Search Results (378)

Background: Dicarbonyls and advanced glycation end-products (AGEs) contribute to oxidative stress, inflammation, and complications in type 2 diabetes mellitus (T2DM). Menaquinone-7 (MK-7), a vitamin K2 subtype, has shown benefits for glucose tolerance and vascular health in some studies. We evaluated the impact of MK-7 on dicarbonyls, free AGEs, and protein nitration/oxidation adducts in a rat model of T2DM. Methods: Male heterozygous (fa/+, control) and homozygous (fa/fa, diabetic) Zucker Diabetic Fatty rats were fed a diabetogenic diet without or with MK-7 for 12 weeks. After sacrifice, plasma dicarbonyls as well as plasma and urinary levels of free AGEs and protein nitration/oxidation adducts were quantified by isotope dilution tandem mass spectrometry. Results: Diabetic rats showed significantly increased plasma glyoxal, 3-deoxyglucosone, and fructosyl-lysine with non-significant trends toward increased methylglyoxal-derived hydroimidazolone and methionine sulfoxide, as well as reductions in methylglyoxal and dityrosine. Urinary carboxyethyl-lysine, carboxymethyl-lysine, fructosyl-lysine (all significant), and dityrosine (non-significant) were elevated in diabetic rats; glucosepane (non-significant) was reduced. MK-7 supplementation reduced no measured parameter but was associated with non-significant further increases in plasma glyoxal-derived hydroimidazolone, carboxyethyl-lysine, carboxymethyl-lysine, fructosyl-lysine, 3-nitrotyrosine, and methionine sulfoxide, as well as in urinary glyoxal-derived hydroimidazolone, carboxyethyl-lysine, fructosyl-lysine, and 3-nitrotyrosine, in diabetic rats. Correlation analysis revealed significant associations between glucose, dicarbonyls, AGEs, and oxidative markers. Conclusions: High-dose MK-7 supplementation did not improve dicarbonyl stress, AGE burden, or protein nitration/oxidation. With respect to available scientific evidence and our observations, the combination of glycemia-driven amplification of glycation and oxidative stress, as well as MK-7-induced glutathione depletion, were likely causative. Full article

Background/Objectives: This study investigated the correlation of oxidative stress biomarkers with the activity of idiopathic nephrotic syndrome (INS) in Slovenian children. Methods: In this prospective study, sequential plasma and urine samples from 20 children with INS in different phases of disease activity were taken: at first disease presentation or relapse (before glucocorticoid (GC) treatment), at time of remission achievement, and after discontinuation of GC treatment. This study measured oxidative stress biomarkers, such as 8-hydroxy-2′-deoxyguanosine (8-OHdG), hexanoyl-lysine (HEL) adduct, dityrosine (DiY), and 15-isoprostane F2t, using competitive enzyme-linked immunosorbent assay (ELISA) and assessed oxidative status using the FRAS 5 analytical system, which enables rapid photometric measurement of both oxidative and antioxidant capacity from biological fluids. Two complementary tests were performed: the d-ROMs test (derivatives of reactive oxygen metabolites) and the PAT (plasma antioxidant test). The oxidative stress index (OSI) was calculated as the ratio between them. Results: Concentrations of isoprostanes in urine were statistically significantly lower in patients at first disease presentation or relapse compared to time of remission achievement. Values of PAT test in serum were significantly highest after GC treatment. Values of d-ROMs test in serum were significantly lower at time of remission achievement compared to first disease presentation or relapse. Values of 8-OHdG, HEL, DiY (in plasma and urine), isoprostanes, and OSI in plasma did not statistically significantly differ in various phases of disease activity. Conclusions: Isoprostanes in urine and PAT in serum could serve as potential biomarkers of oxidative stress and disease activity in children with INS. Full article

While omega-6 fatty acids play an important role in normal cell function, their excess in the diet is associated with an increased risk of developing diseases such as obesity, non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD) and Alzheimer’s disease. Furthermore, excessive intake has been shown to lead to chronic inflammation, which is related to increased production of reactive oxygen species (ROS). This conditioncan initiate lipid peroxidation in cell membranes, leading to the degradation of their fatty acids. One of the main products of omega-6 peroxidation is the α,β-unsaturated aldehyde, i.e., 4-hydroxynonenal (4-HNE), which is able to form four diastereoisomeric adducts with guanine. These 4-HNE adducts have been identified in the DNA of humans and rodents. Depending on their stereochemistry, they are able to influence double helix stability and cause DNA–DNA or DNA–Protein cross-links. Moreover, studies have shown that 4-HNE adducts formed in the human genome are considered mutation hotspots in hepatocellular carcinoma. Although the cell possesses defence mechanisms, without a well-balanced diet allowing correct cell function, they may not be sufficient to protect the genetic code. This review provides an overview of the molecular mechanisms underlying oxidative stress, lipid peroxidation, and the formation of DNA adducts. Particular emphasis is placed on the role of an omega-6-rich diet in inflammatory diseases, and on the formation of 4-HNE, which is a major product of lipid peroxidation, and its broader implications for genome stability, ageing, and disease progression. Full article

Heart failure (HF) has become an epidemic, with a prevalence of ~7 million cases in the USA. Despite accounting for nearly 50% of all HF cases, heart failure with a preserved ejection fraction (HFpEF) remains challenging to treat. Common pathophysiological mechanisms in HFpEF include oxidative stress, microvascular dysfunction, and chronic unresolved inflammation. Our lab focuses on oxidative stress-mediated cellular dysfunction, particularly the toxic effects of lipid peroxidation products like 4-hydroxy-2-nonenal (4HNE). Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, plays a vital role in detoxifying 4HNE and thereby protecting the heart against pathological stress. ALDH2 activity is reduced in various metabolic stress-mediated cardiac pathologies. The dysfunction of coronary vascular endothelial cells (CVECs) is critical in initiating HFpEF development. Thus, we hypothesized that ectopic overexpression of ALDH2 in CVECs could mitigate metabolic stress-induced HFpEF pathogenesis. In this study, we tested the efficacy of intracardiac injections of the ALDH2 gene into CVECs in db/db mice—a model of obesity-induced type 2 diabetes mellitus (T2DM)—and their controls, db/m mice, by injection with ALDH2 constructs (AAV9-VE-cadherin-hALDH2-HA tag-P2A) or control constructs (AAV9-VE-cadherin-HA tag-P2A-eGFP). We found that intracardiac ALDH2 gene transfer increased ALDH2 levels specifically in CVECs compared to other myocardial cells. Additionally, we observed increased ALDH2 levels and activity, along with decreased 4HNE adducts, in the hearts of mice receiving ALDH2 gene transfer compared to control GFP transfer. Furthermore, ALDH2 gene transfer to CVECs improved diastolic function compared to GFP control alone. In conclusion, ectopic ALDH2 expression in CVECs can contribute, at least partially, to the amelioration of HFpEF. Full article

Seven lager beers and seven non-alcoholic counterparts, marketed by the same producers, were analyzed for their total phenolic content (TPC), radical scavenging activity (RSA) towards the DPPH radical and ThioBarbituric Index (TBI). All beers were also subjected to spin trapping experiments at 60 °C in the presence of PBN. To our knowledge, this is the first time that non-alcoholic beers (NABs) have been subjected to spin trapping experiments coupled with Electron Spin Resonance (ESR) spectroscopy. The evolution of the intensity of the PBN radical adducts during the first 150 min was represented graphically and the intensity at 150 min (I₁₅₀) and the area under the curve (AUC), were measured. The I₁₅₀ and the AUC of lagers and NABs are significantly different, whereas the TPC, the EC₅₀ of the DPPH assay, and the TBI of the two groups are superimposed. A relationship, previously proposed by us, to correlate ESR spectroscopy parameters with others obtained from UV-Vis spectrophotometry, was also applied, demonstrating its practicability. Multivariate analysis shows that clustering in two separate groups occurs only if I₁₅₀ and AUC are included in the model. Based on these results, ESR spectroscopy can be applied to study the oxidative stability of NABs. Full article

The efficient synthetic routes and evaluates cytotoxic profiles of denitroaristolochic acids II–V (DAA-II–V) were demonstrated in this study. Based on retrosynthetic analysis, a modular synthetic strategy was developed through Suzuki–Miyaura coupling, Wittig reaction, and bismuth triflate-catalyzed intramolecular Friedel–Crafts cyclization to efficiently construct the phenanthrene core. Process optimization significantly improved yields: aryl bromide intermediate A reached 50.8% yield via bromination refinement, while arylboronic ester intermediate B overcame selectivity limitations. Combining Darzens condensation with Wittig reaction enhanced throughput, achieving 88.4% yield in the key cyclization. Structures were confirmed by NMR and mass spectra. CCK-8 cytotoxicity assays in human renal proximal tubular epithelial cells revealed distinct toxicological profiles: DAA-III and DAA-IV exhibited IC₅₀ values of 371 μM and 515 μM, respectively, significantly higher than the nitro-containing prototype AA-I (270 μM), indicating that the absence of nitro group attenuates but does not eliminate toxicity, potentially via altered metabolic activation. DAA-II and DAA-V showed no detectable cytotoxicity within assay limits, suggesting reduced toxicological impact. Structure–activity analysis exhibited that the nitro group is not essential for cytotoxicity, with methoxy substituents exerting limited influence on potency. This challenges the conventional DNA adduct-dependent toxicity paradigm, implying alternative mechanisms like oxidative stress or mitochondrial dysfunction may mediate damage in denitro derivatives. These systematic findings provide new perspectives for AA analog research and a foundation for the rational use and safety assessment of Aristolochiaceae plants. Full article

Bis- and trisphosphines incorporating methylene and aryl spacers readily adsorb on the surface of porous activated carbon (AC). The adsorption can be performed in the absence of solvents, even when the phosphines have high melting points, or from solutions. The diverse phosphines Ph₂PCH₂PPh₂ (dppm), Ph₂P(CH₂)₂PPh₂ (dppe), Ph₂P(CH₂)₃PPh₂ (dppp), Ph₂P(p-C₆H₄)PPh₂ (dppbz), and (Ph₂PCH₂)₃CCH₃ (tdme) were adsorbed in submonolayers on AC. The adsorbed phosphines were studied by ³¹P MAS (magic angle spinning) NMR spectroscopy, and their mobilities on the surface were confirmed by determining the ³¹P T₁ relaxation times. All phosphine groups of each bis- and trisphosphine molecule are in contact with the surface, and the molecules exhibit translational mobility as one unit. All phosphines used here are air-stable. Once a submonolayer is created on the AC surface, oxygen from the air is co-adsorbed and transforms all phosphines quantitatively into phosphine oxides at room temperature. The oxidation proceeds in a consecutive manner with the oxidation of one phosphine group after another until the fully oxidized species are formed. Studies of the kinetics are based on integrating the signals in the solution ³¹P NMR spectra. High temperatures and low surface coverages increase the speed of the oxidation, while light and acid have no impact. The oxidation is fast and complete within one hour for 10% surface coverage at room temperature. In order to study the mechanism and slow down the oxidation, a higher surface coverage of 40% was applied. No unwanted P(V) side products or water adducts were observed. The clean phosphine oxides could be recovered in high yields by washing them off of the AC surface. The oxidation is based on radical activation of O₂ on the AC surface due to delocalized electrons on the AC surface. This is corroborated by the result that AIBN-derived radicals enable the air oxidation of PPh₃ in solution at 65 °C. When the air-stable complex (CO)₂Ni(PPh₃)₂ is applied to the AC surface and exposed to the air, OPPh₃ forms quantitatively. The new surface-assisted air oxidation of phosphines adsorbed on AC renders expensive and hazardous oxidizers obsolete and opens a synthetic pathway to the selective mono-oxidation of bis- and trisphosphines. Full article

Rapid mixing is widely prevalent in the field of microfluidics, encompassing applications such as biomedical diagnostics, drug delivery, chemical synthesis, and enzyme reactions. Mixing efficiency profoundly impacts the overall performance of these devices. However, at the micro-scale, the flow typically presents as laminar flow due to low Reynolds numbers, rendering rapid mixing challenging. Leveraging the vortices within a droplet of the Taylor flow and inducing chaotic convection within the droplet through serpentine channels can significantly enhance mixing efficiency. Based on this premise, we have developed a droplet micromixer that integrates the T-shaped channels required for generating Taylor flow and the serpentine channels required for inducing chaotic convection within the droplet. We determined the range of inlet liquid flow rate and gas pressure required to generate Taylor flow and conducted experimental investigations to examine the influence of the inlet conditions on droplet length, total flow rate, and mixing efficiency. Under conditions where channel dimensions and liquid flow rates are identical, Taylor flow achieves a nine-fold improvement in mixing efficiency compared to single-phase flow. At low Reynolds number (0.57 ≤ Re ≤ 1.05), the chip can achieve a 95% mixing efficiency within a 2 cm distance in just 0.5–0.8 s. The mixer proposed in this study offers the advantages of simplicity in manufacturing and ease of integration. It can be readily integrated into Lab-on-a-Chip devices to perform critical functions, including microfluidic switches, formation of nanocomposites, synthesis of oxides and adducts, velocity measurement, and supercritical fluid fractionation. Full article

Ethylene oxide (EtO) gas is a widely used industrial chemical and known health hazard. Multiple studies have determined that EtO exposure can be measured via hemoglobin adduct levels, and EtO exposure increases the risk of cancer and neurocognitive deficits, especially with occupational exposure. Emerging studies indicate that neighboring communities are also at risk. The purpose of this study is to explore the relationship of known covariates and EtO hemoglobin adduct levels to neurocognitive performance in older U.S. adults. This exploratory study drew its sample from the publicly available NHANES dataset. The 2013–2014 NHANES measured EtO exposure via hemoglobin adducts and the cognitive domain of neurocognitive function using the CERAD, Animal Fluency, and Digit Symbol Substitution (DSST) tests. Motor function was measured using grip strength. Participants were grouped into background (≤27.36 pmol/gHb) or elevated (>27.36 pmol/gHb) EtO exposure. Hierarchical linear regression, independent t-tests, and logistic regression analyses were performed. A total of 10,175 individuals were sampled: 489 were included in the cognitive analyses, and 436 were included in the motor analyss. Elevated EtO adduct levels significantly predicted low Animal Fluency, DSST, CERAD, and combined grip strength scores. Our findings are supported by the extant literature citing neurotoxic EtO exposure effects. Further study in known EtO-exposed communities is warranted. Full article

Antibiotic pollution, particularly via tetracycline (TC), poses significant environmental risks due to its recalcitrance and potential to induce antibiotic resistance. This study employed density functional theory (DFT) and transition state theory (TST) to investigate TC degradation by hydroxyl radicals (·OH), focusing on hydrogen atom transfer (HAT) and radical adduct formation (RAF) pathways. Geometry optimizations and vibrational analysis validated stationary points, while intrinsic reaction coordinate (IRC) calculations confirmed transition states. Key findings reveal that RAF pathways exhibit lower activation barriers (1.23–30.33 kJ/mol) and greater exothermicity (−164.42 kJ/mol) compared to HAT pathways (3.51–42.04 kJ/mol, −109.58 kJ/mol), making them kinetically and thermodynamically dominant. Frontier molecular orbital (FMO) analysis links HAT to TC’s HOMO (π-orbital character on aromatic rings) and RAF to its LUMO (electrophilic sites). Rate constants calculated at 298 K (TST with Wigner correction) confirm RAF’s kinetic superiority (up to 7.0 × 10¹¹ s⁻¹), surpassing HAT’s fastest pathway (6.2 × 10¹¹ s⁻¹). These insights advance the understanding of TC degradation mechanisms and help with the design of efficient photocatalytic oxidation processes for antibiotic removal. Full article

Collagen plays a crucial role in platelet activation and thrombosis, yet the underlying mechanisms involving reactive oxygen species (ROS) remain incompletely understood. This study investigated how collagen modulates ROS generation and platelet aggregation both in vitro and in vivo, as well as evaluating the protective effects of antioxidants. In vitro, collagen induced dose-dependent platelet aggregation and increased ROS generation, evidenced by the enhanced EMPO adduct formation detected via electron spin resonance (ESR). In vivo experiments demonstrated that collagen administration significantly accelerated CAT-1 decay, indicating elevated oxidative stress with a transient peak around 1 minute post-treatment. Furthermore, escalating collagen doses correlated with increased ROS generation and reduced survival rates in mice, underscoring collagen’s impact on oxidative stress and thrombosis severity. Importantly, treatment with enzymatic antioxidants (superoxide dismutase, catalase) and non-enzymatic antioxidants (DMTU, Tiron, mannitol) significantly attenuated collagen-induced oxidative stress and improved animal survival. Collectively, these findings elucidate the pivotal role of ROS in collagen-induced platelet activation and thrombosis and highlight antioxidants as promising therapeutic candidates for preventing thrombotic disorders and managing cardiovascular risk. Full article

Phosphorylated nitrones belong to an important class of compounds with several applications, such as their therapeutic potency to reduce oxidative stress or as spin-trapping agents. This review covers available synthetic methods for the preparation of both non-cyclic and cyclic phosphorylated nitrones, including the possibilities of the modification of structures with selected functional groups, as well as examples of their application. As reported, the incorporation of diethoxyphosphoryl function into the structure of PBN and DMPO resulted in obtaining their phosphorylated analogs, i.e., N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide (PPN) and 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide (DEPMPO), respectively, both forming spin adducts of improved stability in comparison to the reference non-phosphorus nitrones. Moreover, antioxidant and neuroprotective activity observed in the group of phosphorylated nitrones makes them promising candidates for therapeutics. Full article

The [3+2] cycloaddition chemistry of (2S)-5-methylene-2-t-butyl-1,3-dioxolan-4-one, derived from lactic acid, has been examined, and spiro adducts have been obtained with benzonitrile oxide, acetonitrile oxide, diazomethane and diphenyldiazomethane. The structure and absolute stereochemistry of the benzonitrile oxide adduct has been confirmed by X-ray diffraction, and all the adducts have been fully characterised by ¹H and ¹³C NMR. Attempted cycloaddition with a nitrile sulfide, a nitrile imine and azides failed. Pyrolysis results in a range of novel gas-phase reactions, with the nitrile oxide adducts giving pivalaldehyde, CO₂, the nitrile and ketene, the diazomethane adduct losing only N₂ to give a cyclopropane-fused dioxolanone, and the diphenylcyclopropane derived from diphenyldiazomethane giving mainly benzophenone in a sequence involving the loss of pivalaldehyde and methyleneketene. Full article

Background: Products of lipid peroxidation include a number of reactive lipid aldehydes including reactive dicarbonyl electrophiles (DEs) and contribute to disease processes. DEs play a significant role in the development and progression of metabolic-associated steatotic liver disease (MASLD) by contributing to oxidative stress, inflammation, protein dysfunction, and mitochondrial impairment. Reducing DE stress may be a potential strategy for managing MASLD. We hypothesized that the DE scavenger 2-hydroxybenzylamine (2-HOBA) would reduce liver injury by reducing liver protein adduct formation by DE in mouse models of MASLD. Methods: Protein adducts were measured in human livers by immunohistochemistry and immunoblot. The effects of 2-HOBA were assessed in two different mouse models of MASLD. Results: Isolevuglandin (IsoLG) protein adducts were increased in MASH-staged human livers relative to histologically normal controls. Diet-Induced Animal Model of Nonalcoholic Fatty Liver Disease (DIAMOND) mice treated with 2-HOBA exhibited significantly lower fibrosis scores (* p = 0.012) and reduced liver transaminases (AST, p = 0.03) and ALT, p = 0.012) by over 40%. In STAM (Stelic Animal Model) mice, 2-HOBA improved NAFLD activity scores (p = 0.03, NAS), hyperglycemia, and inflammatory cytokines and reduced serum F2-isoprostanes (IsoPs) by 30%, p = 0.05. These improvements were absent mRNA changes in hepatic antioxidant enzymes (Cat, Gpx1, or Sod2) or ROS-generating proteins (p22PHOX, p47PHOX, NOX4 or COX1). Conclusions: DE scavenging with 2-HOBA may be a promising therapeutic strategy for managing MASLD. While findings are currently limited to male mice, a nutraceutical that reduces liver fibrosis could significantly improve the management of MASH by offering a non-invasive treatment option to potentially slow or reverse liver scarring, delay progression to cirrhosis, and improve patient outcomes, while also providing a potential treatment option for patients who may not be suitable for other interventions like liver transplantation. Full article

The current paradigm of low-T combustion and autoignition of hydrocarbons is based on the sequential two-step oxygenation of fuel radicals. The key chain-branching occurs when the second oxygenation adduct (OOQOOH) is isomerized releasing an OH radical and a key ketohydroperoxide (KHP) intermediate. The subsequent homolytic dissociation of relatively weak O–O bonds in KHP generates two more radicals in the oxidation chain leading to ignition. Based on the recently introduced intramolecular “catalytic hydrogen atom transfer” mechanism (J. Phys. Chem. 2024, 128, 2169), abbreviated here as I-CHAT, we have identified a novel unimolecular decomposition channel for KHPs to form their classical isomers—enol hydroperoxides (EHP). The uncertainty in the contribution of enols is typically due to the high computed barriers for conventional (“direct”) keto–enol tautomerization. Remarkably, the I-CHAT dramatically reduces such barriers. The novel mechanism can be regarded as an intramolecular version of the intermolecular relay transfer of H-atoms mediated by an external molecule following the general classification of such processes (Catal. Rev.-Sci. Eng. 2014, 56, 403). Here, we present a detailed mechanistic and kinetic analysis of the I-CHAT-facilitated pathways applied to n-hexane, n-heptane, and n-pentane models as prototype molecules for gasoline, diesel, and hybrid rocket fuels. We particularly examined the formation kinetics and subsequent dissociation of the γ-enol-hydroperoxide isomer of the most abundant pentane-derived isomer γ-C5-KHP observed experimentally. To gain molecular-level insight into the I-CHAT catalysis, we have also explored the role of the internal catalyst moieties using truncated models. All applied models demonstrated a significant reduction in the isomerization barriers, primarily due to the decreased ring strain in transition states. In addition, the longer-range and sequential H-migration processes were also identified and illustrated via a combined double keto–enol conversion of heptane-2,6-diketo-4-hydroperoxide as a potential chain-branching model. To assess the possible impact of the I-CHAT channels on global fuel combustion characteristics, we performed a detailed kinetic analysis of the isomerization and decomposition of γ-C5-KHP comparing I-CHAT with key alternative reactions—direct dissociation and Korcek channels. Calculated rate parameters were implemented into a modified version of the n-pentane kinetic model developed earlier using RMG automated model generation tools (ACS Omega, 2023, 8, 4908). Simulations of ignition delay times revealed the significant effect of the new pathways, suggesting an important role of the I-CHAT pathways in the low-T combustion of large alkanes. Full article