Search Results (1,350)

Isoflurane is a widely used volatile anesthetic with context-dependent effects on neuronal survival, particularly in neurodegenerative conditions. Increasing evidence suggests that brief, sublethal stress exposure can induce adaptive cellular responses through hormesis-based preconditioning mechanisms. In this study, we investigated whether isoflurane preconditioning enhances neuronal tolerance to amyloid-β (Aβ)-induced toxicity and explored the underlying redox-dependent molecular pathways. Using HT-22 murine hippocampal neuronal cells, we demonstrate that short-term exposure to low-dose isoflurane induces a delayed neuroprotective phenotype characterized by improved cell viability, reduced apoptotic signaling, and maintained mitochondrial membrane potential following Aβ challenge. Mechanistically, isoflurane preconditioning elicited a mild and transient increase in intracellular reactive oxygen species (ROS), which is critical for the activation of the PI3K/Akt signaling pathway. Pharmacological scavenging of reactive oxygen species abolished Akt phosphorylation and reduced the protective effects of preconditioning, supporting a hormetic signaling model rather than direct antioxidant action. Following Akt activation, isoflurane preconditioning promoted the inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β), decreased Keap1 protein levels, and facilitated nuclear translocation and transcriptional activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Consequently, the expression of Nrf2-regulated antioxidant genes, including heme oxygenase-1, NAD(P)H quinone dehydrogenase 1 (NQO1), superoxide dismutase 1 and 2 (SOD1/2), and catalase, was significantly upregulated. Collectively, these findings indicate that isoflurane preconditioning confers neuroprotection through hormesis-like mild oxidative signaling and coordinated activation of endogenous antioxidant defenses rather than via direct antioxidant scavenging. Full article

Endophytic fungi associated with date fruits (Phoenix dactylifera) are mostly under-explored, despite their potential as reservoirs of natural compounds. The aims of this study were to characterize the endophytic fungus Aspergillus terreus (SU5) isolated from date fruits, and to investigate its biological activities and chemical profile for the first time. Morphological and molecular methods were utilized to identify Aspergillus terreus. A liquid chromatography–mass spectrometry analysis (LC/MS/MS) was conducted to determine the chemical profile of the crude extract. Biological properties were investigated through acetylcholine esterase and butyrylcholine esterase inhibition, cytotoxicity assays against MCF-7 and MCF-7/Adr, and antioxidant assays. LC/MS/MS of the fungal extract resulted in the detection of 39 of established secondary metabolites, primarily comprising polyketides, quinones, and phenolic derivatives. The crude extract demonstrated significant antioxidant activity, especially in the ABTS assay (IC₅₀ = 50.18 μg/mL), considerable cytotoxicity against MCF-7 breast cancer cells, diminished efficacy against the drug-resistant MCF-7/Adr cell line, and preferential inhibition of butyrylcholinesterase compared to acetylcholinesterase. While none of the identified compounds are novel, numerous metabolites are documented here for the first time from an endophytic A. terreus associated with date fruits. The findings underscore date fruits as a prospective ecological niche for a chemically varied endophytic fungus with potential pharmaceutical significance. Full article

6PPD-Quinone (6PPD-Q) is a tire derivative formed by the oxidation of N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD), a commonly used antioxidant and ozone stabilizer in rubber products, and has emerged as a significant environmental concern in recent years. It is widely present in the atmosphere, surface lakes, and soil. The primary routes of exposure to 6PPD-Q are the digestive tract and respiratory tract. Studies indicate that it is a major factor causing acute mortality in coastal coho salmon (Oncorhynchus kisutch). Reports indicate that 6PPD-Q exhibits greater chemical stability and stronger biological toxicity than 6PPD, demonstrating toxic effects across multiple species. 6PPD-Q has been detected in human urine samples, indicating a need for heightened attention to its potential health risks. 6PPD-Q exhibits multi-organ toxicity in organisms, including intestinal, hepatic, neurotoxic, and reproductive toxicity. Its potential toxic mechanisms are associated with oxidative stress and inflammatory responses, and it can disrupt amino acid metabolism, carbohydrate metabolism, and lipid metabolism while interfering with signal transduction pathways by binding to specific receptors. This paper reviews the environmental contamination of 6PPD-Q, explores its potential toxic effects on organisms and underlying mechanisms, analyzes gaps in the current research and future trends, and contributes to a better understanding of its environmental occurrence and biological hazards. Full article

Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury. Estradiol (E2) and the selective estrogen receptor modulator raloxifene (RAL) reduce organ dysfunction, potentially via heme oxygenase-1 (HO-1)–mediated antioxidant and anti-inflammatory effects. This study examined whether E2 and RAL protect against IRI through G protein-coupled estrogen receptor (GPER)–dependent activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathway in ovariectomized (OVX) mice; OVX IRI mice were pretreated for four weeks with E2, RAL, RAL + ML385 (Nrf2 inhibitor), or RAL + G15 (GPER antagonist). Renal histology, inflammatory and oxidative markers, and nuclear Nrf2 levels were assessed; OVX IRI increased interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and malondialdehyde (MDA) and decreased superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH); nuclear Nrf2 was low in sham and OVX IRI groups. E2 and RAL improved renal function and histology, reduced inflammation and oxidative stress, restored GPER expression, increased nuclear Nrf2, and upregulated HO-1 and NAD(P)H:quinone oxidoreductase 1 (NQO1). Co-treatment with ML385 or G15 reversed RAL’s benefits, reduced nuclear Nrf2, and worsened injury; E2 and RAL exert renoprotective effects against OVX-related renal IRI in a manner consistent with GPER-dependent Nrf2 nuclear translocation, which suggests involvement of the downstream antioxidant gene activation pathway. Full article

Complex I (NADH:quinone oxidoreductase, CI) is central to cellular aerobic energy metabolism. The L-shaped structure of CI is unique, where the hydrophilic arm is responsible for the electron transfer function and the membrane arm operates proton pumping. These two functional sites are spatially far apart yet functionally connected. This basic core subunit architecture is highly conserved from bacterial to mammalian CI. Here, to gain detailed mechanistic insight into the role of the membrane subunit ND2 in the coupling mechanism, we mutated several highly conserved residues in the middle of the membrane axis of NuoN, the E. coli CI homolog of ND2. To more precisely investigate the consequences of mutational effects on highly conserved residues, we purified each mutant CI and compared the mutational effects on electron transfer and proton pumping activity using our instant membrane reconstitution method with E. coli double knockout (DKO) membrane vesicles lacking both CI and alternative NADH dehydrogenase (NDH-2). Thre results were corroborated by conventional proteoliposome reconstitution experiments. We found that Lys247 and Lys395 are absolutely essential for both electron transfer and proton pumping activities, while about 50% reduction of NADH oxidase activity but no reduction in proton pumping activity was observed in Lys217, and no significant decrease was detected in Glu133. Furthermore, unexpectedly, we were able to purify an NuoN knockout (ΔNuoN) mutant, which contained stoichiometric peripheral subunits NuoB, NuoCD, NuoE, NuoF, NuoG, and NuoI; and a substoichiometric amount of NuoH and a reduced amount of quinone. However, surprisingly, this isolated ΔNuoN CI showed CI activities (~30% of the WT) after being reconstituted into DKO membranes but not into proteoliposomes. Later, we confirmed by blue native PAGE that the wild-type CI was partially formed from ΔNuoN CI by recruiting its missing membrane subunits that existed in DKO membranes. Our data strongly suggest that ND2/NuoN plays an essential role in the coupling mechanism in CI. CI is the entry respiratory chain enzyme and is central to cellular energy metabolism. Two highly conserved lysine residues in the center of the antiporter-like membrane subunit ND2 are essential for the coupling mechanism between electron transfer and proton translocation. Full article

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, highlighting the need to identify novel bioactive compounds with antitumor potential. Natural products constitute a valuable source of molecules with anticancer activity. In this study, we performed a comparative analysis of two classes of natural compounds—sesquiterpene lactones (achillin and polymatin A) and naphthoquinones (α, β-lapachone and lapachol)—in human PDAC cell lines on cell proliferation, metabolic activity and cell death induction and early mitochondrial alterations. Achillin showed limited antiproliferative, metabolic, and cytotoxic activity, whereas polymatin A exhibited activity in the micromolar range, yielding LC₅₀ values of 16.11 ± 2.27 μM and 20.00 ± 1.90 μM for PANC-1 and MIAPaCa-2 cells, respectively. The naphtoquinones α- and β-lapachone effectively inhibited proliferation and metabolic activity and triggered cell death in both PDAC cell lines, with β-lapachone consistently displaying the highest activity with an LC₅₀ of 4.00 ± 0.07 μM for PANC-1 cells and 3.89 ± 0.50 μM for MIAPaCa-2. Interestingly, achillin, polymatin A, α- and β-lapachone selectively induced cell death while sparing PBMCs. In contrast, lapachol showed weak activity, failing to achieve 50% inhibition or cell death within the tested concentration range and lacking tumor selectivity. Mechanistically, quinone derivatives promoted early mitochondrial superoxide modulation and membrane depolarization, consistent with a redox-active profile, whereas sesquiterpene lactones induced mitochondrial depolarization with limited mitochondrial superoxide overproduction, suggesting a distinct bioenergetic disruption phenotype. Overall, these findings highlight structure–activity relationships among natural compounds and support further investigation of achillin, polymatin A and α,β-lapachone as promising molecular scaffolds in PDAC research. Full article

Biochar provides a porous scaffold, conductive carbon framework and redox-active surface functional that can promote microbial attachment and extracellular electron flow. However, how feedstock-dependent biochar properties regulate the biochar–cell interface and microbial metabolism during contaminant removal remains insufficiently understood. Here, biochar derived from rice husk, corn straw and corn cob was used to immobilize Pseudomonas chlororaphis for triclocarban removal in batch microcosms. Multiscale analyses, including scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), cyclic voltammetry (CV), (electrochemical impedance spectroscopy (EIS) and liquid chromatography–mass spectrometryLC-MS, were combined to link the biochar structure, interface and extracellular metabolism signatures with triclocarban (TCC) removal. Compared with free cells, all composites enhanced TCC removal and exhibited altered interfacial functional-group features together with substantially reduced fitted charge-transfer resistance, indicating facilitated interfacial electron exchange. Untargeted metabolomics further revealed consistent remodeling of extracellular redox-associated metabolite signatures upon immobilization, with increased quinone/polyphenol-associated features and pathway-level shifts related to redox homeostasis. Among feedstocks, the corn cob composite showed the highest triclocarban removal. Overall, this work proposes an evidence-supported “structure–interface–metabolism” framework for interpreting how agricultural-residue biochars modulate biofilm interfaces and redox-related metabolic signatures to improve triclocarban removal, providing guidance for designing biochar-supported bioprocesses for halogenated micropollutants. Full article

Oxidative stress in intestinal epithelial cells has been increasingly recognized as a key factor in various intestinal disorders. Gastrodia elata polysaccharide-2 (GEP-2), a water-soluble polysaccharide known for its antioxidant properties, has shown potential against intestinal injury. However, its effects on intestinal epithelial cells and the molecular mechanisms involved are not yet fully understood. In this study, we established a hydrogen peroxide (H₂O₂)-induced oxidative stress model using human colonic epithelial cells (NCM460) to evaluate the protective effects of GEP-2. We assessed cell viability, antioxidant enzyme activities, reactive oxygen species (ROS) levels, and mitochondrial membrane potential (MMP). The results demonstrated that GEP-2 pretreatment significantly improved the viability of NCM460 cells subjected to H₂O₂ damage. Additionally, it could enhance the antioxidant defense, reduce the levels of ROS, malondialdehyde (MDA), and maintain the MMP. Transcriptomic analysis identified 169 differentially expressed genes upregulated in the glutathione metabolism. JAK-STAT pathway and downregulated in inflammation. Furthermore, it was shown that GEP-2 treatment activated the Nuclear factor erythroid 2-related factor 2 (Nrf2)/quinone oxidoreductase 1 (NQO1)-mediated antioxidant response and promoted the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Therefore, GEP-2 exerts multi-targeted cell protection by coordinating the Nrf2/NQO1 antioxidant axis and the JAK/STAT survival signaling pathway, providing a theoretical basis for the development of novel antioxidants. Full article

6-PPD quinine (6-PPDQ) affects intestinal barrier function; however, its underlying mechanisms remain largely unknown. In the current study, we examined the role of reduction in phosphatidic acid synthesis in mediating the toxicity of 6-PPDQ in affecting intestinal barrier function. In Caenorhabditis elegans, 6-PPDQ exposure reduced the phosphatidic acid content, which was accompanied by the decreased expression of acl-5 and acl-6 encoding glycerol-3-phosphate acyltransferase. The RNAi of acl-5 and acl-6 lowered the phosphatidic acid content, enhanced intestinal permeability, and resulted in the increased accumulation of 6-PPDQ. Meanwhile, acl-5 and acl-6 RNAi caused susceptibility to 6-PPDQ toxicity by upregulating the expressions of insulin ligands and receptor genes and downregulating the expressions of daf-16 and its target genes. Moreover, the RNAi of acl-5 and acl-6 elevated the expression of let-363, and the RNAi of let-363 could reduce the expressions of insulin ligand genes and confer resistance to 6-PPDQ toxicity. The double RNAi of acl-5 and acl-6 caused more severe enhanced intestinal permeability and 6-PPDQ toxicity. Therefore, 6-PPDQ exposure potentially disrupts phosphatidic acid synthesis to affect intestinal barrier function by downregulating acl-5 and acl-6 expressions. Full article

In this study, sixteen secondary metabolites, including two chromones, four dibenzofurans, three lipids, three depsides, two aromatic compounds, a quinone, and a terpene, were detected in the methanol:acetone (1:1 v/v) extract of the lichen Hypotrachyna enderythraea (Zahlbr.) Hale, using High-Performance Liquid Chromatography coupled to Orbitrap Electrospray Ionization tandem Mass Spectrometry (HPLC-Orbitrap ESI tandem MS/MS). These metabolites were characterized by analysis of their exact molecular masses and corresponding fragmentation patterns. The retention times of the identified metabolites were compared with those of standard compounds, confirming the presence of naturally occurring bioactive compounds. Density Functional Theory (DFT) calculations were employed to investigate preferential deprotonation sites in representative polyprotic metabolites. All these findings may contribute to expanding the spectrum of compounds identified within the genus Hypotrachyna and to evaluating their potential biological activities. Full article

Background/Objectives: Natural medicine analysis remains challenging due to chemical diversity. To the best of our knowledge, the comprehensive identification of multiple chemical constituents in Xiaoban Kangfu (XBKF) capsules has not been reported. Therefore, a combined approach utilizing ultra-high-performance liquid chromatography quadrupole-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap MS) and molecular network analysis needs to be developed to comprehensively characterize the chemical constituents of XBK capsules in heat-clearing and toxin-eliminating granules, thereby enhancing annotation accuracy and enabling visualization. Methods: Firstly, chromatographic and mass spectrometry conditions were optimized to achieve good separation and a rich signal response. Subsequently, the literature searches, database consultations, and reference standards were employed to enhance annotation reliability. Finally, the raw data acquired under optimized conditions were uploaded to Global Natural Products Social (GNPSs), enabling component visualization by linking precursor ions of similar structural features with identical colors. Results: A total of 170 compounds were identified from this medicinal resource for the first time, including 50 flavonoids, 34 phenolic acids, 16 terpenoids, 14 quinones, 14 organic acids, eight coumarins, ive carbohydrates, and 29 other compounds. Conclusions: This study establishes a robust UHPLC-Q-Exactive Orbitrap MS/MS strategy for the comprehensive chemical profiling of XBKF capsules. The use of the presented validated analytical method for the comprehensive quality control of XBKF capsules is highly promising, offering fast, highly sensitive, and reliable analysis. Full article

Our recent work has focused on red light-mediated photoreduction of p-benzoquinones and both o-, and p-naphthoquinones using methylene blue and the chlorophyll metabolite, pheophorbide A as photosensitizers. Photoreduction of biologically relevant quinones mimics photoreduction of plastoquinone by chlorophyll in photosynthesis. We examined photo-oxidation and photoreduction reactions of catechols because their oxidation to o-quinones by reactive oxygen species is implicated in protein damage in neurodegeneration. Photo-oxidation of catecholamines including dopamine, epinephrine and norepinephrine required red light, methylene blue or pheophorbide A, and molecular oxygen. Their cyclized oxidation products, aminochrome, adrenochrome and noradrenochrome, were detected by UV/visible spectroscopy. Hydrogen peroxide was generated during photo-oxidation by singlet oxygen-dependent oxidation of catecholamines. Inclusion of tertiary amine electron donors decreased cyclized products but did not affect hydrogen peroxide yield consistent with concurrent photo-oxidation followed by photoreduction of the o-quinone intermediate. Unreacted dopamine and norepinephrine were quantified using 3-hydroxyphenyl boronic acid following photochemical reactions. Dopamine and norepinephrine boronate esters absorb at 417 and 550 nm. Photo-oxidation of dihydroxycaffeic acid and dihydroxyphenyl acetic acid was also evaluated by detecting their boronate esters at 475 nm. We hypothesize that photoreduction of transient o-quinones by the combination of red light and dietary chlorophyll metabolites may be a path to limit protein damage and to recycle catechol antioxidants. Full article

Compost-derived humic acids (HAs) and fulvic acids (FAs) play an essential role in enhancing soil microbial diversity and activity by facilitating metabolic processes through electron transfer. Herein, the effect of bioleaching dewatered sludge (BDS) in comparison with filter press dewatered sludge (FDS) on the electron transfer capacity (ETC) of humic substances during composting was investigated as a novel attempt. A variety of characterization methods including UV-Vis, FTIR, 3D-EEM, and electrochemical measurements, were used to explore the change in humic substances during composting. The results indicated that bioleaching treatment significantly influenced the organic matter composition and hindered the accumulation of redox-active functional groups during composting. Notably, the ETC of HA increased by 24.07% in the FDS group but declined by 40.62% in the BDS group. This divergence stemmed from the organic matter loss during bioleaching, leading to reduced quinone-like and tryptophan-like substances associated with electron transfer in HA during composting. Furthermore, BDS showed lower pH, water content, and organic matter, but higher concentrations of ammonium nitrogen (${\mathrm{NH}}_4^{+}\text{-}\mathrm{N}$) and ammonia nitrogen ${\mathrm{NH}}_3^{-}\text{-}\mathrm{N}$, all of which potentially influenced humification efficiency. These findings not only clarify the electron-transfer dynamics of humic fractions but also highlight the importance of optimizing sludge pretreatment for improved composting performance and resource recovery. Full article

The development of low-temperature, high-efficiency catalysts for the catalytic elimination of chlorinated volatile organic compounds (CVOCs) remains a significant challenge. Investigating the influence mechanism of catalyst physicochemical properties on chlorobenzene oxidation performance and degradation pathways is particularly important. CuO/WO₃ catalysts were developed using a hydrothermal method in this work. The effects of simultaneous or separate addition of ammonium sulphate and ammonium persulphate on the catalytic performance of the CuO/WO₃ series catalysts were investigated. The results showed that the introduction of ammonium sulphate alone can facilitate the formation of CuWO₄, thereby increasing the chemisorbed oxygen concentration of the CuO/WO₃, and making the overall structure of the catalyst looser and increasing the active sites on the catalyst surface. As the optimal catalyst, CuO/WO₃-2 exhibited 55.9% of chlorobenzene conversion and 32.9% of CO₂ selectivity at 500 °C. Interestingly, although the surface acidity in this work seemed to be one of the reasons for promoting the chlorobenzene oxidation, it could be clearly found that the strong solid acidity of WO₃ was actually a key factor in inhibiting the chlorobenzene oxidation. Finally, based on in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analysis, the primary mechanism for chlorobenzene oxidation on CuO/WO₃ catalysts proceeds through a sequential conversion: chlorobenzene was first transformed into phenolic intermediates, followed by quinone compounds, maleates, aldehydes, bidentate carbonates, and ultimately carbonate species. Full article

A robust analytical method based on Captiva EMR-Lipid solid-phase extraction and HPLC-MS/MS was developed and validated for the simultaneous determination of 19 aromatic amine antioxidants (AAs) and two p-phenylenediamine-derived quinones (PPD-Qs) in human plasma. The optimized protocol effectively removed phospholipid interferences from complex blood matrix, significantly mitigating ion suppression and improving the recovery of hydrophobic AAs compared to conventional liquid–liquid extraction. Method validation demonstrated good accuracy (spike recoveries: 73.0–96.8%), precision (RSD < 11%), and sensitivity with method detection limits ranging from 0.81 to 21 pg/mL. The method was successfully applied to plasma samples from 20 adults, in which 11 AAs were detected at total concentrations of 240–710 pg/mL. Diphenylamine derivatives, particularly bis(4-tert-butylphenyl)amine (DBDPA) and diphenylamine (DPA), were identified as the predominant compounds, contributing over 69% of the total AA burden. No PPDs or PPD-Qs were detected, which may be attributed to their biotransformation and urinary excretion, as well as the limited sample size. This study provides a comprehensive biomonitoring tool for assessing combined human exposure to multiple AAs and establishes a foundation for further investigation into their health implications. Full article