Search

The intrinsic hypoxic tumor microenvironment and limited accumulation of photosensitizers (PSs) result in unsatisfied efficiency of photodynamic therapy (PDT). To enhance the PDT efficiency against solid tumors, a functional oxygen self-supplying and PS-delivering nanosystem is fabricated via the combination of catalase (CAT), chlorin e6 (Ce6) and metal-phenolic network (MPN) capsule. It is demonstrated that the CAT encapsulated in the capsules (named CCM capsules) could catalyze the degradation of hydrogen peroxide (H2O2) to produce molecular oxygen (O2), which could be converted into cytotoxicity reactive oxygen species (ROS) by surface-loaded Ce6 under 660 nm laser irradiation, leading to synergistic anticancer effects in vitro and in vivo. Therefore, the application of CCM capsule could be a promising strategy to improve PDT effectiveness.

The rational integration of chemotherapy and hydroxyl radical (·OH)-mediated chemodynamic therapy (CDT) via functional metal-organic frameworks (MOF) carriers has great potential in cancer therapy. In this work, aminotriazole (3-AT) doped polyhedral metal organic frameworks (denoted as MAF) were prepared by template ligand replacement, where CDT was initiated by Cu2+/Cu+ modulated Fenton reaction and enhanced by effectively regulating the catalase activity with 3-AT. However, a rod-like Cu-MOF with 3-AT served as a ligand was obtained by the hydrothermal method without using template. In contrast to Cu-MOF, pH-responsive MAF was chosen as the carrier for targeted drug delivery due to its higher drug load of 17.6% and relatively uniform size, where doxorubicin (DOX) as a model drug was loaded in its cavity and hyaluronic acid (HA) was coated on its surface via electrostatic interactions (denoted as HA-MAF@DOX). In vitro experiments demonstrated that HA-MAF@DOX had high transport efficiency of DOX, effective regulation of catalase (CAT) activity and enhanced cytotoxicity to HepG2 cells. This work is the first use of enzyme inhibitors as ligands to construct functional MOFs via template ligand replacement for effective regulating enzyme activity, mediating intracellular redox homeostasis and enhancing CDT efficacy, which provides a feasible strategy for the construction the functional MOFs in cancer therapy.

Insulin resistance is one of the earliest pathological features of a suite of diseases including type 2 diabetes collectively referred to as metabolic syndrome. There is a growing body of evidence from both pre-clinical studies and human cohorts indicating that reactive oxygen species, such as the superoxide radical anion and hydrogen peroxide are key players in the development of insulin resistance. Here we review the evidence linking mitochondrial reactive oxygen species generated within mitochondria with insulin resistance in adipose tissue and skeletal muscle, two major insulin sensitive tissues. We outline the relevant mitochondria-derived reactive species, how the mitochondrial redox state is regulated, and methodologies available to measure mitochondrial reactive oxygen species. Importantly, we highlight key experimental issues to be considered when studying the role of mitochondrial reactive oxygen species in insulin resistance. Evaluating the available literature on both mitochondrial reactive oxygen species/redox state and insulin resistance in a variety of biological systems, we conclude that the weight of evidence suggests a likely role for mitochondrial reactive oxygen species in the etiology of insulin resistance in adipose tissue and skeletal muscle. However, major limitations in the methods used to study reactive oxygen species in insulin resistance as well as the lack of data linking mitochondrial reactive oxygen species and cytosolic insulin signaling pathways are significant obstacles in proving the mechanistic link between these two processes. We provide a framework to guide future studies to provide stronger mechanistic information on the link between mitochondrial reactive oxygen species and insulin resistance as understanding the source, localization, nature, and quantity of mitochondrial reactive oxygen species, their targets and downstream signaling pathways may pave the way for important new therapeutic strategies.

Diseases caused by harmful microorganisms pose a serious threat to human health. Safe and environment-friendly disinfectants are, therefore, essential in preventing and controlling such pathogens. This study aimed to investigate the antimicrobial activity and mechanism of a novel hydrogen peroxide and silver (H 2 O 2 -Ag + ) complex (HSC) in combatting Staphylococcus aureus ATCC 29213, Escherichia coli O157:H7 NCTC 12900 and Salmonella typhimurium SL 1344. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against S. aureus were found to be 0.014 % H 2 O 2 -3.125 mg/L Ag + , while 0.028 % H 2 O 2 -6.25 mg/L Ag + for both E. coli and S. typhimurium . Results of the growth curve assay and time-kill trial suggest that the HSC could inhibit the growth of the tested bacteria, as 99.9 % of viable cells were killed following treatment at the 1 MIC for 3 h. Compared with Oxytech D10 disinfectant (0.25 % H 2 O 2 -5 mg/L Ag + ), the HSC exhibited better antibacterial efficacy at a lower concentration (0.045 % H 2 O 2 -10 mg/L Ag + ). The mechanism of antibacterial action of HSC was found including the disruption of the bacterial cell membrane, followed by entry into the bacteria cell to reduce intracellular adenosine triphosphate (ATP) concentration, and inhibit the activity of antioxidases, superoxide dismutase (SOD) and catalase (CAT). The enhanced bactericidal effect of hydrogen peroxide combined with silver indicates a potential for its application in environmental disinfection, particularly in the food industry.

Made available in DSpace on 2022-05-01T09:47:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 This study aimed to evaluate the immunomodulatory effect of vitamin D (VD) on the NLRP1 and NLRP3 inflammasomes in placental explants from preeclamptic (PE) and normotensive (NT) pregnant women. Placental explants from eight PE and eight NT pregnant women were cultured with or without hydrogen peroxide (H2O2), VD or H2O2 + VD. Gene and protein expression of NLRP1, NLRP3, HMGB1, caspase-1, IL-1β, TNF-α and IL-18 were determined by qPCR and Western blotting/ELISA. Compared to NT pregnant women, the endogenous gene expression of NLRP1, NLRP3, HMGB1, IL-1β, TNF-α and IL-18 was significantly higher in explants from PE and became decreased after VD treatment. Similarly, VD decreased the protein expression of NLRP1, NLRP3, caspase-1, HMGB1, IL-1β, TNF-α and IL-18 in PE. Placental explants from NT cultured with H2O2 showed increased gene and protein expression of NLRP1, NLRP3, caspase-1, IL-1β, TNF-α and HMGB1, while H2O2 was also able to increase TNF-α and caspase-1 gene expression in PE. Treatment with H2O2 + VD decreased gene/protein expression of NLRP1, NLRP3, caspase-1, HMGB1, IL-1β, TNF-α and IL-18 in PE and NT explants with H2O2. NLRP1 and NLRP3 are upregulated in the PE. VD may play an immunomodulatory role in the placental inflammation and downregulates oxidative stress induced in vitro by H2O2. Botucatu Medical School Sao Paulo State University (Unesp) Institute of Biosciences Sao Paulo State University (Unesp) Botucatu Medical School Sao Paulo State University (Unesp) Institute of Biosciences Sao Paulo State University (Unesp)

Enhanced postruminal supply of methionine (Met) during the peripartal period alters protein abundance of insulin, AA, and antioxidant signaling pathways in subcutaneous adipose tissue (SAT). Whether SAT is directly responsive to supply of Met and can induce molecular alterations is unknown. Our objective was to examine whether enhanced Met supply during an oxidative stress challenge in vitro alters insulin, AA, inflammation, and antioxidant signaling-related protein networks. Four late-lactation Holstein cows (average 27.0 kg of milk per day) were used for SAT collection. Tissue was incubated in duplicate for 4 h in a humidified incubator with 5% CO2 at 37°C according to the following experimental design: control medium with an “ideal” profile of essential AA (CTR; Lys:Met 2.9:1), CTR plus 100 μM H2O2 (HP), or CTR with greater Met supply plus 100 μM H2O2 (HPMET; Lys:Met 2.5:1). Molecular targets associated with insulin signaling, lipolysis, antioxidant nuclear factor, erythroid 2 like 2 (NFE2L2), inflammation, and AA metabolism were determined through reverse-transcription quantitative PCR and western blotting. Data were analyzed using the MIXED procedure of SAS 9.4 (SAS Institute Inc.). Among proteins associated with insulin signaling, compared with CTR, HP led to lower abundance of phosphorylated AKT serine/threonine kinase (p-AKT) and solute carrier family 2 member 4 (SLC2A4; insulin-induced glucose transporter). Although incubation with HPMET restored abundance of SLC2A4 to levels in the CTR and upregulated abundance of fatty acid synthase (FASN) and phosphorylated 5′-prime-AMP-activated protein kinase (p-AMPK), it did not alter p-AKT, which remained similar to HP. Among proteins associated with AA signaling, compared with CTR, challenge with HP led to lower abundance of phosphorylated mechanistic target of rapamycin (p-MTOR), and HPMET did not restore abundance to CTR levels. Among inflammation-related targets studied, incubation with HPMET led to greater protein abundance of nuclear factor kappa B subunit p65 (NFKB-RELA). The response in NFKB observed with HPMET was associated with a marked upregulation of the antioxidant transcription regulator NFE2L2 and the antioxidant enzyme glutathione peroxidase 1 (GPX1). No effects of treatment were detected for mRNA abundance of proinflammatory cytokines or antioxidant enzymes, underscoring the importance of post-transcriptional regulation. Overall, data indicated that short-term challenge with H2O2 was particularly effective in reducing insulin and AA signaling. Although a greater supply of Met had little effect on those pathways, it seemed to restore the protein abundance of the insulin-induced glucose transporter. Overall, the concomitant upregulation of key inflammation and antioxidant signaling proteins when a greater level of Met was supplemented to oxidant-challenged SAT highlighted the potential role of this AA in regulating the inflammatory response and oxidant status. Further studies should be conducted to assess the role of postruminal supply of Met and other AA in the regulation of immune, antioxidant, and metabolic systems in peripartal cow adipose tissue.

The comparison between salt stress protectants in terms of their ability to increase growth and yield under salinity is of great importance in crop production. Melatonin (MT) and cobalt (Co) have been suggested to promote the plant's salt tolerance by mediating physiological mechanisms. To explore the difference between these protectants in increasing salt tolerance, cucumber plants (Cucumis sativus L., cv. Barracuda F1) were submitted to different levels of salt stress (control = 0.25, 2, 3 and 4 dS m−1) with pretreatment of MT (100 and 200 μM) or Co (15 and 20 mg L−1). The results indicated that the increasing level of salt reduced the growth and productivity of cucumber plants, which may result from ions toxicity (Na+ and Cl− accumulation), oxidative stress (hydrogen peroxide, H2O2 and malondialdehyde, MDA accumulation), and the reduction of essential nutrients content. The concentration used, whether from MT or Co, was instrumental in determining the level of salt tolerance in the cucumber plants. Foliar application with 15 mg L−1 Co and 100 μM MT mitigated, at a similar level, the NaCl- induced inhibition of cucumber growth, fruit number and weight. At the physiological levels, both treatments increased protein content, essential nutrients (N, P, K+, and Ca2+) content, and catalase (CAT) activity of stressed plants. The mitigation was also observed in the reduced levels of H2O2 and MDA. However, Co (15 mg L−1) showed superiority compared to MT in reducing the content of toxic ions (Na+ and Cl−) and increasing the total yield, especially under the high salt stress (4 dS m−1). These results suggest that Co and MT can improve the salt tolerance of the cucumber plants, but the level of improvement may differ in some aspects, and this may be due to the difference in salt tolerance mechanisms among those protectants.

Nanozyme has been regarded as an efficient antibiotic to kill bacteria using the reactive oxygen species (ROS) generated by Fenton-like reaction. However, its activity is still unsatisfied and requires large amount of hydrogen peroxide with side effects toward normal tissues. Herein, spherical mesoporous Fe-N-C single-atom nanozyme (SAzyme) is designed for antibacterial therapy via photothermal treatment enhanced Fenton-like catalysis process. Due to the large pore size (4.0 nm), high specific surface area (413.9 m2 g−1) and uniform diameter (100 nm), the catalytic performance of Fe-N-C SAzyme is greatly improved. The Michaelis-Menten constant (Km) is 4.84 mmol L−1, which is similar with that of horseradish peroxidase (3.7 mmol L−1). Moreover, mesoporous Fe-N-C SAzyme shows high photothermal conversion efficiency (23.3 %) owing to the carbon framework. The catalytic activity can be enhanced under light irradiation due to the elevated reaction temperature. The bacteria can also be killed via physical heat effect. Due to the synergistic effect of nanozyme catalysis and photothermal treatment, the antibacterial performance is much higher than that using single antibacterial method. This work provides an alternative for combined antibacterial treatment via photothermal treatment assisted catalytic process using spherical mesoporous single-atom nanozyme as an antibiotic.

Iron-containing zeolite possesses an active site capable of low-temperature partial oxidation of methane using hydrogen peroxide as an environmentally benign oxidant. However, only a trace number of active sites has been found in zeolite so far. The high turnover frequency was limited to low loading samples, resulting in an upper limit of ~50 mmol‧gcat-1‧h-1 yield of C1 oxygenase. In this study, we synthesized a ZSM-5 catalyst containing a high concentration single Fe site with a high turnover frequency, and achieved the conversion of methane to C1 oxygenase at ~200 mmol‧gcat-1‧h-1 yield. It was important to use ZSM-5 as a carrier, which can be synthesized by hydrothermal treatment of aluminosilicate gel containing only tetra-propyl ammonium cation as the structure-directing agent (SDA). This ZSM-5 carrier has a large fraction of the local environments possessing the nearest framework AlO4 tetrahedra required for fixation of the Fe cation in a mononuclear state while suppressing the co-generation of oligomeric Fe sites, making it possible to design a reaction field for the highly efficient partial oxidation of methane. The findings in the present study clearly showed that the fraction of the single Fe cation, as well as the Al distribution in the zeolite matrix, are the powerful activity descriptor for this class of materials. Furthermore, the Al-distribution modifications based on the previously-established protocols, i.e., rational choice of SDA used in the zeolite synthesis, are a meaningful way to tune not only the fabrication efficiency for the single Fe cation but also the catalytic performance of the Fe/ZSM-5 catalyst.

A huge amount of rice cultivation and consumption occur in Asia particularly in Pakistan and China. However, multiple abiotic stresses especially high and low-temperature proved to be a substantial threat for rice production ultimately risks for food security. To overcome various types of abiotic stress; seed priming is among the effective approaches to improve the rice seed germination and growth vigor. Therefore, the present study was planned to evaluate physiological and biochemical modifications in Chinese and Pakistani rice varieties by Qiangdi 863 biological assistant growth apparatus nano treated water (NTW), Osmopriming Calcium chloride (CaCl2), redox priming hydrogen peroxide (H2O2) and hormonal priming by Salicylic acid (SA) under temperature stress conditions. The experiment was performed with completely randomize design conditions. Five rice varieties, nomenclature as Zhongzoa 39, (Chinese rice variety) KSK 133, KS 282, Super basmati and PK 1121 aromatic (Pakistani rice variety) were sown under low temperature (LT) (17ºC), optimal temperature (OT) 27ºC and high temperature (HT) 37ºC conditions. The present study indicated that nanopriming were the most effective treatments increased Germination Energy Percentage (GEP) (96.1, 100, 100%), Speed of Germination (SG) (27.2, 35.45, 37.1), Final Germination Percentage (FGP) (98.2, 99.1, 99.4%), Seedling Dry Weight Biomass (DWB) (0.1, 0.137, 0.14g), Total Chlorophyll Content (0.502, 13.74, 15.21), antioxidant enzymes Superoxide Dismutase (SOD)(3145, 2559, 3345 µg-1FWh-1), Catalase (CAT) (300, 366, 3243 µg-1FWh-1) and decreased Malondialdehyde (MDA) (6.5, 12.2, 6.5 µmol g-1 FW) for Zhongzao 39 and KSK 133 rice varieties under low (LT+NTW), optimal temperature (OP+NTW) and high temperature (HT+NTW) stress., Therefore, nano-priming is recommended to cope with the high and low-temperature stress conditions along with improved productivity of rice.

BACKGROUND Cooking oil is an indispensable component of the human diet. However, oils usually undergo thermal oxidation. Oxidized soybean oil (OSO) has been shown to have detrimental effects on humans and has emerged as a root cause of many chronic diseases. The objective of this work was to evaluate the effects of puerpera exposure to OSO on kidney damage in the mother and offspring using lactating rats as an experimental model. RESULTS Pathological sections and ultrastructure showed that OSO exposure resulted in various levels of damage to lactating rats and their offspring. OSO induced oxidative stress in the kidneys of lactating rats, as evidenced by increased levels of hydrogen peroxide, interleukin (IL)-1β, and IL-8. OSO increased the activities of glutathione peroxidase and superoxide dismutase. OSO upregulated the expression of apoptosis-related genes, nuclear factor-erythroid 2-related factor 2 (Nrf2), and nuclear factor κB-related inflammatory factor genes. In the offspring of the OSO-exposed mothers, hydrogen peroxide, malondialdehyde, IL-6, and tumor necrosis factor-alpha contents were increased. Furthermore, OSO enhanced the levels of Nrf2, NAD(P)H quinone oxidoreductase 1, heme oxygenase 1, and p65 and decreased B-cell lymphoma 2. CONCLUSION These findings indicated that the kidneys of two generations of rats were compromised by oxidative damage when fed OSO during lactation. This study provides evidence for increasing the genes expression of the Nrf2/heme oxygenase 1 pathway to alleviate the kidney damage caused by OSO in the mother and offspring. © 2021 Society of Chemical Industry.

1,3,5-Tri-O-caffeoyl quinic acid is a caffeoylquinic acid derivative isolated from the roots of Arctium lappa L. Our previous studies have revealed that the ethyl acetate extract of the roots of A. lappa L. and the caffeoylquinic acids contained in it possess antioxidant properties, especially 1,3,5-tri-O-caffeoyl quinic acid. The present study aimed to investigate the protective effects of 1,3,5-tri-O-caffeoyl quinic acid against hydrogen peroxide-induced oxidative stress and explore the underlying mechanism. We found that 1,3,5-tri-O-caffeoyl quinic acid prevented the decline of cell viability and excessive release of lactate dehydrogenase induced by hydrogen peroxide. In addition, Hoechst 33 342 staining and Annexin V-PI double staining showed that 1,3,5-tri-O-caffeoyl quinic acid inhibited hydrogen peroxide-induced neuronal cell apoptosis. 1,3,5-Tri-O-caffeoyl quinic acid reduced the excessive production of intracellular reactive oxygen species, decreased the malondialdehyde content, and improved the activity of superoxide dismutase. Furthermore, 1,3,5-tri-O-caffeoyl quinic acid restored the loss of mitochondrial membrane potential in SH-SY5Y cells induced by hydrogen peroxide. 1,3,5-Tri-O-caffeoyl quinic acid downregulated the overexpression of proapoptotic proteins, including Bax, cytochrome c, cleaved caspase-9, and cleaved caspase-3 as well as promoted the expression of the antiapoptotic protein Bcl-2. Moreover, the phosphorylation of mitogen-activated protein kinases induced by hydrogen peroxide was inhibited by 1,3,5-tri-O-caffeoyl quinic acid. Pretreatment with 1,3,5-tri-O-caffeoyl quinic acid also promoted the activation of phosphorylated Akt. Taken together, these findings suggest that 1,3,5-tri-O-caffeoyl quinic acid exerts protective effects against hydrogen peroxide-induced neuronal apoptosis. In addition, inhibition of the mitogen-activated protein kinase signaling pathway and the activation of Akt are implicated in the antioxidant activity of 1,3,5-tri-O-caffeoyl quinic acid, giving new insight in searching for a compound with antioxidant activity for the treatment of oxidative stress-associated neurological diseases.

AIM Oxidative stress and the inflammatory response contribute to the progression of cardiovascular disease. The present study aimed to investigate whether the mitochondrial-derived peptide MOTS-c could alleviate H2O2-induced oxidative stress and inflammatory status in H9c2 cells through activation of nuclear factor erythroid 2-related Factor 2 (Nrf2)/antioxidative response element (ARE) and inhibition of the NF-κB pathway. METHODS Rat H9c2 cardiomyocytes were obtained, and 10, 20 or 50 μM MOTS-c was pretreated for 24 h before treatment with H2O2. Then, the cell was treated with 100 μM H2O2 for 1 h to induce oxidative stress. An inhibition model of sh-Nrf2 was constructed via a lentivirus expression system, and an activation model of NF-κB was achieved using phorbol 12-myristate-13-acetate (PMA). Cell viability was determined using a Cell Counting kit-8 assay. Relative measurement of relative protein and mRNA expression used western blotting and qRT-PCR, respectively. Intracellular reactive oxygen species (ROS) levels were detected using dichlorodihydrofluorescein diacetate, and malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined via commercial kits. The protein expression and distribution in the cells were visualized by immunofluorescence analysis. Enzyme-linked immunosorbent assay was used to detect the levels of inflammatory cytokines, including TNF-α, IL-6 and IL-1β. RESULTS We found that H2O2 treatment significantly decreased cell viability and the level of SOD, increased the levels of ROS and MDA, and upregulated the expression of inflammatory cytokines, including TNF-α, IL-6 and IL-1β, in H9c2 cells. The expression levels of Nrf2, HO-1 and NQO-1 were significantly downregulated in the H2O2, while the phosphorylation of NF-κBp65 was promoted by H2O2. However, pretreatment with MOTS-c significantly reversed H2O2-induced damage in H9c2 cells. Moreover, both inhibition of the Nrf2/ARE pathway and activation of the NF-κB pathway significantly decreased the effects of MOTS-c, suggesting that MOTS-c might play a role in alleviating oxidative damage via the Nrf2/ARE and NF-κB pathways. CONCLUSIONS Our investigation indicated that MOTS-c could protect against H2O2-induced inflammation and oxidative stress in H9c2 cells by inhibiting NF-κB and activating the Nrf2/ARE pathways.

To prevent postoperative skin tumor recurrence and repair skin wound, a glucose oxidase (GOx)-loaded manganese silicate hollow nanospheres (MS HNSs)-incorporated alginate hydrogel (G/MS-SA) was constructed for starvation-photothermal therapy and skin tissue regeneration. The MS HNSs showed a photothermal conversion efficiency of 38.5%, and endowed composite hydrogels with satisfactory photothermal effect. Taking advantage of the catalytic activity of Mn ions, the composite hydrogels could decompose hydrogen peroxide (H2O2) into oxygen (O2), which can alleviate the problem of tumor hypoxia microenvironment and endow GOx with an ability to consume glucose in the presence of O2 for tumor starvation. Meanwhile, hyperthermia triggered by near infrared (NIR) irradiation could not only accelerate the reaction rate of H2O2 decomposition by MS HNSs and glucose consumption by GOx, but also ablate tumor cells. The anti-tumor results showed that synergistic effect of starvation-photothermal therapy led to the highest death rate of tumor cells among all groups, and its anti-tumor effect was obviously improved as compared with that of single photothermal treatment or starvation treatment. Interestingly, the introduction of MS HNSs into hydrogels could distinctly promote the epithelialization of the wound beds by releasing Mn ions as compared with the hydrogels without MS HNSs. It is expected that such a multifunctional platform with starvation-photothermal therapy will be promising for treating tumor-caused skin defects in combination of its regeneration bioactivity in the future., Graphical abstract Schematic diagram. Schematic illustrations of (a) the fabrication of GOx-loaded MS HNSs-incorporated hydrogels (G/MS-5SA) and (b) the application of G/MS-5SA hydrogels in starvation-photothermal therapy and skin tissue regeneration.Image 1, Highlights • Glucose oxidase-loaded manganese silicate hollow nanospheres-incorporated alginate hydrogels consumed glucose in the presence of O2 for tumor starvation. • Hyperthermia could accelerate the reaction rate of H2O2 decomposition. And starvation-photothermal synergetic anti-tumor therapy effect was better than that of single treatment. • The composite hydrogels promote the epithelialization of the wound beds by releasing Mn ions.

Hypertrophic cardiomyopathy (HCM) is a complex myocardial disorder with no well-established disease-modifying therapy so far. Our study aimed to investigate how autophagy, oxidative stress, inflammation, stress signalling pathways, and apoptosis are hallmark of HCM and their contribution to the cardiac dysfunction. Demembranated cardiomyocytes from patients with HCM display increased titin-based stiffness (Fpassive), which was corrected upon antioxidant treatment. Titin as a main determinant of Fpassive was S-glutathionylated and highly ubiquitinated in HCM patients. This was associated with a shift in the balance of reduced and oxidized forms of glutathione (GSH and GSSG, respectively). Both heat shock proteins (HSP27 and α-s crystalline) were upregulated and S-glutathionylated in HCM. Administration of HSPs in vitro significantly reduced HCM cardiomyocyte stiffness. High levels of the phosphorylated monomeric superoxide anion-generating endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO) bioavailability, decreased soluble guanylyl cyclase (sGC) activity, and high levels of 3-nitrotyrosine were observed in HCM. Many regulators of signal transduction pathways that are involved in autophagy, apoptosis, cardiac contractility, and growth including the mitogen-activated protein kinase (MAPK), protein kinase B (AKT), glycogen synthase kinase 3s (GSK-3s), mammalian target of rapamycin (mTOR), forkhead box O transcription factor (FOXO), c-Jun N-terminal protein kinase (JNK), and extracellular-signal-regulated kinase (ERK1/2) were modified in HCM. The apoptotic factors cathepsin, procaspase 3, procaspase 9 and caspase 12, but not caspase 9, were elevated in HCM hearts and associated with increased proinflammatory cytokines (Interleukin 6 (IL-6), interleukin 18 (IL-18), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), the Toll-like receptors 2 (TLR2) and the Toll-like receptors 4 (TLR4)) and oxidative stress (3-nitrotyrosine and hydrogen peroxide (H2O2)). Here we reveal stress signalling and impaired PQS as potential mechanisms underlying the HCM phenotype. Our data suggest that reducing oxidative stress can be a viable therapeutic approach to attenuating the severity of cardiac dysfunction in heart failure and potentially in HCM and prevent its progression.

The demand for the amino acid l -cysteine is increasing in the food, cosmetic, and pharmaceutical industries. Conventionally, the commercial production of l -cysteine is achieved by its extraction from the acid hydrolysate of hair and feathers. However, this production method is associated with the release of environmentally hazardous wastewater. Additionally, l -cysteine produced from animal sources cannot be halal-certified, which limits the market size. Although recent studies have developed an alternative commercial l -cysteine production method based on microbial fermentation, the production yield was insufficient owing to the cytotoxicity of l -cysteine against the host cells. In a previous study, we had developed an in vitro l -cysteine production method with a combination of 11 thermophilic enzymes, which yielded 10.5 mM l -cysteine from 20 mM glucose. In this study, we performed re-screening for enzymes catalyzing the rate-limiting steps of the in vitro pathway. Subsequently, the genes encoding enzymes necessary for the in vitro synthesis of l -cysteine were assembled in an expression vector and co-expressed in a single strain. To prevent the synthesis of hydrogen peroxide (H2O2), which is a byproduct and inhibits the enzyme activity, the redox balance in this biosynthetic pathway was maintained by replacing the H2O2-forming NADH oxidase with another enzymatic reaction in which pyruvate was used as a sacrificial substrate. The re-designed in vitro synthetic pathway resulted in the production of 28.2 mM l -cysteine from 20 mM glucose with a molar yield of 70.5%.

Oxidative stress inflicts mitochondrial dysfunction, which has been recognized as a key driver of intestinal diseases. Resveratrol (RSV) and its derivative pterostilbene (PTS) are natural antioxidants and exert a protective influence on intestinal health. However, the therapeutic effects and mechanisms of RSV and PTS on oxidative stress-induced mitochondrial dysfunction and intestinal injury remain unclear. The present study used porcine and cellular settings to compare the effects of RSV and PTS on mitochondrial redox homeostasis and function to alleviate oxidative stress-induced intestinal injury. Our results indicated that PTS was more potent than RSV in reducing oxidative stress, maintaining intestinal integrity, and preserving the mitochondrial function of diquat-challenged piglets. In the in vitro study, RSV and PTS protected against hydrogen peroxide (H2O2)-induced mitochondrial dysfunction in intestinal porcine enterocyte cell line (IPEC-J2) by facilitating mitochondrial biogenesis and increasing the activities of mitochondrial complexes. In addition, both RSV and PTS efficiently mitigated mitochondrial oxidative stress by increasing sirtuin 3 protein expression and the deacetylation of superoxide dismutase 2 and peroxiredoxin 3 in H2O2-exposed IPEC-J2 cells. Furthermore, RSV and PTS preserved mitochondrial membrane potential, which restrained the release of cytochrome C from mitochondria to the cytoplasm and caspase-3 activation and further reduced apoptotic rates in H2O2-exposed IPEC-J2 cells. Mechanistically, depletion of sirtuin 1 (SIRT1) abrogated RSV's and PTS's benefits against mitochondrial reactive oxygen species overproduction, mitochondrial dysfunction, and apoptosis in H2O2-exposed IPEC-J2 cells, suggesting that SIRT1 was required for RSV and PTS to protect against oxidative stress-induced intestinal injury. In conclusion, RSV and PTS improve oxidative stress-induced intestinal injury by regulating mitochondrial redox homeostasis and function via SIRT1 signaling pathway. In offering this protection, PTS is superior to RSV.

Two–electron ( 2 e - ) oxygen reduction reaction (ORR) shows great promise for on–site electrochemical synthesis of hydrogen peroxide (H2O2). However, it is still a great challenge to design efficient electrocatalysts for H2O2 synthesis. To address this issue, the logical design of the active site by controlling the geometric and electronic structures is urgently desired. Therefore, using density functional theory (DFT) computations, two kinds of hybrid double–atom supported on C2N nanosheet (RuCu@C2N and PdCu@C2N) are screened out and their H2O2 performances are predicted. PdCu@C2N exhibits higher activity for H2O2 synthesis with a lower overpotential of 0.12 V than RuCu@C2N (0.59 V), Ru3Cu(110) facet (0.60 V), and PdCu(110) facet (0.54 V). In aqueous phase, the adsorbed O2 is further stabilized with bulk H2O and the thermodynamic rate–determining step of 2 e - ORR change. The activation barrier on PdCu@C2N is 0.43 eV lower than the one on RuCu@C2N with 0.68 eV. PdCu@C2N is near the top of 2 e - ORR volcano plot, and exhibits high selectivity of H2O2. This work provides guidelines for designing highly effective hybrid double–atom electrocatalysts (HDACs) for H2O2 synthesis.

Horseradish peroxidase (HRP) was immobilized in calcium alginate beads by extruding an alginate/HRP solution through a syringe onto calcium chloride. The aim of this study was to evaluate their use to remove the azo-dye Orange II (OII), under different experimental conditions, such as the number of beads, pH, reuse of the biocatalyst, hydrogen peroxide feeding strategy. A mathematical model that takes into account the diffusion of reactants, products, and HRP throughout the beads and the effect of the enzyme leakage on the observable oxidation rate was also developed. Results indicated that the immobilization efficiency decreased as a function of the incubation time in CaCl2. Although enzyme-containing beads had a low OII adsorption capacity, under the presence of hydrogen peroxide, the dye removal was highly increased due to the catalytic activity of HRP. Besides, the initial OII oxidation rate (RS0) using 3 beads at pH 9 was higher than at pH 7. Also, RS0 increased as a function of the number of tested beads. The developed model was fitted to experimental data obtained at different conditions. Then, the model was validated against a new data set that was not used for the calibration of the model, obtaining a satisfactory agreement between simulation results and these new data. Simulations demonstrate that 70–90% of the total OII removed was due to its oxidation by hydrogen peroxide catalyzed by HRP in the liquid phase.

Regulation of stress-responsive genes represent one of the best examples of gene induction, and the relevance and involvement of different regulators may change for a given gene depending on the challenging stimulus. The HSP12 gene is induced by very different stimuli; however, the molecular response to stress has been characterized in detail only for heat shock treatments. In this study, we aimed to verify whether the regulation of transcription induced by oxidative stress utilizes the same epigenetic solutions as those employed in the heat shock response. We also monitored HSP12 induction by employing spermidine, a known acetyltransferase inhibitor, and observed an oxidative stress that synergizes with spermidine treatment. Our data show that during transcriptional response to H2O2, histone acetylation and chromatin remodeling occur. However, when the relevance of Gcn5p to these processes was studied, we observed that induction of transcription is GCN5-dependent, and this does not rely on histone acetylation by Gcn5p despite its HAT activity. Chromatin remodeling accompanying gene activation is GCN5 dependent. Thus, GCN5 controls HSP12 transcription after H2O2 treatment by allowing chromatin remodeling, and it is only partially involved in HSP12 histone acetylation regardless of its HAT activity.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by complex pathogenesis, of which oxidative stress has long been regarded as a major mechanism. Previously, the protective effects of estradiol on SH-SY5Y cells against Aβ42-induced injuries were demonstrated. In this study, the protection of SH-SY5Y cells by estradiol from H2O2-caused oxidative stress injury and Alzheimer's mice was further confirmed. H2O2 downregulated, whereas estradiol upregulated miR-223 expression. miR-223 overexpression promoted cell viability, inhibited cell apoptosis, reduced ROS levels, enhanced Superoxide Dismutase (SOD) activity, and decreased malondialdehyde (MDA) content. However, miR-223 inhibition exerted opposite effects. miR-223 directly targeted forkhead box O3 (FOXO3) and inhibited FOXO3 expression. H2O2 increased, whereas estradiol decreased thioredoxin interacting protein (TXNIP) levels; FOXO3 positively regulated TXNIP protein levels. In SH-SY5Y cells, FOXO3 overexpression increased, whereas FOXO3 knockdown reduced the cell apoptosis and ROS levels. FOXO3 bound to TXNIP promoter region and activated TXNIP transcription, whereas the activation could be partially inhibited by estradiol. Collectively, the FOXO3/TXNIP axis is downstream of miR-223. miR-223 enhances the neuroprotection of estradiol against oxidative stress injury through the FOXO3/TXNIP axis.

Methods to detect and quantify disease biomarkers with high specificity and sensitivity in biological fluids play a key role in enabling clinical diagnosis, including point-of-care testing. Myeloperoxidase (MPO) is an emerging biomarker for the detection of inflammation, neurodegenerative diseases, and cardiovascular disease, where excess MPO can lead to oxidative damage to biomolecules in homeostatic systems. While numerous methods have been developed for MPO analysis, most techniques are challenging in clinical applications due to the lack of amplification methods, high cost, or other practical drawbacks. Enzyme-linked immunosorbent assays are currently used for the quantification of MPO in clinical practice, which is often limited by the availability of antibodies with high affinity and specificity and the significant nonspecific binding of antibodies to the analytical surface. In contrast, nucleic acid-based biosensors are of interest because of their simplicity, fast response time, low cost, high sensitivity, and low background signal, but detection targets are limited to nucleic acids and non-nucleic acid biomarkers are rare. Recent studies reveal that the modification of a genome in the form of phosphorothioate is specifically sensitive to the oxidative effects of the MPO/H2O2/Cl- system. We developed an oxidative cleavage-based three-dimensional DNA biosensor for rapid, ratiometric detection of HOCl and MPO in a "one-pot" method, which is simple, stable, sensitive, specific, and time-saving and does not require a complex reaction process, such as PCR and enzyme involvement. The constructed biosensor has also been successfully used for MPO detection in complex samples. This strategy is therefore of great value in disease diagnosis and biomedical research.

The resistant phenotype of pear cultivars includes either complete resistance or tolerance to the attack by the causative agent of fire blight. The effect of ferritin and active iron (Fe2+) concentrations was compared in resistant (Dargazi), tolerant (Harrow Sweet), and susceptible (Bartlett) pear cultivars inoculated with a wild type strain of Erwinia amylovora (Ea273). The examination of necrosis revealed that resistance to the disease manifested itself as a delay in the appearance of symptoms and progression of the disease. Despite a rise in ferritin levels in all cultivars following disease agent inoculation, resistant and tolerant cultivars showed greater ferritin levels than susceptible cultivar. In addition, only resistant and tolerant cultivars displayed a drop in Fe2+ levels. The rate of decrease in Fe2+ content in Dargazi and Harrow sweet cultivars was 28 and 33%, respectively. Hydrogen peroxide (H2O2) and hydroxyl radical (OH•−) accumulation and intensities were considerably distinctive. Furthermore, tolerant and sensitive cultivars started producing OH•− radicals faster than resistant cultivar. According to these findings, different pathways are employed by pear cultivars to respond to the causative agent of fire blight.

Fresh-cut peaches are susceptible to browning when exposed to air. Reducing the browning is important to maintain the quality of the fresh-cut peaches. Nitric oxide (NO) as the signal factor can improve the antioxidant capacity of organisms; sodium alginate (SA) is a natural polysaccharide with good antibacterial and film-forming properties. The study aimed to investigate the antioxidant and anti-browning activities of combined application of sodium alginate and nitric oxide on peaches slices preservation. The activities of some browning-related enzymes and antioxidant enzymes and the content of reactive oxygen species (ROS) and some browning-related components in fresh-cut peaches were determined. Results showed that combined treatment of 1% SA + 10 μmol/L NO slowed down the decrease in firmness, L*, and SSC, restrained the increase in browning degree and the activities of polyphenol oxidase, phenylalanine ammonia-lyase, peroxidase, and lipoxygenase. At the same time, it reduced the accumulation of O2•–, ·OH, H2O2, malondialdehyde, and total phenolic, and increased the activities of catalase and superoxide dismutase in peach slices. Overall, it was concluded that treatment with 1% SA + 10 μmol/L NO maintained quality and extended storage life of fresh-cut peaches.

Hydrogen sulfide (H2S) can alleviate Cd-induced cell death, but the molecular mechanisms are not clear. To shed light on these mechanisms, cell death induced by 200 μM cadmium chloride in cucumber seedlings root tips was used as a model system. Here, we report that the negative effect of Cd stress in mitochondrial physiological functions include changes in cytochrome c/a, mitochondrial membrane permeability transition pores, and adenosine triphosphatase (ATPase). Moreover, Cd stress led to the release of mitochondrial Ca2+ into the cytosol. Exogenous application of sodium hydrosulfide (NaHS, a donor of H2S) inhibited cell death and maintains mitochondrial function by reducing mitochondrial hydrogen peroxide accumulation, increasing ATPase activity and down-regulating CsVDAC and CsANT expression. In summary, H2S suppressed Cd-induced cell death by improving mitochondrial physiological properties.

The autosomal dominant striated muscle disease myoglobinopathy is due to the single point mutation His98Tyr in human myoglobin (MB) [Olive et al. (2019) Nat Comm 10, 1396], the heme protein responsible for binding, storage, and controlled release of O2 in striated muscle. In order to understand the molecular basis of this disease, a comprehensive biochemical and biophysical study on wt MB and the variant H98Y has been performed. Although only small differences exist between the active site architectures of the two proteins, the mutant (a) exhibits an increased reactivity toward hydrogen peroxide, (b) exhibits a higher tendency to form high-molecular-weight aggregates, and (c) is more prone to heme bleaching, possibly as a consequence of the observed H2 O2 -induced formation of the Tyr98 radical close to the metal center. These effects add to the impaired oxygen binding capacity and faster heme dissociation of the H98Y variant compared with wt MB. As the above effects result from bond formation/cleavage events occurring at the distal and proximal heme sites, it appears that the molecular determinants of the disease are localized there. These findings set the basis for clarifying the onset of the cascade of chemical events that are responsible for the pathological symptoms of myoglobinopathy.

Starvation therapy based on glucose oxidase (GOx) has attracted considerable attention in tumor treatment. However, several shortcomings severely hinder its further applications, including limited therapeutic efficacy, poor enzyme stability, and potential side effects. Herein, a strategy of cascade reaction-enhanced combined therapy based on the oxygen-evolving multifunctional nanoreactors is proposed for tumor therapy. The GOx and catalase (CAT) are immobilized in metal-organic frameworks by biomimetic mineralization to improve their stability via spatial confinement. The GOx can consume glucose, reduce ATP levels, and down-regulate the expression of heat shock proteins, which consequently sensitize tumor cells to indocyanine green-based photothermal therapy. Furthermore, the hydrogen peroxide generated by GOx as well as overexpressed in tumor can be decomposed by CAT and continuously generate oxygen, which further enhance the efficacy of oxygen-dependent starvation therapy and photodynamic therapy. The nanoreactors are directly delivered to the superficial tumor by microneedles, achieving efficient tumor accumulation and dramatically strengthened antitumor efficacy without obvious side effects, which provides a valuable paradigm for the application of cascade reaction-based combined therapy.

Superoxide dismutases (SODs) protect the cells by catalyzing the dismutation of harmful superoxide radicals (O2•-) into molecular oxygen (O2) and hydrogen peroxide (H2O2). Here, a Cu, Zn SOD (WT) from a high altitude plant (Potentilla atrosanguinea) was engineered by substituting a conserved residue proline to glycine at position 61 (P61G). The computational analysis showed higher structural flexibility and clusters in P61G than WT. The P61G exhibited moderately higher catalytic efficiency (Km = 0.029 μM, Vmax = 1488) than WT protein (Km = 0.038 μM, Vmax = 1290.11). P61G showed higher thermostability as revealed from residual activity (72.25% for P61G than 59.31% for WT after heating at 80 °C for 60 min), differential calorimetry scanning and CD-spectroscopic analysis. Interestingly, the P61G mutation also resulted in enhanced tolerance to H2O2 inactivation than WT protein. The finding on enhancing the biophysico-chemical properties by mutating conserved residue could stand as an example to engineer other enzymes. Also, the reported mutant can be exploited in food and pharmaceutical industries.

Abiotic stressors, such as drought and high salinity, seriously affect plant growth, productivity, and quality. Maintaining reactive oxygen species (ROS) homeostasis and osmotic balance plays a crucial role in abiotic stress tolerance. β-amylase (BAM) hydrolyzes α-1,4-glycosidic bonds by releasing maltose from starch in the regulation of soluble sugars. However, the function and mechanism of BAMs related to abiotic stress resistance remain unclear in sweetpotato (Ipomoea batatas (L.) Lam.). In this study, we isolated a novel β-amylase gene IbBAM1.1, which was strongly induced by PEG6000, NaCl, and maltose treatments in sweetpotato variety Yanshu25. Overexpression of IbBAM1.1 conferred enhanced tolerance to the drought and high salinity stressors in Arabidopsis thaliana. The activity of β-amylase and the degradation of starch were promoted under drought or salt stress. Accordingly, the contents of osmoprotectants, including maltose and proline were significantly higher in the transgenic lines than those in wild type (WT) plants. Less ROS, such as H2O2 and O2−, accumulated in the overexpressing lines than in WT plants. Superoxide dismutase activity was strongly enhanced and the level of malondialdehyde was lower under the drought or salt treatment in transgenic plants. Taken together, these results demonstrate that IbBAM1.1 acted as a positive regulator, at least in part, by regulating the level of osmoprotectants to balance the osmotic pressure and activate the scavenging system to maintain ROS homeostasis in the plants.

The mesh-type USB piezoelectric ultrasonic transducer (USB-PUT) used in household humidifiers and inhalation therapy devices is very cheap, small, and energy saving. It holds great promise for sonochemistry. However, the microtapered apertures in the center of the stainless steel substrate of mesh-type USB-PUT can lead to rapid atomization of solution, leakage of solutions containing surfactants and organic solvent through the apertures, and high background emission. Herein, we design a new type of USB-PUT by replacing the meshed stainless steel substrate with an apertureless stainless steel substrate. We have found that this apertureless USB-PUT can not only induce intense sonochemiluminescence (SCL) but can also enable sensitive luminol SCL detection of hydrogen peroxide which is practically impossible using mesh-type PUT because of the strong background SCL emission. By using this apertureless device to induce SCL and using smart phone as a detector, a visual hydrogen peroxide SCL detection method with a linear range of 0.5-50 μM and a detection limit of 0.32 μM is established. Moreover, the device can achieve the detection of glucose oxidase (GOD) activity and glucose by enzymatic conversion of glucose to hydrogen peroxide. The linear range of GOD detection is 1-200U/L with a detection limit of 0.86 U/L. The linear range of glucose detection is 0.5-70 μM with a detection limit of 0.43 μM. The cheap (a few dollars) and user-friendly apertureless USB-PUT is promising for sonochemistry applications and chemical education.

During systemic inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H2O2) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that then relaxes arteries via oxidation of protein kinase G 1α. Here we show that arterial glutathione peroxidases and peroxiredoxins that rapidly eliminate H2O2, have little impact on relaxation of IDO1-expressing arteries, and that purified IDO1 forms cis-WOOH in the presence of peroxiredoxin 2. cis-WOOH oxidizes protein thiols in a selective and stereospecific manner. Compared with its epimer trans-WOOH and H2O2, cis-WOOH reacts slower with the major arterial forms of glutathione peroxidases and peroxiredoxins while it reacts more readily with its target, protein kinase G 1α. Our results indicate a paradigm of redox signaling by H2O2 via its enzymatic conversion to an amino acid-derived hydroperoxide that ‘escapes’ effective reductive inactivation to engage in selective oxidative activation of key target proteins., A major question in redox signaling is how H2O2 oxidizes target protein thiols in the presence of glutathione peroxidases and peroxiredoxins. We reveal signaling by H2O2 via its enzymatic conversion to an alkyl hydroperoxide that stereo-specifically escapes peroxidases and oxidizes target proteins.

The current study investigated the exposure of the Mediterranean mussel (Mytilus galloprovincialis) to gold nanoparticles decorated zinc oxide (Au-ZnO NPs) and phosphonate [Diethyl (3-cyano-1-hydroxy-1-phenyl-2-methylpropyl)] phosphate (PC). The mussels were exposed to concentrations of 50 and 100 µg L-1 of both compounds alone, as well as to a mixture of both pollutants (i.e. Mix). The singular and the combined effect of each pollutant was investigated by measuring the concentration of various metals (i.e., Cu, Fe, Mn, Zn and Au) in the the digestive glands and gills of mussels, their filtration capacity (FC), respiration rate (RR) and the response of oxidative biomarkers, respectively, following 14 days of exposure. The concentrations of Cu, Fe, Mn, Zn and Au increased directly with Au-ZnO NPs in mussel tissues, but significantly only for Zn. In contrast, the mixture of Au-ZnO100 NPs and PC100 did not induce any significant increase in the content of metals in digetsve glands and gills, suggesting antagonistic interactions between contaminants. In addition, FC and RR levels decreased following exposure to Au-ZnO100 NPs and PC100 treatments and no significant alterations were observed after the exposure to 50 µg.L-1 of both contaminants and Mix. Hydrogen peroxide (H2O2) level, GSH/GSSG ratio, superoxide dismutase (SOD), catalase (CAT) and acetylcholinesterase (AChE) activities showed significant changes following the exposure to both Au-ZnO NPs and PC, in the gills and the digestive glands of the mussel. However, no significant modifications were observed in both organs following the exposure to Mix. The current study advances the understanding of the toxicity of NPs and phosphonates on M. galloprovincialis and sets the path for future ecotoxicological studies regarding the synergic effects of these substances on marine species. Moreover, the current experiment suggests that the oxidative stress and the neurotoxic pathways are responsive following the exposure of marine invertebrates to both nanoparticles and phosphonates, with potential antagonist interactions of these substances on the physiology of targeted species.

A DNA structure-based nanoreactor has emerged as a promising biomaterial for antitumor therapy with its intrinsic biodegradability, biocompatibility, and tunable multifunctionality. Herein, the intelligent DNA nanohydrogel was reported to target cancer cells, control the size, be pH-responsive, and be loaded with glucose oxidase (GOx). Two kinds of X-shaped DNA monomers and DNA linkers were assembled to form a DNA nanohydrogel by hybridization. GOx was successfully encapsulated in the DNA nanohydrogel. The DNA linker was designed with i-motif sequences and modified with ferrocene (Fc). The i-motif-like quadruplex structures were formed in acidic tumor microenvironments, resulting in the disassembly of the DNA nanohydrogel to release GOx. The GOx could oxidize the intratumoral glucose to produce gluconic acid and H2O2. The generated H2O2 was catalyzed by Fc to induce toxic hydroxyl radicals (•OH), which could effectively kill cancer cells. Both the in vitro and the in vivo results demonstrated that the multifunctional DNA nanohydrogel had high-efficiency tumor suppression through combined chemodynamic and starvation cancer therapies.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene lies within a topologically associated domain (TAD) in which multiple cis-regulatory elements (CREs) and transcription factors (TFs) regulate its cell-specific expression. The CREs are recruited to the gene promoter by a looping mechanism that depends upon both architectural proteins and specific TFs. An siRNA screen to identify TFs coordinating CFTR expression in airway epithelial cells suggested an activating role for BTB domain and CNC homolog 1 (BACH1). BACH1 is a ubiquitous master regulator of the cellular response to oxidative stress. Here, we show that BACH1 may have a dual effect on CFTR expression by direct occupancy of CREs at physiological oxygen (∼8%), while indirectly modulating expression under conditions of oxidative stress. Hence BACH1, can activate or repress the same gene, to fine tune expression in response to environmental cues such as cell stress. Furthermore, our 4C-seq data suggest that BACH1 can also directly regulate CFTR gene expression by modulating locus architecture through occupancy at known enhancers and structural elements, and depletion of BACH1 alters the higher order chromatin structure.

Therapeutic nanosystems triggered by a specific tumor microenvironment (TME) offer excellent safety and selectivity in the treatment of cancer by in situ conversion of a less toxic substance into effective anticarcinogens. However, the inherent antioxidant systems, hypoxic environment, and insufficient hydrogen peroxide (H2O2) in tumor cells severely limit their efficacy. Herein, a new strategy has been developed by loading the chemotherapy prodrug disulfiram (DSF) and coating glucose oxidase (GOD) on the surface of Cu/ZIF-8 nanospheres and finally encapsulating manganese dioxide (MnO2) nanoshells to achieve efficient DSF-based cancer chemotherapy and dual-enhanced chemodynamic therapy (CDT). In an acidic TME, the nanocatalyst can biodegrade rapidly and accelerate the release of internal active substances. The outer layer of MnO2 depletes glutathione (GSH) to destroy the reactive oxygen defensive mechanisms and achieves continuous oxygen generation, thus enhancing the catalytic efficiency of GOD to burst H2O2. Benefiting from the chelation reaction between the released Cu2+ and DSF, a large amount of cytotoxic CuET products is generated, and the Cu+ are concurrently released, thereby achieving efficient chemotherapy and satisfactory CDT efficacy. Furthermore, the release of Mn2+ can initiate magnetic resonance imaging signals for the tracking of the nanocatalyst.

Pathogens associated with onion seeds cause serious problems by decreasing the percentage of germinated seeds and impeding the growth of germinated seedlings leading to pre- and post-emergence damping-off. Two fungal isolates, Aspergillus niger and Fusarium oxysporum, associated with commercial onion seeds were isolated, identified, and tested for their pathogenicity. Different concentrations of hydrogen peroxide (H2O2)-based compounds [peroxyacetic acid (PAA), potassium bicarbonate (PB)] alone or combined with microwave treatment for eight seconds (M8) or ten seconds (M10) were also evaluated against pre- and post-emergence damping-off caused by A. niger and F. oxysporum, as well as their impact on morphological and physiological traits of onion seedlings. Our results revealed that H2O2-based compounds and/or microwave treatments significantly increased the germination percentage and vigor index of onion seeds and decreased the disease incidence of damping-off. The highest germination percentages were achieved when onion seeds without artificial fungal infection were soaked in PPA1 (95.5%), M8 + PPA2 (95%) and PB_2 (93%), compared with their control (85.5%). The three treatments also significantly increased the vigor index of the onion seedlings from 804 to 2311, 2157, and 1916, respectively. Treatment of M10 + PAA_2 significantly reduced disease incidences of pre-emergence damping-off in onion cultivar Giza_20 from 35 and 30 to 18.5 and 9.6 caused by A. niger and F. oxysporum, respectively. All tested treatments were able to induce onion resistance by increasing the concentrations of salicylic acid, phenolic compounds, phenylalanine ammonia-lyase, and polyphenol oxidase. The tested treatments seem to regulate H2O2 in infected onion seedlings by increasing the level of catalase, ascorbate peroxidase, and guaiacol peroxidase.

The sequential cleavage of full-length amyloid precursor protein (APP) by secretases has been at the center of efforts for understanding the onset of Alzheimer's disease (AD). A decrease in α-secretase activity was observed during the progression of AD; however, the precise molecular mechanism involved in the downregulation of α-secretase under oxidative stress is not fully understood. In the present study, we have demonstrated that pharmacological inhibition of mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) by mitogen-activated protein kinase kinase-1 (MEK-1) inhibitor (PD98059) restored the expression of a disintegrin and metalloproteinase 10 (ADAM10) with a concomitant decrease in β-site APP cleavage enzyme 1 (BACE1) under oxidative stress. Silent mating-type information regulation 2 homologue 1 (SIRT1) activation by resveratrol also mitigated alterations in secretase levels through MAPK/ERK signaling. Intracerebroventricular (ICV) administration of streptozotocin in rats showed amyloidogenic processing of APP and altered the SIRT1/ERK axis in the hippocampus. We also observed that the ADAM10 expression is controlled at the transcriptional level by oxidative stress. Using the luciferase reporter activity of ADAM10 promoter deletion constructs, we have identified the region 290 bp upstream of the transcription start site (TSS) possessing regulatory elements responsible for ADAM10 downregulation with hydrogen peroxide (H2O2) treatment. Further, bioinformatics analysis revealed the presence of putative nuclear factor kappa B (NF-κB) binding sites in the ADAM10 promoter region. Treatment of cortical neurons with the NF-κB inhibitor (Bay 11-7082) mitigated the transcriptional upregulation of ADAM10 by PD98059. Overall, our findings suggest that SIRT1/ERK/NF-κB axis contributes to the downregulation of ADAM10, resulting in the shift from nonamyloidogenic to amyloidogenic processing of APP under oxidative stress.

CYP152 peroxygenases catalyze decarboxylation and hydroxylation of fatty acids using H2O2 as cofactor. To understand the molecular basis for the chemo- and regioselectivity of these unique P450 enzymes, herein, we analyze the activities of three representative CYP152 peroxygenases (OleTJE, P450SPα and P450BSβ) towards cis- and trans-dodecenoic acids as substrate probes. The unexpected 6S-hydroxylation of the trans-isomer and 4R-hydroxylation of the cis-isomer by OleTJE, and molecular docking results suggest that the unprecedented selectivity is likely due to OleTJE's preference of C2-C3 cis-configuration. More surprisingly, in addition to the common epoxide products, undecanal is the unexpected major product of P450SPα and P450BSβ regardless the cis/trans-configuration of substrates. The combined isotopically-labeled H218O2 tracing experiments, MD simulations and QM/MM calculations unravel an unusual mechanism for Compound I-mediated aldehyde formation, in which the active site water derived from H2O2 activation is involved in the generation of a four-membered ring lactone intermediate. These findings provide new insights into the unusual mechanisms of CYP152 peroxygenases.

The toxic and non-essential metalloid arsenic (As) is ubiquitous in the environment with its absorption from the soil into the plants’ roots posing detrimental effects on the crop plants and hence the food availability and food security are also threatened. The present study was intended to reduce the As-induced toxicity in rice seedlings (Oryza sativa L.) by phosphate (PO43−). For this, three concentrations of potassium phosphate (KH2PO4), 50, 100 and 150 μM were supplemented along with 50 μM As exposure to hydroponically grown 7-day-old rice seedlings. Supplementation of PO43− significantly recovered arsenic-induced diminutions in growth parameters and photosynthetic pigment contents which were due to the significant increase in superoxide radical (SOR, O2•¯) and hydrogen peroxide (H2O2). Supplementation of 50 μM PO43− could significantly increase the activity of APX (ascorbate peroxidase) and GR (glutathione reductase) while 100 μM PO43− could increase the activity of DHAR (dehydroascorbate reductase) and monodehydroascorbate reductase (MDHAR). As the amount of PO43− was increased, the ratio of AsA/DHA (reduced to oxidized ascorbate) and GSH/GSSG (reduced to oxidized glutathione) was increased significantly due to increase in the reduced form of the non-enzymes i.e. AsA and GSH. The activity of SOD (superoxide dismutase) and GPX (guaiacol peroxidase) decreased significantly after a substantive increase in their activities due to As stress while the CAT (catalase) activity further enhanced after the supplementation of 50 and 100 μM PO43−. Thus, the As-induced oxidative stress in the rice seedlings was managed by concerted modulations in the activities of SOD, GPX, CAT and AsA-GSH cycle enzymes and metabolites.

Targeted cancer treatment is a promising, less invasive alternative to chemotherapy as it is precisely directed against tumor cells whilst leaving healthy tissue unaffected. The plant-derived enzyme horseradish peroxidase (HRP) can be used for enzyme prodrug cancer therapy with indole-3-acetic acid or the analgesic paracetamol (acetaminophen). Oxidation of paracetamol by HRP in the presence of hydrogen peroxide leads to N-acetyl-p-benzoquinone imine and polymer formation via a radical reaction mechanism. N-acetyl-p-benzoquinone imine binds to DNA and proteins, resulting in severe cytotoxicity. However, plant HRP is not suitable for this application since the foreign glycosylation pattern is recognized by the human immune system, causing rapid clearance from the body. Furthermore, plant-derived HRP is a mixture of isoenzymes with a heterogeneous composition. Here, we investigated the reaction of paracetamol with defined recombinant HRP variants produced in E. coli, as well as plant HRP, and found that they are equally effective in paracetamol oxidation at a concentration ≥ 400 µM. At low paracetamol concentrations, however, recombinant HRP seems to be more efficient in paracetamol oxidation. Yet upon treatment of HCT-116 colon carcinoma and FaDu squamous carcinoma cells with HRP–paracetamol no cytotoxic effect was observed, neither in the presence nor absence of hydrogen peroxide. Graphic abstract

Nanozymes are of particular interest due to their enzyme-mimicking activity and high stability that are favorable in biomedical sensing and immunoassays. In this work, we report a highly specific N-doped nanozyme through pyrolysis of framework-confined bovine serum albumin (BSA). This strategy allows one to translate the low-cost and featureless BSA into a highly active enzyme mimic. The obtained carbon nanozyme (denoted as HBF-1-C800) displays 3- to 7-fold enhancement on peroxidase (POD) activity compared with the conventional carbon nanozymes and also shows ca. 5-fold activity enhancement compared to the reported N-doping graphene. Such excellent POD activity originates from high N-doping efficiency, protein-induced defective sites, and the intrinsic porous structure of HBF-1-C800, which provides abundantly accessible active sites and accelerates substrate diffusion simultaneously. Importantly, the HBF-1-C800 nanozyme has highly specific POD activity and also enables resistance to several harsh conditions that should denature natural enzymes. These features allow it with high accuracy, stability, and sensitivity for biosensing applications. Moreover, HBF-1-C800 has been designed as a promising platform for colorimetric biosensing of several biomarkers including H2O2, glutathione, and glucose, with wide linear ranges and low limits of detection that are satisfied with the disease diagnosis.

Reactive oxygen species (ROS) overproduction and oxidative stress are increasingly being implicated in the extracellular matrix (ECM) degradation associated with chronic inflammatory conditions, such as periodontal diseases. The present study investigated the effects of ROS exposure on the proteoglycans of gingival tissues, utilizing an in vitro model system comprised of supra-physiological oxidant concentrations, to ascertain whether gingival proteoglycan modification and degradation by ROS contributed to the underlying mechanisms of ECM destruction during active gingivitis. Proteoglycans were purified from ovine gingival tissues and exposed to increasing H2O2 concentrations or a hydroxyl radical (·OH) flux for 1 h or 24 h, and ROS effects on proteoglycan core proteins and sulfated glycosaminoglycan (GAG) chains were assessed. ROS were capable of degrading gingival proteoglycans, with ·OH species inducing greater degradative effects than H2O2 alone. Degradative effects were particularly manifested as amino acid modification, core protein cleavage, and GAG chain depolymerization. Proteoglycan core proteins were more susceptible to degradation than GAG chains with H2O2 alone, although core proteins and GAG chains were both extensively degraded by ·OH species. Proteoglycan exposure to ·OH species for 24 h induced significant core protein amino acid modification, with decreases in glutamate, proline, isoleucine, and leucine; and concomitant increases in serine, glycine, and alanine residues. As clinical reports have previously highlighted proteoglycan core protein degradation during chronic gingivitis, whereas their sulfated GAG chains remain relatively intact, these findings potentially provide further evidence to implicate ROS in the pathogenesis of active gingivitis, complementing the enzymic mechanisms of periodontal tissue destruction already established.

The present study was aimed to investigate copper (Cu) toxicity alleviatory potential of silicon in Vigna radiata L. (mung bean) seedlings. Moreover, attention has also been paid to find out whether endogenous nitric oxide (NO) has any role in Si-governed alleviation of Cu stress. The length of root and shoot, fresh weight, and biochemical attributes were adversely affected by Cu exposure. However, application of Si rescued negative effects of Cu. Cu exposure decreased cell viability, and enhanced cell death and levels of oxidative stress markers (O2•‾, H2O2 and MDA), but Si significantly mitigated these effects of Cu. Application of Cu substantially stimulated the activities of superoxide dismutase and guaiacol peroxidase while inhibited activity of catalase. However, Si addition reversed this effect of Cu. Ascorbate and glutathione contents in roots and shoots were declined by Cu but stimulated by Si. Moreover, we noticed that addition of Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) and sodium tungstate (Tung) further augmented Cu toxicity but addition of sodium nitroprusside rescued adverse effects of L-NAME and Tung. Altogether, data suggest that though Si was able in alleviating Cu toxicity in mung bean seedlings but it requires endogenous nitric oxide.

The combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) have attracted a great deal of interest, but tumor hypoxia and glutathione (GSH) overproduction still limit their further applications. Herein, an intelligent reactive oxygen species (ROS) nanogenerator Ce6/GOx@ZIF-8/PDA@MnO2 (denoted as CGZPM; Ce6, GOx, ZIF-8, PDA, MnO2 are chlorin e6, glucose oxidase, zeolitic imidazolate framework-8, polydopamine and manganese dioxide respectively) with O2-generating and GSH-/glucose-depleting abilities was constructed by a facile and green one-pot method. After intake by tumor cells, the outer MnO2 was rapidly degraded by the acidic pH, and the overexpression of hydrogen peroxide (H2O2) and GSH with abundant Mn2+ and O2 produced would eventually achieve multifunctionality. The Mn2+ acted as an ideal Fenton-like agent and magnetic resonance (MR) imaging contrast agent, while the O2 promoted the PDT via hypoxia relief and facilitated the intratumoral glucose oxidation by GOx for starvation therapy (ST). Benefiting from the GOx-based glycolysis process, sufficient H2O2 was generated to improve the CDT efficacy through Mn2+-mediated Fenton-like reaction. Notably, MnO2 and PDA could decrease the tumor antioxidant activity by consuming GSH, resulting in remarkably enhanced PDT/CDT. Such a novel cascade bioreactor with tumor microenvironment (TME)-modulating capability opens new opportunities for ROS-based and combinational treatment paradigms.

Drought is a prevalent natural factor limiting crop production in arid regions across the world. To overcome this limitation, seeds are sown much deeper to boost germination by soil moisture produced by underground water. Seed pretreatment can effectively induce deep-sowing tolerance in plants. In the present study, we evaluated whether H2O2 pretreatment of seeds can initiate metabolic changes and lead to improved deep-sowing tolerance in wheat. Pretreatment with 0.05 mu M H2O2 promoted first internode elongation by 13% in the deep-sowing tolerant wheat cultivar Tir and by 32% in the sensitive cultivar Kirac-66 under deep-sowing conditions, whereas internode elongation was inhibited by diphenyleneiodonium chloride. In contrast to Tir seedlings, H2O2 levels in the first internode of Kirac-66 seedlings increased under deep-sowing condition in the H2O2-treated group compared to controls. Moreover, these seedlings had significantly lower catalase (CAT), peroxidase (POX), and ascorbate peroxidase (APX) activities but higher NADPH oxidase (NOX) and superoxide dismutase (SOD) activities under the same conditions, which consequently induced greater H2O2 accumulation. Contrary to Tir, both total glutathione and glutathione S-transferase (GST) activity decreased in Kirac-66 after deep-sowing at 10 cm. However, H2O2 treatment increased the total glutathione amounts and the activities of glutathione-related enzymes (except GST and GPX) in the first internode of Kirac-66. Taken together, these data support that H2O2 acts as a signaling molecule in the activation of antioxidant enzymes (specifically NOX, SOD, and CAT), regulation of both glutathione-related enzymes and total glutathione content, and upregulation of the cell wall-loosening protein gene TaEXPB23., Scientific and Technological Research Council of Turkey (TUBITAK) [114Z034]; Ege University Research Foundation [13-FEN-049], This work was financially supported by The Scientific and Technological Research Council of Turkey (TUBITAK), [Project No 114Z034] and the Ege University Research Foundation, [Project No 13-FEN-049].

The sulfhydryl bioregulator thiourea (TU) is effective in ameliorating the negative impact of different abiotic stresses in plants. To explore the significant performance of TU (5 mM TU, as foliar spray) in conferring mild (25% depletion of water from field capacity, FC), moderate (50% depletion from FC) and severe (75% depletion from FC) drought stress (applied at 25 days after sowing), physiological and biochemical responses of two chickpea (Cicer arietinum L.) cultivars (cv. BARI Chola-7 and BARI Chola-9) were investigated in the current study. Shoot fresh weight, dry weight, chlorophyll content and leaf relative water content reduced noticeably in mild, moderate and severe drought stresses over control. A sharp increase of H2O2 accumulation, thiobarbituric acid reactive substances and proline content were noticed at any level of drought stress which further declined in TU-treated drought-stressed plants. Thiourea-foliar application also increased ascorbate and glutathione contents and upregulated antioxidant enzyme activities, compared to drought-stressed plants alone. Thiourea-induced increased glyoxalase I and glyoxalase II activities are the indications of upregulated methylglyoxal detoxification system. Enhancement of antioxidant defense and glyoxalase system, osmoregulation and protection of photosynthetic pigments by TU improved growth, imparted oxidative stress tolerance, ameliorated ROS toxicity and improved physiology of chickpea plants under drought stress.

In plants, NO has been proved the function of improving abiotic stress resistance. However, the role of NO in the lignin metabolism of okra under cold stress has not been clarified. Here, histochemical staining and lignin content analysis showed that cold stress promoted the lignin accumulation of cold stored okra pods, and NO inhibited the lignin accumulation and delayed lignification process. To better understand the roles of NO in okra cold stress resistance mechanism, the full-length transcriptome data of 'Hokkaido' was analyzed. The SNP-treated okra transcriptome and cPTIO-treated okra transcriptome were obtained. A total of 41957 unigenes were screened out from three groups at 10 d, among which, 33, 78 and 18 DEGs were found in ddH2O-treat, SNP-treat and cPTIO-treat group, respectively. Transcriptomic data suggested that the genes involved in lignin biosynthesis showed downregulation under SNP treatment. Transcriptomic data and enzyme activity showed that exogenous NO significantly promoted the biosynthesis of endogenous NO by enhancing NOS activity. Transcriptomic data and plant hormone data showed that NO played an important role in the process of inhibiting the ethylene and ABA synthesis mechanism of okra and thereby reducing the endogenous ethylene and ABA content under chilling stress. Relevant physiological data showed that NO helped to the protection of ROS scavenging system and removed the MDA and H2O2 induced by cold stress. These results provided a reference for studying the molecular mechanism of nitric oxide delaying the lignification of okra, and also provided a theoretical basis for postharvest storage of vegetables.

The contribution of one major or a combination of several physiological processes in salt tolerance was assessed in three local varieties (Blacklong, Advanta-1103, and Dilpasand) of ridge gourd [Luffa acutangula (L.) Roxb.] at varying salt levels (0, 75, and 150 mM NaCl). Based on growth attributes, var. Dilpasand as salt-tolerant and var. Blacklong as moderately salt-tolerant, while var. Advanta-1103 as salt-sensitive. Inter-varietal differences for photosynthetic pigments and relative water content (RWC) was not observed. The salt-sensitive variety Advanta 1103 had greater Na+ accumulation (73.72%) in the leaves than those in the moderately tolerant and tolerant varieties. Total soluble proteins were relatively lower (58.25%) in the salt-sensitive variety but maximal increase (69.34%) in total free amino acids was observed. However, accumulation of proline was maximal in the salt-tolerant variety (Dilpasand). Salt-tolerant variety exhibited minimal oxidative stress (relative low levels of H2O2) and membrane damage (low content of MDA and electrolytic leakage) and higher activities of antioxidant enzymes (catalase and peroxidase). Although all ridge gourd varieties down-regulated the electron transport through PSII by increasing the safe dissipation of heat Y(NPQ) to lower the ROS generation, this was maximal in the salt-tolerant variety Dilpasand. Relatively greater reduction in Y(ND) and enhancement in Y(NA) indicated PSI-photoinhibition in salt-sensitive variety. The greater salt tolerance in var. Dilpasand was due to the coordinated impact of ion exclusion, higher accumulation of proline, better capacity to manage electron transport from PSII to PSI with higher Y(NPQ) and antioxidant capacity.

Glucose oxidase (GOx)-mediated starvation therapy holds great promise in cancer treatment. However, the worse hypoxia conditions result into low therapeutic efficiency, and undegradability of carriers poses potential threats to living bodies. To address this, herein a bioinspired MnO2 nanosystem with controllable surface was developed for highly efficient starvation/gas synergistic enhanced therapy. Biomimetic design and further surface modification unprecedentedly endowed the nanosystem with ultrahigh loading capacity for GOx and l-Arginine (l-Arg) and special selectivity toward cancer cells. Especially, the dissipative O2 during starvation therapy was well replenished by a positive cycle formed by the nanosystem, which continuously reproduced O2 and accelerated glucose consumption. The abundant H2O2 was further used to oxidize l-Arg into nitric oxide to realize gas therapy. In vitro and in vivo testing confirmed that this new treatment effectively blocked the nutrition and energy sources of cells to obtain excellent therapeutic effect. We reported the first experimental item of this nanosystem for inhibiting cancer cell migration. Considering the novel design concept with facile biomimetic methods, effective co-loading of endogenous substances, and good anti-tumor and anti-migration effects, this work provided new theoretical and experimental basis for starvation therapy and inspired people to design more delicate platform for cancer treatment.

Aims S-glutathionylation is a reversible oxidative modification of protein cysteines that plays a critical role in redox signaling. Glutaredoxin-1 (Glrx), a glutathione-specific thioltransferase, removes protein S-glutathionylation. Glrx, though a cytosolic protein, can activate a nuclear protein Sirtuin-1 (SirT1) by removing its S-glutathionylation. Glrx ablation causes metabolic abnormalities and promotes controlled cell death and fibrosis in mice. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a key enzyme of glycolysis, is sensitive to oxidative modifications and involved in apoptotic signaling via the SirT1/p53 pathway in the nucleus. We aimed to elucidate the extent to which S-glutathionylation of GAPDH and glutaredoxin-1 contribute to GAPDH/SirT1/p53 apoptosis pathway. Results Exposure of HEK 293T cells to hydrogen peroxide (H2O2) caused rapid S-glutathionylation and nuclear translocation of GAPDH. Nuclear GAPDH peaked 10–15 min after the addition of H2O2. Overexpression of Glrx or redox dead mutant GAPDH inhibited S-glutathionylation and nuclear translocation. Nuclear GAPDH formed a protein complex with SirT1 and exchanged S-glutathionylation to SirT1 and inhibited its deacetylase activity. Inactivated SirT1 remained stably bound to acetylated-p53 and initiated apoptotic signaling resulting in cleavage of caspase-3. We observed similar effects in human primary aortic endothelial cells suggesting the GAPDH/SirT1/p53 pathway as a common apoptotic mechanism. Conclusions Abundant GAPDH with its highly reactive-cysteine thiolate may function as a cytoplasmic rheostat to sense oxidative stress. S-glutathionylation of GAPDH may relay the signal to the nucleus where GAPDH trans-glutathionylates nuclear proteins such as SirT1 to initiate apoptosis. Glrx reverses GAPDH S-glutathionylation and prevents its nuclear translocation and cytoplasmic-nuclear redox signaling leading to apoptosis. Our data suggest that trans-glutathionylation is a critical step in apoptotic signaling and a potential mechanism that cytosolic Glrx controls nuclear transcription factors.