zhang

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 6, 2023

Abstract This study aimed to investigate the role of N6-methyladenosine (m 6 A) reader protein YTHDC1 in heart development and its potential molecular mechanisms. Animal experiments were conducted using cardiac-specific Ythdc1 knockout ( Ythdc1- CKO) mice, human samples collected from aborted fetuses. Echocardiography, immunoblotting, RNA-Seq, ATAC-Seq performed assess cardiac function, gene expression, chromatin accessibility. The results revealed that expression was highest during embryonic early postnatal stages gradually decreased with age. Cardiac-specific deletion resulted abnormal development, dilated cardiomyopathy, severe failure. RNA-Seq analysis significant changes profiles, particularly genes related contraction transmembrane transport. demonstrated accessibility, binding motifs transcription factors Mef2a, Mef2b, Mef2c, Mef2d, which are essential for switched off CKO mouse hearts. In conclusion, this demonstrates plays a critical deficiency leads function. findings provide insights into mechanisms underlying suggest therapeutic targets diseases.

Language: Английский

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles DOI
Meina Zhu,

Zhaohui Lan,

Joo‐Hyun Park

et al.

Neuropathology and Applied Neurobiology, Journal Year: 2024, Volume and Issue: 50(2)

Published: April 1, 2024

Abstract Neuroinflammation, blood–brain barrier (BBB) dysfunction, neuron and glia injury/death myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), its human orthologue SERPINA3, is an acute‐phase inflammatory glycoprotein secreted primarily by the liver into bloodstream response to systemic inflammation. Clinically, SERPINA3 dysregulated brain cells, cerebrospinal fluid plasma conditions. Although it has been widely accepted that Serpina3n/SERPINA3 a reliable biomarker of reactive astrocytes diseased CNS, recent data have challenged this well‐cited concept, suggesting instead oligodendrocytes neurons primary sources Serpina3n/SERPINA3. The debate continues regarding whether induction represents pathogenic or protective mechanism. Here, we propose possible interpretations for previously controversial present perspectives potential role CNS pathologies, including demyelinating disorders where targets. We hypothesise ‘good’ ‘bad’ aspects depend on cellular sources, subcellular distribution (or mis‐localisation) and/or disease/injury types. Furthermore, circulating may cross BBB impact pathologies. Cell‐specific genetic tools critically important tease out roles cell type‐dependent Serpina3n diseases/injuries.

Language: Английский

Citations

8
Pulsatile Flow Increases METTL14-induced m6A modification and attenuates septic cardiomyopathy: an experimental study DOI Creative Commons
Shenyu Zhu, Kai Wang, Zhexuan Yu

et al.

International Journal of Surgery, Journal Year: 2024, Volume and Issue: unknown

Published: March 28, 2024

Introduction: Septic cardiomyopathy is a sepsis-mediated cardiovascular complication with severe microcirculatory malperfusion. Emerging evidence has highlighted the protective effects of pulsatile flow in case disturbance, yet underlying mechanisms are still elusive. The objective this study was to investigate N6-methyladenosine (m 6 A) modification alleviation septic associated extracorporeal membrane oxygenation (ECMO)-generated flow. Methods: Rat model established and supported under ECMO either or non-pulsatile Peripheral perfusion index (PPI) cardiac function parameters were measured using ultrasonography. Dot blot assay applied examine m A level, while qRT-PCR, Western blot, immunofluorescence, immunohistochemistry used measure expressions related genes. RNA immunoprecipitation performed validate interaction between molecules. Results: ECMO-generated significantly elevates PPI, improves myocardial function, protects endothelium, prolongs survival rat models cardiomyopathy. mediates METTL14-mediated zonula occludens- (ZO-) 1 mRNA which stabilizes ZO-1 depending on presence YTHDF2. suppresses PI3K-Akt signaling pathway, downstream molecule Foxo1, negative transcription factor METTL14, binds METTL14 promoter inhibits METTL14-induced modification. Conclusion: increases attenuates progression cardiomyopathy, suggesting that pulsatility might be new therapeutic strategy by alleviating disturbance.

Language: Английский

Citations

6
RNA m6A methylation regulators in sepsis DOI
Lin Zhu, Hairong Zhang, Xiaoyu Zhang

et al.

Molecular and Cellular Biochemistry, Journal Year: 2023, Volume and Issue: 479(9), P. 2165 - 2180

Published: Sept. 2, 2023

Language: Английский

Citations

16
YTHDC1 inhibits autophagy-dependent NF-κB signaling by stabilizing Beclin1 mRNA in macrophages DOI Creative Commons
Zhou Li, Ling Zhang, Yan Lv

et al.

Journal of Inflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: June 14, 2024

Abstract Background YTHDC1, a key m(6)A nuclear reader, plays crucial role in regulating mRNA splicing, export, and stability. However, the functional significance regulatory mechanisms of YTHDC1 inflammatory bowel disease (IBD) remain to be explored. Methods We established dextran sulfate sodium (DSS)-induced murine colitis model vivo LPS/IFN-γ-stimulated macrophage inflammation vitro. The expression was determined. Colocalization macrophages assayed by immunofluorescence staining. LV-YTHDC1 or shYTHDC1 lentiviruses were applied for overexpression inhibition. For NF-κB inhibition, JSH-23 utilized. interaction Beclin1 determined RIP, m6A modification confirmed MeRIP. Results In DSS-induced LPS/IFN-γ-treated RAW264.7 macrophages, we observed significant downregulation YTHDC1. Overexpression resulted decreased levels iNOS , CD86 IL-6 mRNA, along with inhibited activation cells. Conversely, promoted autophagy. Additionally, effect knockdown on induced LPS/IFN-γ abolished inhibitor JSH-23. Mechanistically, interacted thereby stabilizing enhancing These effects ultimately led inhibition signaling LPS/IFN-γ-challenged macrophages. Conclusions macrophage-mediated response which may potential therapeutic target treatment IBD.

Language: Английский

Citations

3
N6-methyladenosine modification: Regulatory mechanisms and therapeutic potential in sepsis DOI Open Access
Wei Wang, Huaili Wang, Tongwen Sun

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115719 - 115719

Published: Oct. 14, 2023

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection and characterized multiple biological clinical features. N6-methyladenosine (m6A) modification the most common type of RNA modifications in eukaryotes plays an important regulatory role various processes. Recently, m6A has been found be involved regulation immune responses sepsis. In addition, several studies have shown that sepsis-induced dysfunctions, including cardiovascular dysfunction, acute lung injury (ALI), kidney (AKI) etc. Considering complex pathogenesis sepsis lack specific therapeutic drugs, may bond pathophysiological process even targets. This review systematically highlights recent advances regarding roles sheds light on their use as treatment targets for

Language: Английский

Citations

7
Utilizing omics technologies in the investigation of sepsis-induced cardiomyopathy DOI Creative Commons
Han Zheng,

Zhen Quan,

Siyao Zeng

et al.

IJC Heart & Vasculature, Journal Year: 2024, Volume and Issue: 54, P. 101477 - 101477

Published: July 30, 2024

Sepsis-induced cardiomyopathy (SIC) is a common and high-mortality complication among critically ill patients. Uncertainties persist regarding the pathogenesis, pathophysiology, diagnosis of SIC, underscoring necessity to investigate potential biological mechanisms. With rise omics technologies, leveraging their high throughput big data advantages, systems biology perspective employed study processes SIC. This approach aids in gaining better understanding disease's onset, progression, outcomes, ultimately providing improved guidance for clinical practices. review summarizes currently applied studies related relevant databases.

Language: Английский

Citations

2
Unravelling the impact of RNA methylation genetic and epigenetic machinery in the treatment of cardiomyopathy DOI Creative Commons
Li Liu,

Linxing Yu,

Y Wang

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 207, P. 107305 - 107305

Published: July 11, 2024

Cardiomyopathy (CM) represents a heterogeneous group of diseases primarily affecting cardiac structure and function, with genetic epigenetic dysregulation playing pivotal role in its pathogenesis. Emerging evidence from the burgeoning field epitranscriptomics has brought to light significant impact various RNA modifications, notably N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N1-methyladenosine (m1A), 2′-O-methylation (Nm), 6,2′-O-dimethyladenosine (m6Am), on cardiomyocyte function broader processes vascular remodelling. These modifications have been shown influence key pathological mechanisms including mitochondrial dysfunction, oxidative stress, apoptosis, inflammation, immune response, myocardial fibrosis. Importantly, aberrations methylation machinery observed human CM cases animal models, highlighting critical methylating enzymes their potential as therapeutic targets or biomarkers for CM. This review underscores necessity deeper understanding context CM, illuminate novel avenues diagnostic tools, thereby addressing gap current management strategies this complex disease.

Language: Английский

Citations

2
ZC3H13 may participate in the ferroptosis process of sepsis-induced cardiomyopathy by regulating the expression of Pnn and Rbm25 DOI

Wenji Lin,

Haihong Li, Jing Chang

et al.

Gene, Journal Year: 2024, Volume and Issue: unknown, P. 148944 - 148944

Published: Sept. 1, 2024

Language: Английский

Citations

1
YTHDC1 Mitigates Apoptosis in Bone Marrow Mesenchymal Stem Cells by Inhibiting NfƙBiα and Augmenting Cardiac Function Following Myocardial Infarction DOI Creative Commons

Weiyu Han,

Weidong Xiong, Weixing Sun

et al.

Cell Transplantation, Journal Year: 2024, Volume and Issue: 33

Published: Jan. 1, 2024

The therapeutic efficacy of bone marrow mesenchymal stem cells (BMSCs) in myocardial infarction (MI) is hindered by poor cell survival. This study explored the role N6-methyladenosine (m6A) regulation, specifically YTHDC1, improving BMSC transplantation for MI. By screening m6A-related regulators hypoxia and serum deprivation (HSD)-induced apoptosis, YTHDC1 was found to be downregulated. Overexpression Ythdc1 BMSCs reduced apoptosis markers, reactive oxygen species (ROS) release, improved survival under HSD conditions. Conversely, knockdown enhanced apoptosis. In rat MI models, Ythdc1-overexpressing cardiac function fibrosis. Mechanistically, interacts with nuclear factor kappa B (NF-κB) inhibitor-alpha mRNA, suggesting its involvement pathways. identifies as a potential target enhance therapy.

Language: Английский

Citations

1
Identification of key regulatory factors for m6A in myasthenia gravis and characteristics of the immune characteristics DOI Creative Commons

Yaoqi Wu,

Xiaoqing Cai,

Yingying Jiao

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Abstract Myasthenia gravis (MG), a rare autoimmune disorder, presents complex pathogenesis involving various immune molecules. The modification of N6-methyladenosine (m6A) regulates diverse metabolic and immunopathological processes; however, its role in MG remains unclear. We downloaded dataset GSE85452 from the GEO database to identify differentially expressed genes regulated by m6A. Random Forest (RF) method was utilized pivotal regulatory associated with m6A modification. Subsequently, prognostic model crafted confirmed using this gene set. Patients were stratified according expression levels these key genes. Additionally, MG-specific signatures delineated examining cell infiltration patterns their correlations. Further functional annotation, protein-protein interaction mapping, molecular docking analyses performed on biomarkers, leading discovery three that exhibited significant differential within dataset: RBM15, CBLL1, YTHDF1.The random forest algorithm as MG, validated constructing clinical prediction model. Based expression, we divided patients into two groups, revealing distinct varying abundances. also discovered 61 phenotype conducted an in-depth exploration biological roles. YTHDF1 found positively correlated CD56dim natural killer cells, T type 1 helper cells. These stable diagnostic m6A-related markers both validation cohorts. Our findings suggest for MG. analysis may elucidate roles microenvironment

Language: Английский

Citations

0