Redox Homeostasis Research Articles

Self-assembling gelatin based delivery of multienzyme activity nanozyme and photosensitizer for ROS storm based cancer therapy

Nanozymes with multienzyme activity for reactive oxygen species (ROS) generation and intracellular redox imbalance are attractive strategy for cancer therapy. However, it is severely limited by low biocompatibility and catalytic efficiency, hypoxic and high levels of GSH in the tumor microenvironment. To address these issues, a copper doping carbon nanozyme (CC) with multienzyme activity was designed and integrated with photosensitizer Ce6 and gelatin to fabricate ROS amplifier (CCC). Gelatin endowed CCC with good biocompatibility, low hemolysis, and enzyme responsive degradation. CCC with high CAT-like, POD-like, OXD-like, and GSHox-like activities can induce the intracellular ROS storm formation to eliminate the cancer cells. The OXD-like activity and PDT performance mediated 1O2 generation was markedly potentiated by the CAT-like activity of CCC via catalyzing high expression of H2O2 to generate O2. At the same time, a large amount of ·OH were produced through POD-like activity of CCC and GSH was depleted by the GSHox-like activities of CCC, resulting in a destructive ROS storm formation and cellular redox homeostasis disruption. Both in vivo and in vitro experiments showed that CCC displayed satisfactory anti-tumor activity and biocompatibility. Our work provides a novel strategy for the development of nanozyne enhanced photodynamic therapy of cancer.

Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis

Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2′-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations.Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.

Hesperetin-7-O-rhamnoglucoside ameliorates dichlorvos-facilitated cardiotoxicity in rats by counteracting ionoregulatory, ion pumps, redox, and lipid homeostasis disruptions

The contamination of edible agricultural goods with pesticides, including dichlorvos (DVDP), poses a substantial public health risk, promoting severe morbidity and mortality, especially in developing countries. It has been shown that hesperidin (hesperetin-7-O-rhamnoglucoside or Hes-7-RGlc) preserves cytomembrane, redox, and lipid homeostasis; unfortunately, its function on dichlorvos-incited heart damage has not been investigated. This work explored the ameliorative influence of Hes-7-RGlc on DVDP-activated cardiotoxicity. For this end, forty-two rats were randomly appropriated into seven groups (6 rats/group): Control, DVDP alone (8 mg.kg⁻¹day⁻¹), DVDP supplied with either Hes-7-RGlc (50 and 100 mg.kg⁻¹day⁻¹) or the reference medication atropine (0.2 mg.kg⁻¹day⁻¹), and Hes-7-RGlc alone (50 and 10 mg.kg⁻¹day⁻¹) were the seven groups investigated. DVDP was administered orally for seven days, followed by fourteen days of Hes-7-RGlc therapy. Then the rats were euthanized, and their blood and hearts were removed. Hes-7-RGlc chemotherapy substantially (p<0.05) restored DVDP-elicited dynamics in plasma and cardiac/myocardium creatine kinase isoenzyme (CK-MB), major lipids (cholesterol, triacylglycerol, and phospholipids), electrolytes (Na⁺, K⁺, Ca²⁺, Mg²⁺, Cl⁻), and total protein. Hes-7-RGlc remedy decidedly (p<0.05) abolished DDVP-stimulated amplification in the cardiac concentration of H₂O₂, NO and malondialdehyde; annulled DVDP-educed decreases in heart GSH levels, activities of GST, SOD, catalase, and glutathione peroxidase, ion transporters (Na⁺/K⁺-ATPase and Ca²⁺/Mg²⁺-ATPase), ALT, AST, ALP, and LDH-1. Collectively, Hes-7-RGlc can be advocated as a natural supplementary candidate and blocker of DVDP-provoked heart deficits via its capacity to reverse disruptions of electrolytes, ion pumps, redox status, and lipid homeostasis.

Diel transcriptional responses of coral-Symbiodiniaceae holobiont to elevated temperature

Coral exhibits diel rhythms in behavior and gene transcription. However, the influence of elevated temperature, a key factor causing coral bleaching, on these rhythms remains poorly understood. To address this, we examined physiological, metabolic, and gene transcription oscillations in the Acropora tenuis-Cladocopium sp. holobiont under constant darkness (DD), light-dark cycle (LD), and LD with elevated temperature (HLD). Under LD, the values of photosystem II efficiency, reactive oxygen species leakage, and lipid peroxidation exhibited significant diel oscillations. These oscillations were further amplified during coral bleaching under HLD. Gene transcription analysis identified 24-hour rhythms for specific genes in both coral and Symbiodiniaceae under LD. Notably, these rhythms were disrupted in coral and shifted in Symbiodiniaceae under HLD. Importantly, we identified over 20 clock or clock-controlled genes in this holobiont. Specifically, we suggested CIPC (CLOCK-interacting pacemaker-like) gene as a core clock gene in coral. We observed that the transcription of two abundant rhythmic genes encoding glycoside hydrolases (CBM21) and heme-binding protein (SOUL) were dysregulated by elevated temperature. These findings indicate that elevated temperatures disrupt diel gene transcription rhythms in the coral-Symbiodiniaceae holobiont, affecting essential symbiosis processes, such as carbohydrate utilization and redox homeostasis. These disruptions may contribute to the thermal bleaching of coral.

In Vivo-Matured Oocyte Resists Post-Ovulatory Aging through the Hub Genes DDX18 and DNAJC7 in Pigs.

Assisted reproduction technology (ART) procedures are often impacted by post-ovulatory aging (POA), which can lead to reduced fertilization rates and impaired embryo development. This study used RNA sequencing analysis and experimental validation to study the similarities and differences between in vivo- and vitro-matured porcine oocytes before and after POA. Differentially expressed genes (DEGs) between fresh in vivo-matured oocyte (F_vivo) and aged in vivo-matured oocyte (A_vivo) and DEGs between fresh in vitro-matured oocyte (F_vitro) and aged in vitro-matured oocyte (A_vitro) were intersected to explore the co-effects of POA. It was found that "organelles", especially "mitochondria", were significantly enriched Gene Ontology (GO) terms. The expression of genes related to the "electron transport chain" and "cell redox homeostasis" pathways related to mitochondrial function significantly showed low expression patterns in both A_vivo and A_vitro groups. Weighted correlation network analysis was carried out to explore gene expression modules specific to A_vivo. Trait-module association analysis showed that the red modules were most associated with in vivo aging. There are 959 genes in the red module, mainly enriched in "RNA binding", "mRNA metabolic process", etc., as well as in GO terms, and "spliceosome" and "nucleotide excision repair" pathways. DNAJC7, IK, and DDX18 were at the hub of the gene regulatory network. Subsequently, the functions of DDX18 and DNAJC7 were verified by knocking down their expression at the germinal vesicle (GV) and Metaphase II (MII) stages, respectively. Knockdown at the GV stage caused cell cycle disorders and increase the rate of abnormal spindle. Knockdown at the MII stage resulted in the inefficiency of the antioxidant melatonin, increasing the level of intracellular oxidative stress, and in mitochondrial dysfunction. In summary, POA affects the organelle function of oocytes. A_vivo oocytes have some unique gene expression patterns. These genes may be potential anti-aging targets. This study provides a better understanding of the detailed mechanism of POA and potential strategies for improving the success rates of assisted reproductive technologies in pigs and other mammalian species.

Disruption of Cell Membranes and Redox Homeostasis as an Antibacterial Mechanism of Dielectric Barrier Discharge Plasma against Fusarium oxysporum.

Direct barrier discharge (DBD) plasma is a potential antibacterial strategy for controlling Fusarium oxysporum (F. oxysporum) in the food industry. The aim of this study was to investigate the inhibitory effect and mechanism of action of DBD plasma on F. oxysporum. The result of the antibacterial effect curve shows that DBD plasma has a good inactivation effect on F. oxysporum. The DBD plasma treatment severely disrupted the cell membrane structure and resulted in the leakage of intracellular components. In addition, flow cytometry was used to observe intracellular reactive oxygen species (ROS) levels and mitochondrial membrane potential, and it was found that, after plasma treatment, intracellular ROS accumulation and mitochondrial damage were accompanied by a decrease in antioxidant enzyme activity. The results of free fatty acid metabolism indicate that the saturated fatty acid content increased and unsaturated fatty acid content decreased. Overall, the DBD plasma treatment led to the oxidation of unsaturated fatty acids, which altered the cell membrane fatty acid content, thereby inducing cell membrane damage. Meanwhile, DBD plasma-induced ROS penetrated the cell membrane and accumulated intracellularly, leading to the collapse of the antioxidant system and ultimately causing cell death. This study reveals the bactericidal effect and mechanism of the DBD treatment on F. oxysporum, which provides a possible strategy for the control of F. oxysporum.

Simultaneous induction of systemic hyperglycaemia and stress impairs brain redox homeostasis in the adult zebrafish

For diabetic patients it is crucial to constantly monitor blood glucose levels to mitigate complications due to hyperglycaemia, including neurological issues and cognitive impairments. This activity leads to psychological stress, called “diabetes distress,” a problem for most patients living with diabetes. Diabetes distress can exacerbate the hyperglycaemia effects on brain and negatively impact the quality of life, but the underlying mechanisms remain poorly explored. We simulated diabetes distress in adult zebrafish by modelling hyperglycaemia, through exposure to dextrose solution, along with chronic unpredictable mild stress (CUMS), and evaluated brain redox homeostasis by assessing reactive oxygen species (ROS) content, the antioxidant system, and effects on mitochondrial biogenesis and fission/fusion processes. We also evaluated the total, cytosolic and nuclear content of nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of redox balance, in the whole brain and total NRF2 in specific brain emotional areas. The combined CUMS + Dextrose challenge, but not the individual treatments, reduced total NRF2 levels in the entire brain, but strongly increased its levels in the nuclear fraction. Compensatory upregulation of antioxidant genes appeared inadequate to combat elevated levels of ROS, leading to lowering of the reduced glutathione content and total antioxidant capacity. CUMS + Dextrose treatment also upregulated transcription factors implicated in mitochondrial biogenesis and dynamics with a predominance of fission, which is consistent with increased oxidative stress. In conclusion, this study highlights the close interplay between hyperglycaemia and psychological distress causing overriding oxidative stress in the brain, rendering the organism vulnerable to the development of disease complications.

The Effect of Phytocannabinoids and Endocannabinoids on Nrf2 Activity in the Central Nervous System and Periphery.

The relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) and phytocannabinoids/endocannabinoids (pCBs/eCBs) has been investigated in a variety of models of peripheral illnesses, with little clarification on their interaction within the central nervous system (CNS). In this context, evidence suggests that the Nrf2-pCBs/eCBS interaction is relevant in modulating peroxidation processes and the antioxidant system. Nrf2, one of the regulators of cellular redox homeostasis, appears to have a protective role toward damaging insults to neurons and glia by enhancing those genes involved in the regulation of homeostatic processes. Specifically in microglia and macroglia cells, Nrf2 can be activated, and its signaling pathway modulated, by both pCBs and eCBs. However, the precise effects of pCBs and eCBs on the Nrf2 signaling pathway are not completely elucidated yet, making their potential clinical employment still not fully understood.

The GATA transcription factor BcWCL2 regulates citric acid secretion to maintain redox homeostasis and full virulence in Botrytis cinerea.

Botrytis cinerea is a typical necrotrophic plant pathogenic fungus which can deliberately acidify host tissues and trigger oxidative bursts therein to facilitate its virulence. The white collar complex (WCC), consisting of BcWCL1 and BcWCL2, is recognized as the primary light receptor in B. cinerea. Nevertheless, the specific mechanisms through which the WCC components, particularly BcWCL2 as a GATA transcription factor, control virulence are not yet fully understood. This study demonstrates that deletion of BcWCL2 results in the loss of light-sensitive phenotypic characteristics. Additionally, the Δbcwcl2 strain exhibits reduced secretion of citrate, delayed infection cushion development, weaker hyphal penetration, and decreased virulence. The application of exogenous citric acid was found to restore infection cushion formation, hyphal penetration, and virulence of the Δbcwcl2 strain. Transcriptome analysis at 48 h post-inoculation revealed that two citrate synthases, putative citrate transporters, hydrolytic enzymes, and reactive oxygen species scavenging-related genes were down-regulated in Δbcwcl2, whereas exogenous citric acid application restored the expression of the above genes involved in the early infection process of Δbcwcl2. Moreover, the expression of Bcvel1, a known regulator of citrate secretion, tissue acidification, and secondary metabolism, was down-regulated in Δbcwcl2 but not in Δbcwcl1. ChIP-qPCR and electrophoretic mobility shift assays revealed that BcWCL2 can bind to the promoter sequences of Bcvel1. Overexpressing Bcvel1 in Δbcwcl2 was found to rescue the mutant defects. Collectively, our findings indicate that BcWCL2 regulates the expression of the global regulator Bcvel1 to influence citrate secretion, tissue acidification, redox homeostasis, and virulence of B. cinerea.IMPORTANCEThis study illustrated the significance of the fungal blue light receptor component BcWCL2 protein in regulating citrate secretion in Botrytis cinerea. Unlike BcWCL1, BcWCL2 may contribute to redox homeostasis maintenance during infection cushion formation, ultimately proving to be essential for full virulence. It is also demonstrated that BcWCL2 can regulate the expression of Bcvel1 to influence host tissue acidification, citrate secretion, infection cushion development, and virulence. While the role of organic acids secreted by plant pathogenic fungi in fungus-host interactions has been recognized, this paper revealed the importance, regulatory mechanisms, and key transcription factors that control organic acid secretion. These understanding of the pathogenetic mechanism of plant pathogens can provide valuable insights for developing effective prevention and treatment strategies against fungal diseases.

Increased level of TXNIP and nuclear translocation of TXN is associated with end stage renal disease and development of multiplex renal tumours

BackgroundEnd-stage and acquired cystic renal disease (ESRD/ACRD) kidneys are characterized by inflammatory remodelling and multiplex renal cell carcinomas (RCC). Eosinophilic vacuolated tumour (EVT) occurs exclusively in ACRD. The aim of this study was to identify the involvement of thioredoxin-interacting protein (TXNIP) and thioredoxin (TXN) in ESRD/ACRD pathology.MethodsExpression of TXNIP and TXN was examined in histological slides of 6 ESRD and 6 ACRD kidneys, precursor lesions and associated tumours as well as of RCCs from the general population by immunohistochemistry.ResultsStrong TXNIP expression was seen in epithelial cells, myo-fibroblasts and endothelial cells and weak TXN expression in ESRD/ACRD kidneys and tumours. In ACRD specific EVT and its precursors TXN were translocated into nuclei.ConclusionThe impaired TXNIP/TXN redox homeostasis might be associated with development of multiplex cancer especially of EVT in ESRD/ACRD kidney.

Cr(VI) behaves differently than Cr(III) in the uptake, translocation and detoxification in rice roots

Excessive accumulation of chromium (Cr) causes severe damage to both physiological and biochemical processes and consequently growth repression in plants. Hexavalent chromium [Cr(VI)]-elicited alterations in plants have been widely elucidated at either physiological or molecular level, whereas little is known about trivalent chromium [Cr(III)]. Here, we found that both Cr(III) and Cr(VI) significantly inhibited root growth in rice plants. However, rice plants under Cr(VI) showed significantly less inhibition in root growth than those under Cr(III) at low levels, which might be attributed to the different hormetic effects of Cr(III) and Cr(VI) on rice plants. It was unexpected that Cr(III) could be actively taken up by rice roots similarly to Cr(VI); whereas they exhibited different kinetic uptake patterns. Furthermore, root-to-shoot Cr translocation under Cr(VI) was much lower than that under Cr(III). These results indicate that the uptake, translocation, and toxicity of Cr(III) differed greatly from those of Cr(VI). Transcriptome profiling of rice roots revealed that a series of gene families involved in detoxification, including ATP-binding cassette (ABC) transporters, multidrug and toxic compound extrusion proteins (MATEs), and Tau class glutathione S-transferases (GSTUs), were significantly associated with Cr accumulation and detoxification in rice roots. In addition, much more members of these gene families were upregulated by Cr(VI) compared to Cr(III), suggesting their vital roles in Cr uptake, translocation, and detoxification, especially under Cr(VI) stress. Further comparison of gstu9 and gstu10/50 mutants with their wild type confirmed that GSTUs play complex roles in the intracellular Cr transport and redox homeostasis during Cr(III) or Cr(VI) stress. Taken together, our findings provides new insights into the differential behaviors of Cr(III) and Cr(VI) in rice roots, as well as new candidate genes such as OsABCs and OsGSTUs, to further elucidate the mechanisms of the uptake, translocation, and detoxification of Cr(III) and Cr(VI).

Coordination regulation of enhanced performance reveals the tolerance mechanism of Chlamys farreri to azaspiracid toxicity

Azaspiracids (AZAs) are lipid biotoxins produced by the marine dinoflagellates Azadinium and Amphidoma spp. that can accumulate in shellfish and cause food poisoning in humans. However, the mechanisms underlying the tolerance of shellfish to high levels of such toxins remain poorly understood. This study investigated the combined effects of detoxification metabolism and stress-related responses in scallops Chlamys farreri exposed to AZA. Scallops accumulated a maximum of 361.81 μg AZA1 eq/kg and 41.6 % AZA residue remained after 21 days of exposure. A range of AZA2 metabolites, including AZA19, AZA11, and AZA23, and trace levels of AZA2-GST, were detected. Total hemocyte counts significantly increased and ROS levels remained consistently high until gradually decreasing. Immune system activation mediated mitochondrial dysfunction and severe energy deficiency. DEGs increased over time, with key genes CYP2J6 and GPX6 contributing to AZA metabolism. These transcriptome and metabolic results identify the regulation of energy metabolism pathways, including inhibition of the TCA cycle and activation of carbohydrates, amino acids, and lipids. AZA also induced autophagy through the MAPK-AMPK signaling pathways, and primary inhibited PI3K/AKT to decrease mTOR pathway expression. Our results provide additional insights into the resistance of C. farreri to AZA, characterized by re-establishing redox homeostasis toward a more oxidative state.

The Interplay between Endogenous and Foodborne Pro-Oxidants and Antioxidants in Shaping Redox Homeostasis.

Oxidative stress has been known about in biological sciences for several decades; however, the understanding of this concept has evolved greatly since its foundation. Over the past years, reactive oxygen species, once viewed as solely deleterious, have become recognized as intrinsic components of life. In contrast, antioxidants, initially believed to be cure-all remedies, have failed to prove their efficacy in clinical trials. Fortunately, research on the health-promoting properties of antioxidants has been ongoing. Subsequent years showed that the former assumption that all antioxidants acted similarly was greatly oversimplified. Redox-active compounds differ in their chemical structures, electrochemical properties, mechanisms of action, and bioavailability; therefore, their efficacy in protecting against oxidative stress also varies. In this review, we discuss the changing perception of oxidative stress and its sources, emphasizing everyday-life exposures, particularly those of dietary origin. Finally, we posit that a better understanding of the physicochemical properties and biological outcomes of antioxidants is crucial to fully utilize their beneficial impact on health.

JAK2/STAT3 signaling pathway mediates methylmercury toxicity in mouse astrocyte neuronal C8-D1A cell line.

Methylmercury (MeHg) is an environmental pollutant. Consumption of contaminated fish is the main exposure route in humans, leading to severe neurological disorders. Upon ingestion MeHg reaches the brain and selectively accumulates in astrocytes disrupting glutamate and calcium homeostasis and increasing oxidative stress. Despite extensive research, the molecular mechanisms underlying MeHg neurotoxicity remain incompletely understood. The induction of nuclear factor erythroid 2-related factor 2 (Nrf2) and its role activating antioxidant responses during MeHg-induced oxidative injury have garnered significant attention as a potential therapeutic target against MeHg toxicity. However, recent studies indicate that the Nrf2 signaling pathway alone may not be sufficient to mitigate MeHg-induced damage, suggesting the existence of other protective mechanisms. The signal transducer and activator of transcription 3 (STAT3) plays a crucial role in cell growth and survival. Several studies have also highlighted its involvement in regulating redox homeostasis, thereby preventing oxidative stress through mechanisms that involve modulation of nuclear genes that encode electron transport complexes (ETC) and antioxidant enzymes. These characteristics suggest that STAT3 could serve as a viable mechanism to mitigate MeHg toxicity, either in conjunction with or as an alternative to Nrf2 signaling. Our previous findings demonstrated that MeHg activates the STAT3 signaling pathway in the GT1-7 hypothalamic neuronal cell line, suggesting its potential role in promoting neuroprotection. Here, to elucidate the role of the STAT3 signaling pathway in MeHg neurotoxicity, we pharmacologically inhibited STAT3 using AG490 in the C8D1A astrocytic cell line exposed to 10 µM MeHg. Our data demonstrated that pharmacological inhibition of STAT3 phosphorylation exacerbates MeHg-induced mortality, antioxidant responses, and ROS production, suggesting that STAT3 may contribute to neuroprotection against MeHg exposure in astrocytes.

Metabolic engineering of Komagataella phaffii for the efficient utilization of methanol

BackgroundKomagataella phaffii, a type of methanotrophic yeast, can use methanol, a favorable non-sugar substrate in eco-friendly bio-manufacturing. The dissimilation pathway in K. phaffii leads to the loss of carbon atoms in the form of CO2. However, the ΔFLD strain, engineered to lack formaldehyde dehydrogenase—an essential enzyme in the dissimilation pathway—displayed growth defects when exposed to a methanol-containing medium.ResultsInhibiting the dissimilation pathway triggers an excessive accumulation of formaldehyde and a decline in the intracellular NAD+/NADH ratio. Here, we designed dual-enzyme complex with the alcohol oxidase1/dihydroxyacetone synthase1 (Aox1/Das1), enhancing the regeneration of the formaldehyde receptor xylulose-5-phosphate (Xu5P). This strategy mitigated the harmful effects of formaldehyde accumulation and associated toxicity to cells. Concurrently, we elevated the NAD+/NADH ratio by overexpressing isocitrate dehydrogenase in the TCA cycle, promoting intracellular redox homeostasis. The OD600 of the optimized combination of the above strategies, strain DF02-1, was 4.28 times higher than that of the control strain DF00 (ΔFLD, HIS4+) under 1% methanol. Subsequently, the heterologous expression of methanol oxidase Mox from Hansenula polymorpha in strain DF02-1 resulted in the recombinant strain DF02-4, which displayed a growth at an OD600 4.08 times higher than that the control strain DF00 in medium containing 3% methanol.ConclusionsThe reduction of formaldehyde accumulation, the increase of NAD+/NADH ratio, and the enhancement of methanol oxidation effectively improved the efficient utilization of a high methanol concentration by strain ΔFLD strain lacking formaldehyde dehydrogenase. The modification strategies implemented in this study collectively serve as a foundational framework for advancing the efficient utilization of methanol in K. phaffii.

NIR-II-Responsive Versatile Nanozyme Based on H2O2 Cycling and Disrupting Cellular Redox Homeostasis for Enhanced Synergistic Cancer Therapy.

Disturbing cellular redox homeostasis within malignant cells, particularly improving reactive oxygen species (ROS), is one of the effective strategies for cancer therapy. The ROS generation based on nanozymes presents a promising strategy for cancer treatment. However, the therapeutic efficacy is limited due to the insufficient catalytic activity of nanozymes or their high dependence on hydrogen peroxide (H2O2) or oxygen. Herein, we reported a nanozyme (CSA) based on well-defined CuSe hollow nanocubes (CS) uniformly covered with Ag nanoparticles (AgNPs) to disturb cellular redox homeostasis and catalyze a cascade of intracellular biochemical reactions to produce ROS for the synergistic therapy of breast cancer. In this system, CSA could interact with the thioredoxin reductase (TrxR) and deplete the tumor microenvironment-activated glutathione (GSH), disrupting the cellular antioxidant defense system and augmenting ROS generation. Besides, CSA possessed high peroxidase-mimicking activity toward H2O2, leading to the generation of various ROS including hydroxyl radical (•OH), superoxide radicals (•O2-), and singlet oxygen (1O2), facilitated by the Cu(II)/Cu(I) redox and H2O2 cycling, and plentiful catalytically active metal sites. Additionally, due to the absorption and charge separation performance of AgNPs, the CSA exhibited excellent photothermal performance in the second near-infrared (NIR-II, 1064 nm) region and enhanced the photocatalytic ROS level in cancer cells. Owing to the inhibition of TrxR activity, GSH depletion, high peroxidase-mimicking activity of CSA, and abundant ROS generation, CSA displays remarkable and specific inhibition of tumor growth.

3-Hydroxy-3-Methylglutaric Acid Disrupts Brain Bioenergetics, Redox Homeostasis, and Mitochondrial Dynamics and Affects Neurodevelopment in Neonatal Wistar Rats.

3-Hydroxy-3-methylglutaric acidemia (HMGA) is a neurometabolic inherited disorder characterized by the predominant accumulation of 3-hydroxy-3-methylglutaric acid (HMG) in the brain and biological fluids of patients. Symptoms often appear in the first year of life and include mainly neurological manifestations. The neuropathophysiology is not fully elucidated, so we investigated the effects of intracerebroventricular administration of HMG on redox and bioenergetic homeostasis in the cerebral cortex and striatum of neonatal rats. Neurodevelopment parameters were also evaluated. HMG decreased the activity of glutathione reductase (GR) and increased catalase (CAT) in the cerebral cortex. In the striatum, HMG reduced the activities of superoxide dismutase, glutathione peroxidase, CAT, GR, glutathione S-transferase, and glucose-6-phosphate dehydrogenase. Regarding bioenergetics, HMG decreased the activities of succinate dehydrogenase and respiratory chain complexes II-III and IV in the cortex. HMG also decreased the activities of citrate synthase and succinate dehydrogenase, as well as complex IV in the striatum. HMG further increased DRP1 levels in the cortex, indicating mitochondrial fission. Finally, we found that the HMG-injected animals showed impaired performance in all sensorimotor tests examined. Our findings provide evidence that HMG causes oxidative stress, bioenergetic dysfunction, and neurodevelopmental changes in neonatal rats, which may explain the neuropathophysiology of HMGA.

Regulation of nitro-oxidative homeostasis: an effective approach to enhance salinity tolerance in plants.

Soil salinity is a major constraint for sustainable agricultural productivity, which together with the incessant climate change may be transformed into a severe threat to the global food security. It is, therefore, a serious concern that needs to be addressed expeditiously. The overproduction and accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the key events occurring during salt stress, consequently employing nitro-oxidative stress and programmed cell death in plants. However, very sporadic studies have been performed concerning different aspects of nitro-oxidative stress in plants under salinity stress. The ability of plants to tolerate salinity is associated with their ability to maintain the cellular redox equilibrium mediated by both non-enzymatic and enzymatic antioxidant defense mechanisms. The present review emphasizes the mechanisms of ROS and RNS generation in plants, providing a detailed evaluation of how redox homeostasis is conserved through their effective removal. The uniqueness of this article stems from its incorporation of expression analyses of candidate genes for different antioxidant enzymes involved in ROS and RNS detoxification across various developmental stages and tissues of rice, utilizing publicly available microarray data. It underscores the utilization of modern biotechnological methods to improve salinity tolerance in crops, employing different antioxidants as markers. The review also explores how various transcription factors contribute to plants' ability to tolerate salinity by either activating or repressing the expression of stress-responsive genes. In summary, the review offers a thorough insight into the nitro-oxidative homeostasis strategy for extenuating salinity stress in plants.

Expression analysis of thg1l during Xenopus laevis development.

The tRNA-histidine guanylyltransferase 1-like (THG1L), also known as induced in high glucose-1 (IHG-1), encodes for an essential mitochondria-associated protein highly conserved throughout evolution, that catalyses the 3'-5' addition of a guanine to the 5'-end of tRNA-histidine (tRNAHis). Previous data indicated that THG1L plays a crucial role in the regulation of mitochondrial biogenesis and dynamics, in ATP production, and is critically involved in the modulation of apoptosis, cell-cycle progression and survival, as well as in cellular stress responses and redox homeostasis. Dysregulations of THG1L expression play a central role in various pathologies, including nephropathies, and neurodevelopmental disorders often characterized by developmental delay and cerebellar ataxia. Despite the essential role of THG1L, little is known about its expression during vertebrate development. Herein, we examined the detailed spatio-temporal expression of this gene in the developing Xenopus laevis. Our results show that thg1l is maternally inherited and its temporal expression suggests a role during the earliest stages of embryogenesis. Spatially, thg1l mRNA localizes in the ectoderm and marginal zone mesoderm during early stages of development. Then, at tadpole stages, thg1l transcripts mostly localise in neural crests and their derivatives, somites, developing kidney and central nervous system, therefore largely coinciding with territories displaying intense energy metabolism during organogenesis in Xenopus.

Progress in Research on the Role of the Thioredoxin System in Chemical Nerve Injury.

(1) Background: Various factors, such as oxidative stress, mitochondrial dysfunction, tumors, inflammation, trauma, immune disorders, and neuronal toxicity, can cause nerve damage. Chemical nerve injury, which results from exposure to toxic chemicals, has garnered increasing research attention. The thioredoxin (Trx) system, comprising Trx, Trx reductase, nicotinamide adenine dinucleotide phosphate, and Trx-interacting protein (TXNIP; endogenous Trx inhibitor), helps maintain redox homeostasis in the central nervous system. The dysregulation of this system can cause dementia, cognitive impairment, nerve conduction disorders, movement disorders, and other neurological disorders. Thus, maintaining Trx system homeostasis is crucial for preventing or treating nerve damage. (2) Objective: In this review study, we explored factors influencing the homeostasis of the Trx system and the involvement of its homeostatic imbalance in chemical nerve injury. In addition, we investigated the therapeutic potential of the Trx system-targeting active substances against chemical nerve injury. (3) Conclusions: Chemicals such as morphine, metals, and methylglyoxal interfere with the activity of TXNIP, Trx, and Trx reductase, disrupting Trx system homeostasis by affecting the phosphatidylinositol-3-kinase/protein kinase B, extracellular signal-regulated kinase, and apoptotic signaling-regulated kinase 1/p38 mitogen-activated protein kinase pathways, thereby leading to neurological disorders. Active substances such as resveratrol and lysergic acid sulfide mitigate the symptoms of chemical nerve injury by regulating the Ras/Raf1/extracellular signal-regulated kinase pathway and the miR-146a-5p/TXNIP axis. This study may guide the development of Trx-targeting modulators for treating neurological disorders and chemical nerve injuries.