Restore Redox Homeostasis Research Articles

Acid-Triggered Cascaded Responsive Supramolecular Peptide Alleviates Myocardial Ischemia‒Reperfusion Injury by Restoring Redox Homeostasis and Protecting Mitochondrial Function.

Redox imbalance, including excessive production of reactive oxygen species (ROS) caused by mitochondrial dysfunction and insufficient endogenous antioxidant capacity, is the primary cause of myocardial ischemia‒reperfusion (I/R) injury. In the exploration of reducing myocardial I/R injury, it is found that protecting myocardial mitochondrial function after reperfusion not only reduces ROS bursts but also inhibits cell apoptosis triggered by the release of cytochrome c. Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2) is considered a potential therapeutic target for treating myocardial I/R injury by enhancing the cellular antioxidant capacity through the induction of endogenous antioxidant enzymes. In this study, a peptide‒drug conjugate OI-FFG-ss-SS31(ISP) is developed by integrating the Nrf2 activator 4-octyl itaconate (OI) and the mitochondria-targeting protective peptide elamipretide (SS31), and its therapeutic potential for myocardial I/R injury is explored. The results showed that ISP could self-assemble into nanofibers in response to the acidic microenvironment and bind to Keap-1 with high affinity, thereby activating Nrf2 and enhancing antioxidant capacity. Simultaneously, the release of SS31 could improve mitochondrial function and reduce ROS, ultimately providing a restoration of redox homeostasis to effectively alleviate myocardial I/R injury. This study presents a promising acid-triggered peptide-drug conjugate for treating myocardial I/R injury.

Oral Akkermansia muciniphila Biomimetic Nanotherapeutics for Ulcerative Colitis Targeted Treatment by Repairing Intestinal Epithelial Barrier and Restoring Redox Homeostasis.

The structural disruption of intestinal barrier and excessive reactive oxygen/nitrogen species (RONS) generation are two intertwined factors that drive the occurrence and development of ulcerative colitis (UC). Synchronously restoring the intestinal barrier and mitigating excess RONS is a promising strategy for UC management, but its treatment outcomes are still hindered by low drug accumulation and retention in colonic lesions. Inspired by intestine colonizing bacterium, we developed a mucoadhesive probiotic Akkermansia muciniphila-mimic entinostat-loaded hollow mesopores prussian blue (HMPB) nanotherapeutic (AM@HMPB@E) for UC-targeted therapy via repairing intestinal barrier and scavenging RONS. After oral administration, the negatively charged AM@HMPB@E specifically bind to the positively charged inflamed colon lesions via electrostatic interactions and Akkermansia muciniphila membrane-mediated bioadhesion mechanism. Subsequently, the superoxide dismutase (SOD)-, and catalase (CAT)-like HMPB eliminated RONS, thereby alleviating RONS-mediated inflammation and intestinal epithelial damage. Meanwhile, the UC-site locally released entinostat could repair the damaged intestinal epithelial barrier by inhibiting intestinal endothelial cell apoptosis and up-regulating the expression of tight junctions. Both in vitro and in vivo results shown that AM@HMPB@E not only exhibited an exceptional retention in the colitis site but also demonstrated superior therapeutic efficacy compared to the first-line drug sulfasalazine, as evidenced by the longer colon, less rectal bleeding and body weight loss. Collectively, our findings highlight the clinical application prospects of this synchronous nanotherapeutic strategy for UC treatment, offering a paradigm for the rational design of oral nanomedicine.

Multifunctional peptide-drug conjugate CORM-401@R9: A novel approach to combat oxidative stress in cataracts.

Cataracts, the leading cause of blindness globally, are primarily driven by oxidative stress and protein aggregation in the lens. Effective pharmacological treatments for cataracts are still elusive. This study developed a novel multifunctional peptide-drug conjugate, CORM-401@R9 (CO-R9), which activates in response to reactive oxygen species (ROS) and releases carbon monoxide (CO). The conjugate combines poly-arginine-9 peptide (R9) with CORM-401 to improve cellular uptake and CO delivery, targeting the elevated ROS levels characteristic of cataract pathology. In vitro, CO-R9 effectively reduced ROS levels and prevented senescence and apoptosis induced by oxidative stress. Further investigation into the molecular mechanisms reveals that CO-R9 restored redox homeostasis by modulating the expression of key genes and proteins involved in antioxidant defense, anti-apoptotic responses, and molecular chaperoning. This study highlights CO-R9 as a promising therapeutic agent with potential for cataract prevention and treatment.

INTERPLAY BETWEEN EPIGENETICS, SENESCENCE AND CELLULAR REDOX METABOLISM IN CANCER AND ITS THERAPEUTIC IMPLICATIONS

There is accumulating evidence indicating a close crosstalk between key molecular events regulating cell growth and proliferation, which could profoundly impact carcinogenesis and its progression. Here we focus on reviewing observations highlighting the interplay between epigenetic modifications, irreversible cell cycle arrest or senescence, and cellular redox metabolism. Epigenetic alterations, such as DNA methylation and histone modifications, dynamically influence tumour transcriptome, thereby impacting tumour phenotype, survival, growth and spread. Interestingly, the acquisition of senescent phenotype can be triggered by epigenetic changes, acting as a double-edged sword via its ability to suppress tumorigenesis or by facilitating an inflammatory milieu conducive for cancer progression. Concurrently, an aberrant redox metabolism, which is a function of the balance between reactive oxygen species (ROS) generation and intracellular anti-oxidant defences, influences signalling cascades and genomic stability in cancer cells by serving as a critical link between epigenetics and senescence. Recognizing this intricate interconnection offers a nuanced perspective for therapeutic intervention by simultaneously targeting specific epigenetic modifications, modulating senescence dynamics, and restoring redox homeostasis.

Novel application of cyclo(-Phe-Pro) in mitigating aluminum toxicity through oxidative stress alleviation in wheat roots

Microbial secondary metabolites are crucial in plant-microorganism interactions, regulating plant growth and stress responses. In this study, we found that cyclo(-Phe-Pro), a proline-based cyclic dipeptide secreted by many microorganisms, alleviated aluminum toxicity in wheat roots by increasing root growth, decreasing callose deposition, and decreasing Al accumulation. Cyclo(-Phe-Pro) also significantly reduced Al-induced reactive oxygen species (ROS) with H2O2, O2•-, and •OH levels decreasing by 19.1%, 42.8%, and 17.9% in root tips, thus protecting the plasma membrane from oxidative damage. Although Al stress increased the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX) in wheat roots, cyclo(-Phe-Pro) application reduced these enzyme activities. However, compared to the Al treatment, cyclo(-Phe-Pro) application increased DPPH and FRAP activities by 16.8% and 14.9%, indicating increased non-enzymatic antioxidant capacity in wheat roots. We observed that Al caused the oxidation of ascorbate (AsA) and glutathione (GSH) to dehydroascorbate (DHA) and glutathione disulfide (GSSG), respectively. Under Al stress, cyclo(-Phe-Pro) treatment maintained reduced AsA and GSH levels, as well as high AsA/DHA and GSH/GSSG redox pair ratios in wheat roots. High AsA/DHA and GSH/GSSG ratios can reduce Al toxicity by neutralizing free radicals and restoring redox homeostasis via antioxidant properties. These results suggest that cyclo(-Phe-Pro) maintains ASA- and GSH-dependent redox homeostasis to alleviate oxidative and Al stress in wheat roots. Findings of this study establishes a theoretical foundation for using microbial metabolites to mitigate Al toxicity in acidic soils, highlighting their potential in sustainable agriculture.

Melatonin ameliorates chronic sleep deprivation against memory encoding vulnerability: Involvement of synapse regulation via the mitochondrial-dependent redox homeostasis-induced autophagy inhibition

Voluntary sleep curtailment is increasingly more rampant in modern society and compromises healthy cognition, including memory, to varying degrees. However, whether memory encoding is impaired after chronic sleep deprivation (CSD) and the underlying molecular mechanisms involved remain unclear. Here, using the mice, we tested the impact of CSD on the encoding abilities of social recognition-dependent memory and object recognition-dependent memory. We found that memory encoding was indeed vulnerable to CSD, while memory retrieval remained unaffected. The hippocampal neurons of mice with memory encoding deficits exhibited significant synapse damage and hyperactive autophagy, which dissipates during regular sleep cycles. This excessive autophagy appeared to be triggered by damage to mitochondrial DNA (mtDNA), resulting from oxidative stress within the mitochondria. The relief at the behavioral and molecular biological levels can be achieved with intraperitoneal injections of the antioxidant compound melatonin. Moreover, our in vitro experiments using HT-22 cells demonstrated that oxidative stress induced by hydrogen peroxide led to oxidative damage, including mtDNA damage, and activation of autophagy. Melatonin treatment effectively countered these effects, restoring redox homeostasis and reducing excessive autophagic activity. Notably, this protective effect was not observed when melatonin was administered as a pre-treatment. Together, our findings reveal the vulnerability of memory encoding during chronic sleep curtailment, which is caused by oxidative stress and consequent enhancement of autophagy, suggest a potential therapeutic strategy for addressing these effects following prolonged wakefulness through melatonin intervention, and reiterate the significance of adequate sleep for memory formation and retention.

Empagliflozin impact on experimentally induced acetaminophen toxicity: Imprint of mitochondrial dynamics, biogenesis, and cGAS/STING signal in amending liver insult.

Acetaminophen (APAP) is one of the most clinically relevant medications associated with acute liver damage. A prolific deal of research validated the hepatoprotective effect of empagliflozin (EMPA); however, its effect on APAP-induced hepatotoxicity has still not been investigated. In this study, the prospective hepatoprotective impact of EMPA against APAP-induced hepatotoxicity was investigated. Twenty-eight Balb-C mice were assigned to four groups: control, APAP, EMPA10/APAP, and EMPA25/APAP. At the end of the experiment, serum hepatotoxicity biomarkers, MDA level, and GSH content were estimated. Hepatic mitofusin-2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission 1 protein (FIS1) were immunoassayed. PGC-1α, cGAS, and STING mRNA expression were assessed by real-time PCR. Histopathological changes and immunohistochemistry of INF-β, p-NF-κB, and iNOS were evaluated. APAP treatment caused significant hepatic functional impairment and increased hepatic MDA levels, as well as a concomitant decrease in GSH content. Marked elevation in Drp1 and FIS1 levels, INF-ß, p-NF-κB, and iNOS immunoreactivity, and reduction in MFN2 and OPA1 levels in the APAP-injected group, PGC-1α downregulation, and high expression of cGAS and STING were also documented. EMPA effectively ameliorated APAP-generated structural and functional changes in the liver, restored redox homeostasis and mitochondrial dynamics balance, and enhanced mitochondrial biogenesis, remarkably diminished hepatic expression of cGAS and STING, and elicited a reduction in hepatic inflammation. Moreover, the computational modeling data support the interaction of APAP with antioxidant system-related proteins as well as the interactions of EMPA against Drp1, cGAS, IKKA, and iNOS proteins. Our findings demonstrated for the first time that EMPA has an ameliorative impact against APAP-induced hepatotoxicity in mice via modulation of mitochondrial dynamics, biogenesis, and cGAS/STING-dependent inflammation. Thus, this study concluded that EMPA could be a promising therapeutic modality for acute liver toxicity.

Mechanistic exploration of 6-shogaol’s preventive effects on azoxymethane and dextran sulfate sodium -induced colorectal cancer: involvement of cell proliferation, apoptosis, carcinoembryonic antigen, wingless-related integration site signaling, and oxido-inflammation

Colorectal cancer (CRC) poses a significant global health burden, being the third most prevalent cancer and the second most significant contributor to cancer-related deaths worldwide. Preventive strategies are crucial to combat this rising incidence. 6-shogaol, derived from ginger, has shown promise in preventing and treating various cancers. This study investigated the preventive effects of 6-shogaol on azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC in mice. Forty male BALB/c mice were randomly divided into control, 6-shogaol, AOM + DSS, and 6-shogaol + AOM + DSS. Mice in the control group received corn oil for 16 weeks, while those in the 6-Shogaol group were administered 20 mg/kg of 6-shogaol for 16 weeks. The AOM + DSS group received a single intraperitoneal dose (ip) of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The 6-shogaol + AOM + DSS group received both 6-shogaol for 16 weeks and a single ip of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The AOM + DSS-treated mice exhibited reduced food consumption, colon weight, and colon length, along with increased tumor formation. Co-administration of 6-shogaol effectively reversed these changes, inhibiting CRC development. Histopathological analysis revealed protective effects of 6-shogaol against colonic insults and modulation of inflammatory responses. 6-shogaol significantly reduced Carcinoembryonic antigen and Kiel 67 levels, indicating inhibition of tumor cell proliferation. Mechanistically, 6-shogaol promoted apoptosis by upregulating protein 53 and caspase-3 expression, and it effectively restored the balance of the Wingless-related integration site signaling pathway by regulating β-catenin and adenomatous polyposis coli levels. Moreover, 6-shogaol demonstrated anti-inflammatory effects, reducing myeloperoxidase, Tumor necrosis factor alpha, and cyclooxygenase-2 levels in AOM/DSS-treated mice. Additionally, 6-shogaol restored redox homeostasis by reducing lipid peroxidation and nitrosative stress and enhancing antioxidant enzyme activities. The findings suggest that 6-shogaol inhibits cell proliferation, induces apoptosis, regulates Wnt signaling, suppresses inflammation, and restores redox homeostasis, providing comprehensive insights into its potential therapeutic benefits for CRC.

Oxidative Stress and the Nrf2/PPARγ Axis in the Endometrium: Insights into Female Fertility.

Successful pregnancy depends on precise molecular regulation of uterine physiology, especially during the menstrual cycle. Deregulated oxidative stress (OS), often influenced by inflammatory changes but also by environmental factors, represents a constant threat to this delicate balance. Oxidative stress induces a reciprocally regulated nuclear factor erythroid 2-related factor 2/peroxisome proliferator-activated receptor-gamma (Nrf2/PPARγ) pathway. However, increased PPARγ activity appears to be a double-edged sword in endometrial physiology. Activated PPARγ attenuates inflammation and attenuates OS to restore redox homeostasis. However, it also interferes with physiological processes during the menstrual cycle, such as hormonal signaling and angiogenesis. This review provides an elucidation of the molecular mechanisms that support the interplay between PPARγ and OS. Additionally, it offers fresh perspectives on the Nrf2/PPARγ pathway concerning endometrial receptivity and its potential implications for infertility.

Protective effect of feed additive ferulic acid on respiratory depression and oxidation imbalance of carp induced by pesticide difenoconazole via ROS/NF-κB/NLRP3 axis

Difenoconazole (DFZ), classified as a "low-toxicity pesticide," has seen widespread application in recent years. Nevertheless, the non-target toxicity of the substance, particularly towards aquatic creatures, has generated considerable apprehension. The anti-inflammatory and antioxidant effects of Ferulic Acid (FA) have attracted considerable study in this particular setting. This study established a chronic exposure model to DFZ and investigated the protective effects of FA on chronic respiratory inhibition leading to gill damage in freshwater carp. Histological analyses via HE staining indicated that FA effectively alleviated gill tissue damage induced by chronic DFZ exposure. The qRT-PCR results showed that the addition of FA reduced the expression of IL-1β, IL-6 and TNF-α while boosting the expression of IL-10 and TGF-β1. Biochemical analyses and DHE staining revealed that FA reduced MDA levels and increased CAT and GSH activities, along with T-AOC, decreased ROS accumulation in response to chronic DFZ exposure. The results obtained from Western blotting analysis demonstrated that the addition of FA effectively suppressed the activation of the NF-κB signalling pathway and the NLRP3 inflammasome pathway in the gills subjected to prolonged exposure to DFZ. In summary, FA ameliorated gill tissue inflammation and blocked ROS accumulation in carp exposed to chronic DFZ, mitigating tissue inflammation and restoring redox homeostasis through the NF-κB-NLRP3 signaling pathway. Hence, the application of FA has been found to be efficacious for improving respiratory inhibition and mitigating gill tissue inflammation and oxidative stress resulting from DFZ pollution in aquatic habitats.

Resveratrol protects against myocardial ischemic injury in obese mice via activating SIRT3/FOXO3a signaling pathway and restoring redox homeostasis

BackgroundIncreasing global overweight and obesity rates not only increase the prevalence of myocardial infarction (MI), but also exacerbate ischemic injury and result in worsened prognosis. Currently, there are no drugs that can reverse myocardial damage once MI has occurred, therefore discovering drugs that can potentially limit the extent of ischemic damage to the myocardium is critical. Resveratrol is a polyphenol known for its antioxidant properties, however whether prolonged daily intake of resveratrol during obesity can protect against MI-induced damage remains unexplored. MethodsWe established murine models of obesity via high-fat/high-fructose diet, along with daily administrations of resveratrol or vehicle, then performed surgical MI to examine the effects and mechanisms of resveratrol in protecting against myocardial ischemic injury. ResultsDaily administration of resveratrol in obese mice robustly protected against myocardial ischemic injury and improved post-MI cardiac function. Resveratrol strongly inhibited oxidative and DNA damage via activating SIRT3/FOXO3a-dependent antioxidant enzymes following MI, which were completely prevented upon administration of 3-TYP, a selective SIRT3 inhibitor. Hence, the cardioprotective effects of prolonged resveratrol intake in protecting obese mice against myocardial ischemic injury was due to reestablishment of intracellular redox homeostasis through activation of SIRT3/FOXO3a signaling pathway. ConclusionOur findings provide important new evidence that supports the daily intake of resveratrol, especially in those overweight or obese, which can robustly decrease the extent of ischemic damage following MI. Our study therefore provides new mechanistic insight and suggests the therapeutic potential of resveratrol as an invaluable drug in the treatment of ischemic heart diseases.

Molecular insights into the antioxidative and anti-inflammatory effects of P-coumaric acid against bisphenol A-induced testicular injury: In vivo and in silico studies

This study investigated the protective effects of p-coumaric acid (PCA) against bisphenol A (BPA)-induced testicular toxicity in male rats. The rats were divided into control, BPA, BPA+PCA50, BPA+PCA100, and PCA100 groups. Following a 14-day treatment period, various analyses were conducted on epididymal sperm quality and testicular tissues. PCA exhibited dose-dependent cytoprotective, antioxidant, and anti-inflammatory effects, ameliorating the decline in sperm quality induced by BPA. The treatment elevated antioxidant enzyme activities (SOD, GPx, CAT) and restored redox homeostasis by increasing cellular glutathione (GSH) and reducing malondialdehyde (MDA) levels. PCA also mitigated BPA-induced proinflammatory responses while reinstating anti-inflammatory IL-10 levels. Apoptotic parameters (p53 and p38-MAPK) were normalized by PCA in BPA-treated testicular tissue. Immunohistochemical and immunofluorescent analyses confirmed the cytoprotective and anti-inflammatory effects of PCA, evidenced by the upregulation of HO-1, Bcl-2, and Nrf-2 and the downregulation of the proapoptotic gene Bax in BPA-induced testicular intoxication. PCA corrected the disturbance in male reproductive hormone levels and reinstated testosterone biosynthetic capacity after BPA-induced testicular insult. In silico analyses suggested PCA's potential modulation of the oxidative stress KEAP1/NRF2/ARE pathway, affirming BPA's inhibitory impact on P450scc. This study elucidates BPA's molecular disruption of testosterone biosynthesis and highlights PCA's therapeutic potential in mitigating BPA's adverse effects on testicular function, showcasing its cytoprotective, anti-inflammatory, and hormone-regulating properties. The integrated in vivo and in silico approach offers a comprehensive understanding of complex mechanisms, paving the way for future research in reproductive health and toxicology, and underscores the importance of employing BPA-free plastic wares in semen handling.

The Redox Stress Test: A novel technique reveals oxidative stress in Parkinson’s disease

A novel Redox Stress Test has been developed to identify symptoms of diseases associated with oxidative stress by observing symptom changes induced by short-term activation of the transcription factor Nrf2, to restore redox homeostasis. The Nrf2 pathway is triggered by a herbal preparation, Broccoli Seed Tea, developed to deliver a therapeutic dose of highly bioavailable sulforaphane, a potent activator of Nrf2. We discuss the rationale behind the tea and describe the methods used to optimise the bioavailability of sulforaphane to match the pharmacodynamics of Nrf2 activation. When consumed by people with Parkinson’s disease, the Redox Stress Test induced powerful and concurrent attenuation of a diverse group of Parkinson’s non-motor symptoms, including fatigue, constipation and urinary urgency. Motor symptoms were strictly unaffected. This observation indicates that oxidative stress may be a common factor contributing to non-motor symptoms involving sites in the CNS and peripheral organs. We tentatively interpret the results in terms of a hypothetical model for Parkinson’s Syndrome which we describe as a multisystem redox disorder with reservoirs of the disease in peripheral organs as well as in the brain. Eliminating the disease in peripheral organs is therefore a prerequisite to stopping disease progression in the brain. According to this model, the redox disorder in the brain provokes progressive neurological damage, which is not recognised as such in the early years. More specific neurological symptoms only come to light many years later, when damage to dopaminergic neurons creates a dopamine deficiency which eventually exceeds the threshold required for normal motor control, generating a new coherent group of neurological symptoms which define movement disorder. Given the apparent ease with which oxidative stress can be quenched in several locations simultaneously, we briefly discuss possible implications for public health, medical research, patients and patient advocacy groups. We note that the Redox Stress Test may have the potential to explore symptoms of other diseases where oxidative stress is believed to play a major role, although this remains subject to validation by further research.

Physiological and Transcriptomic Analysis Reveals That Melatonin Alleviates Aluminum Toxicity in Alfalfa (Medicago sativa L.).

Aluminum (Al) toxicity is the most common factor limiting the growth of alfalfa in acidic soil conditions. Melatonin (MT), a significant pleiotropic molecule present in both plants and animals, has shown promise in mitigating Al toxicity in various plant species. This study aims to elucidate the underlying mechanism by which melatonin alleviates Al toxicity in alfalfa through a combined physiological and transcriptomic analysis. The results reveal that the addition of 5 μM melatonin significantly increased alfalfa root length by 48% and fresh weight by 45.4% compared to aluminum treatment alone. Moreover, the 5 μM melatonin application partially restored the enlarged and irregular cell shape induced by aluminum treatment, resulting in a relatively compact arrangement of alfalfa root cells. Moreover, MT application reduces Al accumulation in alfalfa roots and shoots by 28.6% and 27.6%, respectively. Additionally, MT plays a crucial role in scavenging Al-induced excess H2O2 by enhancing the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), consequently reducing malondialdehyde (MDA) levels. More interestingly, the RNA-seq results reveal that MT application significantly upregulates the expression of xyloglucan endotransglucosylase/hydrolase (XTH) and carbon metabolism-related genes, including those involved in the glycolysis process, as well as sucrose and starch metabolism, suggesting that MT application may mitigate Al toxicity by facilitating the binding of Al to the cell walls, thereby reducing intracellular Al accumulation, and improving respiration and the content of sucrose and trehalose. Taken together, our study demonstrates that MT alleviates Al toxicity in alfalfa by reducing Al accumulation and restoring redox homeostasis. These RNA-seq results suggest that the alleviation of Al toxicity by MT may occur through its influence on cell wall composition and carbon metabolism. This research advances our understanding of the mechanisms underlying MT's effectiveness in mitigating Al toxicity, providing a clear direction for our future investigations into the underlying mechanisms by which MT alleviates Al toxicity in alfalfa.

Injectable hydrogel with selenium nanoparticles delivery for sustained glutathione peroxidase activation and enhanced osteoarthritis therapeutics

Reactive oxygen burst in articular chondrocytes is a major contributor to osteoarthritis progression. Although selenium is indispensable role in the antioxidant process, the narrow therapeutic window, delicate toxicity margins, and lack of an efficient delivery system have hindered its translation to clinical applications. Herein, transcriptomic and biochemical analyses revealed that osteoarthritis was associated with selenium metabolic abnormality. A novel injectable hydrogel to deliver selenium nanoparticles (SeNPs) was proposed to intervene selenoprotein expression for osteoarthritis treatment. The hydrogels based on oxidized hyaluronic acid (OHA) cross-linked with hyaluronic acid-adipic acid dihydrazide (HA-ADH) was formulated to load SeNPs through a Schiff base reaction. The hydrogels were further incorporated with SeNPs, which exhibited minimal toxicity, mechanical properties, self-healing capability, and sustained drug release. Encapsulated with SeNPs, the hydrogels facilitated cartilage repair through synergetic effects of scavenging reactive oxygen species (ROS) and depressing apoptosis. Mechanistically, the hydrogel restored redox homeostasis by targeting glutathione peroxidase-1 (GPX1). Therapeutic outcomes of the SeNPs-laden hydrogel were demonstrated in an osteoarthritis rat model created by destabilization of the medial meniscus, including cartilage protection, subchondral bone sclerosis improvement, inflammation attenuation, and pain relief were demonstrated. These results highlight therapeutic potential of OHA/HA-ADH@SeNPs hydrogels, providing fundamental insights into remedying selenium imbalance for osteoarthritis biomaterial development.

Ecotoxicology of Polystyrene Microplastic Fragments: Oxidative Stress Effects in Neonate Versus Adult Daphnia magna

Polystyrene is an inert polymer; however, sublethal effects have been observed in aquatic organisms exposed to microparticles of this plastic. Information on microplastic-related oxidative stress and related antioxidative responses as adverse effects and the underlying mechanisms of toxicity are limited. Daphnids are key contributors in aquatic ecosystems, linking primary producers to consumers and predators, facilitating energy transfer and thus being considered an ideal bioindicator organism to study the adverse effects of polystyrene fragments on the oxidative stress status and subsequent enzymatic antioxidant response. In the present study, neonates (≤ 24 h) and adult daphnids were acutely exposed to polystyrene fragments sieved to three size factions (< 25 µm, 45—63 µm, and 100—500 µm), and adverse effects were evaluated after 24 and 48 h. In adults, larger particles elicited reactive oxygen species by 61%, which was met with elevated superoxide dismutase (17%) and catalase activities (98%), restoring redox homeostasis within 48 h. However, in neonates, the reactive oxygen species increased with exposure to all polystyrene sizes within 24 h, and homeostasis was regained within 48 h without eliciting the enzymatic antioxidant defense. The adverse effects were associated with size fractions that were too large to be consumed, suggesting that leached additives may be involved. Further studies are needed to determine whether nonenzymatic antioxidants were responsible for neutralizing excess reactive oxygen species in neonates.

Plasma-Activated Solutions Mitigates DSS-Induced Colitis via Restoring Redox Homeostasis and Reversing Microbiota Dysbiosis.

Ulcerative colitis is a chronic disease that increases the risk of developing colorectal cancer. Conventional medications are limited by drug delivery and a weak capacity to modulate the inflammatory microenvironment. Further, gut microbiota dysbiosis caused by mucosal damage and dysregulated redox homeostasis leads to frequent recurrence. Therefore, promoting mucosal healing and restoring redox homeostasis is considered the initial step in treating ulcerative colitis. Plasma-activated solutions (PAS) are liquids rich in various reactive nitrogen species (RNS) and reactive oxygen species (ROS) and are used to treat multiple diseases. However, its effect on ulcerative colitis remains to be examined. Therefore, using a DSS-induced mice colitis model, it is found that PAS has the potential to treat colitis and prevent its recurrence by promoting intestinal mucosal repair, reducing inflammation, improving redox homeostasis, and reversing gut microbiota dysbiosis. Further, an equipment is designed for preparing PAS without using nitrogen; however, after treatment with the Nitro-free PAS, the therapeutic effect of PAS is significantly weakened or even lost, indicating that RNS may be the main mediator by which PAS exerts its therapeutic effects. Overall, this study demonstrates the treatment of ulcerative colitis as a novel application of PAS.

The evolution of selective autophagy as a mechanism of oxidative stress response: The evolutionarily acquired ability of selective autophagy receptors to respond to oxidative stress is beneficial for human longevity.

Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity of protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age-related diseases associated with impaired autophagy and oxidative stress.

Biomarkers of Oxidative Stress in Systemic Lupus Erythematosus Patients with Active Nephritis.

Oxidative stress plays an important role in systemic lupus erythematosus (SLE) and especially in lupus nephritis (LN). The aim of this study was to compare redox-related biomarkers between patients with active LN, quiescent SLE (Q-SLE) and healthy controls (HC) and to explore their association with clinical characteristics such as disease activity in patients. We investigated levels of plasma free thiols (R-SH, sulfhydryl groups), levels of soluble receptor for advanced glycation end products (sRAGE) and levels of malondialdehyde (MDA) in SLE patients with active LN (n = 23), patients with quiescent SLE (n = 47) and HC (n = 23). Data of LN patients who previously participated in Dutch lupus nephritis studies and longitudinal samples up to 36 months were analyzed. Thiol levels were lower in active LN at baseline and Q-SLE patients compared to HC. In generalized estimating equation (GEE) modelling, free thiol levels were negatively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) over time (p < 0.001). sRAGE and MDA were positively correlated with the SLEDAI over time (p = 0.035 and p = 0.016, respectively). These results indicate that oxidative stress levels in LN patients are increased compared to HC and associated with SLE disease activity. Therefore, interventional therapy to restore redox homeostasis may be useful as an adjunctive therapy in the treatment of oxidative damage in SLE.

Kartogenin-enhanced dynamic hydrogel ameliorates intervertebral disc degeneration via restoration of local redox homeostasis

IntroductionOver-activation of oxidative stress due to impaired antioxidant functions in nucleus pulpous (NP) has been identified as a key factor contributing to intervertebral disc degeneration (IVDD). While Kartogenin (KGN) has previously demonstrated antioxidant properties on articular cartilage against osteoarthritis, its effects on NP degeneration have yet to be fully understood. ObjectivesThis study aimed to investigate the protective effects of KGN on nucleus pulpous cells (NPCs) against an inflammatory environment induced by interleukin (IL)-1β, as well as to explore the therapeutic potential of KGN-enhanced dynamic hydrogel in preventing IVDD. MethodsNPCs were isolated from rat caudal IVDs and subjected to treatment with KGN at varying concentrations (ranging from 0.01 to 1 ​μM) in the presence of IL-1β. The expression of extracellular matrix (ECM) anabolism markers was quantitatively assessed at both the mRNA and protein levels. Additionally, intracellular reactive oxygen species and antioxidant enzyme expression were evaluated, along with the role of nuclear factor erythroid 2-related factor 2 (NRF2). Based on these findings, a dynamic self-healing hydrogel loaded with KGN was developed through interconnecting networks. Subsequently, KGN-enhanced dynamic hydrogel was administered into rat caudal IVDs that had undergone puncture injury, followed by radiographic analysis and immunohistochemical staining to evaluate the therapeutic efficacy. ResultsIn vitro treatments utilizing KGN were observed to maintain ECM synthesis and inhibit catabolic activities in IL-1β-stimulated NPCs. The mechanism behind this protective effect of KGN on NPCs was found to involve the asctivation of NRF2 and downstream antioxidant enzymes, including glutathione peroxidase 1 and heme oxygenase 1. This was further supported by the loss of both antioxidant and anabolic effects upon pharmacological inhibition of NRF2. Furthermore, a self-healing hydrogel was developed and loaded with KGN to achieve localized and sustained release of the compound. The injection of KGN-enhanced hydrogel effectively ameliorated the degradation of NP ECM and mitigated inflammation in a rat model of puncture-induced IVDD. ConclusionsOur results indicate that KGN exhibits potential as a therapeutic agent for NP degeneration, and that KGN-enhanced dynamic hydrogel represents a novel approach for treating IVDD by restoring redox homeostasis in NP.The translational potential of this article: The dysregulation of oxidant and antioxidant balance has been shown to impede the repair and regeneration of NP, thereby hastening the progression of IVDD following injury. The present investigation has demonstrated that the sustained release of KGN promotes the synthesis of ECM in vitro and mitigates the progression of IVDD in vivo by restoring redox equilibrium, thereby presenting a novel therapeutic candidate based on the antioxidant properties of KGN for the treatment of IVDD.