Effect of selected B-ring-substituted oxysterols on artificial model erythrocyte membrane and isolated red blood cells

Targosz‐Korecka, Marta; Wnętrzak, Anita; Chachaj‐Brekiesz, Anna; Gonet-Surówka, Agnieszka; Kubisiak, Agata; Filiczkowska, Anna; Szymoński, Marek; Dynarowicz-Łątka, Patrycja

doi:10.1016/j.bbamem.2019.183067

Cited by 14 publications

(9 citation statements)

References 72 publications

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“…For example, several studies demonstrated that TSPO ligands 4'-chlorodiazepam and TRO40403 delayed mPTP opening following I/R due to decrease in mitochondrial cholesterol accumulation (Paradis et al, 2013;Musman et al, 2017) and associated decrease in the formation of auto-oxidized oxysterols (Paradis et al, 2013). Auto-oxidized oxysterols are formed due to cholesterol oxidation by ROS (Paradis et al, 2013) and affect membrane fluidity and permeability (Targosz-Korecka et al, 2020). Furthermore, a direct TSPO-independent inhibitory effect of PK11195 on F 0 F 1 -ATP synthase at oligomycin sensitivity conferral protein (OSCP) subunit (Cleary et al, 2007) has been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

PK11195 Protects From Cell Death Only When Applied During Reperfusion: Succinate-Mediated Mechanism of Action

et al. 2021

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Aim: Reperfusion after myocardial ischemia causes cellular injury, in part due to changes in mitochondrial Ca2+ handling, oxidative stress, and myocyte energetics. We have previously shown that the 18-kDa translocator protein of the outer mitochondrial membrane (TSPO) can modulate Ca2+ handling. Here, we aim to evaluate the role of the TSPO in ischemia/reperfusion (I/R) injury.Methods: Rabbit ventricular myocytes underwent simulated acute ischemia (20 min) and reperfusion (at 15 min, 1 h, and 3 h) in the absence and presence of 50 μM PK11195, a TSPO inhibitor. Cell death was measured by lactate dehydrogenase (LDH) assay, while changes in mitochondrial Ca2+, membrane potential (ΔΨm), and reactive oxygen species (ROS) generation were monitored using confocal microscopy in combination with fluorescent indicators. Substrate utilization was measured with Biolog mitochondrial plates.Results: Cell death was increased by ~200% following I/R compared to control untreated ventricular myocytes. Incubation with 50 μM PK11195 during both ischemia and reperfusion did not reduce cell death but increased mitochondrial Ca2+ uptake and ROS generation. However, application of 50 μM PK11195 only at the onset and during reperfusion effectively protected against cell death. The large-scale oscillations in ΔΨm observed after ~1 h of reperfusion were significantly delayed by 1 μM cyclosporin A and almost completely prevented by 50 μM PK11195 applied during 3 h of reperfusion. After an initial increase, mitochondrial Ca2+, measured with Myticam, rapidly declined during 3 h of reperfusion after the initial transient increase. This decline was prevented by application of PK11195 at the onset and during reperfusion. PK11195 prevented a significant increase in succinate utilization following I/R and succinate-induced forward-mode ROS generation. Treatment with PK11195 was also associated with a significant increase in glutamate and a decrease in leucine utilization.Conclusion: PK11195 administered specifically at the moment of reperfusion limited ROS-induced ROS release and cell death, likely in part, by a shift from succinate to glutamate utilization. These data demonstrate a unique mechanism to limit cardiac injury after I/R.

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Section: Discussionmentioning

confidence: 99%

PK11195 Protects From Cell Death Only When Applied During Reperfusion: Succinate-Mediated Mechanism of Action

et al. 2021

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“…in the two regions 0 ≤ φ 0 < 1/ξ and 1/ξ < φ 0 ≤ 1. The red dashed lines in the left diagram of Figure 4 show the piece-wise linear approximations for the function φ v (φ 0 ) according to Equation (28). The corresponding lateral pressure obtained by inserting φ v (φ 0 ) according to Equation (28) into Equation ( 22) is shown in the right diagram of Figure 4 by the red dashed lines.…”

Section: Analytic Solution For φmentioning

confidence: 99%

“…There are many examples for such shoulders and their interpretation in terms of orientational changes. Cyclosporin A [ 21 ], amphotericin B [ 22 , 23 ], nystatin [ 24 ], stearylspermine [ 25 ], monoacylated

-cyclodextrins [ 26 ], cholesterol derivatives such as 7

-hydroxycholesterol [ 27 ] or oxysterol [ 28 , 29 ], carboxylic acid with a symmetrical triphenylbenzene ring system [ 30 ], certain dumbbell-like molecules like amphiphilic bistable rotaxanes [ 31 ] or polyoxometalate (POM)-based inorganic–organic–inorganic molecular hybrids [ 32 ], tri-podal amphiphiles [ 33 ], and alpha-helical peptides [ 34 , 35 , 36 ] have all been reported to undergo orientational adjustments—typically between two orientations—when being used as surface-active molecules in Langmuir monolayers at varying lateral pressure. Other examples include organic–inorganic nanoparticles such as derivatives of varying amphiphilicity of fully condensed polyhedral oligomeric silsesquioxanes (POSS) [ 37 ], matrix organosilane amphiphiles (and also mixed monolayers of vitamin

mimics with these organosilane amphiphiles) [ 38 ], and organic–inorganic hybrid molecular films consisting of a Keggin-type polyoxometalate PW

and a series of gemini amphiphiles with various lengths of the flexible spacers [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

Incorporation of Molecular Reorientation into Modeling Surface Pressure-Area Isotherms of Langmuir Monolayers

2021

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Langmuir monolayers can be assembled from molecules that change from a low-energy orientation occupying a large cross-sectional area to a high-energy orientation of small cross-sectional area as the lateral pressure grows. Examples include cyclosporin A, amphotericin B, nystatin, certain alpha-helical peptides, cholesterol oxydation products, dumbbell-shaped amphiphiles, organic–inorganic nanoparticles and hybrid molecular films. The transition between the two orientations leads to a shoulder in the surface pressure-area isotherm. We propose a theoretical model that describes the shoulder and can be used to extract the energy cost per molecule for the reorientation. Our two-state model is based on a lattice–sublattice approximation that hosts the two orientations and a corresponding free energy expression which we minimize with respect to the orientational distribution. Inter-molecular interactions other than steric repulsion are ignored. We provide an analysis of the model, including an analytic solution for one specific lateral pressure near a point of inflection in the surface pressure-area isotherm, and an approximate solution for the entire range of the lateral pressures. We also use our model to estimate energy costs associated with orientational transitions from previously reported experimental surface pressure-area isotherms.

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“…Zmiana płynności błony komórkowej zależy od rodzaju cząsteczki oksysterolu i jego stężenia. Stężenia w zakresie 1-100 µM mogą wywoływać apoptozę komórek w hodowli in vitro [14]. Zaburzenia elastyczności błony komórkowej mogą doprowadzić do apoptozy komórki.…”

Section: Wprowadzenieunclassified

Od glejaka po COVID-19 - rola oksysteroli w organizmie człowieka

Gonet-Surówka¹,

Dynarowicz-Łątka²

2021

Postepy Biochem

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Cholesterol jest prekursorem w syntezie witaminy D, kwasów żółciowych i hormonów sterydowych. Jego utlenione formy zwane oksysterolami są produktem pośrednim w syntezach, ale także regulują metabolizmem cholesterolu poprzez oddziaływanie na receptory komórkowe. Cholesterol jest ważnym składnikiem błon komórkowych. Oksysterole wykazują większą aktywność biologiczną niż sam cholesterol, mając działanie plejotropowe na różne typy komórek organizmu wywołują często przeciwstawne efekty. Oksysterole w przeciwieństwie do cholesterolu mogą przenikać barierę krew-mózg i wpływać na działanie układu nerwowego. Utlenione formy cholesterolu mogą oddziaływać na etiopatogenezę chorób nowotworowych. Podwyższony poziom oksysteroli w tkankach często towarzyszy wielu stanom patologicznym: jak cukrzyca, miażdżyca, demencja lub endometrioza. Utlenione formy cholesterolu mogą hamować lub aktywować różne komórki układu odpornościowego regulując procesami odpowiedzi immunologicznej w przebiegu chorób wirusowych i zapalnych.

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Effect of selected B-ring-substituted oxysterols on artificial model erythrocyte membrane and isolated red blood cells

Cited by 14 publications

References 72 publications

PK11195 Protects From Cell Death Only When Applied During Reperfusion: Succinate-Mediated Mechanism of Action

PK11195 Protects From Cell Death Only When Applied During Reperfusion: Succinate-Mediated Mechanism of Action

Incorporation of Molecular Reorientation into Modeling Surface Pressure-Area Isotherms of Langmuir Monolayers

Od glejaka po COVID-19 - rola oksysteroli w organizmie człowieka

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