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1.  Aldose Reductase Inhibition Suppresses Oxidative Stress-Induced Inflammatory Disorders 
Chemico-biological interactions  2011;191(1-3):330-338.
Oxidative stress-induced inflammation is a major contributor to several disease conditions including sepsis, carcinogenesis and metastasis, diabetic complications, allergic asthma, uveitis and after cataract surgery posterior capsular opacification. Since reactive oxygen species (ROS)-mediated activation of redox-sensitive transcription factors and subsequent expression of inflammatory cytokines, chemokines and growth factors are characteristics of inflammatory disorders, we envisioned that by blocking the molecular signals of ROS that activate redox-sensitive transcription factors, various inflammatory diseases could be ameliorated. We have indeed demonstrated that ROS –induced lipid peroxidation-derived lipid aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) and their glutathione-conjugates (e.g. GS-HNE) are efficiently reduced by aldose reductase to corresponding alcohols which mediate the inflammatory signals. Our results showed that inhibition of aldose reductase (AKR1B1) significantly prevented the inflammatory signals induced by cytokines, growth factors, endotoxins, high glucose, allergens and auto-immune reactions in cellular as well as animal models. We have demonstrated that AKR1B1 inhibitor, fidarestat, significantly prevents tumor necrosis factor-alpha (TNF-α)-, growth factors-, lipopolysachharide (LPS)-, and environmental allergens-induced inflammatory signals that cause various inflammatory diseases. In animal models of inflammatory diseases such as diabetes, cardiovascular, uveitis, asthma, and cancer (colon, breast, prostate and lung) and metastasis, inhibition of AKR1B1 significantly ameliorated the disease. Our results from various cellular and animal models representing a number of inflammatory conditions suggest that ROS-induced inflammatory response could be reduced by inhibition of AKR1B1, thereby decreasing the progression of the disease and if the therapy is initiated early, the disease could be eliminated. Since fidarestat has already undergone phase III clinical trial for diabetic neuropathy and found to be safe, though clinically not very effective, our results indicate that it can be developed for the therapy of a number of inflammation- related diseases. Our results thus offer a novel therapeutic approach to treat a wide array of inflammatory diseases.
PMCID: PMC3103634  PMID: 21354119
inflammation; oxidative stress; aldose reductase; ROS; colon cancer; uveitis; asthma
2.  Aldose reductase deficiency in mice prevents azoxymethane-induced colonic preneoplastic aberrant crypt foci formation 
Carcinogenesis  2008;30(5):799-807.
Aldose reductase (AR; EC, an nicotinamide adenine dinucleotide phosphate-dependent aldo–keto reductase, has been shown to be involved in oxidative stress signaling initiated by inflammatory cytokines, chemokines and growth factors. Recently, we have shown that inhibition of this enzyme prevents the growth of colon cancer cells in vitro as well as in nude mice xenografts. Herein, we investigated the mediation of AR in the formation of colonic preneoplastic aberrant crypt foci (ACF) using azoxymethane (AOM)-induced colon cancer mice model. Male BALB/c mice were administrated with AOM without or with AR inhibitor, sorbinil and at the end of the protocol, all the mice were euthanized and colons were evaluated for ACF formation. Administration of sorbinil significantly lowered the number of AOM-induced ACF. Similarly, AR-null mice administered with AOM demonstrated significant resistance to ACF formation. Furthermore, inhibition of AR or knockout of AR gene in the mice significantly prevented AOM-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 proteins as well as their messenger RNA. AR inhibition or knockdown also significantly decreased the phosphorylation of protein kinase C (PKC) β2 and nuclear factor kappa binding protein as well as expression of preneoplastic marker proteins such as cyclin D1 and β-catenin in mice colons. Our results suggest that AR mediates the formation of ACF in AOM-treated mice and thereby inhibition of AR could provide an effective chemopreventive approach for the treatment of colon cancer.
PMCID: PMC2722145  PMID: 19028703
3.  Human and rodent aldo-keto reductases from the AKR1B subfamily and their specificity with retinaldehyde 
Chemico-biological interactions  2011;191(1-3):199-205.
NADP(H)-dependent cytosolic aldo-keto reductases (AKR) are mostly monomeric enzymes which fold into a typical (α/β)8-barrel structure. Substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable loops (A, B, and C). Based on sequence identity, AKR have been grouped into families, namely AKR1–AKR15, containing multiple subfamilies. Two human enzymes from the AKR1B subfamily (AKR1B1 and AKR1B10) are of special interest. AKR1B1 (aldose reductase) is related to secondary diabetic complications, while AKR1B10 is induced in cancer cells and is highly active with all-trans-retinaldehyde. Residues interacting with all-trans-retinaldehyde and differing between AKR1B1 and AKR1B10 are Leu125Lys and Val131Ala (loop A), Leu301Val, Ser303Gln, and Cys304Ser (loop C). Recently, we demonstrated the importance of Lys125 as a determinant of AKR1B10 specificity for retinoids. Residues 301 and 304 are also involved in interactions with substrates or inhibitors, and thus we checked their contribution to retinoid specificity. We also extended our study with retinoids to rodent members of the AKR1B subfamily: AKR1B3 (aldose reductase), AKR1B7 (mouse vas deferens protein), AKR1B8 (fibroblast-growth factor 1-regulated protein), and AKR1B9 (Chinese hamster ovary reductase), which were tested against all-trans isomers of retinaldehyde and retinol. All enzymes were active with retinaldehyde, but with kcat values (0.02–0.52 min−1) much lower than that of AKR1B10 (27 min−1). None of the enzymes showed oxidizing activity with retinol. Since these enzymes (except AKR1B3) have Lys125, other residues should account for retinaldehyde specificity. Here, by using site-directed mutagenesis and molecular modeling, we further delineate the contribution of residues 301 and 304. We demonstrate that besides Lys125, Ser304 is a major structural determinant for all-trans-retinaldehyde specificity of AKR1B10.
PMCID: PMC3103653  PMID: 21329680
aldo-keto reductases; aldose reductase; retinoic acid; side-directed mutagenesis
4.  Aldo–Keto Reductase 1B10 and Its Role in Proliferation Capacity of Drug-Resistant Cancers 
The human aldo–keto reductase AKR1B10, originally identified as an aldose reductase-like protein and human small intestine aldose reductase, is a cytosolic NADPH-dependent reductase that metabolizes a variety of endogenous compounds, such as aromatic and aliphatic aldehydes and dicarbonyl compounds, and some drug ketones. The enzyme is highly expressed in solid tumors of several tissues including lung and liver, and as such has received considerable interest as a relevant biomarker for the development of those tumors. In addition, AKR1B10 has been recently reported to be significantly up-regulated in some cancer cell lines (medulloblastoma D341 and colon cancer HT29) acquiring resistance toward chemotherapeutic agents (cyclophosphamide and mitomycin c), suggesting the validity of the enzyme as a chemoresistance marker. Although the detailed information on the AKR1B10-mediated mechanisms leading to the drug resistance process is not well understood so far, the enzyme has been proposed to be involved in functional regulations of cell proliferation and metabolism of drugs and endogenous lipids during the development of chemoresistance. This article reviews the current literature focusing mainly on expression profile and roles of AKR1B10 in the drug resistance of cancer cells. Recent developments of AKR1B10 inhibitors and their usefulness in restoring sensitivity to anticancer drugs are also reviewed.
PMCID: PMC3269042  PMID: 22319498
aldo–keto reductase 1B10; chemotherapy; resistance; proliferation
5.  Molecular Mechanisms and Clinical Implications of Reversible Protein S-Glutathionylation 
Antioxidants & Redox Signaling  2008;10(11):1941-1988.
Sulfhydryl chemistry plays a vital role in normal biology and in defense of cells against oxidants, free radicals, and electrophiles. Modification of critical cysteine residues is an important mechanism of signal transduction, and perturbation of thiol–disulfide homeostasis is an important consequence of many diseases. A prevalent form of cysteine modification is reversible formation of protein mixed disulfides (protein–SSG) with glutathione (GSH). The abundance of GSH in cells and the ready conversion of sulfenic acids and S-nitroso derivatives to S-glutathione mixed disulfides suggests that reversible S-glutathionylation may be a common feature of redox signal transduction and regulation of the activities of redox sensitive thiol-proteins. The glutaredoxin enzyme has served as a focal point and important tool for evolution of this regulatory mechanism, because it is a specific and efficient catalyst of protein–SSG deglutathionylation. However, mechanisms of control of intracellular Grx activity in response to various stimuli are not well understood, and delineation of specific mechanisms and enzyme(s) involved in formation of protein–SSG intermediates requires further attention. A large number of proteins have been identified as potentially regulated by reversible S-glutathionylation, but only a few studies have documented glutathionylation-dependent changes in activity of specific proteins in a physiological context. Oxidative stress is a hallmark of many diseases which may interrupt or divert normal redox signaling and perturb protein–thiol homeostasis. Examples involving changes in S-glutathionylation of specific proteins are discussed in the context of diabetes, cardiovascular and lung diseases, cancer, and neurodegenerative diseases. Antioxid. Redox Signal, 10, 1941–1988.
Potential Mechanisms of Protein–SSG Formation
Thiol-disulfide exchange
Sulfenic acid intermediates
Sulfenylamide intermediates
Thiyl radical intermediates
Thiosulfinate intermediates
S-Nitrosylated intermediates
Potential Catalysis of Protein Glutathionylation
Flavoprotein sulfhydryl oxidease (QSOX)
Other potential mechanisms of catalysis/control of protein S-glutathionylation
Proteomics of Discovery of Potential Protein–SSG Intermediates
Deglutathionylation (Reversal) of Protein–SSG: Properties of the Glutaredoxin Enzymes
Glutaredoxin Mechanism of Action
Modualtion of Grx Expression
Diabetes and Implications of Changes in S-Glutathionylation Status
Mechanism of hyperglycemic damage and ROS
Insulin-glucose dynamics and diabetes complications
Glucose metabolism: aldose reductase–SSG (Fig. 3, step 1a)
K+ channels: Grx regulated (Fig. 3, step 2a)
ATP-sensitive potassium channels
Voltage-gated potassium channels
Ca2+ channels: SERCA-SSG and Grx-reversible RyR-SSG (Fig. 3, step 3a)
Insulin exocytosis: Grx regulated (Fig. 3 step 6a)
Insulin receptor: Grx-reversible PTP1B-SSG (Fig. 3, step 6b)
Signal transduction [Fig. 3, Ras-SSG (step 7b), MEKK-SSG (step 8b), c-Jun-SSG (step 9b), Akt-SSG (step 10b), IKK-SSG (step 11b), NF-κB(p50)-SSG (steps 5a and 12b), and PKC-SSG (step 4a)]
Summary and discussion: Grx as a therapeutic target in diabetic complications
Cardiovascular Diseases and Alterations in Protein-S-Glutathionylation Status
Myocardial infarction
Protein kinase C (PKC)
Protein kinase A (PKA)
Nuclear factor κB (NF-κB)
Nonspecific oxidative injury
Cardiac hypertrophy
Implications of Protein S-Glutathionylation in Lung Disease
Tobacco exposure
Hyperoxic injury
Fibrotic and granulomatous diseases
Chronic obstructuve pulmonary disease (COPD)
Implications of Reversible Protein S-Glutathionylation in Cancer
Thiol oxidation and cancer
S-Glutathionylation and signal transduction in cancer
S-Glutathionylation and modulation of kinase/phosphatase signaling pathways
Protein kinase C (PKC)
I3 kinase and Akt
Protein tryosine phosphatase
c-Jun N-terminal kinase (JKN)
S-Glutathionylation and modulation of the proteasome pathway
S-Glutathionylation and modulation of transcription factors (c-Jun, NF-κB, p53, AP-1)
AP-1, c-Jun
Modulation of S-glutathionylation as a chemotherapeutic strategy for cancer
Implications of Protein S-Glutathionylation in Neurodegenerative Diseases
Oxidative stress and neurodegeneration
Sources of reactive oxygen and nitrogen species in brain
Alzheimer's disease
Parkinson's disease
Huntington's disease
Amyotrophic lateral sclerosis
Freidreich's ataxia
Glutaredoxin and neurodegeneration
Proteins associated with neurodegeneration that are redox regulated through S-glutathionylation
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDPm)
Tyrosine hydroxylase
Cytosolic calcium regulators
Proteasome degradation pathway
α-Ketoglutarate dehydrogenase
Summary and Conclusions
Frontier Areas of Investigation
PMCID: PMC2774718  PMID: 18774901
6.  Aldo-keto reductase 1 family B7 is the gene induced in response to oxidative stress in the livers of Long-Evans Cinnamon rats 
International journal of oncology  2006;29(4):829-838.
The Long-Evans Cinnamon (LEC) rat strain (Atp7b m/m), which accumulates copper in the liver due to mutations in the Atp7b gene, is a useful model for investigating the relationship between oxidative stress and hepatocarcinogenesis. To determine the effect of this mutation on oxidative stress marker genes, we performed oligonucleotide array analysis (Affymetrix), and compared the results in Atp7b m/m rats with those of a sibling line with the Atp7b w/w genotype. We focused our studies on the expression of the aldo-keto reductase 1 family B7 (AKR1B7)-like protein gene, since this gene codes for reductase enzymes involved in the detoxification of oxidizing compounds (e.g., aldehydes) and was differentially expressed in Atp7b m/m and Atp7b w/w rat liver. Akr1B7 mRNA expression was significantly increased in comparison with the expression of 4 other known oxidative stress responsive genes, haem-oxygenase-1 (HO-1), thioredoxin (Trx), aldehyde reductase (AKR1A1), and glucose-6-phosphate dehydrogenase (G6PDH). By searching binding motifs, five nuclear factor kappa B (NF-κB) binding sites were located in the 5′-upstream region of the Akr1b7 gene. Transient co-transfection with both I-κBα and the Akr1b7 6 kb promoter (p6.0-AKR-Luc) inhibited luciferase activity of p6.0-AKR-Luc in HepG2 cells. Cuprous ion however did not affect the transcription activity induced by p6.0-AKR-Luc. Gel-shift assay showed that the DNA binding activity of NF-κB increased in the livers of LEC rats, suggesting that the oxidative stress is mediated through NF-κB. The results indicate conclusively that in LEC rat liver, Akr1b7 might be up-regulated by oxidative stress mediated through NF-κB, but not that mediated directly by copper.
PMCID: PMC2329797  PMID: 16964378
AKR1B7; oxidative stress; oligonucleotide array; real-time PCR; Long Evans Cinnamon rat
7.  ALDOSE REDUCTASE: New Insights for an Old Enzyme 
Biomolecular concepts  2011;2(1-2):103-114.
In the past years aldose reductase (AKR1B1; AR) is thought to be involved in the pathogenesis of secondary diabetic complications such as retinopathy, neuropathy, nephropathy and cataractogenesis. Subsequently, a number of AR inhibitors have been developed and tested for diabetic complications. Although, these inhibitors have found to be safe for human use, they have not been successful at the clinical studies because of limited efficacy. Recently, the potential physiological role of AR has been reassessed from a different point of view. Diverse groups suggested that AR besides reducing glucose, also efficiently reduces oxidative stress-generated lipid peroxidation-derived aldehydes and their glutathione conjugates. Since lipid aldehydes alter cellular signals by regulating the activation of transcription factors such as NF-kB and AP1, inhibition of AR could inhibit such events. Indeed, a wide array of recent experimental evidence indicates that the inhibition of AR prevents oxidative stress-induced activation of NF-kB and AP1 signals that lead to cell death or growth. Further, AR inhibitors have been shown to prevent inflammatory complications such as sepsis, asthma, colon cancer and uveitis in rodent animal models. The new experimental in-vitro and in-vivo data has provided a basis for investigating the clinical efficacy of AR inhibitors in preventing other inflammatory complications than diabetes. This review describes how the recent studies have identified novel plethoric physiological and pathophysiological significance of AR in mediating inflammatory complications, and how the discovery of such new insights for this old enzyme could have considerable importance in envisioning potential new therapeutic strategies for the prevention or treatment of inflammatory diseases.
PMCID: PMC3085285  PMID: 21547010
Aldose reductase; inflammation; oxidative stress; sepsis; cancer; uveitis; diabetes
8.  Aldose Reductase Mediates Endotoxin-Induced Production of Nitric oxide and Cytotoxicity in Murine Macrophages. 
Free radical biology & medicine  2007;42(8):1290-1302.
Aldose reductase (AR) is a ubiquitously expressed protein with pleiotrophic roles as an efficient catalyst for the reduction of toxic lipid aldehydes and mediator of hyperglycemia, cytokine and growth factor –induced redox sensitive signals that cause secondary diabetic complications. Although AR inhibition has been shown to be protective against oxidative stress signals, the role of AR in regulating nitric oxide (NO) synthesis and NO-mediated apoptosis has not been elucidated to date. We therefore investigated the role of AR in regulating lipopolysaccharide (LPS)-induced NO synthesis and apoptosis in RAW 264.7 macrophages. Inhibition or RNA interference ablation of AR suppressed LPS-stimulated production of NO and over-expression of iNOS mRNA. Inhibition or ablation of AR also prevented the LPS-induced apoptosis, cell cycle arrest, activation of caspase-3, p38-MAPK, JNK, NF-κB and AP1. In addition, AR inhibition prevented the LPS-induced down-regulation of Bcl-xl and up-regulation of Bax and Bak in macrophages. L-arginine increased and L-NAME decreased the severity of cell death caused by LPS and AR inhibitors prevented it. Furthermore, inhibition of AR prevents cell death caused by HNE and GS-HNE, but not GS-DHN. Our findings for the first time suggest that AR catalyzed lipid aldehyde-glutathione conjugates regulates the LPS-induced production of inflammatory marker NO and cytotoxicity in RAW 264.7 cells. Inhibition or ablation of AR activity may be potential therapeutic target in endotoximia and other inflammatory diseases.
PMCID: PMC1885210  PMID: 17382209
aldose reductase; sepsis; apoptosis; LPS; nitric oxide
9.  Inhibition of Aldose Reductase Prevents Angiogenesis in vitro and in vivo 
Angiogenesis  2011;14(2):209-221.
We have recently shown that aldose reductase (AR, EC a nicotinamide adenine dinucleotide phosphate-dependent aldo-keto reductase, known to be involved in oxidative stress-signaling, prevents human colon cancer cell growth in culture as well as in nude mice xenografts. Inhibition of AR also prevents azoxymethane-induced aberrant crypt foci formation in mice. In order to understand the chemopreventive mechanism(s) of AR inhibition in colon cancer, we have investigated the role of AR in the mediation of angiogenic signals in vitro and in vivo models. Our results show that inhibition of AR significantly prevented the VEGF- and FGF -induced proliferation and expression of proliferative marker Ki67 in the human umbilical vein endothelial cells (HUVEC). Further, AR inhibition or ablation with siRNA prevented the VEGF-and FGF –induced invasion and migration in HUVEC. AR inhibition also prevented the VEGF-and FGF- induced secretion/expression of IL-6, MMP2, MMP9, ICAM, and VCAM. The anti-angiogenic feature of AR inhibition in HUVEC was associated with inactivation of PI3K/AKT and NF-κB (p65) and suppression of VEGF receptor 2 protein levels. Most importantly, matrigel plug model of angiogenesis in rats showed that inhibition of AR prevented infiltration of blood cells, invasion, migration and formation of capillary like structures, and expression of blood vessels markers CD31 and vWF. Thus, our results demonstrate that AR inhibitors could be novel agents to prevent angiogenesis.
PMCID: PMC3103619  PMID: 21409599
Aldose reductase; angiogenesis; endothelial cells; cancer; inflammation
10.  Identification of biochemical pathways for the metabolism of oxidized low-density lipoprotein derived aldehyde-4-hydroxy trans-2-nonenal in vascular smooth muscle cells 
Atherosclerosis  2001;158(2):339-350.
Oxidation of low-density lipoproteins (LDL) generates high concentrations of unsaturated aldehydes, such as 4-hydroxy trans-2-nonenal (HNE). These aldehydes are mitogenic to vascular smooth muscle cells and sustain a vascular inflammation. Nevertheless, the processes that mediate and regulate the vascular metabolism of these aldehydes have not been examined. In this communication, we report the identification of the major metabolic pathways and products of [3H]-HNE in rat aortic smooth muscle cells in culture. High-performance liquid chromatography separation of the radioactivity recovered from these cells revealed that a large (60–65%) proportion of the metabolism was linked to glutathione (GSH). Electrospray mass spectrometry showed that glutathionyl-1,4 dihydroxynonene (GS-DHN) was the major metabolite of HNE in these cells. The formation of GS-DHN appears to be due aldose reductase (AR)-catalyzed reduction of glutathionyl 4-hydroxynonanal (GS-HNE), since inhibitors of AR (tolrestat or sorbinil) prevented GS-DHN formation, and increased the fraction of the glutathione conjugate remaining as GS-HNE. Gas chromatography–chemical ionization mass spectroscopy of the metabolites identified a subsidiary route of HNE metabolism leading to the formation of 4-hydroxynonanoic acid (HNA). Oxidation to HNA accounted for 25–30% of HNE metabolism. The formation of HNA was inhibited by cyanamide, indicating that the acid is derived from an aldehyde dehydrogenase (ALDH)-catalyzed pathway. The overall rate of HNE metabolism was insensitive to inhibition of AR or ALDH, although inhibition of HNA formation by cyanamide led to a corresponding increase in the fraction of HNE metabolized by the GSH-linked pathway, indicating that ALDH-catalyzed oxidation competes with glutathione conjugation. These metabolic pathways may be the key regulators of the vascular effects of HNE and oxidized LDL.
PMCID: PMC3469324  PMID: 11583712
Lipid peroxidation; 4-Hydroxy-trans-2-nonenal; Glutathione conjugates; Aldose reductase; Vascular smooth muscle cells; Atherosclerosis
11.  AKR1B10 is induced by hyperglycaemia and lipopolysaccharide in patients with diabetic nephropathy 
Cell Stress & Chaperones  2013;19(2):281-287.
Aldose reductase family member B10 (AKR1B10) belongs to the aldo–keto reductase gene superfamily and is closely related to aldose reductase (AKR1B1). It has been shown that AKR1B10 is present in many of the same human tissues as AKR1B1. The objective of this study was to investigate whether AKR1B10 has a role in diabetic nephropathy (DN) by investigating its response to high glucose and inflammation, both of which have been associated with the development and progression of DN. Expression levels of AKR1B10 were determined in peripheral blood mononuclear cells (PBMCs) obtained from 25 patients with type 1 diabetes and nephropathy, 25 without DN and 25 normal healthy controls that were exposed to high glucose (25 mM d-glucose) and also the inflammatory stressor lipopolysaccharide (LPS, 10 μm). Under high glucose and LPS conditions, there was a significant increase in the expression of AKR1B10 in the PBMCs from patients with DN compared to those without DN and the normal controls. In conclusion, these results suggest that AKR1B10 may have an important role in the development and progression of DN.
PMCID: PMC3933614  PMID: 23975544
Aldose reductase family member B10; Aldose reductase; Diabetic nephropathy; High glucose; Inflammation; Type 1 diabetes
12.  Purification and Characterization of a Novel Erythrose Reductase from Candida magnoliae 
Erythritol biosynthesis is catalyzed by erythrose reductase, which converts erythrose to erythritol. Erythrose reductase, however, has never been characterized in terms of amino acid sequence and kinetics. In this study, NAD(P)H-dependent erythrose reductase was purified to homogeneity from Candida magnoliae KFCC 11023 by ion exchange, gel filtration, affinity chromatography, and preparative electrophoresis. The molecular weights of erythrose reductase determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel filtration chromatography were 38,800 and 79,000, respectively, suggesting that the enzyme is homodimeric. Partial amino acid sequence analysis indicates that the enzyme is closely related to other yeast aldose reductases. C. magnoliae erythrose reductase catalyzes the reduction of various aldehydes. Among aldoses, erythrose was the preferred substrate (Km = 7.9 mM; kcat/Km = 0.73 mM−1 s−1). This enzyme had a dual coenzyme specificity with greater catalytic efficiency with NADH (kcat/Km = 450 mM−1 s−1) than with NADPH (kcat/Km = 5.5 mM−1 s−1), unlike previously characterized aldose reductases, and is specific for transferring the 4-pro-R hydrogen of NADH, which is typical of members of the aldo/keto reductase superfamily. Initial velocity and product inhibition studies are consistent with the hypothesis that the reduction proceeds via a sequential ordered mechanism. The enzyme required sulfhydryl compounds for optimal activity and was strongly inhibited by Cu2+ and quercetin, a strong aldose reductase inhibitor, but was not inhibited by aldehyde reductase inhibitors and did not catalyze the reduction of the substrates for carbonyl reductase. These data indicate that the C. magnoliae erythrose reductase is an NAD(P)H-dependent homodimeric aldose reductase with an unusual dual coenzyme specificity.
PMCID: PMC165123  PMID: 12839736
13.  Generation and Biological Activities of Oxidized Phospholipids 
Antioxidants & Redox Signaling  2010;12(8):1009-1059.
Glycerophospholipids represent a common class of lipids critically important for integrity of cellular membranes. Oxidation of esterified unsaturated fatty acids dramatically changes biological activities of phospholipids. Apart from impairment of their structural function, oxidation makes oxidized phospholipids (OxPLs) markers of “modified-self” type that are recognized by soluble and cell-associated receptors of innate immunity, including scavenger receptors, natural (germ line-encoded) antibodies, and C-reactive protein, thus directing removal of senescent and apoptotic cells or oxidized lipoproteins. In addition, OxPLs acquire novel biological activities not characteristic of their unoxidized precursors, including the ability to regulate innate and adaptive immune responses. Effects of OxPLs described in vitro and in vivo suggest their potential relevance in different pathologies, including atherosclerosis, acute inflammation, lung injury, and many other conditions. This review summarizes current knowledge on the mechanisms of formation, structures, and biological activities of OxPLs. Furthermore, potential applications of OxPLs as disease biomarkers, as well as experimental therapies targeting OxPLs, are described, providing a broad overview of an emerging class of lipid mediators. Antioxid. Redox Signal. 12, 1009–1059.
I. Mechanisms of Phospholipid Oxidation
A. Oxidation of PLs: General mechanisms and biologically acitive products
B. Initiation of oxidation
1. Nonenzymatic oxidation of PL-PUFAs
2. Sources of free radicals inducing oxidation of PLs
3. Oxidation of PUFAs by nonradical ROS
4. Nitration and halogenation of PLs
5. Enzymatic oxidation of PUFA-PLs
C. Evolution of OxPLs
1. Formation of polyoxygenated PLs
2. Cyclization of peroxyl radical/generation of nonfragmented OxPLs
a. Esterified isoprostanes
b. Esterified isothromboxanes
c. Esterified isolevuglandins
d. Esterified isofurans
3. Oxidative cleavage/formation of fragmented OxPL species
a. Oxidatively truncated unsaturated OxPLs
b. Oxidatively truncated saturated OxPLs
D. Termination of PL-oxidation and detoxification of reactive OxPLs
1. Enzymatic reduction of hydroperoxides
2. Reduction of carbonyls in OxPLs by aldo-keto reductases
3. OxPL cleavage
E. Formation of adducts
II. (Patho)physiological Effects of OxPLs
A. OxPLs as markers of “modified self”
1. OxPLs as antigens
2. OxPLs as ligands for scavenger receptors
3. OxPLs as ligands for CRP
B. Modulation of intracellular signalling by OxPLs
1. Signal-transducing receptors initiating effects of OxPLs
a. PAF receptors
b. Prostaglandin receptors
c. Scavenger receptors
d. VEGF receptors
e. Sphingosine-1-phosphate (S1P) receptor 1
f. Toll-like receptor 4
g. PPARα and PPARγ
h. Nonreceptor mechanisms
2. Second messengers upregulated by OxPLs
a. Elevation of Ca2+i
b. Elevation of cAMP
3. Intracellular signalling pathways activated by OxPLs
a. Protein kinases and phosphatases activated by OxPLs
b. Small GTPases regulated by OxPLs
4. Transcription factors mediating effects of OxPLs
5. Cellular stress pathways activated by OxPLs
a. Electrophilic stress response
b. Unfolded protein response
c. Membrane stress
d. Apoptosis-related signaling
III. Accumulation and Potential Role of OxPLs in Pathology
A. Major biological activities of OxPLs
1. Proinflammatory effects of OxPLs
a. Cell adhesion molecules activated by OxPLs
b. Chemokines
c. Direct effects of OxPLs on leukocytes
2. Effects of OxPLs on generation of ROS
3. Effects of OxPLs on blood coagulation and activation of platelets
a. Modulation of blood coagulation
b. Activation of platelets
4. Modulation of vascular smooth muscle cell phenotype
5. Angiogenic activity of OxPLs
6. Calcification of atherosclerotic lesions and bone
7. Anti-inflammatory activities
a. Modulation of TLR activity
b. Induction of antioxidant and anti-inflammatory genes
c. Inhibition of oxidative burst
d. Lung barrier protection
8. Effects of OxPLs on cytoskeleton, noninflammmatory cell adhesion, and permeability of endothelium
a. Cytoskeletal mechanisms of endothelial permeability
b. OxPAPC and EC permeability
c. OxPAPC and cytoskeletal remodeling
d. OxPAPC and assembly of adherens junctions
e. OxPAPC induces FA-AJ interactions
f. Gap junctions and tight junctions
9. Regulation of adaptive immunity
a. Modulation of dendritic cell function by OxPLs
b. Induction of T cell anergy by OxPLs
B. Accumulation and role of OxPLs in specific pathologies
1. Atherosclerosis
2. Acute inflammation
3. Lung injury
a. Oxidative stress and generation of OxPLs in lungs
b. Proinflammatory effects of OxPLs in the lungs: SARS, anthrax, H5N1 avian influenza virus, and acid-induced lung injury
c. Anti-inflammatory and barrier-protective effects of OxPAPC in models of acute lung injury
d. Summary: Dual effects of OxPLs in lung pathology
4. Ischemia
5. Light- and radiation-induced stress
6. Leprosy
7. Multiple sclerosis
IV. OxPLs as Biomarkers of Disease and Targets for Therapy
A. Association of OxPL levels with disease
1. Methods of quantification of OxPLs
B. Experimental therapies involving inactivation of OxPLs
1. HDL and apolipoprotein peptide mimetics
2. CS-1 fibronectin peptide mimetics
3. Immunization against OxPLs: Vaccine against atherosclerosis?
C. OxPLs as targets for imaging techniques
V. Open Questions and Perspectives
PMCID: PMC3121779  PMID: 19686040
14.  Glutathionylated Lipid Aldehydes Are Products of Adipocyte Oxidative Stress and Activators of Macrophage Inflammation 
Diabetes  2013;63(1):89-100.
Obesity-induced insulin resistance has been linked to adipose tissue lipid aldehyde production and protein carbonylation. Trans-4-hydroxy-2-nonenal (4-HNE) is the most abundant lipid aldehyde in murine adipose tissue and is metabolized by glutathione S-transferase A4 (GSTA4), producing glutathionyl-HNE (GS-HNE) and its metabolite glutathionyl-1,4-dihydroxynonene (GS-DHN). The objective of this study was to evaluate adipocyte production of GS-HNE and GS-DHN and their effect on macrophage inflammation. Compared with lean controls, GS-HNE and GS-DHN were more abundant in visceral adipose tissue of ob/ob mice and diet-induced obese, insulin-resistant mice. High glucose and oxidative stress induced production of GS-HNE and GS-DHN by 3T3-L1 adipocytes in a GSTA4-dependent manner, and both glutathionylated metabolites induced secretion of tumor necrosis factor-α from RAW 264.7 and primary peritoneal macrophages. Targeted microarray analysis revealed GS-HNE and GS-DHN induced expression of inflammatory genes, including C3, C4b, c-Fos, igtb2, Nfkb1, and Nos2. Transgenic overexpression of GSTA4 in mouse adipose tissue led to increased production of GS-HNE associated with higher fasting glucose levels and moderately impaired glucose tolerance. These results indicated adipocyte oxidative stress results in GSTA4-dependent production of proinflammatory glutathione metabolites, GS-HNE and GS-DHN, which may represent a novel mechanism by which adipocyte dysfunction results in tissue inflammation and insulin resistance.
PMCID: PMC3868039  PMID: 24062247
15.  Inhibition of Aldose Reductase Prevents Experimental Allergic Airway Inflammation in Mice 
PLoS ONE  2009;4(8):e6535.
The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR), contributes to the pathogenesis of oxidative stress–induced inflammation by affecting the NF-κB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma.
Methods and Findings
Primary Human Small Airway Epithelial Cells (SAEC) were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE)-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-κB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS), cycloxygenase (COX)-2, Prostaglandin (PG) E2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and airway hyperresponsiveness. Our results indicate that inhibition of AR prevents airway inflammation and production of inflammatory cytokines, accumulation of eosinophils in airways and sub-epithelial regions, mucin production in the bronchoalveolar lavage fluid and airway hyperresponsiveness in mice.
These results suggest that airway inflammation due to allergic response to RWE, which subsequently activates oxidative stress-induced expression of inflammatory cytokines via NF-κB-dependent mechanism, could be prevented by AR inhibitors. Therefore, inhibition of AR could have clinical implications, especially for the treatment of airway inflammation, a major cause of asthma pathogenesis.
PMCID: PMC2717330  PMID: 19657391
16.  255 Chronic Obstructive Pulmonary Disease and Lung Cancer Share Inflammation Pathways 
The World Allergy Organization Journal  2012;5(Suppl 2):S100-S101.
The relationship between inflammation, air obstruction and lung cancer is complex and there is still great uncertainty regarding their underlying pathophysiology. Our aim was to investigate the inflammation pathways that are implicated in both chronic obstructive pulmonary disease (COPD) and lung cancer.
A literature search was performed in PubMed to identify relative studies published until June 2011.
The pathophysiology of both COPD and lung cancer includes dysregulation of the inflammation process, but the cascade of signaling events is not yet fully understood. Both lung cancer and COPD are associated with cigarette smoking that induces a chronic inflammatory state in the lung by generating reactive oxidant species. It is considered that shared inflammatory pathways involve genetic and epigenetic changes due to chronic tissue injury and abnormal tumor immunity in susceptible hosts. The proposed role of chronic inflammation is based on the 2-stage model of carcinogenesis. According to this model, genotoxic injury is crucial in tumorigenesis, followed by promotional events that result in clonal growth of modulated cells. Research has shown that chronic inflammation creates the necessary environment for the development of lung cancer, acting as a tumor promoter. This environment, in combination with cigarette smoke, induces the upregulation of mediators of the inflammatory response, such as cyclooxygenase-2. This leads to the production of inflammatory cytokines through lymphocytes, such as IL-1, IL-6, IL-8 and IL-10, as well as to the increased formation of chemotactic factors. Some of the latter mediators may suppress cell mediated immune response and promote angiogenesis. They also impact cell growth, resulting in the inhibition of apoptosis. Inflammatory factors promote oxidative stress, contribute to the generation of reactive oxygen, and cause oxidative DNA base modification. COX-2 also plays an important role in promoting epithelial-to-mesenchymal transition, present in both lung cancer and COPD. Thus, chronic inflammation plays a pathogenic role in lung cancer by inducing preneoplastic mutations and cellular damage.
Additional research is required to understand the cellular and molecular mechanisms that link COPD and lung cancer, in an effort to discover new methods of prevention and treatment.
PMCID: PMC3513135
17.  Inhibition of Aldose Reductase Prevents Growth Factor – Induced G1/S Phase Transition via AKT/PI3K/E2F-1 Pathway in Human Colon Cancer Cells 
Molecular cancer therapeutics  2010;9(4):813-824.
Colon cancer is the leading cause of cancer death in both men and women worldwide. The deregulated cell cycle control or decreased apoptosis of normal epithelial cells leading to uncontrolled proliferation is one of the major features of tumor progression. We have previously shown that aldose reductase (AR), a NADPH dependent- aldo-keto reductase, has been shown to be involved in growth factors–induced proliferation of colon cancer cells. Herein, we report that inhibition of AR prevents epidermal growth factor (EGF) - and basic fibroblast growth factor (bFGF)–induced HT29 cell proliferation by accumulating cells at G1 phase of cell cycle. Similar results were observed in SW480 and HCT-116 colon cancer cells. Treatment of HT29 cells with AR inhibitor, sorbinil or zopolrestat prevented EGF– and bFGF-induced DNA binding activity of E2F-1 and phosphorylation of retinoblastoma protein. Inhibition of AR also prevented EGF– and bFGF-induced phosphorylation of cyclin-dependent kinase (cdk)-2 and expression of G1/S transition regulatory proteins such as cyclin D1, cdk-4, PCNA, cyclin E and c-myc. More importantly, inhibition of AR prevented the EGF– and bFGF-induced activation of PI3K/AKT and reactive oxygen species generation in colon cancer cells. Further, inhibition of AR also prevented the tumor growth of human colon cancer cells in nude mice xenografts. Collectively, these results show that AR mediates EGF– and bFGF–induced colon cancer cell proliferation by activating/expressing G1/S phase proteins such as E2F-1, cdks and cyclins through ROS/PI3K/AKT indicating the use of AR inhibitors in the prevention of colon carcinogenesis.
PMCID: PMC2946635  PMID: 20354121
Aldose reductase; cell cycle; E2F-1; colon cancer; cyclins
18.  Functional studies of aldo-keto reductases in Saccharomyces cerevisiae* 
Biochimica et biophysica acta  2006;1773(3):321-329.
We utilized the budding yeast Saccharomyces cerevisiae as a model to systematically explore physiological roles for yeast and mammalian aldo-keto reductases. Six open reading frames encoding putative aldo-keto reductases were identified when the yeast genome was queried against the sequence for human aldose reductase, the prototypical mammalian aldo-keto reductase. Recombinant proteins produced from five of these yeast open reading frames demonstrated NADPH-dependent reductase activity with a variety of aldehyde and ketone substrates. A triple aldo-keto reductase null mutant strain demonstrated a glucose-dependent heat shock phenotype which could be rescued by ectopic expression of human aldose reductase. Catalytically-inactive mutants of human or yeast aldo-keto reductases failed to effect a rescue of the heat shock phenotype, suggesting that the phenotype results from either an accumulation of one or more unmetabolized aldo-keto reductase substrates or a synthetic deficiency of aldo-keto reductase products generated in response to heat shock stress. These results suggest that multiple aldo-keto reductases fulfill functionally redundant roles in the stress response in yeast.
PMCID: PMC1847606  PMID: 17140678
aldo-keto reductase; aldose reductase; Saccharomyces cerevisiae; mutagenesis; heat shock
19.  Connection between inflammation and carcinogenesis in gastrointestinal tract: Focus on TGF-β signaling 
Inflammation is a primary defense process against various extracellular stimuli, such as viruses, pathogens, foods, and environmental pollutants. When cells respond to stimuli for short periods of time, it results in acute or physiological inflammation. However, if the stimulation is sustained for longer time or a pathological state occurs, it is known as chronic or pathological inflammation. Several studies have shown that tumorigenesis in the gastrointestinal (GI) tract is closely associated with chronic inflammation, for which abnormal cellular alterations that accompany chronic inflammation such as oxidative stresses, gene mutations, epigenetic changes, and inflammatory cytokines, are shared with carcinogenic processes, which forms a critical cross-link between chronic inflammation and carcinogenesis. Transforming growth factor (TGF)-β is a multi-potent cytokine that plays an important role in regulation of cell growth, apoptosis and differentiation. Most importantly, TGF-β is a strong anti-inflammatory cytokine that regulates the development of effector cells. TGF-β has a suppressive effect on carcinogenesis under normal conditions by inhibiting abnormal cell growth, but on the other hand, many GI cancers originate from uncontrolled cell growth and differentiation by genetic loss of TGF-β signaling molecules or perturbation of TGF-β adaptors. Once a tumor has developed, TGF-β exerts a promoting effect on the tumor itself and stromal cells to enhance cell growth, alter the responsiveness of tumor cells to stimulate invasion and metastasis, and inhibited immune surveillance. Therefore, novel development of therapeutic agents to inhibit TGF-β-induced progression of tumor and to retain its growth inhibitory activities, in addition to anti-inflammatory actions, could be useful in oncology. In this review, we discuss the role of TGF-β in inflammation and carcinogenesis of the GI tract related to abnormal TGF-β signaling.
PMCID: PMC2864833  PMID: 20440848
Inflammation; Carcinogenesis; Transforming growth factor-β; Gastrointestinal tract
20.  Disruption of aldo-keto reductase genes leads to elevated markers of oxidative stress and inositol auxotrophy in Saccharomyces cerevisiae 
Biochimica et biophysica acta  2007;1783(2):237-245.
A large family of aldo-keto reductases with similar kinetic and structural properties but unknown physiological roles is expressed in the yeast Saccharomyces cerevisiae. Strains with one or two AKR genes disrupted have apparently normal phenotypes, but disruption of at least three AKR genes results in a heat shock phenotype and slow growth in inositol-deficient culture medium (Ino-). The present study was carried out to identify metabolic or signaling defects that may underlie phenotypes that emerge in AKR deficient strains. Here we demonstrate that pre-treatment of a pentuple AKR null mutant with the anti-oxidative agent N-acetyl-cysteine rescues the heat shock phenotype. This indicates that AKR gene disruption may be associated with defects in oxidative stress response. We observed additional markers of oxidative stress in AKR-deficient strains, including reduced glutathione levels, constitutive nuclear localization of the oxidation-sensitive transcription factor Yap1 and up regulation of a set of Yap1 target genes whose function as a group is primarily involved in response to oxidative stress and redox balance. Genetic analysis of the Ino- phenotype of the null mutants showed that defects in transcriptional regulation of the INO1, which encodes for inositol-1-phosphate synthase, can be rescued through ectopic expression of a functional INO1. Taken together, these results suggest potential roles for AKRs in oxidative defense and transcriptional regulation.
PMCID: PMC2254213  PMID: 17919749
21.  Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell-mediated endothelial cell tube formation: implications for prostate cancer progressioan 
BMC Cancer  2010;10:672.
Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR1C enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we propose a novel pathological function of AKR1C3 in tumor angiogenesis and its potential role in promoting PCa progression.
To recapitulate elevated AKR1C3 expression in cancerous prostate, the human PCa PC-3 cell line was stably transfected with an AKR1C3 expression construct to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analysis were performed to identify AKR1C3-mediated pathways of activation and their potential biological consequences in PC-3 cells. Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and an in vitro Matrigel angiogenesis assays were applied to validate the pro-angiogenic activity of PC3-AKR1C3 transfectants identified by bioinformatics analysis.
Microarray and bioinformatics analysis suggested that overexpression of AKR1C3 in PC-3 cells modulates estrogen and androgen metabolism, activates insulin-like growth factor (IGF)-1 and Akt signaling pathways, as well as promotes tumor angiogenesis and aggressiveness. Levels of IGF-1 receptor (IGF-1R) and Akt activation as well as vascular endothelial growth factor (VEGF) expression and secretion were significantly elevated in PC3-AKR1C3 transfectants in comparison to PC3-mock transfectants. PC3-AKR1C3 transfectants also promoted endothelial cell (EC) tube formation on Matrigel as compared to the AKR1C3-negative parental PC-3 cells and PC3-mock transfectants. Pre-treatment of PC3-AKR1C3 transfectants with a selective IGF-1R kinase inhibitor (AG1024) or a non-selective phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) abolished ability of the cells to promote EC tube formation.
Bioinformatics analysis followed by functional genomics demonstrated that AKR1C3 overexpression promotes angiogenesis and aggressiveness of PC-3 cells. These results also suggest that AKR1C3-mediated tumor angiogenesis is regulated by estrogen and androgen metabolism with subsequent IGF-1R and Akt activation followed by VEGF expression in PCa cells.
PMCID: PMC3013086  PMID: 21134280
22.  Metabolism of the Lipid Peroxidation Product, 4-Hydroxy-trans-2-nonenal, in Isolated Perfused Rat Heart* 
The Journal of biological chemistry  1998;273(18):10893-10900.
The metabolism of 4-hydroxy-trans-2-nonenal (HNE), an α,β-unsaturated aldehyde generated during lipid peroxidation, was studied in isolated perfused rat hearts. High performance liquid chromatography separation of radioactive metabolites recovered from [3H]HNE-treated hearts revealed four major peaks. Based on the retention times of synthesized standards, peak I, which accounted for 20% radioactivity administered to the heart, was identified to be due to glutathione conjugates of HNE. Peaks II and III, containing 2 and 37% radioactivity, were assigned to 1,4-dihydroxy-2-nonene (DHN) and 4-hydroxy-2-nonenoic acid, respectively. Peak IV was due to unmetabolized HNE. The electrospray ionization mass spectrum of peak I revealed two prominent metabolites with m/z values corresponding to [M + H]+ of HNE and DHN conjugates with glutathione. The presence of 4-hydroxy-2-nonenoic acid in peak III was substantiated using gas chromatography-chemical ionization mass spectroscopy. When exposed to sorbinil, an inhibitor of aldose reductase, no GS-DHN was recovered in the coronary effluent, and treatment with cyanamide, an inhibitor of aldehyde dehydrogenase, attenuated 4-hydroxy-2-nonenoic acid formation. These results show that the major metabolic transformations of HNE in rat heart involve conjugation with glutathione and oxidation to 4-hydroxy-2-nonenoic acid. Further metabolism of the GS-HNE conjugate involves aldose reductase-mediated reduction, a reaction catalyzed in vitro by homogenous cardiac aldose reductase.
PMCID: PMC3522116  PMID: 9556565
23.  Biological Role of Aldo–Keto Reductases in Retinoic Acid Biosynthesis and Signaling 
Several aldo–keto reductase (AKR) enzymes from subfamilies 1B and 1C show retinaldehyde reductase activity, having low Km and kcat values. Only AKR1B10 and 1B12, with all-trans-retinaldehyde, and AKR1C3, with 9-cis-retinaldehyde, display high catalytic efficiency. Major structural determinants for retinaldehyde isomer specificity are located in the external loops (A and C for AKR1B10, and B for AKR1C3), as assessed by site-directed mutagenesis and molecular dynamics. Cellular models have shown that AKR1B and 1C enzymes are well suited to work in vivo as retinaldehyde reductases and to regulate retinoic acid (RA) biosynthesis at hormone pre-receptor level. An additional physiological role for the retinaldehyde reductase activity of these enzymes, consistent with their tissue localization, is their participation in β-carotene absorption. Retinaldehyde metabolism may be subjected to subcellular compartmentalization, based on enzyme localization. While retinaldehyde oxidation to RA takes place in the cytosol, reduction to retinol could take place in the cytosol by AKRs or in the membranes of endoplasmic reticulum by microsomal retinaldehyde reductases. Upregulation of some AKR1 enzymes in different cancer types may be linked to their induction by oxidative stress and to their participation in different signaling pathways related to cell proliferation. AKR1B10 and AKR1C3, through their retinaldehyde reductase activity, trigger a decrease in the RA biosynthesis flow, resulting in RA deprivation and consequently lower differentiation, with an increased cancer risk in target tissues. Rational design of selective AKR inhibitors could lead to development of novel drugs for cancer treatment as well as reduction of chemotherapeutic drug resistance.
PMCID: PMC3328219  PMID: 22529810
aldo–keto reductase; retinaldehyde; retinoic acid; retinol; cancer
24.  A potential therapeutic role for aldose reductase inhibitors in the treatment of endotoxin-related inflammatory diseases 
Aldose reductase (AR) initially thought to be involved in the secondary diabetic complications because of its glucose reducing potential. However, evidence from recent studies indicates that AR is an excellent reducer of a number of lipid peroxidation-derived aldehydes as well as their glutathione conjugates, which regulate inflammatory signals initiated by oxidants such as cytokines, growth factors and bacterial endotoxins, and revealed the potential use of AR inhibition as an approach to prevent inflammatory complications.
Areas covered
An extensive Internet and Medline search was performed to retrieve information on understanding the role of AR inhibition in the pathophysiology of endotoxin-mediated inflammatory disorders. Overall, inhibition of AR appears to be a promising strategy for the treatment of endotoxemia, sepsis and other related inflammatory diseases.
Expert opinion
Current knowledge provides enough evidence to indicate that AR inhibition is a logical therapeutic strategy for the treatment of endotoxin-related inflammatory diseases. Since, AR inhibitors have already gone to Phase-iii clinical studies for diabetic complications and found to be safe for human use, their use in endotoxin–related inflammatory diseases could be expedited. However, one of the major challenges will be the discovery of AR regulated clinically-relevant biomarkers to identify susceptible individuals at risk of developing inflammatory diseases, thereby warranting future research in this area.
PMCID: PMC3315185  PMID: 22283786
Aldose Reductase; Endotoxin; Inflammation; Sepsis
25.  Mediation of aldose reductase in lipopolysaccharide –induced inflammatory signals in mouse peritoneal macrophages. 
Cytokine  2006;36(3-4):115-122.
Aldose reductase (AR; AKR1B1) a member of aldoketo reductase super family, that we had shown earlier mediates cytotoxic signals induced by high glucose, cytokines and growth factors, also mediates the inflammatory signals induced by Gram-negative bacterial endotoxin, lipopolysaccharide (LPS). Inhibition of AR by three distinct AR inhibitors sorbinil, tolrestat or zopolrestat suppressed the LPS-induced production of inflammatory cytokines such as TNF-α, IL-6, IL-1β, IFN-γ, and chemokine MCP-1 in murine peritoneal macrophages. Inhibition of AR also prevented the production of nitric oxide, and prostaglandin E2 and expression of iNOS and Cox-2 proteins. The LPS-induced DNA binding activity of NF-κB and AP1 were significantly inhibited by AR inhibitors, and this effect was mediated through the inhibition of phosphorylation of IκB-α, IKK α/β and PKC. These results suggest the therapeutic use of AR inhibitors as anti-inflammatory drugs.
PMCID: PMC1850149  PMID: 17174561
Aldose reductase; sepsis; inflammation; lipopolysaccharide and NF-κB

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