Reactive Aldehydes Research Articles

Neuroprotective effects of Alda-1 mitigate spinal cord injury in mice: involvement of Alda-1-induced ALDH2 activation-mediated suppression of reactive aldehyde mechanisms.

Spinal cord injury (SCI) is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal (4-HNE), a reactive aldehyde, formed by SCI-induced metabolic dysregulation of membrane lipids. Reactive aldehyde load causes redox alteration, neuroinflammation, neurodegeneration, pain-like behaviors, and locomotion deficits. Pharmacological scavenging of reactive aldehydes results in limited improved motor and sensory functions. In this study, we targeted the activity of mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) to detoxify 4-HNE for accelerated functional recovery and improved pain-like behavior in a male mouse model of contusion SCI. N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1), a selective activator of ALDH2, was used as a therapeutic tool to suppress the 4-HNE load. SCI was induced by an impactor at the T9-10 vertebral level. Injured animals were initially treated with Alda-1 at 2 hours after injury, followed by once-daily treatment with Alda-1 for 30 consecutive days. Locomotor function was evaluated by the Basso Mouse Scale, and pain-like behaviors were assessed by mechanical allodynia and thermal algesia. ALDH2 activity was measured by enzymatic assay. 4-HNE protein adducts and enzyme/protein expression levels were determined by western blot analysis and histology/immunohistochemistry. SCI resulted in a sustained and prolonged overload of 4-HNE, which parallels with the decreased activity of ALDH2 and low functional recovery. Alda-1 treatment of SCI decreased 4-HNE load and enhanced the activity of ALDH2 in both the acute and the chronic phases of SCI. Furthermore, the treatment with Alda-1 reduced neuroinflammation, oxidative stress, and neuronal loss and increased adenosine 5'-triphosphate levels stimulated the neurorepair process and improved locomotor and sensory functions. Conclusively, the results provide evidence that enhancing the ALDH2 activity by Alda-1 treatment of SCI mice suppresses the 4-HNE load that attenuates neuroinflammation and neurodegeneration, promotes the neurorepair process, and improves functional outcomes. Consequently, we suggest that Alda-1 may have therapeutic potential for the treatment of human SCI. Animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of MUSC (IACUC-2019-00864) on December 21, 2019.

Lipoperoxide Nanoemulsion as Adjuvant in Cisplatin Cancer Therapy: In Vitro Study on Human Colon Adenocarcinoma DLD-1 Cells.

Cisplatin is a first-choice chemotherapeutic agent used to treat solid tumors even though the onset of multi-drug resistance and the time–dose side-effects impair its mono-therapeutic application. Therefore, new drug-delivery approaches, based on nanomedicine strategies, are needed to enhance its therapeutic potential in favor of a dose-reduction of cisplatin. Polyunsaturated fatty acids and their metabolism-derived intermediates, as well as lipid peroxidation end-products, are used as adjuvants to improve the effectiveness of chemotherapy. Lipid hydroperoxides, derived from the oxidation of edible oils, can contribute to cell death, generating breakdown products (e.g., reactive aldehydes). In this regard, the aim of this present study was to evaluate an invitro combinatory strategy between a lecithin-based nanoemulsion system of K600, a patented mixture of peroxidated oil and peroxidated cholesterol, and cisplatin on DLD1 human adenocarcinoma cells. Our findings showed that nanoemulsions, acting in synergy with cisplatin, improve cisplatin bioactivity, in terms of enhancing its anti-cancer activity, towards DLD1 cells. Indeed, this combination approach, whilst maintaining cisplatin at low concentrations, induces a significant reduction in DLD1 cell viability, an increase in pro-apoptotic markers, and genotoxic damage. Therefore, K600 nanoemulsions as an efficient targeted delivery system of cisplatin allow for the reduction in the chemotherapeutic agent doses.

Rapidly Adaptive All-covalent Nanoparticle Surface Engineering.

Emerging nanotechnologies demand the manipulation of nanoscale components with the same predictability and programmability as is taken for granted in molecular synthetic methodologies. Yet installing appropriately reactive chemical functionality on nanomaterial surfaces has previously entailed compromises in terms of reactivity scope, functionalization density, or both. Here, we introduce an idealized dynamic covalent nanoparticle building block for divergent and adaptive post‐synthesis modification of colloidal nanomaterials. Acetal‐protected monolayer‐stabilized gold nanoparticles are prepared via operationally simple protocols and are stable to long‐term storage. Tunable surface densities of reactive aldehyde functionalities are revealed on‐demand, leading to a wide range of adaptive surface engineering options from one nanoscale synthon. Analytically tractable with molecular precision, interfacial reaction kinetics and dynamic surface constitutions can be probed in situ at the ensemble level. High functionalization densities combined with rapid equilibration kinetics enable environmentally adaptive surface constitutions and rapid nanoparticle property switching in response to simple chemical effectors.

Synthesis of Thio-lignan Analogues, Bioequivalent Salvinal without Unfavored Aldehyde.

The oxygen in the benzofuran (BF) of three antiproliferative natural neolignans, salvinal (1), obovaten (2), and 2-[7-methoxy-2-(4-methoxyphenyl)-3-methylbenzofuran-5-yl]ethanol (3), was replaced with sulfur to form the new biological scaffold benzothiophene (BT) thio-lignans 4-6. Compounds 1-6 and 18 synthesized derivatives were evaluated for antiproliferative activity against five human cancer cell lines, including a multidrug-resistant cell line. Thio-salvinal (4) displayed significant antiproliferative effects with half-maximal inhibitory concentration (IC50) values of 0.57-0.95 μM against all tested cell lines, except for the HER2 negative breast cancer cell line MCF-7. This thio-lignan was 6.5-9.4 times more potent than parent 1. However, the related thio-lignans, 5 and 6, showed much weaker antiproliferative effects than 4 and were less potent than the parent natural benzofuran lignans 2 and 3. Newly synthesized thio-lignan 33 affected cell cycle progression at 24 and 48 h in the G2/M transition and S phase, respectively, as well as promoted sub-G1 induction by stimulating microtubule depolymerization and nuclear fragmentation. Since a highly reactive aldehyde in salvinal is generally not appropriate for drug development, we have successfully found nonaldehyde derivative 33 showing biological activity similar to salvinal by replacing BF with BT and an aldehyde with 1,3-dioxolane.

The plant pathogen enzyme AldC is a long‐chain aliphatic aldehyde dehydrogenase

Aldehyde dehydrogenases are versatile enzymes that serve a range of biochemical functions. Although traditionally considered metabolic housekeeping enzymes because of their ability to detoxify reactive aldehydes, like those generated from lipid peroxidation damage, the contributions of these enzymes to other biological processes are widespread. For example, the plant pathogen Pseudomonas syringae strain PtoDC3000 uses an indole-3-acetaldehyde dehydrogenase to synthesize the phytohormone indole-3-acetic acid to elude host responses. Here we investigate the biochemical function of AldC from PtoDC3000. Analysis of the substrate profile of AldC suggests that this enzyme functions as a long-chain aliphatic aldehyde dehydrogenase. The 2.5 Å resolution X-ray crystal of the AldC C291A mutant in a dead-end complex with octanal and NAD+ reveals an apolar binding site primed for aliphatic aldehyde substrate recognition. Functional characterization of site-directed mutants targeting the substrate- and NAD(H)-binding sites identifies key residues in the active site for ligand interactions, including those in the “aromatic box” that define the aldehyde-binding site. Overall, this study provides molecular insight for understanding the evolution of the prokaryotic aldehyde dehydrogenase superfamily and their diversity of function.

Clinically Relevant Activity of the Novel RASP Inhibitor Reproxalap in Allergic Conjunctivitis: The Phase 3 ALLEVIATE Trial

To assess the post-acute activity and clinical utility of reproxalap, a novel reactive aldehyde species (RASP) inhibitor, versus vehicle in patients with seasonal allergic conjunctivitis. Parallel-group, double-masked, randomized Phase 3 trial. Two topical ocular reproxalap concentrations (0.25% and 0.5%) were evaluated versus vehicle in patients with allergic conjunctivitis randomized 1:1:1 and treated with test article 10 minutes prior to conjunctival seasonal allergen challenge. The primary endpoint was area under the post-acute ocular itching score (range=0-4) curve from 10 to 60 minutes after challenge. The key secondary endpoint was the proportion of subjects with ≥2 points improvement from their peak ocular itching score at baseline. A total of 318 patients were randomized at 11 US sites. Both concentrations of reproxalap (0.25% and 0.5%) achieved the primary endpoint (P < .0001 and P=.003, respectively) and the key secondary endpoint (P=.0005 and P=.02, respectively). Time to complete resolution of ocular itching was statistically faster for both reproxalap concentrations than for vehicle (P < .0001 and P=.001, respectively). No safety or tolerability concerns were noted. The most common adverse event was mild and transient instillation site irritation. Reproxalap was effective at reducing ocular itching in patients with allergic conjunctivitis. Reproxalap activity was clinically relevant, as assessed by responder-based and distributional analyses. ALLEVIATE represents one of the first allergic conjunctivitis Phase 3 trials of a novel mechanism of action in decades, and is unique among conjunctival allergen challenge trials in assessing clinical relevance with standard and validated techniques.

Role of Novel Redox Regulator, MnTnBuOE‐2‐PyP 5+ in Rotenone Induced 4‐HNE Aggresosome Degradation through Autophagy in Cardiomyocytes

Oxidative stress has been linked to pathogenesis of cardiovascular disease. Mitochondria is the major site where reactive oxygen species (ROS) are produced and mainly generated from complex I and complex III of electron transport chain. ROS leads to generation of reactive aldehydes known as 4-hydroxynonenal (4-HNE) through lipid peroxidation. 4-HNE modifies protein through covalent adduction thereby causing their crosslinking, aggregation, and inactivation. It has been little known about degradation of 4-HNE adducted proteins. Autophagy is a dynamic process which maintains cellular homeostasis by removing damaged organelles and protein. There has been use of antioxidant in cardiovascular disease in order to detoxify ROS and ameliorate disease process. Superoxide dismutase (SOD) mimetic, MnTnBuOE-2-PyP5+ has shown to be promising treatment in oxidative stress induced disease pathology because of its specificity to superoxide (O −), high lipophilicity and less toxic profile. In this study, we are trying to explore the role of, MnTnBuOE-2-PyP5+on rotenone induced 4-HNE aggresosome formation and its degradation process in HL-1 cardiomyocyte. Rotenone, a complex I inhibitor treatment (500nM) for 24 hours increased ROS in HL-1 cardiomyocytes. Rotenone treatment led to increase accumulation 4-HNE aggresosome in HL-1 cardiomyocytes. Rotenone treatment induce increase in LC3-II shown by immunoblotting and immunofluorescence. Pre-treatment with MnTnBuOE-2-PyP5+(20 µM) for 24 hours attenuated rotenone induced ROS formation. In addition, pre-treatment with mimetic decreased 4-HNE aggresosome and LC3-II. Rotenone induced increase in autophagosome was attenuated by pre-treatment with MnTnBuOE-2-PyP5+ as shown by fluorescent-tagged LC3 (tfLC3). Rotenone induced tubulin hyperacetylation through ROS mediated pathway which was attenuated by MnTnBuOE-2-PyP5+. These results indicate that pre-treatment with MnTnBuOE-2-PyP5+ decrease rotenone induced 4-HNE aggresosome by enhancing their degradation process.

Direct Resinification of Konjac Glucomannan via Hot-Press Compression Molding

Hot-press compression molding was used to resinify a renewable source-derived linear 1,4-linked β-D-glucan copolymer, i.e., konjac glucomannan (KGM), via the generation of reactive aldehyde groups that tend to crosslink with hydroxyl groups of the glucans. The optimal molding temperature was found to be around 170 °C, with keeping the pressure at 20 MPa for 3.5 min and controlling the water content of the starting KGM powder to be around 22%. The molded KGM resin sheets were found to be crystallized in the annealed KGM polymorph form. Dynamic mechanical analysis revealed that the softening initiation temperature of the KGM resin was ca. 100 °C due to an onset of an increase in the loss modulus, E’’. The representative KGM resin sheets obtained under the optimal molding conditions were transparent, colored brown, and exhibited a tensile strength of 20.8 ± 4.5 MPa, Young’s modulus of 2.2 ± 0.3 GPa and elongation at break of 1.1 ± 0.2%.

Para‐Functionalization of N‐Substituted 4‐amino[2.2]paracyclophanes by Regioselective Formylation

AbstractHerein, we report a simple and convenient procedure to prepare para‐disubstituted [2.2]paracyclophanes in a straightforward manner. Our approach relies on a regioselective formylation of N‐substituted 4‐amino[2.2]paracyclophanes, which allows an easy access to a series of products incorporating a reactive aldehyde function para to the electron‐donating group. These compounds can be engaged in a variety of orthogonal late‐stage derivatization processes involving either the carbonyl group or the amine function, and can serve as precursors to rapidly access more complex paracyclophane derivatives. Control of planar chirality is also possible by performing a kinetic resolution of key racemic intermediates through asymmetric transfer hydrogenation. The formylation can be run on a synthetically useful scale, thus confirming the practical applicability of our method.

The Onset of Systemic Oxidative Stress Associated with the Accumulation of Lipid Peroxidation Product Acrolein in the Skin of Patients with Small-Vessel Vasculitis.

Small-vessel vasculitis (SVV) is the inflammation of the vessel wall that can result in hemorrhage and/or ischemia. Among the histological findings in SVV are increased infiltrating neutrophils, which, due to their oxidative burst and myeloperoxidase activity, release excessive reactive oxygen species, triggering a chain reaction of lipid peroxidation and yielding reactive aldehydes such as acrolein. The implication of oxidative stress in the pathogenesis of SVV was studied, focusing on acrolein immunohistochemistry in the affected skin vessels and systemic stress response. Samples from SVV patients and healthy subjects were collected and analyzed for total serum peroxides, total antioxidant capacity, inflammatory and immunological parameters, as well as for the presence of acrolein–protein adducts in the skin tissue specimens. The obtained data showed that systemic redox homeostasis and iron metabolism are altered in SVV patients. Possible biomarkers in the evaluation of oxidative status, disease activity and prevalence were indicated. Furthermore, a strong correlation between the accumulation of acrolein–protein adducts in the skin and the progression of the disease was revealed. Thus, the results of this study demonstrate that SVV is not only associated with systemic oxidative stress but also with tissue-specific oxidative stress that promotes acrolein formation and protein modification correlating with the severity of cutaneous vasculitis.

Autoantibodies Against Methylglyoxal-Modified Apolipoprotein B100 and ApoB100 Peptide Are Associated With Less Coronary Artery Atherosclerosis and Retinopathy in Long-Term Type 1 Diabetes

OBJECTIVEMethylglyoxal (MGO), a reactive aldehyde forming advanced glycation end products (AGEs), is increased in diabetes and recognized by the immune system, resulting in anti-AGE–specific autoantibodies. The association of these immune responses with macro- and microvascular complications in type 1 diabetes remains unclarified. We investigated associations between MGO-modified apolipoprotein B100 (apoB100) and apoB100 peptide 5 (MGO-p5) autoantibodies and coronary atherosclerosis and retinopathy in type 1 diabetes.RESEARCH DESIGN AND METHODSIgM and IgG against MGO-apoB100 and MGO-p5 were measured by ELISA in plasma from 103 subjects with type 1 diabetes and 63 control subjects (Dialong study) and in a replication cohort of 27 subjects with type 1 diabetes (Oslo study). Coronary atherosclerosis was assessed by computed tomography coronary angiography or intravascular ultrasound. Retinopathy was classified by retinal photos.RESULTSMGO-apoB100 IgM and MGO-p5 IgM levels were higher in subjects with diabetes with no coronary artery stenosis compared with subjects with significant stenosis (median [interquartile range]: 96.2 arbitrary units [AU] [71–126.8] vs. 54 AU [36.1–85.4], P = 0.003 for MGO-apoB100; and 77.4 AU [58–106] vs. 36.9 AU [28.9–57.4], P = 0.005 for MGO-p5). MGO-apoB100 IgM and MGO-p5 IgM were associated with less severe coronary stenosis after adjusting for confounders (odds ratio 0.2 [95% CI 0.05–0.6], P = 0.01; and 0.22 [0.06–0.75], P = 0.02). The inverse association of MGO-p5 IgM and coronary stenosis was confirmed in the replication cohort. Subjects with proliferative retinopathy had significantly lower MGO-apoB100 IgM and MGO-p5 IgM than those with background retinopathy.CONCLUSIONSAutoantibodies against AGE-modified apoB100 are inversely associated with coronary atherosclerosis and proliferative retinopathy, suggesting vascular protective effects of these autoantibodies in type 1 diabetes.

Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite β-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.

Knowns and Unknowns of Vitamin B6 Metabolism in Escherichia coli.

Vitamin B6 is an ensemble of six interconvertible vitamers: pyridoxine (PN), pyridoxamine (PM), pyridoxal (PL), and their 5'-phosphate derivatives, PNP, PMP, and PLP. Pyridoxal 5'-phosphate is a coenzyme in a variety of enzyme reactions concerning transformations of amino and amino acid compounds. This review summarizes all known and putative PLP-binding proteins found in the Escherichia coli MG1655 proteome. PLP can have toxic effects since it contains a very reactive aldehyde group at its 4' position that easily forms aldimines with primary and secondary amines and reacts with thiols. Most PLP is bound either to the enzymes that use it as a cofactor or to PLP carrier proteins, protected from the cellular environment but at the same time readily transferable to PLP-dependent apoenzymes. E. coli and its relatives synthesize PLP through the seven-step deoxyxylulose-5-phosphate (DXP)-dependent pathway. Other bacteria synthesize PLP in a single step, through a so-called DXP-independent pathway. Although the DXP-dependent pathway was the first to be revealed, the discovery of the widespread DXP-independent pathway determined a decline of interest in E. coli vitamin B6 metabolism. In E. coli, as in most organisms, PLP can also be obtained from PL, PN, and PM, imported from the environment or recycled from protein turnover, via a salvage pathway. Our review deals with all aspects of vitamin B6 metabolism in E. coli, from transcriptional to posttranslational regulation. A critical interpretation of results is presented, in particular, concerning the most obscure aspects of PLP homeostasis and delivery to PLP-dependent enzymes.

Overproduction of docosahexaenoic acid in Schizochytrium sp. through genetic engineering of oxidative stress defense pathways

BackgroundOxidation and peroxidation of lipids in microorganisms result in increased levels of intracellular reactive oxygen species (ROS) and reactive aldehydes, and consequent reduction of cell growth and lipid accumulation.ResultsTo reduce oxygen-mediated cell damage and increase lipid and docosahexaenoic acid (DHA) production in Schizochytrium sp., we strengthened the oxidative stress defense pathways. Overexpression of the enzymes thioredoxin reductase (TRXR), aldehyde dehydrogenase (ALDH), glutathione peroxidase (GPO), and glucose-6-phosphate dehydrogenase (ZWF) strongly promoted cell growth, lipid yield, and DHA production. Coexpression of ZWF, ALDH, GPO, and TRXR enhanced ROS-scavenging ability. Highest values of dry cell weight, lipid yield, and DHA production (50.5 g/L, 33.1 g/L, and 13.3 g/L, respectively) were attained in engineered strain OaldH-gpo-trxR by shake flask fed-batch culture; these were increases of 18.5%, 80.9%, and 114.5% relative to WT values.ConclusionsOur findings demonstrate that engineering of oxidative stress defense pathways is an effective strategy for promoting cell robustness, lipid yield, and DHA production in Schizochytrium.

Glyceraldehyde-derived advanced glycation end-products having pyrrolopyridinium-based crosslinks

Reducing sugars and reactive aldehydes, such as glyceraldehyde, non-enzymatically react with amino or guanidino groups of proteins to form advanced glycation end-products (AGEs) by the Maillard reaction that involves Schiff base formation followed by Amadori rearrangement. AGEs are found relatively in abundance in the human eye and to accumulate at a higher rate in diseases that impair vision such as cataract, diabetic retinopathy or age-related macular degeneration. We identified two novel AGEs of pyrrolopyridinium lysine dimer derived from glyceraldehyde, PPG1 and PPG2, in the Maillard reaction of Nα-acetyl-l-lysine with glyceraldehyde under physiological conditions. Having fluorophores similar to that of vesperlysine A, which was isolated from the human lens, PPGs were found to act as photosensitizers producing singlet oxygen in response to blue light irradiation. Moreover, PPG2 interacts with receptor for AGE (RAGE) in vitro with a higher binding affinity than GLAP, a well-known ligand of the receptor. We also proposed a pathway to form PPGs and discussed how they would be formed in vitro. As glyceraldehyde-derived AGEs have been studied extensively in connection with various hyperglycemia-related diseases, further studies will be required to find PPGs in vivo such as in the lens or other tissues.

Cytotoxicity of adducts formed between quercetin and methylglyoxal in PC-12 cells

Quercetin (Que) or quercetin-containing food stuffs are widely incorporated in bakery foods for improving food texture and health effects, and scavenging reactive aldehydes, such as methylglyoxal (MGO) that exhibits various deleterious effects including contribution to neurodegeneration. This study aimed to investigate the cytotoxicity of the adducts formed between quercetin and MGO resulted from the incorporation of quercetin in foods. Two highly-purified adducts (Que-mono-MGO and Que-di-MGO) were found to display higher cytotoxicity than their precursor MGO and quercetin. They elevated apoptosis via upregulation of expression of apoptotic markers, including p-P38, cleaved caspase-9 and -3, and pro-apoptotic Bax. They induced mitochondrial dysfunction via decreasing mitochondrial membrane potential and increasing lactate dehydrogenase release. Moreover, they attenuated levels of p-Akt, Nrf2, NQO-1, and HO-1, proving that they induced neurodegeneration apoptosis through mitochondria-mediated signaling pathways (PI3K-Akt and Nrf2-HO-1/NQO-1). These findings indicated that the safety consequence of MGO after scavenged by polyphenols needs to be concerned.

The Role of Lipoxidation in the Pathogenesis of Diabetic Retinopathy.

Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.

The Effects of Systemic Use of Epigallocatechin Gallate in Thermal Injury Progression

The burn wound progression is a complex process caused by inadequate tissue perfusion, free radical damage, and altered cytokine levels in burn patients. Epigallocatechin gallate (EGCG) has vasodilator, antioxidant, and skin protective properties. In this study, we investigated the effects of epigallocatechin gallate (EGCG) on burn wounds. Nine male Wistar albino rats were randomly assigned to the control group and received no burn insult. The other rats were exposed to thermal injury with a brass comb and randomly divided into two groups: burn with no further treatment (group 1, n:3) and burn with enteral EGCG treatment (group 2, n:3). The administration of EGCG was initiated 5 min after the burn procedure at a dose of 1 mg/kg by gastric lavage and repeated for 3 days at an infusion rate of 1 mg/kg/day. Skin sections were stained with Hematoxylin-Eosin and Masson’s trichrome for histochemistry. The primary antibodies used for immunohistochemistry included rabbit anti-4-hydroxynonenal (protein-HNE), rabbit anti-malondialdehyde (protein-MDA, mouse monoclonal anti-acrolein (protein-ACR), rabbit anti-ALDH1A1, and rabbit anti-ALDH2. Systemic administration of EGCG after burn injury significantly ameliorated the histological alterations in burn sites, especially in the zone of stasis. The expression of reactive aldehyde products (HNE, MDA, ACR) as a result of thermal injury significantly decreased in the EGCG group. EGCG reduced reactive aldehyde products independent of ALDH1 and ALDH2 pathway and improved histological alterations with cytoprotective and antioxidant effects. Early systemic use of EGCG prevents burn wound from progressing to deep structures and limits its extension to the adjacent zones.

Micelles of ferrocene/aldehyde-containing triblock polynorbornene: Preparation, biocompatibility, dual-cargo-loading and oxidation/pH-sensitive release behavior

Using the ring-opening metathesis polymerization, a new amphipathic triblock polynorbornene-based copolymer containing reactive aldehyde, redox-active ferrocene, and dendritic oligoethylene glycols units (PNCHO-PNFc-PNTEG), was controllably synthesized and exhibited the dual-cargo loading capacity with the oxidation/pH stimuli-responsive behavior. PNCHO-PNFc-PNTEG could conjugate the amino-containing doxorubicin (DOX) by the acid-sensitive Schiff base reaction. The DOX-grafted PNCHO-PNFc-PNTEG could further self-assemble into spherical nanoscale polymeric micelles that can encapsulate the second model cargo rhodamine B (RhB). The step-by-step release behavior of the loaded two cargos was observed. Namely, the loaded RhB could be firstly released under the stimulus of oxidant, and the grafted DOX could be then released under acidic condition. Moreover, PNCHO-PNFc-PNTEG micelles showed excellent biocompatibility both in in vitro L929 cell test and in vivo zebrafish embryo toxicity experiments. Thus, PNCHO-PNFc-PNTEG as polymeric carrier has great application potential in the medical field for controllable drug release.

Protective effect of lutein against acrolein-induced ototoxicity in rats

BackgroundAcrolein is a reactive aldehyde that forms during burning of wood and other fuels. It is also a product of lipid peroxidation (LPO) reactions and is present in cigarette smoke. Acrolein is known to cause oxidative stress and inflammatory nerve tissue damage. Lutein is a tetraterpenoid molecule with antioxidant and anti-inflammatory properties. There appear to be no studies on the effect of lutein on vestibulocochlear nerve damage induced by acrolein. The aim of this study was to investigate the effect of lutein on vestibulocochlear nerve damage induced by acrolein in rats using biochemical and histopathological methods. MethodsThe rats were divided into three groups (n = 6, for each group) a healthy control group (HG), an acrolein (ACR) group and a lutein and acrolein (LACR) group. In the LACR group, lutein was administered (1 mg/kg) via oral gavage. The ACR and HG groups received saline via oral gavage. Then, 1 h after the administration of lutein and saline, the LACR and ACR groups were treated with 3 mg/kg of acrolein via oral gavage. This procedure was repeated once a day for 30 days. ResultsThe results of biochemical experiments showed that in the vestibulocochlear nerve tissues of the animals treated with acrolein, the levels of malondialdehyde, total oxidants, nuclear factor kappa b, tumor necrosis factor alpha and interleukin 1 beta significantly increased, whereas the levels of total glutathione and total antioxidants decreased as compared to those in the HG and LACR groups. In addition, severe histopathological damage was observed in vestibulocochlear nerve tissue of the acrolein group, whereas this damage was alleviated in the lutein group. ConclusionLutein protected vestibulocochlear nerve tissue from acrolein-associated oxidative and proinflammatory damage. This suggests that lutein might be useful in preventing or treating acrolein-induced ototoxicity.