Metastable aldehydes produced by lipid peroxidation act as 'toxic second messengers' that extend the injurious potential of free radicals. 4-hydroxy 2-nonenal (HNE), a highly toxic and most abundant ...stable end product of lipid peroxidation, has been implicated in the tissue damage, dysfunction, injury associated with aging and other pathological states such as cancer, Alzheimer, diabetes, cardiovascular and inflammatory complications. Further, HNE has been considered as a oxidative stress marker and it act as a secondary signaling molecule to regulates a number of cell signaling pathways. Biological activity of HNE depends on its intracellular concentration, which can differentially modulate cell death, growth and differentiation. Therefore, the mechanisms responsible for maintaining the intracellular levels of HNE are most important, not only in the defense against oxidative stress but also in the pathophysiology of a number of disease processes. In this review, we discussed the significance of HNE in mediating various disease processes and how regulation of its metabolism could be therapeutically effective.
The present investigation deals with the synthesis of ternary transition metal alloy nanoparticles of FeCoNi and graphene templated FeCoNi (FeCoNi@GS) by one-pot reflux method and there use as a ...catalyst for hydrogen sorption in MgH2. It has been found that the MgH2 catalyzed by FeCoNi@GS (MgH2: FeCoNi@GS) has the onset desorption temperature of ~255 °C which is 25 °C and 100 °C lower than MgH2 catalyzed by FeCoNi (MgH2: FeCoNi) (onset desorption temperature 280 °C) and the ball-milled (B.M) MgH2 (onset desorption temperature 355 °C) respectively. Also MgH2: FeCoNi@GS shows enhanced kinetics by absorbing 6.01 wt% within just 1.65 min at 290 °C under 15 atm of hydrogen pressure. This is much-improved sorption as compared to MgH2: FeCoNi and B.M MgH2 for which hydrogen absorption is 4.41 wt% and 1.45 wt% respectively, under the similar condition of temperature, pressure and time. More importantly, the formation enthalpy of MgH2: FeCoNi@GS is 58.86 kJ/mol which is 19.26 kJ/mol lower than B.M: MgH2 (78.12 kJ/mol). Excellent cyclic stability has also been found for MgH2: FeCoNi@GS even up to 24 cycles where it shows only negligible change from 6.26 wt% to 6.24 wt%. A feasible catalytic mechanism of FeCoNi@GS on MgH2 has been put forward based on X-ray diffraction (XRD), Raman spectroscopy, Fourier Transform Infrared Spectroscopy (FTIR), X-Ray Photoelectron Spectroscopy (XPS), and microstructural (electron microscopic) studies.
Synthesis of ternary FeCoNi@GS alloy by one pot method and its application as catalyst for improving de/rehydrogenation properties of MgH2. Display omitted
•Synthesis of FeCoNi@GS by one pot method.•FeCoNi@GS has been used as catalyst for MgH2.•MgH2 catalyzed by FeCoNi@GS show excellent cyclability.•Formation enthalpy of MgH2: FeCoNi@GS is reduced by 19.26 kJ/mol of H2 as compared to ball milled MgH2.
Aldose reductase (AR) is widely expressed aldehyde-metabolizing enzyme. The reduction of glucose by the AR-catalyzed polyol pathway has been linked to the development of secondary diabetic ...complications. Although treatment with AR inhibitors has been shown to prevent tissue injury in animal models of diabetes, the clinical efficacy of these drugs remains to be established. Recent studies suggest that glucose may be an incidental substrate of AR, which appears to be more adept in catalyzing the reduction of a wide range of aldehydes generated from lipid peroxidation. Moreover, inhibition of the enzyme has been shown to increase inflammation-induced vascular oxidative stress and prevent myocardial protection associated with the late phase of ischemic preconditioning. On the basis of these studies, several investigators have ascribed an important antioxidant role to the enzyme. Additionally, ongoing work indicates that AR is a critical component of intracellular signaling, and inhibition of the enzyme prevents high glucose-, cytokine-, or growth factor-induced activation of protein kinase C and nuclear factor-κ-binding protein. Thus, treatment with AR inhibitors prevents vascular smooth muscle cell growth and endothelial cell apoptosis in culture and inflammation and restenosis in vivo. Additional studies indicate that the antioxidant and signaling roles of AR are interlinked and that AR regulates protein kinase C and nuclear factor-κB via redox-sensitive mechanisms. These data underscore the need for reevaluating anti-AR interventions for the treatment of diabetic complications. Potentially, the development of newer drugs that selectively inhibit ARmediated glucose metabolism and signaling, without affecting aldehyde detoxification, may be useful in preventing inflammation associated with the development of diabetic complications, particularly micro- and macrovascular diseases.
Timely identification of individuals "at-risk" for myopia progression is the leading requisite for myopia practice as it aids in the decision of appropriate management. This study aimed to develop ...'myopia progression risk assessment score' (MPRAS) based on multiple risk factors (10) to determine whether a myope is "at-risk" or "low-risk" for myopia progression. Two risk-score models (model-1: non-weightage, model-2: weightage) were developed. Ability of MPRAS to diagnose individual "at-risk" for myopia progression was compared against decision of five clinicians in 149 myopes, aged 6-29 years. Using model-1 (no-weightage), further 7 sub-models were created with varying number of risk factors in decreasing step-wise manner (1a: 10 factors to 1g: 4 factors). In random eye analysis for model-1, the highest Youden's J-index (0.63-0.65) led to the MPRAS cut-off score of 41.50-43.50 for 5 clinicians with a sensitivity ranging from 78 to 85% and specificity ranging from 79 to 87%. For this cut-off score, the mean area under the curve (AUC) between clinicians and the MPRAS model ranged from 0.89 to 0.90. Model-2 (weighted for few risk-factors) provided similar sensitivity, specificity, and AUC. Sub-model analysis revealed greater AUC with high sensitivity (89%) and specificity (94%) in model-1g that has 4 risk factors compared to other sub-models (1a-1f). All the MPRAS models showed good agreement with the clinician's decision in identifying individuals "at-risk" for myopia progression.
Although we have shown earlier that aldose reductase (AR) inhibitors prevent colorectal cancer cell (CRC) growth in culture as well as in nude mice xenografts, the mechanism(s) is not well ...understood. In this study, we have investigated how AR inhibition prevents CRC growth by regulating the mitochondrial biogenesis via Nrf2/HO-1 pathway. Incubation of CRC cells such as SW-480, HT29, and HCT116 with AR inhibitor, fidarestat that non-covalently binds to the enzyme, increases the expression of Nrf2. Further, fidarestat augmented the EGF-induced expression of Nrf2 in CRC cells. Fidarestat also increased the Nrf2 -DNA binding activity as well as expression of HO-1 and NQO1 and activation of SOD and catalase in SW480 cells. Similarly, in nude mice xenograft tumor tissues, Nrf2 and HO-1 levels were significantly higher in fidarestat-treated mice compared to controls. Further, stimulation of CRC cells with EGF in the presence of fidarestat increased the mRNA levels of PGC-1α, Nrf1 and TFAM and protein levels of PGC-1α, TFAM and COX-IV and decreased the mitochondrial DNA damage as measured by 8-hydroxy-2′-deoxyguanosine levels. AR inhibitor also modulated the phosphorylations of AMPK and mTOR and expression of p53 in EGF-treated cells. Collectively, our results indicate that AR inhibitor prevents CRC growth by increasing mitochondrial biogenesis via increasing the expression of Nrf2/HO-1/AMPK/p53 and decreasing the mitochondrial DNA damage.
Display omitted Aldose reductase inhibitor, fidarestat prevents cancer cell growth by upregulating AMPK/Nrf2/HO-1/PGC-1α signals.
•Aldose reductase inhibitor increases the activation of Nrf2 and HO-1 in colon cancer cells.•Fidarestat augments EGF-induced increase in the expression of Nrf2 and HO-1.•Fidarestat increases EGF-induced increase in anti-oxidative proteins.•Aldose reductase inhibition enhances mitochondrial biogenesis.•Aldose reductase inhibition prevents mitochondrial DNA Damage.
Anthracycline drugs such as doxorubicin (DOX) and daunorubicin remain some of the most active wide-spectrum and cost-effective drugs in cancer therapy. However, colorectal cancer (CRC) cells are ...inherently resistant to anthracyclines which at higher doses cause cardiotoxicity. Our recent studies indicate that aldose reductase (AR) inhibitors such as fidarestat inhibit CRC growth in vitro and in vivo. Here, we show that treatment of CRC cells with fidarestat increases the efficacy of DOX-induced death in HT-29 and SW480 cells and in nude mice xenografts. AR inhibition also results in higher intracellular accumulation of DOX and decreases the expression of drug transporter proteins MDR1, MRP1, and ABCG2. Further, fidarestat also inhibits DOX-induced increase in troponin-I and various inflammatory markers in the serum and heart and restores cardiac function in mice. These results suggest that fidarestat could be used as adjuvant therapy to enhance DOX sensitivity of CRC cells and to reduce DOX-associated cardiotoxicity.
Aldose reductase (AR), that catalyzes the rate limiting step of the polyol pathway of glucose metabolism, besides reducing glucose to sorbitol, reduces a number of lipid peroxidation – derived ...aldehydes and their glutathione conjugates. Recent studies suggest that apart from its involvement in diabetic complications, AR's catalytic activity plays a key role in a number of inflammatory diseases such as atherosclerosis, sepsis, asthma, uveitis, and colon cancer. Furthermore, AR is overexpressed in human cancers such as liver, colon, breast, cervical and ovarian. Since AR inhibitors have already undergone up to phase-iii clinical trials for diabetic complications, they could be safe anti-inflammatory drugs. Therefore the future use of AR inhibitors in down-regulating major inflammatory pathologies such as cancer and cardiovascular diseases could relieve some of the major health concerns of worldwide.
Abstract
Despite recent studies that show oxidative stress–generated reactive oxygen species (ROS) regulate NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome–mediated innate ...immune response in various diabetic complications, the mechanism by which ROS activate innate immune response is not well understood. We have shown previously that aldose reductase (AR), besides reducing glucose, reduces lipid aldehydes and their glutathione conjugates and participates in various oxidative stress–induced inflammatory pathways. To understand the role of AR in ROS-induced innate immune response, we have investigated the mechanism(s) by which AR activates hyperglycemia-induced NLRP3 inflammsome–initiated innate immune response in Thp1 monocytes and in streptozotocin (STZ)-induced diabetic mice. In Thp1 monocytes, inhibition or ablation of AR prevented high-glucose–induced activation of NLRP3 inflammasome and caspase-1 and release of the innate immune cytokines interleukin (IL)-1β and IL-18. AR inhibition in Thp1 cells also prevented the high-glucose–induced generation of ROS, influx of Ca2+, efflux of K+, and activation of Lyn, Syk, and PI3K. Furthermore, the AR inhibitor fidarestat prevented the expression of NLRP inflammasome components in STZ-induced diabetic mouse heart and aorta, and also prevented the release of various cytokines in the serum. Collectively, our data suggest that AR regulates hyperglycemia-induced NLRP3 inflammasome–mediated innate immune response by altering the ROS/Lyn/Syk/PI3K/Ca2+/K+ signals.
This study identifies the role of aldose reductase in regulation of NLRP3 inflammasome–mediated processing of IL-1β in high-glucose–treated Thp1 cells via modulation of ROS/Ca2+/Syk/Lyn pathway.
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Despite doxorubicin (Dox) being one of the most widely used chemotherapy agents for breast, blood and lung cancers, its use in colon cancer is limited due to increased drug resistance ...and severe cardiotoxic side effects that increase mortality associated with its use at high doses. Therefore, better adjuvant therapies are warranted to improve the chemotherapeutic efficacy and to decrease cardiotoxicity. We have recently shown that aldose reductase inhibitor, fidarestat, increases the Dox-induced colon cancer cell death and reduces cardiomyopathy. However, the efficacy of fidarestat in the prevention of Dox-induced endothelial dysfunction, a pathological event critical to cardiovascular complications, is not known. Here, we have examined the effect of fidarestat on Dox-induced endothelial cell toxicity and dysfunction in vitro and in vivo. Incubation of human umbilical vein endothelial cells (HUVECs) with Dox significantly increased the endothelial cell death, and pre-treatment of fidarestat prevented it. Further, fidarestat prevented the Dox-induced oxidative stress, formation of reactive oxygen species (ROS) and activation of Caspase-3 in HUVECs. Fidarestat also prevented Dox-induced monocyte adhesion to HUVECs and expression of ICAM-1 and VCAM-1. Fidarestat pre-treatment to HUVECs restored the Dox-induced decrease in the Nitric Oxide (NO)-levels and eNOS expression. Treatment of HUVECs with Dox caused a significant increase in the activation of NF-κB and expression of various inflammatory cytokines and chemokines which were prevented by fidarestat pre-treatment. Most importantly, fidarestat prevented the Dox-induced mouse cardiac cell hypertrophy and expression of eNOS, iNOS, and 3-Nitrotyrosine in the aorta tissues. Further, fidarestat blunted the Dox-induced expression of various inflammatory cytokines and chemokines in vivo. Thus, our results suggest that by preventing Dox-induced endothelial cytotoxicity and dysfunction, AR inhibitors could avert cardiotoxicity associated with anthracycline chemotherapy.
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