Nr1d1 inhibition mitigates intermittent hypoxia-induced pulmonary hypertension via Dusp1-mediated Erk1/2 deactivation and mitochondrial fission attenuation DOI Creative Commons
Pan Zhou, Yan Yao, Xu Liu

et al.

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Oct. 29, 2024

Abstract Intermittent hypoxia (IH) precipitates pulmonary vasoconstriction, culminating in the onset of hypertension (PH) among individuals afflicted with sleep apnea. While Nuclear receptor subfamily 1 group D member (Nr1d1) is progressively recognized as pivotal regulator cellular physiology, role pathogenesis IH-induced PH remains largely uncharted. The expression Nr1d1 was examined rodent and IH-treated PASMCs. To elucidate contribution to development PH, we employed siRNA modulate vitro serotype adeno-associated virus (AAV1) vivo. levels were elevated rodents lung tissues Knocking down by AAV1 effectively inhibited progression chronic models. Mechanistic investigations identified dual specificity phosphatase (Dusp1), a direct target that trans-repressed, mediating Nr1d1’s regulatory influence on Erk1/2/Drp1 signaling. deficiency ameliorates mitochondrial dysfunction fission restoring Dusp1 dysregulation Drp1 phosphorylation. Activation Erk1/2 PMA reversed Dusp1-mediated regulation phosphorylation, indicating involvement pathway phosphorylation controlled Dusp1. Meanwhile, intermittent induced more severe knockout mice compared wild-type mice. Our data unveil novel for an undisclosed Nr1d1-Dusp1 axis PASMCs regulation.

Language: Английский

Dual-specificity phosphatase 1 interacts with prohibitin 2 to improve mitochondrial quality control against type-3 cardiorenal syndrome DOI Creative Commons
Nanyang Liu,

Yanqiu Ding,

Hao Zhou

et al.

International Journal of Medical Sciences, Journal Year: 2024, Volume and Issue: 21(3), P. 547 - 561

Published: Jan. 1, 2024

Type-3 cardiorenal syndrome (CRS-3) is acute kidney injury followed by cardiac injury/dysfunction. Mitochondrial may impair myocardial function during CRS-3. Since dual-specificity phosphatase 1 (DUSP1) and prohibitin 2 (PHB2) both promote mitochondrial quality control, we assessed whether these proteins were dysregulated CRS-3-related depression. We found that DUSP1 was downregulated in heart tissues from a mouse model of transgenic (DUSP1

Language: Английский

Citations

5
Erbin alleviates sepsis-induced cardiomyopathy by inhibiting RIPK1-dependent necroptosis through activating PKA/CREB pathway DOI
Huimin Zhou, Hailong Gong, Huifan Liu

et al.

Cellular Signalling, Journal Year: 2024, Volume and Issue: 123, P. 111374 - 111374

Published: Aug. 30, 2024

Language: Английский

Citations

5
Astragaloside IV alleviates septic myocardial injury through DUSP1-Prohibitin 2 mediated mitochondrial quality control and ER-autophagy DOI Creative Commons
Junyan Wang,

Xiangyi Pu,

Haowen Zhuang

et al.

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Septic cardiomyopathy (SCM) is a complication of myocardial injury in patients with severe sepsis. This study highlights the potential Astragaloside IV(AS) treatment septic and provides reference for developing cardioprotective drugs targeting DUSP1-PHB2-related mitochondria-ER interaction. Dual specificity phosphatase-1 (DUSP1)/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2CKO) /DUSP1 transgenic (DUSP1/PHB2TG) were used to generate LPS-induced sepsis models. The pathological mechanism by which AS-IV improves heart was detected using cardiac ultrasound, fluorescence staining, transmission electron microscopy, western blotting. After siRNA cardiomyocytes DUSP-1/PHB2, changes mitochondrial function morphology determined qPCR, blotting, ELISA, laser confocal targeted therapeutic effects further examined. SCM leads dysfunction. However, IV (AS) normalizes homeostasis ER function. Notably, protective effect blocked DUSP1/Prohibitin but remained unaffected DUSP1 (DUSP1/PHB2TG). AS DUSP1-PHB2 related

Language: Английский

Citations

5
DNA-PKcs Phosphorylates Cofilin2 to Induce Endothelial Dysfunction and Microcirculatory Disorder in Endotoxemic Cardiomyopathy DOI Creative Commons
Yingzhen Du, Pingjun Zhu, Yukun Li

et al.

Research, Journal Year: 2024, Volume and Issue: 7

Published: Jan. 1, 2024

The presence of endotoxemia is strongly linked to the development endothelial dysfunction and disruption myocardial microvascular reactivity. These factors play a crucial role in progression endotoxemic cardiomyopathy. Sepsis-related multiorgan damage involves participation catalytic subunit DNA-dependent protein kinase (DNA-PKcs). However, whether DNA-PKcs contributes during remains unclear. Hence, we conducted experiments mice subjected lipopolysaccharide (LPS)-induced cardiomyopathy, as well assays primary mouse cardiac cells. Results showed that endothelial-cell-specific ablation markedly attenuated DNA damage, sustained microvessel perfusion, improved barrier function, inhibited capillary inflammation, restored endothelium-dependent vasodilation, heart function under conditions. Furthermore, show upon LPS stress, recognizes TQ motif cofilin2 consequently induces its phosphorylation at Thr 25 . Phosphorylated shows increased affinity for F-actin promotes depolymerization, resulting into integrity, defective eNOS-dependent vasodilation. Accordingly, cofilin2-knockin expressing phospho-defective (T25A) mutant integrity induction findings highlight novel mechanism whereby mediates Thr25 subsequent depolymerization contribute endotoxemia-related dysfunction.

Language: Английский

Citations

4
BMAL1 alleviates myocardial damage in sepsis by activating SIRT1 signaling and promoting mitochondrial autophagy DOI
Wen Tang,

Rennan Guo,

Congyu Hu

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 133, P. 112111 - 112111

Published: April 27, 2024

Language: Английский

Citations

4
PTEN suppresses renal cell carcinoma proliferation and migration via inhibition of the PI3K/AKT pathway DOI Creative Commons

Xu Xu,

Ya‐ling Tang,

Xiaohong Liang

et al.

World Journal of Surgical Oncology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 5, 2025

Renal cell carcinoma (RCC) is a frequent and aggressive type of kidney cancer with limited therapeutic options. Although phosphatase tensin homolog (PTEN) have been recognized as potential tumor suppressor in all kinds cancers, its function RCC remains to be thoroughly elucidated. This article was recruited examine the PTEN's role managing PI3K/AKT pathway impact on proliferation migration. study collected renal adjacent non-cancerous tissue samples from our hospital. HK-2 786-O cells were used, divided into control, vector, oe-PTEN groups. PTEN related protein levels detected using RT-qPCR Western blot. Statistical analyses performed Mann-Whitney U test Kruskal-Wallis H test. Cell viability migration assessed CCK-8 assay wound healing assay. All conducted SPSS 22.0 software, statistical significance defined p < 0.05. results showed that expression significantly increased tissues compared normal (p 0.01). However, mRNA reduced In low expression, further induction overexpression inhibited signaling activity 0.01), accompanied by decreased ability. These indicate pattern complex, but can exert tumor-suppressive effects inhibiting pathway. Our findings demonstrate leads signaling, decreasing highlights critical progression suggests targets for intervention.

Language: Английский

Citations

0
Altered Gut Microbiota as a Potential Risk Factor for Coronary Artery Disease in Diabetes: A Two-Sample Bi-Directional Mendelian Randomization Study DOI Creative Commons

Zhaopei Zeng,

Junxiong Qiu, Yu Chen

et al.

International Journal of Medical Sciences, Journal Year: 2023, Volume and Issue: 21(2), P. 376 - 395

Published: Dec. 26, 2023

The current body of research points to a notable correlation between an imbalance in gut microbiota and the development type 2 diabetes mellitus (T2D) as well its consequential ailment, coronary artery disease (CAD). complexities underlying association, especially context diabetic (DCAD), are not yet fully understood, causal links require further clarification. In this study, bidirectional Mendelian randomization (MR) methodology was utilized explore relationships microbiota, T2D, CAD. By analyzing data from DIAGRAM, GERA, UKB, FHS, mibioGen cohorts examining GWAS databases, we sought uncover genetic variants linked CAD, variations metabolites, aiming shed light on potential mechanisms connecting with DCAD. Our investigation uncovered marked link presence

Language: Английский

Citations

5
PKM2 interacts with and phosphorylates PHB2 to sustain mitochondrial quality control against septic cerebral-cardiac injury DOI Creative Commons

Yuanchen Zhao,

Yawen Pan, Mengyuan Chen

et al.

International Journal of Medical Sciences, Journal Year: 2024, Volume and Issue: 21(4), P. 633 - 643

Published: Jan. 1, 2024

Sepsis induces profound disruptions in cellular homeostasis, particularly impacting mitochondrial function cardiovascular and cerebrovascular systems.This study elucidates the regulatory role of Pyruvate Kinase M2 (PKM2)-Prohibitin 2 (PHB2) axis quality control during septic challenges its protective effects against myocardial cerebral injuries.Employing LPS-induced mouse models, we demonstrate a significant downregulation PKM2 PHB2 both heart brain tissues post-sepsis, with corresponding impairments dynamics, including fission, fusion, mitophagy.Overexpression not only restores function, as evidenced by normalized ATP production membrane potential but also confers resistance to oxidative stress mitigating reactive oxygen species generation.These mechanisms translate into substantial vivo benefits, transgenic mice overexpressing or displaying remarkable sepsis-induced cardiomyocyte neuronal apoptosis, organ dysfunction.Our findings highlight PKM2-PHB2 interaction novel therapeutic target for sepsis, providing foundation future research mitochondrial-based interventions treat this condition.The study's insights molecular underpinnings failure pave way clinical applications management sepsis related pathologies.

Language: Английский

Citations

1
PPARA ameliorates sepsis-induced myocardial injury via promoting macrophage M2 polarization by interacting with DUSP1 DOI Creative Commons

Li Cheng,

Dezhi Liu,

Shanglan Gao

et al.

Regenerative Therapy, Journal Year: 2024, Volume and Issue: 26, P. 33 - 41

Published: May 18, 2024

The morbidity and mortality of sepsis are increasing year by year. Statistically, 40–50% patients with have concomitant myocardial injury, its rate is higher than that only. Therefore, it great significance to elucidate the mechanism sepsis-induced injury. Human monocytes (THP-1) were used induce M0 macrophages, followed treated lipopolysaccharide (LPS). Cardiomyocytes (AC16) co-cultured conditioned medium LPS-induced macrophages Quantitative real-time PCR was employed detect mRNA levels peroxisome proliferator-activated receptor α (PPARA) dual specificity phosphatase 1 (DUSP1). Protein PPARA, macrophage polarization-related markers, apoptosis-related mitochondria-related proteins, DUSP1 analyzed Western blot. Flow cytometry assess M1/M2 cell rates apoptosis. Low PPARA expression could serve as a biomarker for sepsis. overexpression enhanced M2 polarization suppressed M1 in alleviate cardiomyocyte injury system. bound promoter region facilitated expression. knockdown reversed effect on attenuated promoting through expression, suggesting might be therapy target

Language: Английский

Citations

1
High-Throughput Screening of an FDA-Approved Compound Library Reveals a Novel GAS6 Receptor Agonist for Therapeutic Intervention in Septic Myocardial and microvascular Injury via Modulation of Danger-Associated Molecular Patterns DOI Creative Commons

Haowen Zhuang,

Chun Guang Li, Lingjun Wang

et al.

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(15), P. 6222 - 6240

Published: Nov. 11, 2024

PGAM5 and VDAC1 have both been reported to regulate mitophagy. However, the mechanisms by which they sepsis-induced inflammatory microvascular injury remain unverified. In previous studies, we established role of this regulatory axis in various phenotypic processes, including mitophagy, mitochondrial biogenesis, unfolded protein response, dynamics, while further confirming interactive proteins within axis. validation elucidation these phenotypes primarily focused on ischemic heart diseases such as myocardial failure. Sepsis-related is currently recognized a significant cardiac impairment, although there are cardioprotective nutritional agents available for supportive therapy, fundamental research validating upstream targets still lacking. Based our research, explored mitophagy dysfunction mediated its coronary injury. We also confirmed material basis metabolic pathway regulation targeting PGAM5- mechanism with relevant drugs. Our findings suggest that PGAM5-mediated may be crucial factor leading injury, interacting VDAC1-mediated membrane dysfunction. Animal experiments revealed cardiac-specific knockout could reverse LPS-induced damage, restoring ejection function functionality. vitro studies PGAM5-VDAC1 interaction can normalize normal morphology structure mitochondria maintaining energy metabolism levels respiratory chain function. Further pharmacological indicated active ingredients traditional Chinese medicine-Puerarin (TCM, GAS6 Receptor Agonist) target inhibit necrotic apoptosis cardiomyocytes, potentially reversing pathway-related TCM emerge prospective therapeutic agent

Language: Английский

Citations

1