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Cells: Mitochondria, Glycocalyx vs. Free radical processes

Cells: Mitochondria, Glycocalyx vs. Free radical processes. … a brain storming session … with hypotheses & speculations. Cell anatomy. Cells differ tremendously in morphology, but the main features of mammalian cells are quite similar. N = from some dozens to many thousands. M itochondrion.

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Cells: Mitochondria, Glycocalyx vs. Free radical processes

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  1. Cells: Mitochondria, Glycocalyxvs.Free radical processes … a brain storming session … with hypotheses & speculations L. Šoltés

  2. Cell anatomy Cells differ tremendously in morphology, but the main features of mammalian cells are quite similar L. Šoltés

  3. N = from some dozens to many thousands L. Šoltés

  4. Mitochondrion Mitochondria of an adult absorb about 400 liters of oxygenper day Mitochondria (sing. mitochondrion) are known as the powerhouses of the cell, producing the majority - about 95% - of the ATP that is used in cell metabolism L. Šoltés

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  6. Oxyhaemoglobin Cell membrane Cytosol molecules of dioxygen O2 Matrix e O2 <≡> ●O–O● → ●O–O <≡> O2●  O2●  → O–O→ HO–OH → H2O2 HO–OH <≡> HO●●OH→ HO+●OH HO + ●OH → HO + OH→ 2H2O O2+ 4e+ 4H+→ 2H2O 2H+ e e 2H+ e L. Šoltés

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  8. MitochondrionROS; O2●  • It has been estimated that 0.1% to 2.0% of O2 • consumed by mitochondria generates O2●  • There are the following leak events; corresponding to 0.4-8.0 liters O2 per day: • Complex I leaks O2●  towards the matrix • Complex III leaks O2●  towards the intermembrane space • Complex III leaks O2●  towards thematrix L. Šoltés

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  10. MitochondrionROS; H2O2 • Long-living H2O2 molecules are “freely” movable • (even to cytosol) • H2O2 can attack the components in the intermembrane space • H2O2 can attack the components in thematrix L. Šoltés

  11. mROS leak (O2●  ; H2O2) Nature = genius architect !!! L. Šoltés

  12. Scavenging mROS ROS production should be controlled, not stopped Human = genius being !!! mito-Antioxidant (+) Cytosol mTA Cell L. Šoltés

  13. MitoSNO1 SkQ2M Mitochondrially targeted antioxidant +P … can be substituted e.g. by +N X … is an efficient antioxidant 1x L. Šoltés

  14. Chemical structure of SkQ1a promising compound L. Šoltés

  15. MitoQ vs. SkQ1 Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J.Biol.Chem. 276 (2001) 4588-4596 2e; 2H+ MitoQuinone MitoQuinol 2e; 2H+ Plastoquinone SkQ1 SkQ1 is based on plastoquinone, an antioxidant from plant chloroplasts(2004) L. Šoltés

  16. mTA series N+ P+ L. Šoltés

  17. V. P. Skulachevs’ offer The main purpose of the Institute of Mitoengineering is to organize large-scale research projects aimed at development and practical application of novel highly effective drugs Maxim Vladimirovich Skulachev; biologist Director of the Institute of Mitoengineering L. Šoltés

  18. Skulachev’s tenets • The “ideal” antioxidant should be specifically targeted to mitochondria where ROS are produced. • This antioxidant should effectively remove not all the ROS but just their excess. • It is also important for an antioxidant not to be toxic and not to be recognized and eliminated by cell enzymes. • Unfortunately none of the antioxidants discovered by the end of the 20th century fits all these criteria. L. Šoltés

  19. Skulachev’s observations • Extremely high effectiveness of SkQ1 (hundreds-fold higher when compared to analogic MitoQ) can be explained by SkQ1 ability to “get regenerated”. • Having accomplished its function as ROS neutralizer and changed into an oxygenated form, SkQ1 is easily restored by a mitochondrial respiratory chain. • It is due to this ability for multiple restorations that SkQ1 proves to be effective even in extremely low nanomolar concentrations. • SkQ-type compounds allows them to act as therecyclable antioxidants, in contrast to conventional antioxidants that are usually inactivated after interaction with a free radical. L. Šoltés

  20. L. Šoltés idea Constructing & patenting the “Tamer’s membranes” SkQ1 L. Šoltés

  21. + mTA Biomembrane + mTA Wound healing Patent pending - confidential L. Šoltés & M. Tamer

  22. Preclinical test for wound dressing containing antioxidant Healing time 3 days 7 days 10 days 14 days 18 days 21 days Control Complex hydrogel Hydrogel + antioxidant L. Šoltés & M. Tamer

  23. Cells: Mitochondria, Glycocalyxvs.Free radical processes … a brain storming session … with hypotheses & speculations L. Šoltés

  24. … a tissue … L. Šoltés

  25. Extracellular fluid nm Cytosol … detail of the cell surface … L. Šoltés

  26. The outer cell space The protein and lipid cell membrane is covered with a layer of carbohydrate chains The content of carbohydrate chains is about 3% L. Šoltés

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  28. Glycocalyx Glycocalyx is a sticky cell envelope composed of oligo- and poly-saccharides that surround the cells L. Šoltés

  29. Glycocalyx functions • Has a negative electrical charge which repels negatively charged ions • Protect cells against damages • Serve to attach cells to one another • Act as a part of the receptor sites • Enter into immune reactions L. Šoltés

  30. Glycocalyx functions • Has a negative electrical charge which repels negatively charged ions • Protect cells against damages • Serve to attach cells to one another • Act as a part of the receptor sites • Enter into immune reactions L. Šoltés

  31. Fibroblasts in synovium “Glycocalyx” protective function ? HAs of MDa molar mass move into the synovial fluid and protect cartilage from damages L. Šoltés

  32. “Glycocalyx” protective function !!! HAs of MDa molar mass ECM with HAs of MDa molar mass protect cartilage chondrocytes against damages L. Šoltés

  33. Glycocalyx functions • Has a negative electrical charge which repels negatively charged ions • Protect cells against damages • Serve to attach cells to one another • Act as a part of the receptor sites • Enter into immune reactions L. Šoltés

  34. “Glycocalyx” in cell attachment !!! HMM L. Šoltés

  35. Glycocalyx functions • Has a negative electrical charge which repels negatively charged ions • Protect cells against damages • Serve to attach cells to one another • Act as a part of the receptor sites • Enter into immune reactions L. Šoltés

  36. “Glycocalyx” vs. immune reactions !!! L. Šoltés

  37. immunogenic “Glycocalyx” - masking tumor cells by native HMM HAs !!! L. Šoltés

  38. “Glycocalyx” - masking tumor cells Native HMM HAs ………..…. = not immunogenic • “Unmasking” tumor(s): Lower-molar-mass HAs ….. stimulates immunity responses • Depolymerizing action of HYALs ??? • Degrading action of ROS/RNS !!! … papers of Šoltés et al. Liberation of HMM HAs by lower-molar-mass hyaluronans, which are nontoxic and not immunogenic … Šoltés speculation L. Šoltés

  39. “Glycocalyx” - unmasking tumor cells Lower MM HAs …… = immunogenic One of the current trends Lower-molar-mass HAs ….. stimulates immunity responses L. Šoltés

  40. Generation of .OHbiogenic components … degrading action of ROS … [100] [1] H2O2 + Cu(I)---complex .OH +Cu(II)catalyst L. Šoltés

  41. Hyaluronan degradationstep 1 H L. Šoltés

  42. Hyaluronan degradationstep 2 L. Šoltés

  43. Hyaluronan degradationstep 3 fragment 3.1 fragment 3.2 L. Šoltés

  44. VEGA project2011-2014 • Degrading action of ROS/RNS on HMM HAs papers of Šoltés et al. L. Šoltés

  45. Publishing activity4 years L. Šoltés

  46. Acknowledgements L. Šoltés

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