7-Keto-Cholesterol and Cholestan-3beta, 5alpha, 6beta-Triol Induce Eryptosis through Distinct Pathways Leading to NADPH Oxidase and Nitric Oxide Synthase Activation

Attanzio, Alessandro; Frazzitta, Anna; Cilla, Antonio; Livrea, M. A.; Tesoriere, Luisa; Allegra, Mario

doi:10.33594/000000186

Cited by 17 publications

(13 citation statements)

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“…In line with our data, other studies in endothelial cells have demonstrated that CSE treatment has no effect on GSH content [ 35 ] and that antioxidants exhibit only a minimal protective effect in CSE-triggered cell death [ 36 ]. In addition, our data exclude that activities of enzymes that generate reactive either oxygen or nitrogen species in the erythrocytes, such as NADPH oxidase, nitric oxide synthase or xanthine oxido-reductase, are up-regulated by the CSE-treatment [ 37 ]. However, RBC isolated from smokers’ subjects showed reduced GSH levels with respect to those in non-smokers ones [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

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Cigarette Smoke Extract Induces p38 MAPK-Initiated, Fas-Mediated Eryptosis

Restivo

Attanzio

Giardina

et al. 2022

IJMS

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Eryptosis is a physiological mechanism for the clearance of senescent or damaged erythrocytes by phagocytes. Excessive eryptosis is stimulated under several pathologies and associated with endothelial injury and thrombosis. Cigarette smoke (CS) is an established risk factor for vascular diseases and cigarette smokers have high-levels of eryptotic erythrocytes. This study, for the first time, investigates the mechanism by which CS damages red blood cells (RBCs). CS extract (CSE) from commercial cigarettes was prepared and standardized for nicotine content. Cytofluorimetric analysis demonstrated that treatment of human RBCs with CSE caused dose-dependent, phosphatidylserine externalization and cell shrinkage, hallmarks of apoptotic death. CSE did not affect cellular levels of Ca2+, reactive oxygen species (ROS) or glutathione (GSH). Immununoprecipitation and immunoblotting revealed the assembly of the death-inducing signaling complex (DISC) and oligomerization of Fas receptor as well as cleaved caspase-8 and caspase-3 within 6 h from the treatment. At the same time-interval, CSE elicited neutral sphyngomielinase (nSMase) activity-dependent ceramide formation and phosphorylation of p38 MAPK. Through specific inhibitors’ nSMase, caspase-8 or p38 MAPK activities, we demonstrated that p38 MAPK activation is required for caspase-8-mediated eryptosis and that ceramide generation is initiator caspase-dependent. Finally, ex vivo analysis detected phosphorylated p38 MAPK (p-p38) and Fas-associated signaling complex in erythrocytes from cigarette smokers. In conclusion, our study demonstrates that CSE exposure induces in erythrocytes an extrinsic apoptotic pathway involving p38 MAPK-initiated DISC formation followed by activation of caspase-8/caspase-3 via ceramide formation.

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Section: Discussionmentioning

confidence: 99%

“…DCFDA, at 10 µM final concentration, was added to 1.0 × 10 5 cells 30 min before the end of the treatment, in the dark. RBCs were collected by centrifugation (2000× g , 4 °C, 5 min), washed, resuspended in phosphate-buffered saline (PBS), and analysed as reported by Attanzio et al [ 37 ].…”

Section: Methodsmentioning

confidence: 99%

Cigarette Smoke Extract Induces p38 MAPK-Initiated, Fas-Mediated Eryptosis

Restivo

Attanzio

Giardina

et al. 2022

IJMS

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“…It was shown that eryptosis induced by cholesterol metabolism products is mediated mainly by NADPH oxidase and nitric oxide synthase, with only a complementary action of XO. 22 We speculate that other enzymes may play a more critical role in the RBC ROS genesis. 6 Importantly, our data contrast with Lewis et al, 23 which suggests the absence of XO activity in healthy RBC.…”

Section: Discussionmentioning

confidence: 89%

Effect of hypoxia and uremia on oxidative stress on erythrocytes from hemodialysis patients

Dias

Tozoni

Bohnen

et al. 2022

Cell Biochemistry & Function

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Oxidative stress (OS) is essential in uremia‐associated comorbidities, including renal anemia. Complications experienced by hemodialysis (HD) patients, such as hypoxemia and uremic toxins accumulation, induce OS and premature death of red blood cells (RBC). We aimed to characterize reactive oxygen species (ROS) production and antioxidant pathways in HD‐RBC and RBC from healthy controls (CON‐RBC) and evaluate the role of uremia and hypoxia in these pathways. ROS production, xanthine oxidase (XO) and superoxide dismutase (SOD) activities, glutathione (GSH), and heme oxygenase‐1 (HO‐1) levels were measured using flow cytometry or spectrophotometry in CON‐RBC and HD‐RBC (pre‐ and post‐HD), at baseline and after 24 h incubation with uremic serum (S‐HD) and/or under hypoxic conditions (5% O2). Ketoprofen was used to inhibit RBC uremic toxins uptake. HD‐RBC showed higher ROS levels and lower XO activity than CON‐RBC, particularly post‐HD. GSH levels were lower, while SOD activity and HO‐1 levels of HD‐RBC were higher than control. Hypoxia per se triggered ROS production in CON‐RBC and HD‐RBC. S‐HD, on top of hypoxia, increased ROS levels. Inhibition of uremic toxins uptake attenuated ROS of CON and HD‐RBC under hypoxia and uremia. CON‐RBC in uremia and hypoxia showed lower GSH levels than cells in normoxia and non‐uremic conditions. Redox mechanisms of HD‐RBC are altered and prone to oxidation. Uremic toxins and hypoxia play a role in unbalancing these systems. Hypoxia and uremia participate in the pathogenesis of OS in HD‐RBC and might induce RBC death and thus compound anemia.

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“…Consistently, 7KC enhances ROS production, promotes the translocation of NOX components from the cytosol to the cellular membrane, inhibits HO-1 expression, and stimulates lysozyme release in human neutrophils [ 51 ]. In human red blood cells, 7KC is reported to activate NOX and induce eryptosis by mediating Rac GTPase and PKCζ [ 52 ]. NOX4 is an important source of ROS production and is highly expressed in MC3T3-E1 cells [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

7-Ketocholesterol Induces Oxiapoptophagy and Inhibits Osteogenic Differentiation in MC3T3-E1 Cells

Ouyang

Xiao

Ren

et al. 2022

Cells

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7-Ketocholesterol (7KC) is one of the oxysterols produced by the auto-oxidation of cholesterol during the dysregulation of cholesterol metabolism which has been implicated in the pathological development of osteoporosis (OP). Oxiapoptophagy involving oxidative stress, autophagy, and apoptosis can be induced by 7KC. However, whether 7KC produces negative effects on MC3T3-E1 cells by stimulating oxiapoptophagy is still unclear. In the current study, 7KC was found to significantly decrease the cell viability of MC3T3-E1 cells in a concentration-dependent manner. In addition, 7KC decreased ALP staining and mineralization and down-regulated the protein expression of OPN and RUNX2, inhibiting osteogenic differentiation. 7KC significantly stimulated oxidation and induced autophagy and apoptosis in the cultured MC3T3-E1 cells. Pretreatment with the anti-oxidant acetylcysteine (NAC) could effectively decrease NOX4 and MDA production, enhance SOD activity, ameliorate the expression of autophagy-related factors, decrease apoptotic protein expression, and increase ALP, OPN, and RUNX2 expression, compromising 7KC-induced oxiapoptophagy and osteogenic differentiation inhibition in MC3T3-E1 cells. In summary, 7KC may induce oxiapoptophagy and inhibit osteogenic differentiation in the pathological development of OP.

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7-Keto-Cholesterol and Cholestan-3beta, 5alpha, 6beta-Triol Induce Eryptosis through Distinct Pathways Leading to NADPH Oxidase and Nitric Oxide Synthase Activation

Cited by 17 publications

References 0 publications

Cigarette Smoke Extract Induces p38 MAPK-Initiated, Fas-Mediated Eryptosis

Cigarette Smoke Extract Induces p38 MAPK-Initiated, Fas-Mediated Eryptosis

Effect of hypoxia and uremia on oxidative stress on erythrocytes from hemodialysis patients

7-Ketocholesterol Induces Oxiapoptophagy and Inhibits Osteogenic Differentiation in MC3T3-E1 Cells

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