Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network

Skácel, Jan; Slusher, Barbara S.; Tsukamoto, Takashi

doi:10.1021/acs.jmedchem.0c01664

Cited by 35 publications

(20 citation statements)

References 151 publications

(308 reference statements)

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“…Targeting enzymes that generate ceramide and S1P to restore a rheostat of ceramide-S1P have been considered as a therapeutic strategy in various diseases (reviewed in [ 283 , 284 ]). In the same line, the application of compounds that can reduce the ratio of ceramide/S1P by targeting the enzymes involved in ceramide production and SphKs would be beneficial to prevent oxidant-induced kidney injury ( Table 4 ) [ 27 , 43 , 62 , 66 , 71 , 74 , 75 , 76 , 78 , 85 , 94 , 198 , 200 , 207 , 219 , 226 , 260 , 264 , 281 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 ].…”

Section: A Rheostat Of Ceramide-s1p In the Regulation Of Oxidative St...mentioning

confidence: 99%

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

Ueda

2022

IJMS

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Reactive oxygen species (ROS) modulate sphingolipid metabolism, including enzymes that generate ceramide and sphingosine-1-phosphate (S1P), and a ROS-antioxidant rheostat determines the metabolism of ceramide-S1P. ROS induce ceramide production by activating ceramide-producing enzymes, leading to apoptosis, while they inhibit S1P production, which promotes survival by suppressing sphingosine kinases (SphKs). A ceramide-S1P rheostat regulates ROS-induced mitochondrial dysfunction, apoptotic/anti-apoptotic Bcl-2 family proteins and signaling pathways, leading to apoptosis, survival, cell proliferation, inflammation and fibrosis in the kidney. Ceramide inhibits the mitochondrial respiration chain and induces ceramide channel formation and the closure of voltage-dependent anion channels, leading to mitochondrial dysfunction, altered Bcl-2 family protein expression, ROS generation and disturbed calcium homeostasis. This activates ceramide-induced signaling pathways, leading to apoptosis. These events are mitigated by S1P/S1P receptors (S1PRs) that restore mitochondrial function and activate signaling pathways. SphK1 promotes survival and cell proliferation and inhibits inflammation, while SphK2 has the opposite effect. However, both SphK1 and SphK2 promote fibrosis. Thus, a ceramide-SphKs/S1P rheostat modulates oxidant-induced kidney injury by affecting mitochondrial function, ROS production, Bcl-2 family proteins, calcium homeostasis and their downstream signaling pathways. This review will summarize the current evidence for a role of interaction between ROS-antioxidants and ceramide-SphKs/S1P and of a ceramide-SphKs/S1P rheostat in the regulation of oxidative stress-mediated kidney diseases.

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Section: A Rheostat Of Ceramide-s1p In the Regulation Of Oxidative St...mentioning

confidence: 99%

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

Ueda

2022

IJMS

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“…A study in mice by Bhat et al demonstrated that ceramide plays a critical role in phenotype transition and mineral deposition in arterial smooth muscle cells leading to arterial medial calcification and increased PWV [ 129 ]. Further, attempts to alleviate vascular dysfunction and atherosclerosis via ceramide synthesis inhibition in animal models have been encouragingly successful [ 130 , 131 , 132 ].…”

Section: ‘Arteriometabolomics’ Approachmentioning

confidence: 99%

Metabolomics of Arterial Stiffness

Paapstel

Kals

2022

Metabolites

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Arterial stiffness (AS) is one of the earliest detectable signs of structural and functional alterations of the vessel wall and an independent predictor of cardiovascular events and death. The emerging field of metabolomics can be utilized to detect a wide spectrum of intermediates and products of metabolism in body fluids that can be involved in the pathogenesis of AS. Research over the past decade has reinforced this idea by linking AS to circulating acylcarnitines, glycerophospholipids, sphingolipids, and amino acids, among other metabolite species. Some of these metabolites influence AS through traditional cardiovascular risk factors (e.g., high blood pressure, high blood cholesterol, diabetes, smoking), while others seem to act independently through both known and unknown pathophysiological mechanisms. We propose the term ‘arteriometabolomics’ to indicate the research that applies metabolomics methods to study AS. The ‘arteriometabolomics’ approach has the potential to allow more personalized cardiovascular risk stratification, disease monitoring, and treatment selection. One of its major goals is to uncover the causal metabolic pathways of AS. Such pathways could represent valuable treatment targets in vascular ageing.

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“…The chemical structure of ceramides consists of a sphingoid base (e.g., dihydrosphingosine, sphingosine, phytosphingosine or 6-hydroxy sphingosine), which is a long-chain amino alcohol, and one among several fatty acids, different in chain length and degree of saturation, joined by an amide linkage (Figure 1) [20]. The addition of polar groups results in sphingolipid classes that vary in their underlying ceramide, whereas the addition of variable sugar groups results in different glycosphingolipids, adding a further level of complexity and heterogeneity [20]. There are three major pathways by which ceramides are synthesized (Figure 2) [21,22]:…”

Section: Chemical Structure and Productionmentioning

confidence: 99%

Plasma Ceramides Pathophysiology, Measurements, Challenges, and Opportunities

2021

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Ceramides are a family of lipid molecules, composed of sphingosine and a fatty acid, and transported by lipoproteins (primarily by low-density lipoproteins) in the bloodstream. They are not only structural lipids, but multifunctional and bioactive molecules with key roles in many important cellular pathways, such as inflammatory processes and apoptosis, representing potential biomarkers of cardiometabolic diseases as well as pharmacological targets. Recent data reported ceramide modulation by diet and aerobic exercise, suggesting nutrients and exercise-targeting sphingolipid pathways as a countermeasure, also in combination with other therapies, for risk and progression of chronic disease prevention and health maintenance. In this review, we focus on the available data regarding remarks on ceramide structure and metabolism, their pathophysiologic roles, and the effect of dietary habit and aerobic exercise on ceramide levels. Moreover, advancements and limitations of lipidomic techniques and simplification attempts to overcome difficulties of interpretation and to facilitate practical applications, such as the proposal of scores, are also discussed.

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Small Molecule Inhibitors Targeting Biosynthesis of Ceramide, the Central Hub of the Sphingolipid Network

Cited by 35 publications

References 151 publications

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

Metabolomics of Arterial Stiffness

Plasma Ceramides Pathophysiology, Measurements, Challenges, and Opportunities

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