Failure of Oxysterols Such as Lanosterol to Restore Lens Clarity from Cataracts

Damian M. Daszynski, Puttur Santhoshkumar, Ashutosh S. Phadte, K. Krishna Sharma, Haizhen A. Zhong, Marjorie F. Lou, Peter F. Kador

Research output: Contribution to journalArticle

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Abstract

The paradigm that cataracts are irreversible and that vision from cataracts can only be restored through surgery has recently been challenged by reports that oxysterols such as lanosterol and 25-hydroxycholesterol can restore vision by binding to αB-crystallin chaperone protein to dissolve or disaggregate lenticular opacities. To confirm this premise, in vitro rat lens studies along with human lens protein solubilization studies were conducted. Cataracts were induced in viable rat lenses cultured for 48 hours in TC-199 bicarbonate media through physical trauma, 10 mM ouabain as Na+/K+ ATPase ion transport inhibitor, or 1 mM of an experimental compound that induces water influx into the lens. Subsequent 48-hour incubation with 15 mM of lanosterol liposomes failed to either reverse these lens opacities or prevent the further progression of cataracts to the nuclear stage. Similarly, 3-day incubation of 47-year old human lenses in media containing 0.20 mM lanosterol or 60-year-old human lenses in 0.25 and 0.50 mM 25-hydroxycholesterol failed to increase the levels of soluble lens proteins or decrease the levels of insoluble lens proteins. These binding studies were followed up with in silico binding studies of lanosterol, 25-hydroxycholesterol, and ATP as a control to two wild type (2WJ7 and 2KLR) and one R120G mutant (2Y1Z) αB-crystallins using standard MOETM (Molecular Operating Environment) and Schrödinger’s Maestro software. Results confirmed that compared to ATP, both oxysterols failed to reach the acceptable threshold binding scores for good predictive binding to the αB-crystallins. In summary, all three studies failed to provide evidence that lanosterol or 25-hydroxycholesterol have either anti-cataractogenic activity or bind aggregated lens protein to dissolve cataracts.

Original languageEnglish (US)
Article number8459
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Lanosterol
Crystallins
Cataract
Lenses
Adenosine Triphosphate
Ion Transport
Ouabain
Bicarbonates
Oxysterols
Liposomes
Computer Simulation
Software
25-hydroxycholesterol
Water
Wounds and Injuries

ASJC Scopus subject areas

  • General

Cite this

Failure of Oxysterols Such as Lanosterol to Restore Lens Clarity from Cataracts. / Daszynski, Damian M.; Santhoshkumar, Puttur; Phadte, Ashutosh S.; Sharma, K. Krishna; Zhong, Haizhen A.; Lou, Marjorie F.; Kador, Peter F.

In: Scientific reports, Vol. 9, No. 1, 8459, 01.12.2019.

Research output: Contribution to journalArticle

Daszynski, Damian M. ; Santhoshkumar, Puttur ; Phadte, Ashutosh S. ; Sharma, K. Krishna ; Zhong, Haizhen A. ; Lou, Marjorie F. ; Kador, Peter F. / Failure of Oxysterols Such as Lanosterol to Restore Lens Clarity from Cataracts. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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