Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Breiden, Bernadette; Sandhoff, Konrad

doi:10.3390/ijms22169001

Cited by 34 publications

(25 citation statements)

References 191 publications

(271 reference statements)

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“…Lysolipids, generated by phospholipase activity toward membrane phospholipids, were elevated with kawain treatments, suggesting increased lipase activity [ 33 ]. Also consistent with increased lipase activity, several monoacylglycerols and long-chain fatty acids were more abundant with kawain treatment [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism

et al. 2023

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UPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcinoma in these mice. The mice were fed at six weeks of age with vehicle control or kawain (6 g/kg) formulated food for approximately five months. Seventy-eight percent of the mice or more fed with kawain food survived more than six months of age, whereas only 32% control food-fed male mice survived, (p = 0.0082). The mean wet bladder weights (a surrogate for tumor burden) of UPII-mutant Ha-ras transgenic mice with kawain diet was decreased by approximately 56% compared to those fed with the control diet (p = 0.035). The kawain diet also significantly reduced the occurrence of hydronephrosis and hematuria in UPII-mutant Ha-ras transgenic mice. Histological examination and immunohistochemistry analysis revealed that vehicle control-treated mice displayed more urothelial carcinoma and Ki67-positive cells in the bladder compared to kawain treated mice. Global metabolic profiling of bladder tumor samples from mice fed with kawain food showed significantly more enrichment of serotonin and less abundance of xylulose, prostaglandin A2, D2 and E2 compared to those from control diet-fed mice, suggesting decreased shunting of glucose to the pentose phosphate pathway (PPP) and reduced inflammation. In addition, kawain selectively inhibited the growth of human bladder cancer cell lines with a significant suppression of 4E-BP1 expression and rpS6 phosphorylation. These observations indicate a potential impact of kawain consumption on bladder cancer prevention by rewiring the metabolic programs of the tumor cells.

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Section: Discussionmentioning

confidence: 99%

Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism

et al. 2023

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“…In this study, we used imipramine, which attached to the lysosomal membrane instead of ASMase [ 31 , 46 ]. ASMase is most activated 2–3 h after injury [ 51 , 52 ]. Therefore, we confirmed ASMase activity levels at 3 h after TBI.…”

Section: Discussionmentioning

confidence: 99%

Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury

Lee

Kho

Lee

et al. 2022

IJMS

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Traumatic brain injury (TBI) broadly degrades the normal function of the brain after a bump, blow, or jolt to the head. TBI leads to the aggravation of pre-existing brain dysfunction and promotes neurotoxic cascades that involve processes such as oxidative stress, loss of dendritic arborization, and zinc accumulation. Acid sphingomyelinase (ASMase) is an enzyme that hydrolyzes sphingomyelin to ceramide in cells. Under normal conditions, ceramide plays an important role in various physiological functions, such as differentiation and apoptosis. However, under pathological conditions, excessive ceramide production is toxic and activates the neuronal-death pathway. Therefore, we hypothesized that the inhibition of ASMase activity by imipramine would reduce ceramide formation and thus prevent TBI-induced neuronal death. To test our hypothesis, an ASMase inhibitor, imipramine (10 mg/kg, i.p.), was administrated to rats immediately after TBI. Based on the results of this study, we confirmed that imipramine significantly reduced ceramide formation, dendritic loss, oxidative stress, and neuronal death in the TBI-imipramine group compared with the TBI-vehicle group. Additionally, we validated that imipramine prevented TBI-induced cognitive dysfunction and the modified neurological severity score. Consequently, we suggest that ASMase inhibition may be a promising therapeutic strategy to reduce hippocampal neuronal death after TBI.

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“…In particular, alkaline SMase expression is restricted to the intestinal mucosa and liver, whereas the acidic and neutral isoforms are ubiquitously expressed throughout the body [51]. In addition, acid sphingomyelinase (aSMase) is mainly located in the endolysosomal compartment but can be secreted into the extracellular space under certain conditions [52]. The secreted isoform of aSMase is directly implicated in the pathogenesis of atherosclerosis, as it has been demonstrated that its release can be promoted by atherogenic proinflammatory cytokines and its activity increases ceramide levels by hydrolysis of SM on lipoprotein particles [53].…”

Section: Ceramide and Sphingosine-1-phosphate Metabolismmentioning

confidence: 99%

Sphingolipids and Atherosclerosis: The Dual Role of Ceramide and Sphingosine-1-Phosphate

et al. 2023

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Sphingolipids are bioactive molecules that play either pro- and anti-atherogenic roles in the formation and maturation of atherosclerotic plaques. Among SLs, ceramide and sphingosine-1-phosphate showed antithetic properties in regulating various molecular mechanisms and have emerged as novel potential targets for regulating the development of atherosclerosis. In particular, maintaining the balance of the so-called ceramide/S1P rheostat is important to prevent the occurrence of endothelial dysfunction, which is the trigger for the entire atherosclerotic process and is strongly associated with increased oxidative stress. In addition, these two sphingolipids, together with many other sphingolipid mediators, are directly involved in the progression of atherogenesis and the formation of atherosclerotic plaques by promoting the oxidation of low-density lipoproteins (LDL) and influencing the vascular smooth muscle cell phenotype. The modulation of ceramide and S1P levels may therefore allow the development of new antioxidant therapies that can prevent or at least impair the onset of atherogenesis, which would ultimately improve the quality of life of patients with coronary artery disease and significantly reduce their mortality.

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Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Cited by 34 publications

References 191 publications

Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism

Kavalactone Kawain Impedes Urothelial Tumorigenesis in UPII-Mutant Ha-Ras Mice via Inhibition of mTOR Signaling and Alteration of Cancer Metabolism

Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury

Sphingolipids and Atherosclerosis: The Dual Role of Ceramide and Sphingosine-1-Phosphate

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