Oxidative Redox Research Articles

Spermidine protects cellular redox status and ionic homeostasis in D-galactose induced senescence and natural aging rat models.

Impaired redox homeostasis is an important hallmark of aging. Among various anti-aging interventions, caloric restriction mimetics (CRMs) are the most effective inpromoting health and longevity. The potential role of spermidine (SPD) as a CRM in modulating oxidative stress and redox homeostasis during aging remains unclear. Thisstudy aimed to investigate the protective effect of SPD inD-galactose (D-gal) accelerated induced senescence model and naturally aged rats. Young male rats (4months), D-gal induced (500 mg/kg b. w., subcutaneously) aging model and naturally aged (22months) rats were supplemented with SPD (10 mg/kg b. w., orally) for 6weeks. The results showed that SPD supplementation suppresses the age induced increase in reactive oxygen species, lipid peroxidation andprotein oxidation. Additionally, it increases the level ofantioxidants, plasma membrane redox system in erythrocytes and membrane. These results also indicate that membrane transporter activity is correlated with the susceptibility of the erythrocyte towards oxidative damage. We therefore present evidence that SPD improves redox status and membrane impairments in erythrocytes in experimental and naturally aging rat models, however, more research is required to recommend a potential therapeutic role for SPD as an anti-aging intervention strategy.

Effects of oxidation reduction potential levels on bacterial density in Portuguese oysters (Crassostrea angulata) utilising a sonoelectrochemical depuration system

ABSTRACT The consumption of raw oysters is on the rise and poses a significant health risk because of the presence of bacteria such as Escherichia coli, Salmonella spp., and Vibrio spp. Sonoelectrochemical technology offers a promising solution by creating nanobubbles charged with negative ions, which effectively kill bacteria in oysters without affecting human health, and is also environmentally friendly. This study evaluated the bacterial reduction capability of this technology on Portuguese oysters (Crassostrea angulata) using different oxidation redox potential (ORP) levels of 450, 600 and 750 mV compared with clean seawater (control) after 8, 16 and 24 hours. The results showed that extended exposure time did not significantly decrease E. coli and Salmonella spp. densities, except for the 750 mV treatment. The ORP level of 750 mV for 16 hours was the most effective in reducing bacterial population in oysters with total Vibrio, E. coli and Salmonella spp. reduced by 1.14, 0.95, and 0.85 logCFU/g, respectively. Further research is needed to optimise oyster depuration using sonoelectrochemical technology to enhance its efficiency and practical application.

Extracting metal oxide redox thermodynamics from TGA measurements requires moving beyond the linearized van ‘t Hoff approach

Thermodynamic modeling of metal oxide reduction is crucial for optimizing chemical processes and materials in systems dependent on off-stoichiometric reduction/re-oxidation cycling. Two prevalent methods for extracting reduction thermodynamics from thermogravimetric data are linearized van ‘t Hoff (VH) analysis and the compound energy formalism (CEF). This work evaluates the accuracy of these methods by constructing invertible ground truth thermodynamic models, generating hypothetical thermogravimetric data, and determining the reduction thermodynamic using both VH and CEF methods. Our findings reveal that the VH method produces absolute errors 3–5 times higher than the CEF in kJ/mol O or J/mol O K for enthalpy and entropy of reduction, respectively. In contrast, the CrossFit CEF (CF-CEF) method yields errors often less than 10 kJ/mol O or J/mol O K. Moreover, the CF-CEF method provides models based on mole fraction, temperature, and extent of reduction, while a typical VH analysis provides thermodynamics of only the specific compositions measured. Although simple to implement, the VH method suffers from significant, non-systematic errors due to entropy/enthalpy compensation and defect modeling. Consequently, we recommend the more complex but robust, CF-CEF method for extracting redox thermodynamics from thermogravimetric measurements.

Free radicals and oxidative stress: Mechanisms and therapeutic targets.

Free radicals are small extremely reactive species that have unpaired electrons. Free radicals include subgroups of reactive species, which are all a product of regular cellular metabolism. Oxidative stress happens when the free radicals production exceeds the capacity of the antioxidant system in the body's cells. The current review clarifies the prospective role of antioxidants in the inhibition and healing of diseases. Information on oxidative stress, free radicals, reactive oxidant species, and natural and synthetic antioxidants was obtained by searching electronic databases like PubMed, Web of Science, and Science Direct, with articles published between 1987 and 2023 being included in this review. Free radicals exhibit a dual role in living systems. They are toxic byproducts of aerobic metabolism that lead to oxidative injury and tissue disorders and act as signals to activate appropriate stress responses. Endogenous and exogenous sources of reactive oxygen species are discussed in this review. Oxidative stress is a component of numerous diseases, including diabetes mellitus, atherosclerosis, cardiovascular disease, Alzheimer's disease, Parkinson's disease, and cancer. Although various small molecules assessed as antioxidants have shown therapeutic prospects in preclinical studies, clinical trial outcomes have been inadequate. Understanding the mechanisms through which antioxidants act, where, and when they are active may reveal a rational approach that leads to more tremendous pharmacological success. This review studies the associations between oxidative stress, redox signaling, and disease, the mechanisms through which oxidative stress can donate to pathology, the antioxidant defenses, the limits of their effectiveness, and antioxidant defenses that can be increased through physiological signaling, dietary constituents, and probable pharmaceutical interference. Prospective clinical applications of enzyme mimics and current progress in metal- and non-metal-based materials with enzyme-like activities and protection against chronic diseases have been discussed. This review discussed oxidative stress as one of the main causes of illnesses, as well as antioxidant systems and their defense mechanisms that can be useful in inhibiting these diseases. Thus, the positive and deleterious effects of antioxidant molecules used to lessen oxidative stress in numerous human diseases are discussed. The optimal level of vitamins and minerals is the amount that achieves the best feed benefit, best growth rate, and health, including immune efficiency, and provides sufficient amounts to the body.

Intracellular Redox Environment Determines Cancer-normal Cell Selectivity of Selenium Nanoclusters.

Elucidating the chemical structure and intracellular action mechanisms is still the critical limit for the clinical translation of nanomedicines. Intracellular redox environments originating from cell metabolism are key factors affecting internalized drug efficacy. Herein, we engineer Se-Se/Se-S bond to assemble selenium nanoclusters with intracellular redox environment-driven selective structure. Chemical structure analysis reveals that, the bonding of sulfur atom in intermediates to the two neighboring or interposition selenium atoms in selenium rings is the key internal driving force for nanoparticle cluster formation. This nanocluster can be predominantly transformed to selenocysteine to facilitate selenoproteins synthesis in normal cells, while metabolize to cytotoxic SeO32- based on the oxidative intracellular redox environment of cancer cells. Resultantly, selenium nanoclusters exhibit significant cell proliferation inhibition ability to cancer cells and impressive safety to normal cells. Taken together, this study not only clarifies the chemical nature of the atom engineering of selenium nanocluster, but also elucidates its intracellular redox environment-oriented anticancer mechanism.

Intracellular Redox Environment Determines Cancer‐normal Cell Selectivity of Selenium Nanoclusters

Elucidating the chemical structure and intracellular action mechanisms is still the critical limit for the clinical translation of nanomedicines. Intracellular redox environments originating from cell metabolism are key factors affecting internalized drug efficacy. Herein, we engineer Se‐Se/Se‐S bond to assemble selenium nanoclusters with intracellular redox environment‐driven selective structure. Chemical structure analysis reveals that, the bonding of sulfur atom in intermediates to the two neighboring or interposition selenium atoms in selenium rings is the key internal driving force for nanoparticle cluster formation. This nanocluster can be predominantly transformed to selenocysteine to facilitate selenoproteins synthesis in normal cells, while metabolize to cytotoxic SeO32‐ based on the oxidative intracellular redox environment of cancer cells. Resultantly, selenium nanoclusters exhibit significant cell proliferation inhibition ability to cancer cells and impressive safety to normal cells. Taken together, this study not only clarifies the chemical nature of the atom engineering of selenium nanocluster, but also elucidates its intracellular redox environment‐oriented anticancer mechanism.

Vulnerability of Antioxidant Drug Therapies on Targeting the Nrf2-Trp53-Jdp2 Axis in Controlling Tumorigenesis.

Control of oxidation/antioxidation homeostasis is important for cellular protective functions, and disruption of the antioxidation balance by exogenous and endogenous ligands can lead to profound pathological consequences of cancerous commitment within cells. Although cancers are sensitive to antioxidation drugs, these drugs are sometimes associated with problems including tumor resistance or dose-limiting toxicity in host animals and patients. These problems are often caused by the imbalance between the levels of oxidative stress-induced reactive oxygen species (ROS) and the redox efficacy of antioxidants. Increased ROS levels, because of abnormal function, including metabolic abnormality and signaling aberrations, can promote tumorigenesis and the progression of malignancy, which are generated by genome mutations and activation of proto-oncogene signaling. This hypothesis is supported by various experiments showing that the balance of oxidative stress and redox control is important for cancer therapy. Although many antioxidant drugs exhibit therapeutic potential, there is a heterogeneity of antioxidation functions, including cell growth, cell survival, invasion abilities, and tumor formation, as well as the expression of marker genes including tumor suppressor proteins, cell cycle regulators, nuclear factor erythroid 2-related factor 2, and Jun dimerization protein 2; their effectiveness in cancer remains unproven. Here, we summarize the rationale for the use of antioxidative drugs in preclinical and clinical antioxidant therapy of cancer, and recent advances in this area using cancer cells and their organoids, including the targeting of ROS homeostasis.

Fabrication and performance assessment of coin cell supercapacitors with multiwalled carbon nanotube-supported mixed metal oxide nanocomposites and redox additive electrolyte

In the realm of supercapacitor applications, the fabrication of coin cell supercapacitors with superior performances played a crucial role. In this work, an asymmetrical type coin supercapacitor was fabricated with multiwalled carbon nanotube supported mixed metal oxide (CuO/CoO@MWCNT - CCM) nanocomposites (NCs) and potassium ferrocyanide incorporated KOH based redox additive electrolyte (RAE). The synergistic effect and the enhanced conductivity by the mixed metal oxides and MWCNT, respectively, were acted as the performance enhancer for electrode performances. On the other hand, RAE with optimized concentration provided additional redox active sites for superior performances. The combined effect of CCM NCs and RAE, were responsible for the superior performances. CCM NCs were prepared by one-pot hydrothermal technique and characterized. Working electrodes with CCM NCs were fabricated by doctor blade method and evaluated in KOH and RAE. It exhibited 1838.55 Fg−1 of specific capacitance (Csp) in RAE. Assembled asymmetrical supercapacitors with CCM NCs modified working electrode and activated carbon based anode, delivered 123.91 Fg−1 of Csp at 2.75 Ag−1 in RAE. The assembled supercapacitors delivered the highest energy density of 27.53 Wh kg−1 and power density of 1875 W kg−1 in RAE with an impressive 82.89 % of cyclic retention after 5000 GCD cycles. Finally, an asymmetric coin cell supercapacitor (CR2302) was fabricated with CCM NCs and RAE. The fabricated coin cell delivered the charge and discharge capacities of 157.72 and 55.99 mAh g−1, respectively in KOH, whereas these values were significantly improved 172.46 and 126.2 mAh g−1 respectively, in RAE. It proved that the fabricated coin cell supercapacitors performed well in terms of maximum charge and discharge performances in RAE compared to conventional KOH.

Roles of Glyco-redox in Epithelial Mesenchymal Transition and Mesenchymal Epithelial Transition, Cancer, and Various Diseases.

Reduction-oxidation (redox) regulation is an important biological phenomenon that provides a balance between antioxidants and the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) under pathophysiological conditions. Structural and functional changes in glycans are also important as post-translational modifications of proteins. The integration of glycobiology and redox biology, called Glyco-redox has provided new insights into the mechanisms of epithelial-mesenchymal transition (EMT)/mesenchymal-epithelial transition (MET), cancer, and various diseases including Alzheimer's disease (AD), chronic obstructive lung disease (COPD), type 2 diabetes, interstitial pneumonitis, and ulcerative colitis (UC), . Glycans are biosynthesized by specific glycosyltransferases and each glycosyltransferase is either directly or indirectly regulated by oxidative stress and redox regulation. A typical example of Glyco-redox is the role of N-glycan referred to as core fucose in superoxide dismutase 3 (SOD3). This glycan was found to be involved in the growth inhibition of cancer cell lines. The significance of Glyco-redox in EMT/MET, cancer and various diseases was found in major N-glycan branching glycosyltransferases GnT-III, GnT-IV, GnT-V, VI, GnT-IX, Fut8, and ST6Gal1. Herein, we summarize previous reports on the target proteins and how this relates to oxidative stress. We also discuss the products of these processes and their significance to cancer and various diseases.

P66Shc Protein—Oxidative Stress Sensor or Redox Enzyme: Its Potential Role in Mitochondrial Metabolism of Human Breast Cancer

This work presents a comprehensive evaluation of the role of p66Shc protein in mitochondrial physiology in MDA-MB-231 breast cancer cells. The use of human breast cancer cell line MDA-MB-231 and its genetically modified clones (obtained with the use of the CRISPR-Cas9 technique), expressing different levels of p66Shc protein, allowed us to demonstrate how the p66Shc protein affects mitochondrial metabolism of human breast cancer cells. Changes in the level of p66Shc (its overexpression, and overexpressing of its Serine 36-mutated version, as well as the knockout of p66Shc) exert different effects in breast cancer cells. Interestingly, knocking out p66Shc caused significant changes observed mostly in mitochondrial bioenergetic parameters. We have shown that an MDA-MB-231 (which is a strong metastatic type of breast cancer) clone lacking p66Shc protein is characterized by a significant shift in the metabolic phenotype in comparison to other MDA-MB-231 clones. Additionally, this clone is significantly more vulnerable to doxorubicin treatment. We have proved that p66Shc adaptor protein in human breast cancer cells may exert a different role than in noncancerous cells (e.g., fibroblasts).

REDOX SIGNALLING IN THE PANCREAS IN HEALTH AND DISEASE.

This review addresses oxidative stress and redox signaling in the pancreas under physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross-talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, acting PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the trans-sulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial ROS, which trigger acinar-to-ductal metaplasia and progression to PanIN. ROS are maintained at sufficient level to promote cell proliferation, whilst avoiding cell death or senescence through formation of NADPH and GSH, and activation of NRF-2, HIF-1/2α, and CREB. Redox signalling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.

The onset and the development of cardiometabolic aging: an insight into the underlying mechanisms.

Metabolic compromise is crucial in aggravating age-associated chronic inflammation, oxidative stress, mitochondrial damage, increased LDL and triglycerides, and elevated blood pressure. Excessive adiposity, hyperglycemia, and insulin resistance due to aging are associated with elevated levels of damaging free radicals, inducing a proinflammatory state and hampering immune cell activity, leading to a malfunctioning cardiometabolic condition. The age-associated oxidative load and redox imbalance are contributing factors for cardiometabolic morbidities via vascular remodelling and endothelial damage. Recent evidence has claimed the importance of gut microbiota in maintaining regular metabolic activity, which declines with chronological aging and cardiometabolic comorbidities. Genetic mutations, polymorphic changes, and environmental factors strongly correlate with increased vulnerability to aberrant cardiometabolic changes by affecting key physiological pathways. Numerous studies have reported a robust link between biological aging and cardiometabolic dysfunction. This review outlines the scientific evidence exploring potential mechanisms behind the onset and development of cardiovascular and metabolic issues, particularly exacerbated with aging.

Neuroinflammation and oxidative redox imbalance drive memory dysfunction in adolescent rats prenatally exposed to Datura Stramonium

Although there have been reports indicating that Datura Stramonium (D. stramonium) may induce anticholinergic and neuropsychiatry effects, the compound is still being used for recreational and medicinal purposes while ingestion during pregnancy has been documented. Intriguingly, minimal studies have investigated the potential neurotoxic impact of D. stramonium exposure at various stages of gestation, including its potential implication on neurophysiological well-being later in life. The present study, therefore, examined spontaneous working memory and the expression of specific neurochemicals modulating crucial neural processes in adolescent rats exposed to high and low D. stramonium doses during different stages of gestation. Pregnant rats were orally infused with 150- or 500- mg/kg/day of D. stramonium either during mid- (second week; days 8–14) or late- (third week; days 15–21) gestation, while control rats received PBS at dosing periods. Behavioral characterization of offspring between postnatal days (PD) 40 and 41 in the Y-maze revealed that D. stramonium perturbed spatial working memory in rats, although locomotor activity was generally unaltered. In addition to SOD and nitric oxide downregulation, induction of oxidative stress in the hippocampus and prefrontal cortex (PFC) of young adult rats prenatally exposed to D. stramonium was corroborated by depletion of key antioxidant regulatory elements glutathione peroxidase, glutathione reductase and catalase, which was accompanied by lipid peroxidation shown by increased MDA levels. Whereas increased expression of acetylcholinesterase and LDH was seen in adolescent rats prenatally infused D. stramonium, acetylcholine levels were downregulated in both hippocampal and PFC lysates, suggesting cholinergic and metabolic dysfunctions. Immunohistochemical labelling of GFAP and IBA-1 revealed increased expression of reactive astrocytes and microglia respectively, while the accompanying TNFα upregulation in both the hippocampus (dentate gyrus) and PFC causally linked intrauterine D. stramonium exposure with neuroinflammatory responses postnatally. Overall, our data correlated postnatal spatial working memory dysfunction evoked by D. stramonium exposure during critical stages of embryonic development to oxidative redox impairment, cholinergic disruption and neuroinflammatory perturbations in rats.

Diabetic Kidney Disease: Contribution of Phenyl Sulfate Derived from Dietary Tyrosine upon Gut Microbiota Catabolism.

Deranged gut microbiota can release increased levels of uremic toxins leading to exacerbated kidney injury. In diabetic kidney disease (DKD), phenyl sulfate (PS) derived from tyrosine catabolism by gut microbiota has been demonstrated to be both an early diagnostic marker and a therapeutic target. In this perspective article, we summarize PS generation pathways and recent findings on PS and kidney injury in DKD. Increasing evidence has shown that the underlying mechanisms of PS-induced kidney injury mainly involve oxidative stress, redox imbalance, and mitochondrial dysfunction, which all may be targeted to attenuate PS-induced kidney injury. For future research directions, we think that a deeper understanding of the pathogenic role of PS in kidney injury using a variety of diabetic animal models should be investigated. Moreover, we also suggest beneficial approaches that could be used to mitigate the deleterious effect of PS on the kidney. These approaches include caloric restriction, tyrosine restriction, and administration of ketogenic drugs, ketogenic diets or natural products; all of which should be conducted under obese and diabetic conditions.

Clostridium autoethanogenum alters cofactor synthesis, redox metabolism, and lysine-acetylation in response to elevated H2:CO feedstock ratios for enhancing carbon capture efficiency

BackgroundClostridium autoethanogenum is an acetogenic bacterium that autotrophically converts carbon monoxide (CO) and carbon dioxide (CO2) gases into bioproducts and fuels via the Wood–Ljungdahl pathway (WLP). To facilitate overall carbon capture efficiency, the reaction stoichiometry requires supplementation of hydrogen at an increased ratio of H2:CO to maximize CO2 utilization; however, the molecular details and thus the ability to understand the mechanism of this supplementation are largely unknown.ResultsIn order to elucidate the microbial physiology and fermentation where at least 75% of the carbon in ethanol comes from CO2, we established controlled chemostats that facilitated a novel and high (11:1) H2:CO uptake ratio. We compared and contrasted proteomic and metabolomics profiles to replicate continuous stirred tank reactors (CSTRs) at the same growth rate from a lower (5:1) H2:CO condition where ~ 50% of the carbon in ethanol is derived from CO2. Our hypothesis was that major changes would be observed in the hydrogenases and/or redox-related proteins and the WLP to compensate for the elevated hydrogen feed gas. Our analyses did reveal protein abundance differences between the two conditions largely related to reduction–oxidation (redox) pathways and cofactor biosynthesis, but the changes were more minor than we would have expected. While the Wood–Ljungdahl pathway proteins remained consistent across the conditions, other post-translational regulatory processes, such as lysine-acetylation, were observed and appeared to be more important for fine-tuning this carbon metabolism pathway. Metabolomic analyses showed that the increase in H2:CO ratio drives the organism to higher carbon dioxide utilization resulting in lower carbon storages and accumulated fatty acid metabolite levels.ConclusionsThis research delves into the intricate dynamics of carbon fixation in C. autoethanogenum, examining the influence of highly elevated H2:CO ratios on metabolic processes and product outcomes. The study underscores the significance of optimizing gas feed composition for enhanced industrial efficiency, shedding light on potential mechanisms, such as post-translational modifications (PTMs), to fine-tune enzymatic activities and improve desired product yields.

Oxidative stress and food as medicine.

There has been a sea of change in our understanding of the contribution of food to both our well-being and disease states. When one addresses "food as medicine," the concept of oxidative stress needs to be included. This review interconnects the basic science findings of oxidative stress and redox balance with the medicinal use of food, emphasizing optimization of the redox balance. To better illustrate the impacts of oxidative stress, the concept of the "triple oxidant sink" is introduced as a theoretical gauge of redox balance. Utilizing the concept, the true importance of dietary and lifestyle factors can be emphasized, including the limitations of supplements or a handful of "superfoods," if the remainder of the factors are pro-oxidant. The effects of a whole plant food diet compared with those of dietary supplements, processed foods, animal based nutrients, or additional lifestyle factors can be visually demonstrated with this concept. This paper provides an overview of the process, acknowledging that food is not the only mechanism for balancing the redox status, but one that can be strategically used to dramatically improve the oxidative state, and thus should be used as medicine.

Unique expression and critical role of metallothionein 3 in the control of osteoclastogenesis and osteoporosis

Bone homeostasis is maintained by an intricate balance between osteoclasts and osteoblasts, which becomes disturbed in osteoporosis. Metallothioneins (MTs) are major contributors in cellular zinc regulation. However, the role of MTs in bone cell regulation has remained unexplored. Single-cell RNA sequencing analysis discovered that, unlike the expression of other MT members, the expression of MT3 was unique to osteoclasts among various macrophage populations and was highly upregulated during osteoclast differentiation. This unique MT3 upregulation was validated experimentally and supported by ATAC sequencing data analyses. Downregulation of MT3 by gene knockdown or knockout resulted in excessive osteoclastogenesis and exacerbated bone loss in ovariectomy-induced osteoporosis. Transcriptome sequencing of MT3 knockdown osteoclasts and gene set enrichment analysis indicated that the oxidative stress and redox pathways were enriched, which was verified by MT3-dependent regulation of reactive oxygen species (ROS). In addition, MT3 deficiency increased the transcriptional activity of SP1 in a manner dependent on intracellular zinc levels. This MT3-zinc-SP1 axis was crucial for the control of osteoclasts, as zinc chelation and SP1 knockdown abrogated the promotion of SP1 activity and osteoclastogenesis by MT3 deletion. Moreover, SP1 bound to the NFATc1 promoter, and overexpression of an inactive SP1 mutant negated the effects of MT3 deletion on NFATc1 and osteoclastogenesis. In conclusion, MT3 plays a pivotal role in controlling osteoclastogenesis and bone metabolism via dual axes involving ROS and SP1. The present study demonstrated that MT3 elevation is a potential therapeutic strategy for osteolytic bone disorders, and it established for the first time that MT3 is a crucial bone mass regulator.

Supersulfide formation in the sinus mucosa of chronic rhinosinusitis.

Disruption of the oxidative stress defense system is involved in developing various diseases. Sulfur compounds such as glutathione (GSH) and cysteine (CysSH) are representative antioxidants in the body. Recently, supersulfides, including reactive persulfide and polysulfide species, have gained attention as potent antioxidants regulating oxidative stress and redox signaling. However, their involvement in the pathogenesis of chronic rhinosinusitis (CRS) remains unclear. To clarify the changes in sulfur compounds within the sinus mucosa of each CRS subtype, we measured sulfur compound levels in the sinus mucosa of control individuals (n = 9), patients with eosinophilic CRS (ECRS) (n = 13), and those with non-ECRS (nECRS) (n = 11) who underwent sinus surgery using mass spectrometry. GSH and CysSH levels were significantly reduced, and the glutathione disulfide (GSSG)/GSH ratio, an oxidative stress indicator, was increased in patients with ECRS. Despite the absence of notable variations in supersulfides, patients with ECRS and nECRS exhibited a significant reduction in glutathione trisulfide (GSSSG), which serves as the precursor for supersulfides. This study is the first quantitative assessment of supersulfides in normal and inflamed sinus mucosa, suggesting that sulfur compounds contribute to the pathogenesis of CRS. N/A.

ER Oxidative Stress Promotes Glutathione-Dependent Oxidation of Collagen-1A1 and Promotes Lung Fibroblast Activation.

Changes in the oxidative (redox) environment accompany idiopathic pulmonary fibrosis (IPF). S-glutathionylation of reactive protein cysteines is a post-translational event that transduces oxidant signals into biological responses. We recently demonstrated that increases in S-glutathionylation promote pulmonary fibrosis, which was mitigated by the deglutathionylating enzyme glutaredoxin (GLRX). However, the protein targets of S-glutathionylation that promote fibrogenesis remain unknown. In the present study we addressed whether the extracellular matrix is a target for S-glutathionylation. We discovered increases in collagen 1A1 S-glutathionylation (COL1A1-SSG) in lung tissues from IPF subjects compared to control subjects in association with increases in ER oxidoreductin 1 (ERO1A) and enhanced oxidation of ER-localized peroxiredoxin 4 (PRDX4) reflecting an increased oxidative environment of the endoplasmic reticulum (ER). Human lung fibroblasts exposed to transforming growth factor beta 1 (TGFB1) show increased secretion of COL1A1-SSG. Pharmacologic inhibition of ERO1A diminished oxidation of PRDX4, attenuated COL1A1-SSG and total COL1A1 levels and dampened fibroblast activation. Absence of Glrx enhanced COL1A1-SSG and overall COL1A1 secretion and promoted activation of mechanosensing pathways. Remarkably, COL1A1-SSG resulted in marked resistance to collagenase degradation. Compared to COL1, lung fibroblasts plated on COL1-SSG proliferated more rapidly, and increased expression of genes encoding extracellular matrix crosslinking enzymes and genes linked to mechanosensing pathways. Overall, these findings suggest that glutathione-dependent oxidation of COL1A1 occurs in settings of IPF in association with enhanced ER oxidative stress and may promote fibrotic remodeling due to increased resistance to collagenase-mediated degradation and fibroblast activation.

Traffic-related ultrafine particles impair mitochondrial functions in human olfactory mucosa cells – Implications for Alzheimer's disease

Constituents of air pollution, the ultrafine particles (UFP) with a diameter of ≤0.1 μm, are considerably related to traffic emissions. Several studies link air pollution to Alzheimer's disease (AD), yet the exact relationship between the two remains poorly understood. Mitochondria are known targets of environmental toxicants, and their dysfunction is associated with neurodegenerative diseases. The olfactory mucosa (OM), located at the rooftop of the nasal cavity, is directly exposed to the environment and in contact with the brain. Mounting evidence suggests that the UFPs can impact the brain directly through the olfactory tract. By using primary human OM cultures established from nasal biopsies of cognitively healthy controls and individuals diagnosed with AD, we aimed to decipher the effects of traffic-related UFPs on mitochondria. The UFP samples were collected from the exhausts of a modern heavy-duty diesel engine (HDE) without aftertreatment systems, run with renewable diesel (A0) and petroleum diesel (A20), and from an engine of a 2019 model diesel passenger car (DI-E6d) equipped with state-of-the-art aftertreatment devices and run with renewable diesel (Euro6). OM cells were exposed to three different UFPs for 24-h and 72-h, after which cellular processes were assessed on the functional and transcriptomic levels. Our results show that UFPs impair mitochondrial functions in primary human OM cells by hampering oxidative phosphorylation (OXPHOS) and redox balance, and the responses of AD cells differ from cognitively healthy controls. RNA-Seq and IPA® revealed inhibition of OXPHOS and mitochondrial dysfunction in response to UFPs A0 and A20. Functional validation confirmed that A0 and A20 impair cellular respiration, decrease ATP levels, and disturb redox balance by altering NAD and glutathione metabolism, leading to increased ROS and oxidative stress. RNA-Seq and functional assessment revealed the presence of AD-related alterations in human OM cells and that different fuels and engine technologies elicit differential effects.