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Search Results: 1 - 10 of 311124 matches for " J. Mark Petrash "
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Inhibition of Aldose Reductase by Gentiana lutea Extracts
Chandrasekhar Akileshwari,Puppala Muthenna,Branislav Nastasijevi ,Gordana Joksi ,J. Mark Petrash,Geereddy Bhanuprakash Reddy
Experimental Diabetes Research , 2012, DOI: 10.1155/2012/147965
Abstract: Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. Thus, ALR2 inhibition could be an effective strategy in the prevention or delay of certain diabetic complications. Gentiana lutea grows naturally in the central and southern areas of Europe. Its roots are commonly consumed as a beverage in some European countries and are also known to have medicinal properties. The water, ethanol, methanol, and ether extracts of the roots of G. lutea were subjected to in vitro bioassay to evaluate their inhibitory activity on the ALR2. While the ether and methanol extracts showed greater inhibitory activities against both rat lens and human ALR2, the water and ethanol extracts showed moderate inhibitory activities. Moreover, the ether and methanol extracts of G. lutea roots significantly and dose-dependently inhibited sorbitol accumulation in human erythrocytes under high glucose conditions. Molecular docking studies with the constituents commonly present in the roots of G. lutea indicate that a secoiridoid glycoside, amarogentin, may be a potential inhibitor of ALR2. This is the first paper that shows G. lutea extracts exhibit inhibitory activity towards ALR2 and these results suggest that Gentiana or its constituents might be useful to prevent or treat diabetic complications.
The Isolation and Characterization of β-Glucogallin as a Novel Aldose Reductase Inhibitor from Emblica officinalis
Muthenna Puppala, Jessica Ponder, Palla Suryanarayana, Geereddy Bhanuprakash Reddy, J. Mark Petrash, Daniel V. LaBarbera
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031399
Abstract: Diabetes mellitus is recognized as a leading cause of new cases of blindness. The prevalence of diabetic eye disease is expected to continue to increase worldwide as a result of the dramatic increase in the number of people with diabetes. At present, there is no medical treatment to delay or prevent the onset and progression of cataract or retinopathy, the most common causes of vision loss in diabetics. The plant Emblica officinalis (gooseberry) has been used for thousands of years as a traditional Indian Ayurvedic preparation for the treatment of diabetes in humans. Extracts from this plant have been shown to be efficacious against the progression of cataract in a diabetic rat model. Aldose reductase (ALR2) is implicated in the development of secondary complications of diabetes including cataract and, therefore, has been a major drug target for the development of therapies to treat diabetic disease. Herein, we present the bioassay-guided isolation and structure elucidation of 1-O-galloyl-β-D-glucose (β-glucogallin), a major component from the fruit of the gooseberry that displays selective as well as relatively potent inhibition (IC50 = 17 μM) of AKR1B1 in vitro. Molecular modeling demonstrates that this inhibitor is able to favorably bind in the active site. Further, we show that β-glucogallin effectively inhibits sorbitol accumulation by 73% at 30 μM under hyperglycemic conditions in an ex-vivo organ culture model of lenses excised from transgenic mice overexpressing human ALR2 in the lens. This study supports the continued development of natural products such as β-glucogallin as therapeutic leads in the development of novel therapies to treat diabetic complications such as cataract.
Deletion of Aldose Reductase from Mice Inhibits Diabetes-Induced Retinal Capillary Degeneration and Superoxide Generation
Jie Tang, Yunpeng Du, J. Mark Petrash, Nader Sheibani, Timothy S. Kern
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0062081
Abstract: Purpose Pharmacologic inhibition of aldose reductase (AR) previously has been studied with respect to diabetic retinopathy with mixed results. Since drugs can have off-target effects, we studied the effects of AR deletion on the development and molecular abnormalities that contribute to diabetic retinopathy. Since recent data suggests an important role for leukocytes in the development of the retinopathy, we determined also if AR in leukocytes contributes to leukocyte-mediated death of retinal endothelial cells in diabetes. Methods Wild-type (WT; C57BL/6J) and AR deficient (AR?/?) mice were made diabetic with streptozotocin. Mice were sacrificed at 2 and 10 months of diabetes to evaluate retinal vascular histopathology, to quantify retinal superoxide production and biochemical and physiological abnormalities in the retina, and to assess the number of retinal endothelial cells killed by blood leukocytes in a co-culture system. Results Diabetes in WT mice developed the expected degeneration of retinal capillaries, and increased generation of superoxide by the retina. Leukocytes from diabetic WT mice also killed more retinal endothelial cells than did leukocytes from nondiabetic animals (p<0.0001). Deletion of AR largely (P<0.05) inhibited the diabetes-induced degeneration of retinal capillaries, as well as the increase in superoxide production by retina. AR-deficiency significantly inhibited the diabetes-induced increase in expression of inducible nitric oxide synthase (iNOS) in retina, but had no significant effect on expression of intercellular adhesion molecule-1 (ICAM-1), phosphorylated p38 MAPK, or killing of retinal endothelial cells by leukocytes. Conclusions AR contributes to the degeneration of retinal capillaries in diabetic mice. Deletion of the enzyme inhibits the diabetes-induced increase in expression of iNOS and of superoxide production, but does not correct a variety of other pro-inflammatory abnormalities associated with the development of diabetic retinopathy.
New Horizons in Research on Diabetic Complications of the Eye: Special Emphasis on Diabetic Cataracts and Retinopathy
Kavita R. Hegde,Renu A. Kowluru,Susanne Mohr,Ram H. Nagaraj,J. Mark Petrash
Journal of Ophthalmology , 2010, DOI: 10.1155/2010/979040
Abstract:
Inhibition of Aldose Reductase by Gentiana lutea Extracts
Chandrasekhar Akileshwari,Puppala Muthenna,Branislav Nastasijevi?,Gordana Joksi?,J. Mark Petrash,Geereddy Bhanuprakash Reddy
Journal of Diabetes Research , 2012, DOI: 10.1155/2012/147965
Abstract: Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. Thus, ALR2 inhibition could be an effective strategy in the prevention or delay of certain diabetic complications. Gentiana lutea grows naturally in the central and southern areas of Europe. Its roots are commonly consumed as a beverage in some European countries and are also known to have medicinal properties. The water, ethanol, methanol, and ether extracts of the roots of G. lutea were subjected to in vitro bioassay to evaluate their inhibitory activity on the ALR2. While the ether and methanol extracts showed greater inhibitory activities against both rat lens and human ALR2, the water and ethanol extracts showed moderate inhibitory activities. Moreover, the ether and methanol extracts of G. lutea roots significantly and dose-dependently inhibited sorbitol accumulation in human erythrocytes under high glucose conditions. Molecular docking studies with the constituents commonly present in the roots of G. lutea indicate that a secoiridoid glycoside, amarogentin, may be a potential inhibitor of ALR2. This is the first paper that shows G. lutea extracts exhibit inhibitory activity towards ALR2 and these results suggest that Gentiana or its constituents might be useful to prevent or treat diabetic complications. 1. Introduction According to the latest WHO estimates, currently approximately 200 million people all over the world are suffering from diabetes. This may increase to at least 350 million by the year 2025, which could have a severe impact on human health [1]. Prolonged exposure to chronic hyperglycemia in diabetes can lead to various complications affecting the cardiovascular, renal, neurological, and visual systems [2]. Although mechanisms leading to diabetic complications are not completely understood, many biochemical pathways associated with hyperglycemia have been implicated [2]. Among these, the polyol pathway has been extensively studied [3]. Aldose reductase (ALR2; EC: 1.1.1.21) belongs to aldo-keto reductases (AKR) super family. It is the first and rate-limiting enzyme in the polyol pathway where it reduces glucose to sorbitol utilizing NADPH as a cofactor. Subsequently, sorbitol dehydrogenase catalyzes the conversion of sorbitol to fructose, thus constituting the polyol pathway [3]. Accumulation of sorbitol leads to osmotic swelling, changes in membrane permeability, and also oxidative stress culminating in tissue injury [4]. Experimental animal models suggest
Aldo-Keto Reductases in the Eye
Shun Ping Huang,Suryanarayana Palla,Philip Ruzycki,Ross Arjun Varma,Theresa Harter,G. Bhanuprakesh Reddy,J. Mark Petrash
Journal of Ophthalmology , 2010, DOI: 10.1155/2010/521204
Abstract: Aldose reductase (AKR1B1) is an NADPH-dependent aldo-keto reductase best known as the rate-limiting enzyme of the polyol pathway. Accelerated glucose metabolism through this pathway has been implicated in diabetic cataract and retinopathy. Some human tissues contain AKR1B1 as well as AKR1B10, a closely related member of the aldo-keto reductase gene superfamily. This opens the possibility that AKR1B10 may also contribute to diabetic complications. The goal of the current study was to characterize the expression profiles of AKR1B1 and AKR1B10 in the human eye. Using quantitative reverse transcriptase-PCR and immunohistochemical staining, we observed expression of both AKR genes in cornea, iris, ciliary body, lens, and retina. Expression of AKR1B1 was the highest in lens and retina, whereas AKR1B10 was the highest in cornea. Lenses from transgenic mice designed for overexpression of AKR1B10 were not significantly different from nontransgenic controls, although a significant number developed a focal defect in the anterior lens epithelium following 6 months of experimentally induced diabetes. However, lenses from AKR1B10 mice remained largely transparent following longterm diabetes. These results indicate that AKR1B1 and AKR1B10 may have different functional properties in the lens and suggest that AKR1B10 does not contribute to the pathogenesis of diabetic cataract in humans.
Aldo-Keto Reductases in the Eye
Shun Ping Huang,Suryanarayana Palla,Philip Ruzycki,Ross Arjun Varma,Theresa Harter,G. Bhanuprakesh Reddy,J. Mark Petrash
Journal of Ophthalmology , 2010, DOI: 10.1155/2010/521204
Abstract: Aldose reductase (AKR1B1) is an NADPH-dependent aldo-keto reductase best known as the rate-limiting enzyme of the polyol pathway. Accelerated glucose metabolism through this pathway has been implicated in diabetic cataract and retinopathy. Some human tissues contain AKR1B1 as well as AKR1B10, a closely related member of the aldo-keto reductase gene superfamily. This opens the possibility that AKR1B10 may also contribute to diabetic complications. The goal of the current study was to characterize the expression profiles of AKR1B1 and AKR1B10 in the human eye. Using quantitative reverse transcriptase-PCR and immunohistochemical staining, we observed expression of both AKR genes in cornea, iris, ciliary body, lens, and retina. Expression of AKR1B1 was the highest in lens and retina, whereas AKR1B10 was the highest in cornea. Lenses from transgenic mice designed for overexpression of AKR1B10 were not significantly different from nontransgenic controls, although a significant number developed a focal defect in the anterior lens epithelium following 6 months of experimentally induced diabetes. However, lenses from AKR1B10 mice remained largely transparent following longterm diabetes. These results indicate that AKR1B1 and AKR1B10 may have different functional properties in the lens and suggest that AKR1B10 does not contribute to the pathogenesis of diabetic cataract in humans. 1. Introduction Diabetes mellitus is recognized as a leading cause of new cases of blindness among Americans between the ages of 20 and 74. At least 5,000 new cases of legalblindness result each year from diabetic retinopathy alone [1]. The incidence of cataract is also much higher in diabetic than in nondiabetic individuals [2]. Many theories have been advanced to explain the pathogenesis of diabetic eye disease. These include excess formation of advanced glycation end-products [3], activation of PKC isoforms [4], activation of the polyol pathway [5], and excessive oxidative stress [6]. Considerable evidence points to excess conversion of glucose to sorbitol, mediated by aldose reductase (AKR1B1),as a key factor in diabetic cataract formation. AKR1B1-mediated polyol accumulation causes osmotic imbalances that lead to fiber cell swelling, liquefaction, and eventually cataract [5]. Compelling evidence to support this hypothesis came from Lee and coworkers, who created a transgenic mouse model that expressed high levels of AKR1B1 in lens fiber cells [7]. These mice developed cataracts following diabetes induction, demonstrating an essential role for AKR1B1 in mediating high
Visionary genomics
J Petrash, Philip A Ruzycki, Gregory J Zablocki
Human Genomics , 2011, DOI: 10.1186/1479-7364-5-6-519
Abstract: We have come a very long way since the days of John Dalton and his 1794 paper on the origins of colour blindness, a condition he shared with his brother [1]. Investigators from the vision research community have worked out the major pathways of how visual information is received, processed and transmitted to the brain, and how specialised tissues such as the cornea and lens work together to focus light on the retina and filter out harmful ultraviolet light. Molecular pathways responsible for the expression and accumulation of crystallins, the specialised proteins that make up 35 per cent of the wet weight of the ocular lens, have been discovered and studied in great detail. Genes for virtually all components of the phototransduction cascade have been identified and studied to define a host of molecular defects associated with anomalous perception of the visual world.Now that we have a comprehensive understanding of the genes responsible for the organisation and functional integration of the visual system, it is reasonable to consider the challenges posed by major heritable vision diseases that either are not treatable or for which current therapies cannot meet the global burden of disease. We can ponder whether the emergence of next-generation genome technologies will lead us closer to discovering new therapeutic strategies and achieving improved care of patients with vision disorders. Two major blinding conditions, age-related macular degeneration (AMD) and glaucoma, can serve as useful examples to highlight how far we have come, and how far we have yet to go, in our understanding of genetic influence on disease pathogenesis.AMD is the leading cause of blindness in people aged over 60 years in North America. Many commonalities have been associated with the complex manifestation of AMD, including accumulation of excess oxidised lipoproteins in the form of drusen; atrophy of the retinal pigment epithelium; formation of new blood vessels in the choroid; and environmen
On Some Numbers Related to the Erdös-Szekeres Theorem  [PDF]
Mark J. Nielsen, William Webb
Open Journal of Discrete Mathematics (OJDM) , 2013, DOI: 10.4236/ojdm.2013.33030
Abstract:

A crossing family of segments is a collection of segments each pair of which crosses. Given positive integers j and k,a(j,k) grid is the union of two pairwise-disjoint collections of segments (with j and k members, respectively) such that each segment in the first collection crosses all members of the other. Let c(k) be the least integer such that any planar set of c(k) points in general position generates a crossing family of k segments. Also let #(j,k) be the least integer such that any planar set of #(j,k) points in general position generates a (j,k)-grid. We establish here the facts 9≤c(3)≤16 and #(1,2)=8.


Do Clusters Influence Productivity in China’s Software Industry?  [PDF]
Mark J. Purdy, Xiao Chang
Theoretical Economics Letters (TEL) , 2014, DOI: 10.4236/tel.2014.41005
Abstract:

Based on data from 2007 to 2011 across 29 provinces in China, this paper employs a panel-based econometric model to investigate the impact of clusters (of firms and educational institutions) and R & D investment in driving productivity in China’s software industry. In respect of clusters, our results show that a one percent increase in the density of firm clusters leads to a 0.10 percent increase in productivity; for clusters of educational institutions, a significantly positive impact on productivity in coastal regions has been identified. In terms of R & D investment, a one percent increase in R & D expenditure per R & D worker leads to a 0.22 percent increase in productivity, although the effect is significantly reduced in coastal region. For policymakers, the results of this study shed light on the effectiveness of different levers in narrowing regional productivity gaps. It can also help business leaders make better decisions regarding their innovation activities.

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