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- Peter F. Kador, Ph.D., F.A.R.V.O., is the President/CEO. Dr. Kador is trained as a medicinal chemist. After a 25 year... morePeter F. Kador, Ph.D., F.A.R.V.O., is the President/CEO. Dr. Kador is trained as a medicinal chemist. After a 25 year career at the National Eye Institute, National Institutes of Health, Bethesda, MD, Dr. Kador retired as Chief of the Laboratory of Ocular Therapeutics and moved to Omaha, NE where he holds a faculty position as Professor of Pharmaceutical Sciences at the University of Nebraska Medical Center. He is internationally recognized as an expert of cataract formation, ocular diabetic complications, ocular pharmacology and toxicology of the lens.edit
Under oxidative stress mediated by H(2)O(2), significant activation of purified aldose reductase from bovine small intestine was observed in the presence of purified thioredoxin from bovine small intestine.
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ABSTRACT
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A differential effect on protein synthesis has been demonstrated in the lenses of galactosemic rats. During galactose cataract development the synthesis of lens crystallins is depressed, whereas that of noncrystallin proteins is... more
A differential effect on protein synthesis has been demonstrated in the lenses of galactosemic rats. During galactose cataract development the synthesis of lens crystallins is depressed, whereas that of noncrystallin proteins is unaffected. This effect correlates with the influx of Na+ and loss of K+ from the lens. Removal of the galactose diet results in a gradual recovering of crystallin synthesis to normal levels. In vitro the nuclear cataractous lenses leak crystallins into the media; however, upon 5 day's recovery no leak-out of crystallins could be detected. Both decreased synthesis and leak-out probably account for the marked loss of dry weight of cataractous lenses. These results support the hypothesis that crystallin synthesis may be affected by cation imbalance or changes concomitant with such an imbalance.
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The susceptibility of human lens aldose reductase (HLAR), human placental aldose reductase (HPAR), and rat lens aldose reductase (RLAR) to inhibition by 10 structurally diverse inhibitors is compared. Significant differences in the... more
The susceptibility of human lens aldose reductase (HLAR), human placental aldose reductase (HPAR), and rat lens aldose reductase (RLAR) to inhibition by 10 structurally diverse inhibitors is compared. Significant differences in the susceptibility of these enzymes was observed; however, no trends could be predicted. In general, HPAR appeared to be less susceptible to inhibition than either HLAR or RLAR, with the susceptibility of HLAR being more similar to RLAR than to HPAR. These findings indicate that the evaluation of aldose reductase inhibitors for potential clinical use may require the use of human aldose reductase from the appropriate target tissue.
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info:eu-repo/semantics/publishe
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Research Interests: Chemistry, Ophthalmology, Medicine, Cell Division, DNA, and 8 morePubmed, Animals, Male, Cataract, Rats, Epithelium, Cataracts, and Galactose Binding
The Philly mouse is a new model for genetic cataracts, in which there is an apparent defect in lens membrane permeability. This abnormality results in electrolyte imbalance and lens hydration, typical of an osmotic cataract. Since... more
The Philly mouse is a new model for genetic cataracts, in which there is an apparent defect in lens membrane permeability. This abnormality results in electrolyte imbalance and lens hydration, typical of an osmotic cataract. Since membrane glycoproteins are believed to be involved in transport processes, we have studied the changes in these polypeptides in the Philly mouse lens during cataract development and compared them with those in the control Swiss-Webster mouse. The membrane glycoproteins were labeled by treatment with galactose oxidase and tritiated borohydride. Radioactivity was found to be incorporated into six glycoproteins of approximate molecular weights of 128 k, 103 k, 82 k, 71 k, 35 k, and 22 k daltons. The 35 k polypeptide is the major glycoprotein in the mouse lens membrane and shows increased incorporation of the tritium label with progression of the cataract. In contrast to the murine lens, the 35 k peptide could not be detected in rabbit lens membranes. Other changes observed in glycoproteins of the Philly mouse lens during cataract development were a loss of the 103 k and 71 k polypeptides and a corresponding increase in the 66 k polypeptide. These changes in glycoproteins may be related to the permeability changes and cataract development in the Philly mouse lens.
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Research Interests: Biochemistry, Chemistry, Kinetics, Polymers, Medicine, and 15 moreBiological Sciences, Xylitol, Animals, Biochemical, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, CHEMICAL SCIENCES, Rats, Polyol, Xylose, Sorbitol, Superoxides, aldose, aldose reductase, polyol pathway, and Medical and Health Sciences
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Niemann-Pick C1 (NPC1) is a fatal neurodegenerative disease caused by aberrant cholesterol metabolism. The progression of the disease can be slowed by removing excess cholesterol with high-doses of 2-hyroxypropyl-beta-cyclodextrin... more
Niemann-Pick C1 (NPC1) is a fatal neurodegenerative disease caused by aberrant cholesterol metabolism. The progression of the disease can be slowed by removing excess cholesterol with high-doses of 2-hyroxypropyl-beta-cyclodextrin (HPβCD). Unfortunately, HPβCD causes hearing loss; the initial first phase involves a rapid destruction of outer hair cells (OHCs) while the second phase, occurring 4-6 weeks later, involves the destruction of inner hair cells (IHCs), pillar cells, collapse of the organ of Corti and spiral ganglion neuron degeneration. To determine whether the first and/or second phase of HPβCD-induced cochlear damage is linked, in part, to excess oxidative stress or neuroinflammation, rats were treated with a single-dose of 3000 mg/kg HPβCD alone or together with one of two combination therapies. Each combination therapy was administered from 2-days before to 6-weeks after the HPβCD treatment. Combination 1 consisted of minocycline, an antibiotic that suppresses neuroinflammation, and HK-2, a multifunctional redox modulator that suppresses oxidative stress. Combination 2 was comprised of minocycline plus N-acetyl cysteine (NAC), which upregulates glutathione, a potent antioxidant. To determine if either combination therapy could prevent HPβCD-induced hearing impairment and cochlear damage, distortion product otoacoustic emissions (DPOAE) were measured to assess OHC function and the cochlear compound action potential (CAP) was measured to assess the function of IHCs and auditory nerve fibers. Cochleograms were prepared to quantify the amount of OHC, IHC and pillar cell (PC) loss. HPβCD significantly reduced DPOAE and CAP amplitudes and caused significant OHC, IHC and OPC losses with losses greater in the high-frequency base of the cochlea than the apex. Neither minocycline + HK-2 (MIN+ HK-2) nor minocycline + NAC (MIN+NAC) prevented the loss of DPOAEs, CAPs, OHCs, IHCs or IPCs caused by HPβCD. These results suggest that oxidative stress and neuroinflammation are unlikely to play major roles in mediating the first or second phase of HPβCD-induced cochlear damage. Thus, HPβCD-induced ototoxicity must be mediated by some other unknown cell-death pathway possibly involving loss of trophic support from damaged support cells or disrupted cholesterol metabolism.
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Oxidative stress is a major contributor to noise-induced hearing loss, the most common cause of hearing loss among military personnel and young adults. HK-2 is a potent, orally-active, multifunctional, redox-modulating drug that has been... more
Oxidative stress is a major contributor to noise-induced hearing loss, the most common cause of hearing loss among military personnel and young adults. HK-2 is a potent, orally-active, multifunctional, redox-modulating drug that has been shown to protect against a wide range of neurological disorders with no observed side effects. HK-2 protected cochlear HEI-OC1 cells against various forms of experimentally-induced oxidative stressors similar to those observed during and after intense noise exposure. The mechanisms by which HK-2 protects cells is twofold, first by its ability to reduce oxidative stress generated by free radicals, and second, by its ability to complex biologically active transition metals such as Fe+2, thus reducing their availability to participate in the Fenton reaction where highly toxic hydroxyl radicals are generated. For the rat in vivo studies, HK-2 provided significant protection against noise-induced hearing loss and hair cell loss. Noise-induced hearing loss was induced by an 8-16 kHz octave band noises presented for 8 h/d for 21 days at an intensity of 95 dB SPL. In the Prevention study, HK-2 was administered orally beginning 5 days before the start of the noise and ending 10 days after the noise. Treatment with HK-2 dose-dependently reduced the amount of noise-induced hearing impairment, reflected in the cochlear compound action potential, and noise-induced hair cell loss. In a subsequent Rescue experiment in which HK-2 was administered for 10 days starting after the noise was turned off, HK-2 also significantly reduced the amount of hearing impairment, but the effect size was substantially less than in the Prevention studies. HK-2 alone did not adversely affect HEI-OC1 cell viability, nor did it cause any adverse changes in rat body weight, behavior, cochlear function or hair cell integrity. Thus, HK-2 is a novel, safe, orally-deliverable and highly effective otoprotective compound with considerable potential for preventing hearing loss from noise and other hearing disorders linked to excessive oxidative stress.
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Research Interests: Ophthalmology, Preventive medicine, Medicine, Dogs, Diabetes mellitus, and 15 moreDiabetic Retinopathy, Animals, Male, Retina, Cataract, Retinal, Public health systems and services research, Curriculum and Pedagogy, Cataracts, Imidazoles, Galactose Binding, Retinopathy, Imidazolidines, aldose reductase, and Retinal vessels
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Research Interests: Diabetes, Biology, Cornea, Medicine, Conjunctiva, and 10 moreHumans, Optic Nerve, Retina, Eye, Aged, Middle Aged, Adult, Staining, aldose reductase, and Medical and Health Sciences
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The present management of diabetes consists of attempting to control blood sugar tightly in the normal range and to treat individual complications such as neuropathy and retinopathy as they appear. Whereas these measures are perhaps... more
The present management of diabetes consists of attempting to control blood sugar tightly in the normal range and to treat individual complications such as neuropathy and retinopathy as they appear. Whereas these measures are perhaps effective in slowing the progress of diabetic complications, they do not cure the underlying process. The aldose reductase inhibitors have been investigated as possible remedies for various diabetic complications. Aldose reductase is an enzyme present in several human tissues that reduces glucose to sorbitol. In animal models there is evidence that the production of sorbitol is associated with the development of diabetic complications. Animal and human studies have tested the ability of aldose reductase inhibitors to halt or reverse diabetic complications. The weight of evidence leads to two conclusions: first, that aldose reductase inhibitors may bring significant relief to patients with certain diabetic complications; and second, that the current approach to proving clinical efficacy may not be adequate for these drugs.