Neutral sphingomyelinase inhibition decreases ER stress-mediated apoptosis and inducible nitric oxide synthase in retinal pigment epithelial cells

Kucuksayan, Ertan; Konuk, Esma Kirimlioglu; Demır, Necdet; Mutus, Bülent; Aslan, Mutay

doi:10.1016/j.freeradbiomed.2014.04.013

Cited by 23 publications

(17 citation statements)

References 43 publications

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“…Sphingolipids are also known to play a key role in ER Ca +2 homeostasis and ER stress responses, which also can play a role in mitochondrial-mediated apoptosis. For example, inhibition of neutral sphingomyelinase protected retinal epithelial cells from ER stress-induced apoptosis (Kucuksayan et al 2014). In addition, knockdown of CERT in mouse embryonic fibroblasts induced ER stress that was linked to an accumulation of hexosylceramide, rather than ceramide (Rao et al 2014).…”

Section: Mitochondrial Apoptosismentioning

confidence: 99%

Sphingolipids and mitochondrial apoptosis

Patwardhan

Beverly

Siskind

2015

J Bioenerg Biomembr

110

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The sphingolipid family of lipids modulate several cellular processes, including proliferation, cell cycle regulation, inflammatory signaling pathways, and cell death. Several members of the sphingolipid pathway have opposing functions and thus imbalances in sphingolipid metabolism result in deregulated cellular processes, which cause or contribute to diseases and disorders in humans. A key cellular process regulated by sphingolipids is apoptosis, or programmed cell death. Sphingolipids play an important role in both extrinsic and intrinsic apoptotic pathways depending on the stimuli, cell type and cellular response to the stress. During mitochondrial-mediated apoptosis, multiple pathways converge on mitochondria and induce mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of intermembrane space proteins such as cytochrome c and Apaf1 into the cytosol where they activate the caspases and DNases that execute cell death. The precise molecular components of the pore(s) responsible for MOMP are unknown, but sphingolipids are thought to play a role. Here, we review evidence for a role of sphingolipids in the induction of mitochondrial-mediated apoptosis with a focus on potential underlying molecular mechanisms by which altered sphingolipid metabolism indirectly or directly induce MOMP. Data available on these mechanisms is reviewed, and the focus and limitations of previous and current studies are discussed to present important unanswered questions and potential future directions.

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Section: Mitochondrial Apoptosismentioning

confidence: 99%

Sphingolipids and mitochondrial apoptosis

Patwardhan

Beverly

Siskind

2015

J Bioenerg Biomembr

110

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“…Ionizing radiation activates acid sphingomyelinase to produce ceramide which promotes the induction of apoptosis (Haimovitz-Friedman et al 1994), implicating a crucial role for this enzyme in mediating stress-induced apoptosis (Santana et al 1996). Conversely, a cell permeable and non-competitive inhibitor of neutral sphingomyelinase (GW4869) blocks ceramide synthesis to rescue cell death in numerous cell types, such as cochlear hair cells (Chi et al 2014), retinal pigment epithelial cells (Kucuksayan et al 2014) and fibroblasts (Qin et al 2012). At least four isoforms of neutral sphingomyelinase are expressed in mammalian cells, each with distinct biochemical properties, localizations and physiological roles [for a review, see (Airola and Hannun 2013)].…”

Section: Sphingolipid Metabolismmentioning

confidence: 99%

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

et al. 2014

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Resveratrol, a natural compound endowed with multiple health-promoting effects, has received much attention given its potential for the treatment of cardiovascular, inflammatory, neurodegenerative, metabolic and age-related diseases. However, the translational potential of resveratrol has been limited by its specificity, poor bioavailability and uncertain toxicity. In recent years, there has been an accumulation of evidence demonstrating that resveratrol modulates sphingolipid metabolism. Moreover, resveratrol forms higher order oligomers that exhibit better selectivity and potency in modulating sphingolipid metabolism. This review evaluates the evidence supporting the modulation of sphingolipid metabolism and signaling as a mechanism of action underlying the therapeutic efficacy of resveratrol and oligomers in diseases, such as cancer.

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“…A major pathological hallmark of dry AMD is the presence of age-dependent degenerative damage to the retinal pigment epithelium (RPE), a monolayer of hexagonal epithelial cells located adjacent to, and physically interacting with, retinal photoreceptors, forming the outer blood-retinal barrier (BRB) (6). RPE is a common barrier for solutes and fluids from the choroidal vasculature that must access the inner retina (7,8). Strict control of fluids and solutes across the BRB is achieved by well-developed tight junctions, which mean that the liquid is not able to penetrate the barrier between the two cells.…”

Section: Introductionmentioning

confidence: 99%

Wogonin protects human retinal pigment epithelium cells from LPS-induced barrier dysfunction and inflammatory responses by regulating the TLR4/NF-κB signaling pathway

Chen

Guo

2017

Molecular Medicine Reports

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Inflammation in the retinal pigment epithelium is an important contributor to the pathogenesis of age-related macular degeneration. Wogonin is a flavonoid isolated from the root of Scutellaria baicalensis and has multiple pharmacological effects, including anti‑inflammatory effects. The present study sought to determine if the pharmacological effects of wogonin were relevant to the treatment of AMD. ARPE‑19 cells were pre‑conditioned with different concentrations of wogonin (0‑50 µM) prior to induction of inflammation with LPS (2 µg/ml). Transepithelial electrical resistance analysis demonstrated that 24 h treatment with 10 and 50 µM wogonin ameliorated LPS‑induced changes. Reverse transcription-quantitative polymerase chain reaction (RT‑qPCR) and immunoﬂuorescence analyses revealed that wogonin restrained LPS-induced tight junction proteins, claudin‑1 and ZO‑1. LPS‑induced upregulation of inflammatory mediators in ARPE‑19 cells, including IL‑1β, IL‑6, IL‑8, cyclooxygenase‑2 (COX‑2), inducible nitric oxide synthase (iNOS) and TNF‑α was reduced after pre-treatment with wogonin. In addition, RT‑qPCR and western blotting demonstrated that wogonin inhibited the expression of TLR4 in LPS‑stimulated ARPE‑19 cells. This is a novel mechanism indicating that pre‑treatment with wogonin could attenuate the TLR4/NF‑κB‑mediated inflammatory response in LPS‑stimulated ARPE‑19 cells, and thus could be a potential therapy for the treatment of AMD.

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Neutral sphingomyelinase inhibition decreases ER stress-mediated apoptosis and inducible nitric oxide synthase in retinal pigment epithelial cells

Cited by 23 publications

References 43 publications

Sphingolipids and mitochondrial apoptosis

Sphingolipids and mitochondrial apoptosis

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

Wogonin protects human retinal pigment epithelium cells from LPS-induced barrier dysfunction and inflammatory responses by regulating the TLR4/NF-κB signaling pathway

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