Intracellular Antioxidant Defense Research Articles

Exploring the Neuroprotective Potential of Desmodium Species: Insights into Radical Scavenging Capacity and Mechanisms against 6-OHDA-Induced Neurotoxicity.

In this study, we collected seven prevalent Taiwanese Desmodium plants, including three species with synonymous characteristics, in order to assess their antioxidant phytoconstituents and radical scavenging capacities. Additionally, we compared their inhibitory activities on monoamine oxidase (MAO) and 6-hydroxydopamine (6-OHDA) auto-oxidation. Subsequently, we evaluated the neuroprotective potential of D. pulchellum on 6-OHDA-induced nerve damage in SH-SY5Y cells and delved into the underlying neuroprotective mechanisms. Among the seven Desmodium species, D. pulchellum exhibited the most robust ABTS radical scavenging capacity and relative reducing power; correspondingly, it had the highest total phenolic and phenylpropanoid contents. Meanwhile, D. motorium showcased the best hydrogen peroxide scavenging capacity and, notably, D. sequax demonstrated remarkable prowess in DPPH radical and superoxide scavenging capacity, along with selective inhibitory activity against MAO-B. Of the aforementioned species, D. pulchellum emerged as the frontrunner in inhibiting 6-OHDA auto-oxidation and conferring neuroprotection against 6-OHDA-induced neuronal damage in the SH-SY5Y cells. Furthermore, D. pulchellum effectively mitigated the increase in intracellular ROS and MDA levels through restoring the activities of the intracellular antioxidant defense system. Therefore, we suggest that D. pulchellum possesses neuroprotective effects against 6-OHDA-induced neurotoxicity due to the radical scavenging capacity of its antioxidant phytoconstituents and its ability to restore intracellular antioxidant activities.

Insight into the surface discharge cold plasma efficient inactivation of Pseudomonas fluorescens in water based on exogenous reactive oxygen and nitrogen species: Synergistic mechanism and energy benefits

As well known, surface discharge cold plasma has efficient inactivation ability and a variety of RONS are main active particles for inactivation, but their synergistic mechanism is still not clear. Therefore, surface discharge cold plasma system was applied to treat Pseudomonas fluorescens to study bacterial inactivation mechanism and energy benefit. Results showed that energy efficiency was directly proportional to applied voltage and inversely proportional to initial concentration. Cold plasma treatment for 20 min was inactivated by approximately > 4-log10Pseudomonas fluorescens and application of •OH and 1O2 scavengers significantly improved survival rate. In addition, •OH and 1O2 destroyed cell membrane structure and membrane permeability, which promoted diffusion of RONS into cells and affecting energy metabolism and antioxidant capacity, leading to bacterial inactivation. Furthermore, accumulation of intracellular NO and ONOOH was related to infiltration of exogenous RNS, while accumulation of •OH, H2O2, 1O2, O2- was the result of joint action of endogenous and exogenous ROS. Transcriptome analysis revealed that different RONS of cold plasma were responsible for Pseudomonas fluorescens inactivation and related to activation of intracellular antioxidant defense system and regulation of genes expression related to amino acid metabolism and energy metabolism, which promoting cellular process, catalytic activity and other biochemical pathways.

Precisely Self-Cooperative Nanoassembly Enables Photothermal/Ferroptosis Synergistic Tumor Eradication.

Ferroptosis is identified as a potential target for anticancer therapy. However, most conventional ferroptosis inducers not only fail to trigger intracellular lipid peroxidation storm, but are also prone to cause ferroptosis-related toxicity through off-target destruction of intracellular antioxidant defense systems. Therefore, a potent and highly tumor-specific ferroptosis induction modality is desired. Herein, a self-cooperative nanomedicine for imaging-guided photothermal ferrotherapy, which is fabricated based on molecular nanoassembly (NA) of DiR (a photothermal probe) and ferrocene (Fc, a reactant of the Fenton reaction), is elaborately exploited. DiR-elicited hyperthermia induces both photothermal therapy (PTT) and a significant acceleration of the kinetics of the Fc-involved Fenton reaction, collaboratively causing a lipid peroxidation storm in tumor cells. In turn, plenty of lipid peroxides boost PTT through the downregulation of heat shock protein 90. As expected, such a self-cooperative NA demonstrates synergetic tumor eradication in the 4T1 breast tumor-bearing mice xenograft model. This study offers a novel nanotherapeutic paradigm for precise multimodal cancer therapy.

Combined effect of cold plasma-activated oxygen (CPAO) and microwave on microbial decontamination and quality of milkshake powder

This study presents a new method combining cold plasma-activated oxygen (CPAO) and microwave (MW) to decontaminate milkshake powder, exploring its effectiveness, mechanisms, and quality impact. CPAO (6 min) alone reduced bacterial load by 0.419 log CFU/g, and MW (3 min) by 0.030 log CFU/g. However, their co-application significantly amplified decontamination, achieving a 1.265 log CFU/g reduction. CPAO-MW co-treatment inflicted more oxidative damage on bacterial cell membranes and intracellular antioxidant defense system, leading to higher mortality. It also raised protein and lipid oxidation, while decreasing vitamin C and A levels in the powder. Specifically, CPAO (6 min)-MW (3 min) co-treatment increased the carbonyl content from 0.438 to 0.891 nmol/mg protein, malondialdehyde from 0.824 to 0.996 mg/kg, and lowered vitamin C from 162.151 to 137.640 mg/kg, and vitamin A from 2.05 to 1.38 mg/kg. This study shows CPAO-MW is effective for decontaminating powdered foods but highlights a need to reduce negative effects.

Abstract 659: TR-107 and erastin produce synergistic inhibition of colorectal cancer cell viability in vitro

Abstract Introduction: Ferroptosis is an emerging potential target for the treatment of colorectal cancer (CRC) and has been shown to sensitize cancer cells to combinatory chemotherapy. Our studies show that the TR-107 compound, an agonist of ClpP - the proteolytic subunit of mitochondrial maintenance complex - can synergize with Erastin, an inducer of ferroptosis cell death. TR-107 potently disrupts mitochondrial proteostasis and attenuates oxidative phosphorylation, resulting in excessive oxidative stress. Here, we show that Erastin synergizes with TR-107 activity by downregulating the cofactor of GPX4, a major intracellular antioxidant defense resulting in CRC cell apoptosis. Methods: We first evaluated the efficacy of TR-107 against eight CRC cell lines belonging to four established consensus molecular subtypes. Cells were treated with control (DMSO) or TR-107 (10 nM, 50 nM, 1 µM) for 24, 48, and 72 hours. We determined IC50 values with Cell Titer-Glo, cell proliferation with the Beckman Coulter cell counter, cell cycle with flow cytometry, OXPHOS activity with Seahorse Real-Time ATP Rate assay, mitochondrial protein levels with western blot and proteomics, and differential gene expression using RNA sequencing and RT-PCR. Subsequently, we assessed the efficacy of TR-107 and Erastin co-treatment. Cells were treated with DMSO, TR-107 (10, 50 nM), Erastin (1, 10 µM), or combinations of the abovementioned concentrations. Cell viability was measured 72 hours post-treatment with Cell Titer-Glo. Synergy scores (HSA) were calculated with Synergyfinder on RStudio. Ferroptosis-related protein expression 24 hours after co-treatment was assessed with western blot and densitometry. Results: TR-107 IC50 values ranged from 2-70 nM, producing a dose- and time-dependent inhibitory effect in cell proliferation. Western blot showed that 50 nM TR-107 abolished the expression of critical mitochondrial proteins ClpX, TFAM, and TUFM. Seahorse data showed a significant reduction in OXPHOS activity. Multi-omics revealed downregulation of respiratory chain complex subunits, mtDNA transcription/translation factors, and upregulation of mitophagy and ferroptosis-related pathways in treated cells. Co-treatment with Erastin produced synergistic HSA scores in 63% (5/8) of assessed CRC cell lines. RKO and NCI-H508 were highly sensitive to Erastin treatment, suggesting that lower Erastin concentrations may synergize with TR-107 and thus reduce dose toxicity. Western blot analysis 24 hours post-treatment showed a loss of GPX4 protein levels in co-treated cells compared to 50 nM TR-107 treatment. This suggests a rapid downregulation of intracellular antioxidant defense that may induce ferroptosis sooner and more effectively than single-agent treatment. Conclusion: In vitro results suggest that co-treating with TR-107 and Erastin produces a significant, synergistic reduction in CRC cell viability. Citation Format: Michael Giarrizzo, Joseph F. LaComb, Hetvi R. Patel, Agnieszka B. Bialkowska, Rohan Reddy, Lee M. Graves, Edwin J. Iwanowicz. TR-107 and erastin produce synergistic inhibition of colorectal cancer cell viability in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 659.

Arecoline induces neurotoxicity in HT22 cells via the promotion of endoplasmic reticulum stress and downregulation of the Nrf2/HO-1 pathway.

Arecoline, the predominant bioactive substance extracted from areca nut (AN), is the world's fourth most frequently used psychoactive material. Research has revealed that chewing AN can affect the central nervous system (CNS) and may lead to neurocognitive deficits that are possibly linked to the action of arecoline. However, the mechanism behind the neurotoxicity caused by arecoline remains unclear. This study aimed to investigate the neurotoxic effects of arecoline and its underlying mechanism. The results showed that arecoline caused cytotoxicity against HT22 cells in a dose-dependent manner and induced apoptosis by upregulating the expression of pro-apoptotic caspase and Bcl-2 family proteins. Furthermore, arecoline escalated intracellular reactive oxygen species (ROS) levels and Ca2+ concentration with increasing doses, thereby motivating endoplasmic reticulum stress (ERS) and ERS-associated apoptotic protein expression. Additionally, the study found that arecoline attenuates intracellular antioxidant defense by inhibiting the translocation of NF-E2-related factor-2 (Nrf2) into the nucleus and decreasing downstream Heme oxygenase-1 (HO-1) levels. The specific inhibitor Sodium 4-phenylbutyrate (4-PBA) can dramatically attenuate arecoline-mediated cell apoptosis and ERS-associated apoptotic pathway expression by blocking ERS. The antioxidant N-Acetylcysteine (NAC) also effectively reverses the arecoline-mediated increase of ERS-related apoptotic pathway protein levels by scavenging intracellular ROS accumulation. In conclusion, this study suggests that arecoline induces neurotoxicity in HT22 cells via ERS mediated by oxidative stress- and Ca2+ disturbance, as well as by downregulation of the Nrf2/HO-1 pathway.

Moderate-Intensity Swimming Alleviates Oxidative Injury in Ischemic Heart

The global burden of cardiovascular diseases is indisputable, as it claims nearly 18 million lives a year. In this current study, we aimed to prove that exercise, a cornerstone in cardiovascular disease management, emerges as a powerful tool in the pathology of myocardial ischemia. Male rats were divided into three groups: pre-swimming training + isoproterenol (ISO) treated, isoproterenol-treated, and control-sedentary. Myocardial infarction was induced by the subcutaneous injection of 1.0 mg/kg ISO. After the subsequent rest period, the animals swam for 3 weeks, every day for 25 min. At the end of the experiment, the serum levels of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), as well as the cardiac concentrations of reactive oxygen species (ROS), catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were determined. Our results indicate that both cardiac injury biomarkers (ANP, BNP) and ROS levels were significantly lower in swimming rats compared to the sedentary animals. Moreover, the level of enzymatic components of the intracellular antioxidant system, CAT, SOD, and GPx were increased in swimming animals after ISO-induced myocardial infarction. Our findings support the fact that moderate-intensity swimming training can be efficiently used to prevent myocardial infarction-induced ischemic injury, by inhibiting ROS production and strengthening intracellular antioxidant defense.

Serum Gamma Glutamyl Transferase: Understanding its Contribution as a Potential Predictor of the Occurrence of Type 2 Diabetes.

The liver and kidneys are the primary locations of the glutathione metabolism enzyme gamma-glutamyl transferase (GGT). The two main factors contributing to an increase are hepatic illnesses and excessive alcohol use. This study set out to test a theory on the predictive importance of the association between GGT and Type 2 diabetes mellitus. (T2DM). In order to do this, we combed through PubMed, Google Scholar, Medline, and Science Direct for a wide range of information from previous studies. Attributes were established at the outset and compared to GGT concentration. GGT, present in most cells, absorbs glutathione for intracellular antioxidant defences. This study links GGT to hepatic enzymes including HDL, LDL, and triglyceride. LDL, triglycerides, AST, and ALT increased with GGT concentration, but LDL decreased. Because of obesity, GGT production rises with BMI. We found that greater GGT levels were associated with more T2DM after analysing data from multiple sources. This literature review concludes that GGT is related to other factors such as BMI, HDL, AST, and triglycerides in the development of diabetes mellitus. Serum GGT was found to be a potential predictor of metabolic syndrome and T2DM.

The role of ferroptosis in cardio-oncology.

With the rapid development of new generations of antitumor therapies, the average survival time of cancer patients is expected to be continuously prolonged. However, these therapies often lead to cardiotoxicity, resulting in a growing number of tumor survivors with cardiovascular disease. Therefore, a new interdisciplinary subspecialty called "cardio-oncology"has emerged, aiming to detect and treat cardiovascular diseases associated with tumors and antitumor therapies. Recent studies have highlighted the role of ferroptosis in both cardiovascular and neoplastic diseases. The balance between intracellular oxidative stress and antioxidant defense is crucial in regulating ferroptosis. Tumor cells can evade ferroptosis by upregulating multiple antioxidant defense pathways, while many antitumor therapies rely on downregulating antioxidant defense and promoting ferroptosis in cancer cells. Unfortunately, these ferroptosis-inducing antitumor therapies often lack tissue specificity and can also cause injury to the heart, resulting in ferroptosis-induced cardiotoxicity. A range of cardioprotective agents exert cardioprotective effects by inhibiting ferroptosis. However, these cardioprotective agents might diminish the efficacy of antitumor treatment due to their antiferroptotic effects. Most current research on ferroptosis only focuses on either tumor treatment or heart protection but rarely considers both in concert. Therefore, further research is needed to study how to protect the heart during antitumor therapies by regulating ferroptosis. In this review, we summarized the role of ferroptosis in the treatment of neoplastic diseases and cardiovascular diseases and also attempted to propose further research directions for ferroptosis in the field of cardio-oncology.

A self-healing injectable hydrogel integrated with enzymatic and nonenzymatic antioxidants as artificial antioxidant defense system for diabetic wound healing

Chronic diabetic wounds seriously threaten human health due to their intractable nature in a complex pathological microenvironment that contains oxidative stress, persistent inflammatory status, hypoxia and bacterial infections, of which oxidative damage contributing the most. Applied materials that can mimic the natural intracellular antioxidant defense system are perceived to have huge therapeutic potential. Herein, we present a novel strategy to prepare a versatile nanocomposite hydrogel by incorporating the nanoenzyme (manganese dioxide (MnO2)) and nonenzymatic antioxidant components (polydopamine (PDA)) in a dynamic hydrogel network composed of thioctic acid and tannic acid (TA). The prepared hydrogel exhibited outstanding adhesive and injectable properties, making it adapt perfectly to wounds with different shapes and depths. More importantly, encapsulation of PDA@MnO2 nanoparticles (NPs) conferred the hydrogel with superior antioxidant performance to effectively scavenge multiple types of reactive nitrogen and oxygen species (RNOS) and reduce the inflammatory response by regulating macrophage polarization. Meanwhile, the hydrogel showed high-performance catalyzing ability to transfer hydrogen peroxide (H2O2) into oxygen (O2), which could further alleviate hypoxic wound environment. Moreover, the nanocomposite hydrogel exhibited excellent near-infrared (NIR) photothermal antibacterial effect. Collectively, our findings indicate that the synthesized nanocomposite hydrogel shows potential for use in a clinical setting to treat diabetic wounds.

Comparative secretomic and proteomic analysis reveal multiple defensive strategies developed by Vibrio cholerae against the heavy metal (Cd2+, Ni2+, Pb2+, and Zn2+) stresses

Vibrio cholerae is a common waterborne pathogen that can cause pandemic cholera in humans. The bacterium with heavy metal-tolerant phenotypes is frequently isolated from aquatic products, however, its tolerance mechanisms remain unclear. In this study, we investigated for the first time the response of such V. cholerae isolates (n = 3) toward the heavy metal (Cd2+, Ni2+, Pb2+, and Zn2+) stresses by comparative secretomic and proteomic analyses. The results showed that sublethal concentrations of the Pb2+ (200 μg/mL), Cd2+ (12.5 μg/mL), and Zn2+ (50 μg/mL) stresses for 2 h significantly decreased the bacterial cell membrane fluidity, but increased cell surface hydrophobicity and inner membrane permeability, whereas the Ni2+ (50 μg/mL) stress increased cell membrane fluidity (p < 0.05). The comparative secretomic and proteomic analysis revealed differentially expressed extracellular and intracellular proteins involved in common metabolic pathways in the V. cholerae isolates to reduce cytotoxicity of the heavy metal stresses, such as biosorption, transportation and effluxing, extracellular sequestration, and intracellular antioxidative defense. Meanwhile, different defensive strategies were also found in the V. cholerae isolates to cope with different heavy metal damage. Remarkably, a number of putative virulence and resistance-associated proteins were produced and/or secreted by the V. cholerae isolates under the heavy metal stresses, suggesting an increased health risk in the aquatic products.

Application of Se-Met to CdTe QDs significantly reduces toxicity by modulating redox balance and inhibiting apoptosis

Cadmium tellurium quantum dots (CdTe QDs) as one of the most widely used QDs have been reported the toxicity and biosafety in recent years, little work has been done to reduce their toxicity however. Based on the mechanisms of toxicity of CdTe QDs on liver target organs such as oxidative stress and apoptosis previously reported by other researchers, we investigated the mechanism of action of trace element selenium (Se) to mitigate the hepatotoxicity of CdTe QDs. The experimental results showed that Se-Met at 40–140 μg L−1 could enhance the function of intracellular antioxidant defense system and the molecular structure of related antioxidant enzymes by reduce the production of ROS by 45%, protecting the activity of antioxidants and up-regulating the expression of selenoproteins with antioxidant functions, Gpx1 increase 225% and Gpx4 upregulated 47%. In addition, Se-Met could alleviate CdTe QDs-induced apoptosis by regulating two apoptosis-inducing factors, as intracellular caspase 3/9 expression levels were reduced by 70% and 87%, decreased Ca2+ concentration, and increased mitochondrial membrane potential measurements. Overall, this study indicates that Se-Met has a significant protective effect on the hepatotoxicity of CdTe QDs. Se-Met can be applied to the preparation of CdTe QDs to inhibit its toxicity and break the application limitation.

Positive responses and mechanisms of nitrifying sludge to carbon quantum dots: reactor performance, microbial behavior, and antioxidant defense.

Extensive application of carbon quantum dots (CQDs) enlarges its concentration in sewage treatment system. The response of nitrifying sludge to CQDs after long-term exposure was investigated. Results showed that CQD concentrations of 0-100mg/L presented positive effect to enzymes involved in nitrification, accelerating NH4+-N degradation and NO2--N transformation. The oxidation rate of NO2--N was significantly improved from 3.14 to 7.91mg/(L h) under the stress of 100mg/L CQDs. Besides, CQDs stimulated the production of sludge biomass and kept the stability of sludge settleability. Additionally, CQDs were mainly captured by loosely bound extracellular polymeric substances, reducing aromatic-like protein. Microbes alleviated CQD stress by secreting tryptophan-like protein and polysaccharides. After few CQDs entered cells, intracellular antioxidant defense was activated. Total antioxidant capacity level was heightened at least 31%. The activities of superoxide dismutase and catalase were enhanced at relatively low and high CQD concentration levels. Hence, microbial metabolic pathways, microbial community, and nitrifying bacteria were not significantly affected by CQDs. The findings of this work provide new insight for understanding the environmental implication of CQDs in the biological treatment system.

Detoxification pathways of multiple metals from intensive copper production by indigenous ureolytic microbes coupled with soil nitrogen transformation

The ubiquitous ureolytic microbes were potential to clean up toxic heavy metals from environment. Their responses and detoxification mechanisms are largely unknown for multiple metals in field soils. In this study, high-throughput sequencing of the urease-encoding genes and deep learning from bioinformatic analysis were conducted for identifying ureolytic prokaryote-related processes throughout China. The passive adsorption of heavy metals onto cell walls or cell surfaces was mainly performed by G+ ureolytic bacteria in soils located in the large-scale smelting areas with slightly high Hg and low Cu/Zn/Ni contents. For the large-scale smelting areas with the highest Cr and lowest Cu/As contents, the Cr(VI) was reduced to Cr(III) by G– ureolytic bacteria and then accumulated in their periplasmic spaces or cell surfaces. The G– ureolytic bacteria detoxified high contents of multiple metals by intracellular antioxidant defense mechanisms and extracellular urease-induced (co)precipitation in the medium-scale smelting areas, consistent with high urease activities and ureolytic microbial diversity. In addition, this large-scale field work verified that toxic metals stimulated the bacterial hydrolysis of urea as soil nitrogen fertilizers and depressed the bacterial fixation of nitrogen from air. Simultaneously, the heavy metals used nitrate-N and nitrite-N as alternative electron acceptors, driving the soil denitrification processes.

The response and anti-stress mechanisms of nitrifying sludge under long-term exposure to CdSe quantum dots

The wide application of CdSe quantum dots (QDs) increases its stress risk to sewage treatment systems. This study evaluated the response of nitrification performance, floc characteristics and microbial community of nitrifying sludge under long-term exposure to CdSe QDs. Results showed CdSe QDs (≥1 mg/L) would decrease the activity of ammonia monooxygenase (AMO). Under the stress of 30 mg/L CdSe QDs, the activity of AMO was reduced by 66%, while the activities of hydroxylamine oxidase and nitrite oxidoreductase were enhanced by 19.1% and 26%, respectively. Thus, the final nitrification effects were not adversely affected, and the production rates of NO2−-N and NO3−-N were accelerated. Additionally, CdSe QDs improved biomass concentration in sludge and maintained the stability of sludge settleability. High throughput sequencing analysis showed that CdSe QDs evidently reduced the abundance and diversity of microbial community in nitrifying sludge. The abundances of amino acid metabolism and lipid metabolism were enriched. Moreover, CdSe QDs decreased the fluorescence intensity of tryptophan-like protein from 2,326 to 1,179 a.u. in loosely bound extracellular polymeric substances (EPSs) and from 3,792 to 3,117 a.u. in tightly bound EPSs. To relieve CdSe QD stress, the polysaccharide content increased from 0.31 to 0.61 mg/g MLSS and intracellular antioxidant defense was activated. With CdSe QD level increasing to 30 mg/L, the total antioxygenic capacity and the activities of catalase were enhanced up to 411% and 143.2%, respectively. Thereby, CdSe QDs had little adverse effects on cell membrane integrity, microbial metabolism and the abundance of Nitrospirae.

Green rooibos extract attenuates high glucose induced oxidative stress in a human derived (HepG2) liver cell line

• Oxidative stress biomarkers are attenuated by REE in a glucotoxic HepG2 cell model. • REE enhances antioxidant enzyme profiles of HepG2 cells exposed to high glucose. • REE activates NRF2 antioxidant pathway in HepG2 cells exposed to high glucose. The exposure of hepatocytes to high concentrations of glucose results in a glucotoxic environment and ensuing hepatocellular injury, often due to oxidative stress. The popularly consumed herbal tea, Rooibos ( Aspalathus linearis ), demonstrates pleiotropic pharmacological and antioxidant activities. Our study investigated the molecular events regulating the antioxidant effects of a Rooibos ethanolic extract (REE) in a glucotoxic HepG2 liver cell model. It is hypothesized that REE enhances antioxidant enzyme profiles of HepG2 cells exposed to high glucose to attenuate glucotoxic damage. Glucotoxicity was induced by treating the cells with 25 mM glucose. For this study, colorimetric, luminometric and western blot analyses were used to determine the potential of the REE to reduce biomarkers associated with oxidative damage and its potential to enhance the intracellular antioxidant defense system. The REE was found to be hepatoprotective as evidenced by reduced levels of oxidative damage biomarkers (MDA and protein carbonylation) and enhanced antioxidant capacity under glucotoxic conditions as evidenced by elevated GSH (reduced form). We also observed decreased intracellular hydrogen peroxide levels and caspase activity in the REE treated cells and further showed that the REE enhanced SOD2, CAT, and GPx1 protein expression. These effects were dependent on the transcriptional activity of NRF2. Collectively, our results show that the REE enhances the cellular antioxidant defense capacity and may provide a relevant supportive therapeutic option for treating diabetic complications associated with oxidative stress.

The circadian clock mediates the response to oxidative stress in a cone photoreceptor‒like (661W) cell line via regulation of glutathione peroxidase activity.

Background: The mammalian retina contains an autonomous circadian clock that controls many physiological functions within this tissue. Our previous studies have indicated that disruption of this circadian clock by removing Bmal1 from the retina affects the visual function, retinal circuitry, and cone photoreceptor viability during aging. In the present study, we employed a mouse-derived cone photoreceptor‒like cell, 661W, to investigate which molecular mechanisms of the circadian clock may modulate cone photoreceptor viability during aging. Methods: Bmal1 knockout (BKO) cells were generated from 661W cells using the CRISPR/Cas9 gene editing tool. Deletion of Bmal1 from 661W was verified by western blot and monitoring Per2-luc bioluminescence circadian rhythms. To investigate the effect of Bmal1 removal on an oxidative stress challenge, cells were treated with hydrogen peroxide (H 2O 2,1 mM) for two hours and then cell viability was assessed. Cells were also cultured and harvested for gene expression analysis and antioxidant assay. Results: Our data indicated that 661W cells contain a functional circadian clock that mediates the response to an oxidative stress challenge in vitro and that such a response is no longer present in the BKO cell. We also hypothesized that the effect was due to the circadian regulation of the intracellular antioxidant defense mechanism.Our results revealed that in 661W cells, the antioxidant defense mechanism showed time dependent variation , whereas in BKO cells, there was an overall reduction in this antioxidant defense mechanism, and it no longer showed time dependent variation. Conclusions: Our work supported the notion that the presence of a functional circadian clock and its ability to modulate the response to an oxidative stress is the underlying mechanism that may protect cones during aging.

Engineering biomimetic ATP-responsive Se-containing core-shell cascade nanozyme for efficient tumor combination therapy

The ineffectiveness of cancer chemodynamic treatment (CDT) is intimately connected to intracellular antioxidant defense mechanisms. While great efforts have been made to interfere with the oxidative protection mechanisms within tumor cells, this remains a difficult challenge. Herein, inspired by the glutathione peroxidase (GPx) function for consuming GSH, an artificial selenase was designed to combine with the Fenton reaction to prepare a metal complex nanocarrier (IM-Se-Ph@TA-Fe NPs), in which glucose oxidase (GOx) is loaded to obtain the multienzyme synergic nanozyme GOx@IM-Se-Ph@TA-Fe NPs. In response to the high expression of ATP in the tumor, released GOx could specifically reduce the molecular oxygen to H2O2 by consuming intratumoral glucose and cause tumor starvation. Following that, the generated H2O2 supported the intracellular Fenton reaction and consumed intracellular GSH under the catalysis of selenase to enhance multimodal cancer therapy. The strategy of interfering with the intracellular antioxidant system by utilizing artificial selenase and GOx increases the efficacy of chemodynamic therapy and offers new concepts for cancer combination therapy.

The circadian clock mediates the response to oxidative stress in a cone photoreceptor‒like (661W) cell line via regulation of glutathione peroxidase activity.

Background: The mammalian retina contains an autonomous circadian clock that controls many physiological functions within this tissue. Our previous studies have indicated that disruption of this circadian clock by removing Bmal1 from the retina affects the visual function, retinal circuitry, and cone photoreceptor viability during aging. In the present study, we employed a mouse-derived cone photoreceptor‒like cell, 661W, to investigate which molecular mechanisms of the circadian clock may modulate cone photoreceptor viability during aging. Methods: Bmal1 knockout (BKO) cells were generated from 661W cells using the CRISPR/Cas9 gene editing tool. Deletion of Bmal1 from 661W was verified by western blot and monitoring Per2-luc bioluminescence circadian rhythms. To investigate the effect of Bmal1 removal on an oxidative stress challenge, cells were treated with hydrogen peroxide (H 2O 2,1 mM) for two hours and then cell viability was assessed. Cells were also cultured and harvested for gene expression analysis and antioxidant assay. Results: Our data indicated that 661W cells contain a functional circadian clock that mediates the response to an oxidative stress challenge in vitro and that such a response is no longer present in the BKO cell. We also hypothesized that the effect was due to the circadian regulation of the intracellular antioxidant defense mechanism. Our results indicated that in 661W cells, the antioxidant defense mechanism is under circadian control, whereas in BKO cells, there is an overall reduction in this antioxidant defense mechanism, and it is no longer under circadian control. Conclusions: Our work supported the notion that the presence of a functional circadian clock and its ability to modulate the response to an oxidative stress is the underlying mechanism that may protect cones during aging.

A Review on the Antidiabetic Properties of Moringa oleifera Extracts: Focusing on Oxidative Stress and Inflammation as Main Therapeutic Targets.

Moringa oleifera is one of the popular plants that have shown significant health benefits. Certainly, preclinical evidence (predominantly from animal models) summarized in the current review supports the beneficial effects of Moringa oleifera leaf extracts in combating the prominent characteristic features of diabetes mellitus. This includes effective control of blood glucose or insulin levels, enhancement of insulin tissue sensitivity, improvement of blood lipid profiles, and protecting against organ damage under sustained conditions of hyperglycemia. Interestingly, as major complications implicated in the progression of diabetes, including organ damage, Moringa oleifera leaf and seed extracts could efficiently block the detrimental effects of oxidative stress and inflammation in these preclinical models. Notably, these extracts (especially leaf extracts) showed enhanced effects in strengthening intracellular antioxidant defences like catalase, superoxide dismutase, and glutathione to lower lipid peroxidation products and reduce prominent pro-inflammatory markers such as tumor necrosis factor-α, interleukin (1L)-β, IL-6, monocyte chemoattractant protein-1 and nitric oxide synthase. From animal models of diabetes, the common and effective dose of leaf extracts of Moringa oleifera was 100–300 mg/kg, within the treatment duration of 2–8 weeks. Whereas supplementation with approximately 20 g leaf powder of Moringa oleifera for at least 2 weeks could improve postprandial blood glucose in subjects with prediabetes or diabetes. Although limited clinical studies have been conducted on the antidiabetic properties of Moringa oleifera, current findings provide an important platform for future research directed at developing this plant as a functional food to manage diabetic complications.