Inhibition of SphK1/S1P Signaling Pathway Alleviates Fibrosis and Inflammation of Rat Myocardium after Myocardial Infarction

Xiao-kui, WU; Xu, Junwei; Li, Xiangyu; Dai, Jinghong; Wang, Linlin

doi:10.1155/2022/5985375

Cited by 11 publications

(10 citation statements)

References 31 publications

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“…Treatment with SphK1 inhibitor PF543 improved the myocardial structure and function. C57BL6 mice myocardial infarction model; CFTR knockout mice ( CFTR − / −); Sphk1 −/− and Sphk2 −/ KO mice; murine vascular smooth muscle cells; mouse cerebral arteries; Sprague Dawley rats; H9c2 cells Downstream of TNF-α [ 120 – 122 ] Acute pancreatitis The expression of SphK1/S1P3 and SphK1 activity are increased in peripheral immune cells in the early stage of pancreatitis. Peripheral neutrophils, monocytes/lymphocytes; acute pancreatitis (humans) Upstream (parallel) of TNF-α synthesis [ 123 ] Oxidative stress; neurodegeneration; neuronal survival TNF-α-mediated activation of Mg(2+)-nSMase and NOX in neuronal cells results in the production of the neurotoxic intermediates ceramide and ROS, damages SphK1 signaling, and accelerates neurodegeneration.…”

Section: Sphingolipids As Mediators Facilitators and Inhibitors Of Tn...mentioning

confidence: 99%

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

Sukocheva,

Neganova,

Aleksandrova

et al. 2024

Cell Commun Signal

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Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.

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Section: Sphingolipids As Mediators Facilitators and Inhibitors Of Tn...mentioning

confidence: 99%

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

Sukocheva,

Neganova,

Aleksandrova

et al. 2024

Cell Commun Signal

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“…Furthermore, ketone ester reprograms gene expression of ketone body utilization and normalizes ATP production in post-infarct remodeling ( Yurista et al, 2021 ). Sphingosine kinase one inhibitor PF543 reduces α-SMA, collagen, IL-1β, IL-6, and TNF-α levels to decrease myocardial injury, fibrosis, and inflammation ( Wu et al, 2022a ). Notably, deoxycholic acid-G protein-coupled bile acid receptor pathway activation also decreases inflammation and fibrosis ( Wang et al, 2021a ).…”

Section: Interventions For Cardiac Fibrosismentioning

confidence: 99%

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

Yin

Pan

et al. 2023

Front. Pharmacol.

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Cardiac fibrosis plays an indispensable role in cardiac tissue homeostasis and repair after myocardial infarction (MI). The cardiac fibroblast-to-myofibroblast differentiation and extracellular matrix collagen deposition are the hallmarks of cardiac fibrosis, which are modulated by multiple signaling pathways and various types of cells in time-dependent manners. Our understanding of the development of cardiac fibrosis after MI has evolved in basic and clinical researches, and the regulation of fibrotic remodeling may facilitate novel diagnostic and therapeutic strategies, and finally improve outcomes. Here, we aim to elaborate pathophysiology, examination and intervention of cardiac fibrosis after MI.

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“…SphK1 was shown to be upregulated in patients with pulmonary arterial hypertension (PAH) and its genetic deletion and pharmacologic inhibition protected against the development of hypoxia-mediated pulmonary hypertension (HPH) in mice (doi: 10.1164/rccm.201401-0121OC ). In addition, SphK1 overexpression in human pulmonary artery smooth muscle cells (PASMCs) resulted in an increase of pro-inflammatory cytokines such as the interleukin family cytokine and the TNF super ligand family (DOI: 10.1007/s12013-021-01006-8 ) ( 119 ). Additionally, elevated levels of circulating S1P have been found to be strongly associated with high blood pressure and inflammation in human and mouse models, making it a powerful biomarker for hypertension ( 120 ).…”

Section: Sphingolipids’ Involvement In Inflammation and Cardiovascula...mentioning

confidence: 99%

The therapeutic potential of sphingolipids for cardiovascular diseases

Ya'ar Bar,

Pintel,

Abd Alghne

et al. 2023

Front. Cardiovasc. Med.

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Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide and Inflammation plays a critical role in the development of CVD. Despite considerable progress in understanding the underlying mechanisms and various treatment options available, significant gaps in therapy necessitate the identification of novel therapeutic targets. Sphingolipids are a family of lipids that have gained attention in recent years as important players in CVDs and the inflammatory processes that underlie their development. As preclinical studies have shown that targeting sphingolipids can modulate inflammation and ameliorate CVDs, targeting sphingolipids has emerged as a promising therapeutic strategy. This review discusses the current understanding of sphingolipids’ involvement in inflammation and cardiovascular diseases, the existing therapeutic approaches and gaps in therapy, and explores the potential of sphingolipids-based drugs as a future avenue for CVD treatment.

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Inhibition of SphK1/S1P Signaling Pathway Alleviates Fibrosis and Inflammation of Rat Myocardium after Myocardial Infarction

Cited by 11 publications

References 31 publications

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

The therapeutic potential of sphingolipids for cardiovascular diseases

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