High Levels Of H2O2 Research Articles

Mesoporous cerium oxide nanoenzyme for Efficacious impeding tumor and metastasis via Conferring resistance to anoikis

Tumor cells can survive when detached from the extracellular matrix or lose cell-to-cell connections, leading to a phenomenon known as anoikis resistance (AR). AR is closely associated with the metastasis and proliferation of tumor cells, enabling them to disseminate, migrate, and invade after detachment. Here, we have investigated a novel composite nanoenzyme comprising mesoporous silica/nano-cerium oxide (MSN-Ce@SP/PEG). This nanoenzyme exhibited satisfactory catalase (CAT) activity, efficiently converting high levels of H2O2 within tumor cells into O2, effectively alleviating tumor hypoxia. Furthermore, MSN-Ce@SP/PEG nanoenzyme demonstrated high peroxidase (POD) activity, elevating reactive oxygen species (ROS) levels and attenuating AR in hepatocellular carcinoma (HCC) cells. The MSN-Ce@SP/PEG nanoenzyme exhibited satisfactory dual bioactivity in CAT and POD and was significantly enhanced under favorable photothermal conditions. Through the synergistic effects of these capabilities, the nanoenzyme disrupted the epithelial-mesenchymal transition (EMT) process in detached HCC cells, ultimately inhibiting the recurrence and metastasis potential of anoikis-resistant HCC cells. This study represents the first report of a novel nanoenzyme based on mesoporous silica/nano-cerium oxide for treating AR in HCC cells, thereby suppressing HCC recurrence and metastasis. The findings of this work offer a pioneering perspective for the development of innovative strategies to prevent the recurrence and metastasis of HCC.

Dual-responsive natural killer cell nano-engagers for cancer immunotherapy via inhibiting IL-6/JAK2/STAT3 pathway

Natural killer (NK) cell-based immunotherapy is a promising approach for treating solid tumors and hematological malignancies. However, its therapeutic efficacy is limited by poor tumor infiltration and suppressive tumor microenvironment. Here, we introduce a rapid, simple, and efficient solution: bovine serum albumin-stabilized ultra-small (4 nm) NK cell nano-engagers, termed Bi2Se3@BSA nanodots (Nds). These Nds, responsive to high H2O2 levels in tumor cell environments, enhance near-infrared (NIR)-II photothermic immunotherapy. In vitro and in vivo experiments demonstrate their effectiveness in activating photothermal therapy (PTT)-induced immunogenic cell death (ICD), initiating immune cascade reactions, and stimulating immune response activation. By upregulating NKG2D, RAE-1, and secreting cytokines such as IFN-γ and TNF-α, targeted NK cell infiltration is achieved, reversing the immunosuppressive tumor microenvironment and optimizing NK cell cytotoxicity. Transcriptomic analysis confirms the association of immune response activation with the IL-6/JAK2/STAT3 signaling pathway. Notably, combining these nano-engagers with immune checkpoint inhibitors (aPD-1) significantly enhances therapeutic efficacy, facilitating tumor eradication and reducing recurrence risk. Taken together, NK cell nano-engagers inhibit the IL-6/JAK2/STAT3 signaling pathway, target NK cell activation, stimulate immune functions, and improve the immunosuppressive microenvironment. This study presents an alternative strategy for NK cell-based immunotherapy and highlights this promising tool for cancer immunotherapy.

PH and ROS Dual-Responsive Autocatalytic Release System Potentiates Immunotherapy of Colorectal Cancer.

The immunosuppressive microenvironment severely limits the responsiveness of colorectal cancer (CRC) to immunotherapy. Herein, a pH and reactive oxygen species (ROS) dual-responsive autocatalytic release system (TPDM/PGA) is constructed to reverse the immunosuppressive microenvironment and potentiate CRC immunotherapy. Dihydroartemisinin (DHA) and mitoxantrone (MTO) are conjugated to ROS-responsive polyethylenimine (TP) via a ROS-cleavable linker, respectively, and then coated with polyglutamic acid (PGA) to endow pH and ROS dual-responsiveness. The dissociation of PGA within the acidic TME facilitates its deep penetration and cell internalization, while the intracellular released DHA and MTO in response to high levels of H2O2 further produced a large amount of ROS, forming positive feedback to accelerate drug release and exacerbate oxidative stress. TPDM/PGA collaboratively reversed the immunosuppressive microenvironment and induced a strong anti-tumor immune response when combined with anti-PD-L1 antibody, significantly inhibiting tumor growth and prolonging the survival time of CT26 and MC38 tumor-bearing mice. The excellent therapeutic effect, together with the good tolerance, make TPDM/PGA a promising candidate for enhanced immunotherapy of colorectal cancer.

The regulatory roles of a plant neurotransmitter, acetylcholine, on growth, PSII photochemistry and antioxidant systems in wheat exposed to cadmium and/or mercury stress

Heavy metals increase in nature due to anthropogenic activities and negatively impact the growth, progress, and efficiency of plants. Among the toxic metal pollutants that can cause dangerous effects when accumulated by plants, mercury (Hg) and cadmium (Cd) were investigated in this study. These metals typically inhibit important enzymes and halt their functioning, thereby adversely affecting the capability of plants to achieve photosynthesis, respiration, and produce quality crops. Acetylcholine (ACh) serves as a potent neurotransmitter present in both primitive and advanced plant species. Its significant involvement in diverse metabolic processes, particularly in regulating growth and adaptation to stress, needs to be further elucidated. For this aim, effects of acetylcholine (ACh1, 10 μM; ACh2, 100 μM) were survey in Triticum aestivum under Hg and/or Cd stress (Hg, 50 μM; Cd, 100 μM). Wheat seedlings exhibited a growth retardation of about 24% under Hg or Cd stress. Combined stress conditions (Cd + Hg) resulted in a decrease in RWC by approximately 16%. Two different doses of ACh treatment to stressed plants positively affected growth parameters and regulated the water relations. Gas exchange was limited in stress groups, and the photochemical quantum competency of PSII (Fv/Fm) was suppressed. Cd + ACh1 and Cd + ACh2 treatments resulted in approximately 2-fold and 1.5-fold improvement in stomatal conductance and carbon assimilation rate, respectively. Similarly, improvement was observed with ACh treatments in wheat seedlings under Hg stress. Under Cd and/or Hg stress, high levels of H2O2 accumulated and lipid peroxidation occurred. According to our results, ACh treatment upon Cd and Hg stresses improved the activities of SOD, POX, and APX, thereby reducing oxidative damage. In conclusion, ACh treatment was found to ensure stress tolerance and limit the adverse effects caused by heavy metals.

RESPIRATORY BURST OXIDASE HOMOLOG 5.1 regulates H3K4me3 deposition and transcription after cold priming in cucumber.

Plants can maintain acquired cold tolerance for a long period after cold priming, even after the resumption of warmer temperatures. However, the transcriptional mechanisms active during the recovery period after cold priming remain unknown. Here, we found that in cucumber (Cucumis sativus), cold priming altered the Histone H3 lysine 4 trimethylation (H3K4me3) signal of sustainably-induced (memory) and non-sustainably-induced (NSI) genes during recovery. In addition, H3K4me3 marks on upregulated memory genes exhibited a specific epigenetic memory during recovery. However, the rank of the H3K4me3 signal on memory and NSI genes in the genome was independent of cold priming, which always contributed to and inhibited the formation of transcription patterns of memory and NIS genes, respectively. Furthermore, the short-lived increase of RESPIRATORY BURST OXIDASE HOMOLOG 5.1 (CsRBOH5.1) expression during recovery after cold priming was essential to maintain high levels of NADPH oxidase activity and apoplastic H2O2, causing cucumber to acquire cold priming and enhancing the maintenance of acquired cold tolerance (MACT). Interestingly, the expression of some key H3K4me3 methyltransferase genes and the accumulation of H3K4me3 on memory genes depended on CsRBOH5.1. Surprisingly, CsRBOH5.1 was essential for almost all genes to form the normal H3K4me3 signaling patterns during recovery, and the necessity was more obvious as recovery progressed. Moreover, transcriptional memory was completely lost in Csrboh5.1 mutants, and the transcriptional patterns of about 80% of NSI genes were disrupted. Overall, our results show that CsRBOH5.1 governs H3K4me3 deposition and cold-induced transcription during recovery after cold priming, affecting the acquisition of cold priming and the intensity of MACT.

Inter-subspecies diversity of maize to drought stress with physio-biochemical, enzymatic and molecular responses.

Drought is the most significant factor limiting maize production, given that maize is a crop with a high water demand. Therefore, studies investigating the mechanisms underlying the drought tolerance of maize are of great importance. There are no studies comparing drought tolerance among economically important subspecies of maize. This study aimed to reveal the differences between the physio-biochemical, enzymatic, and molecular mechanisms of drought tolerance in dent (Zea mays indentata), popcorn (Zea mays everta), and sugar (Zea mays saccharata) maize under control (no-stress), moderate, and severe drought stress. Three distinct irrigation regimes were employed to assess the impact of varying levels of drought stress on maize plants at the V14 growth stage. These included normal irrigation (80% field capacity), moderate drought (50% field capacity), and severe drought (30% field capacity). All plants were grown under controlled conditions. The following parameters were analyzed: leaf relative water content (RWC), loss of turgidity (LOT), proline (PRO) and soluble protein (SPR) contents, membrane durability index (MDI), malondialdehyde (MDA), and hydrogen peroxide (H2O2) content, the antioxidant enzyme activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), and catalase (CAT). Additionally, the expression of heat shock proteins (HSPs) was examined at the transcriptional and translational levels. The effects of severe drought were more pronounced in sugar maize, which had a relatively high loss of RWC and turgor, membrane damage, enzyme activities, and HSP90 gene expression. Dent maize, which is capable of maintaining its RWC and turgor in both moderate and severe droughts, and employs its defense mechanism effectively by maintaining antioxidant enzyme activities at a certain level despite less MDA and H2O2 accumulation, exhibited relatively high drought tolerance. Despite the high levels of MDA and H2O2 in popcorn maize, the up-regulation of antioxidant enzyme activities and HSP70 gene and protein expression indicated that the drought coping mechanism is activated. In particular, the positive correlation of HSP70 with PRO and HSP90 with enzyme activities is a significant result for studies examining the relationships between HSPs and other stress response systems. The discrepancies between the transcriptional and translational findings provide an opportunity for more comprehensive investigations into the role of HSPs in stress conditions.

H2O2-Activatable Liposomal Nanobomb Capable of Generating Hypoxia-Irrelevant Alkyl Radicals by Photo-Triggered Cascade Reaction for High-Performance Elimination of Biofilm Bacteria.

High H2O2 levels are widely present at the infection sites or in the biofilm microenvironment. Herein, hemin with peroxidase-like catalytic activity and its substrate, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), are simultaneously introduced into a liposomal nanoparticle containing thermosensitive 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIBI)-loaded bovine serum albumin (BAG), rationally constructing an H2O2-activatable liposomal nanobomb (Lipo@BHA) for combating biofilm-associated bacterial infections with high performance. In the presence of H2O2, hemin can catalyze the conversion of ABTS into its oxidized form (ABTS·+) with strong near-infrared (NIR) absorption, which produces photonic hyperpyrexia to cause the decomposition of AIBI into oxygen-independent alkyl radicals (·R) and nitrogen (N2) microbubbles. The former not only directly damage bacterial cells but also significantly accelerates the oxidization of ABTS to ABTS·+ for augmenting photothermal-triggered generation of ·R. Interestingly, the released N2 can induce transient cavitation to rupture lysosomal nanoparticle and improve the biofilm permeability, thereby enhancing the antibiofilm effect of Lipo@BHA. The proposed Lipo@BHA exhibits satisfactory multi-mode combination antibacterial properties. Through endogenous H2O2-activated cascade reaction, Lipo@BHA achieves remarkable hypoxia-irrelevant ·R therapy of biofilm-associated wound infections with low cytotoxicity and good in vivo biosafety. Therefore, this work presents a versatile H2O2-activatable cascade ·R generation strategy for biofilm-specific therapeutic applications.

Tumor microenvironment-modulated nanoparticles with cascade energy transfer as internal light sources for photodynamic therapy of deep-seated tumors

Photodynamic therapy (PDT) is an appealing modality for cancer treatments. However, the limited tissue penetration depth of external-excitation light makes PDT impossible in treating deep-seated tumors. Meanwhile, tumor hypoxia and intracellular reductive microenvironment restrain the generation of reactive oxygen species (ROS). To overcome these limitations, a tumor-targeted self-illuminating supramolecular nanoparticle T-NPCe6-L-N is proposed by integrating photosensitizer Ce6 with luminol and nitric oxide (NO) for chemiluminescence resonance energy transfer (CRET)-activated PDT. The high H2O2 level in tumor can trigger chemiluminescence of luminol to realize CRET-activated PDT without exposure of external light. Meanwhile, the released NO significantly relieves tumor hypoxia via vascular normalization and reduces intracellular reductive GSH level, further enhancing ROS abundance. Importantly, due to the different ROS levels between cancer cells and normal cells, T-NPCe6-L-N can selectively trigger PDT in cancer cells while sparing normal cells, which ensured low side effect. The combination of CRET-based photosensitizer-activation and tumor microenvironment modulation overcomes the innate challenges of conventional PDT, demonstrating efficient inhibition of orthotopic and metastatic tumors on mice. It also provoked potent immunogenic cell death to ensure long-term suppression effects. The proof-of-concept research proved as a new strategy to solve the dilemma of PDT in treatment of deep-seated tumors.

Computed Tomography Imaging Guided Microenvironment-Responsive Ir@WO3-x Dual-Catalytic Nanoreactor for Selective Radiosensitization.

Radiotherapy (RT) is often administered, either alone or in combination with other therapies, for most malignancies. However, the degree of tumor oxygenation, damage to adjacent healthy tissues, and inaccurate guidance remain issues that result in discontinuation or failure of RT. Here, a multifunctional therapeutic platform based on Ir@WO3-x is developed which simultaneously addresses these critical issues above for precision radiosensitization. Ir@WO3-x nanoreactors exhibit strong absorption of X-ray, acting as radiosensitizers. Moreover, ultrasmall Ir enzyme-mimic nanocrystals (NCs) are decorated onto the surface of the nanoreactor, where NCs have catalyst-like activity and are sensitive to H2O2 in the tumor microenvironment (TME) under near infrared-II (NIR-II) light stimulation. They efficiently catalyze the conversion of H2O2 to O2, thereby ameliorating hypoxia, inhibiting the expression of HIF-1α, and enhancing RT-induced DNA damage in cancerous tissue, further improving the efficiency of RT. Additionally, in response to high H2O2 levels in TME, the Ir@WO3-x nanoreactor also exerts peroxidase-like activity, boosting exogenous ROS, which increases oxidative damage and enhances ROS-dependent death signaling. Furthermore, Ir@WO3-x can serve as a high-quality computed tomography contrast agent due to its high X-ray attenuation coefficient and generation of pronounced tumor-tissue contrast. This report highlights the potential of advanced health materials to enhance precision therapeutic modalities.

A mitochondria-targeted fluorescent probe for revealing H2O2 elevation modulated by basal HClO in HeLa and A549 cells

Hydrogen peroxide, which is mainly produced in mitochondria, plays deleterious and beneficial roles in cells depending on its localized concentration. Tumor cells have been observed to have increased H2O2 levels due to enhanced metabolic activity. Moderately high levels of H2O2 are crucial for the growth and survival of tumor cells. Monitoring mitochondrial H2O2 is essential for revealing the factors that affect cellular redox balance. In the present work, we have developed a fast responsive fluorescent probe for the detection of H2O2 in mitochondria. Hcy-S shows high selectivity, sensitivity and a fast response to H2O2, enabling imaging of basal levels of mitochondrial H2O2 in tumor cells in 1 min. Hcy-S has been applied to the study of the impact of HClO on H2O2 level. The results revealed that endogenous HClO raises the levels of H2O2 by inactivating catalase and glutathione peroxidase in HeLa and A549 cells. This study offers a novel insight into the redox balance in tumor cells.

Differentiated management of ROS level in tumor and kidney to alleviate Cis-platinum induced acute kidney injury with improved efficacy

Cisplatin (DDP) is a prevalent chemotherapeutic agent used in tumor therapy, yet DDP-induced acute kidney injury (AKI) severely limits its clinical application. Antioxidants as reactive oxygen species (ROS) scavengers can circumvent this adverse effect while leading to the decrease of efficacy to tumor. Herein, we report ultrasmall ruthenium nanoparticles (URNPs) as switchable ROS scavengers/generators to alleviate DDP-induced AKI and improve its therapeutic efficacy. In the physiological environment of the kidney, URNPs mimic multi-enzyme activities, such as superoxide dismutase and catalase, effectively protecting the renal cell and tissue by down-regulating the increased ROS level caused by DDP and alleviating AKI. Specifically, URNPs are oxidized by high levels of H2O2 in the tumor microenvironment (TME), resulting in the generation of oxygen vacancies and Ru3+/Ru4+ ions. This unique structure transformation endows URNPs to generate singlet oxygen (1O2) under laser irradiation and hydroxyl radicals (∙OH) through a Fenton-like reaction in tumor cell and tissue. The simultaneous generation of multifarious ROS effectively improves the efficacy of DDP in vitro and in vivo. This TME-responsive ROS scavenger/generator acts as an adjuvant therapeutic agent to minimize side effects and improve the efficacy of chemotherapy drugs, providing a new avenue to chemotherapy and facilitating clinical tumor therapy.Graphical

Hydrogen peroxide responsive theranostics for cancer-selective activation of DNA alkylators and real-time fluorescence monitoring in living cells

Triple negative breast cancer (TNBC) is a notoriously difficult disease to treat, and many of the existing TNBC chemotherapeutics lack tumor selectivity and the capability for simultaneously visualizing and monitoring their own activity in the biological context. However, TNBC cells have been known to generate high levels of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2). To this end, three novel small molecule theranostics 1a, 1c, and 2 consisting of both H2O2-responsive nitrogen mustard prodrug and profluorophore character have been designed, synthesized, and evaluated as targeted cancer therapeutics and bioimaging agents. The three theranostics comprise of boronate esters that deactivate nitrogen mustard functional groups and fluorophores but allow their selective activation through H2O2-specific oxidative deboronation for the release of the active drug and fluorophore. The three theranostics demonstrated H2O2-inducible DNA-alkylating capability and fluorescence turn-on properties in addition to selective anticancer activity. They are particularly effective in killing TNBC MDA-MB-468 cells with high H2O2 level while safe to normal epithelial MCF-10A cell. The conjugated boron-masked fluorophores in 1c and 2 are highly responsive towards H2O2, which enabled tracking of the theranostics in living cellular mitochondria and nucleus organelles. The three theranostics 1a, 1c, and 2 are capable of both selective release of the active drug to take effect in H2O2-rich cancer sites and simultaneously monitoring its activity. This single molecule system is of utmost importance to understand the function, efficacy, and mechanism of the H2O2-activated prodrugs and theranostics within the living recipient.

A coupled model between circadian, cell-cycle, and redox rhythms reveals their regulation of oxidative stress

Most organisms possess three biological oscillators, circadian clock, cell cycle, and redox rhythm, which are autonomous but interact each other. However, whether their interactions and autonomy are beneficial for organisms remains unclear. Here, we modeled a coupled oscillator system where each oscillator affected the phase of the other oscillators. We found that multiple types of coupling prevent a high H2O2 level in cells at M phase. Consequently, we hypothesized a high H2O2 sensitivity at the M phase and found that moderate coupling reduced cell damage due to oxidative stress by generating appropriate phase relationships between three rhythms, whereas strong coupling resulted in an elevated cell damage by increasing the average H2O2 level and disrupted the cell cycle. Furthermore, the multicellularity model revealed that phase variations among cells confer flexibility in synchronization with environments at the expense of adaptability to the optimal environment. Thus, both autonomy and synchrony among the oscillators are important for coordinating their phase relationships to minimize oxidative stress, and couplings balance them depending on environments.

Alleviation of H2O2 toxicity by extracellular catalases in the phycosphere of Microcystis aeruginosa

High levels of environmental H2O2 represent a threat to many freshwater bacterial species, including toxic-bloom-forming Microcystis aeruginosa, particularly under high-intensity light conditions. The highest extracellular catalase activity-possessing Pseudoduganella aquatica HC52 was chosen among 36 culturable symbiotic isolates from the phycosphere in freshly collected M. aeruginosa cells. A zymogram for catalase activity revealed the presence of only one extracellular catalase despite the four putative catalase genes (katA1, katA2, katE, and srpA) identified in the newly sequenced genome (∼6.8 Mb) of P. aquatica HC52. Analysis of secreted catalase using liquid chromatography–tandem mass spectrometry was identified as KatA1, which lacks a typical signal peptide, although the underlying mechanism for its secretion is unknown. The expression of secreted KatA1 appeared to be induced in the presence of H2O2. Proteomic analysis also confirmed the presence of KatA1 inside the outer membrane vesicles secreted by P. aquatica HC52 following exposure to H2O2. High light intensities (> 100 µmol m−2 s−1) are known to kill catalase-less axenic M. aeruginosa cells, but the present study found that the presence of P. aquatica cells supported the growth of M. aeruginosa, while the extracellular catalases in supernatant or purified form also sustained the growth of M. aeruginosa under the same conditions. Our results suggest that the extracellular catalase secreted by P. aquatica HC52 enhances the tolerance of M. aeruginosa to H2O2, thus promoting the formation of M. aeruginosa blooms under high light intensities.

Photochemistry of Imidazole-2-carbaldehyde in Droplets as a Potential Source of H2O2 and Its Oxidation of SO2.

Hydrogen peroxide (H2O2) plays a crucial role as an oxidizing agent within the tropospheric environment, making a substantial contribution to sulfate formation in hydrated aerosols and cloud and fog droplets. Field observations show that high levels of H2O2 are often observed in heavy haze events and polluted air. However, the source of H2O2 remains unclear. Here, using the droplets formed in situ by the deliquescence of hygroscopic compounds under a high relative humidity (RH), the formation of H2O2 by the photochemistry of imidazole-2-carbaldehyde (2-IC) under ultraviolet irradiation was explored. The results indicate that 2-IC produces IM-C•-OH and IM-C•═O radicals via H transfer itself to its excited triplet state and generates H2O2 and organic peroxides in the presence of O2, which has an evident oxidizing effect on SO2, suggesting the potential involvement of this pathway in the formation of atmospheric sulfate. H2O2 formation is limited in acidic droplets or droplets containing ammonium ions, and no H2O2 is detected in droplets containing nitrate, whereas droplets containing citric acid have an obvious promotion effect on H2O2 formation. These findings provide valuable insights into the behaviors of atmospheric photosensitizers, the source of H2O2, and the formation of sulfate in atmospheric droplets.

Tumor microenvironment activated and amplified self-luminescent nano photosensitizers for efficient treatment of triple negative breast cancer

Triple negative cancer (TNBC) is characterized as an aggressive phenotype lacking a specific therapeutic target. To date, self-illuminating photodynamic therapy (PDT) based on chemiluminescence resonance energy transfer (CRET) has emerged as a potential alternative for TNBC treatment by generating singlet oxygen (1O2), overcoming limitations in light penetration. However, this self-illuminating strategy heavily relies on endogenous hydrogen peroxide (H2O2) and oxygen (O2) within the tumor microenvironment (TME), resulting in inefficient therapeutic performance. In this study, we designed CLT@DPD nanoparticles capable of self-illumination via CRET and TME regulation through self-supplying H2O2 and O2. This nanoparticle was constructed by encapsulating luminol-tetreaphenylporphyrin conjugate (LT) and nanoscale CaO2 with DSPE-PEG 2000 and dioleoylphosphatidylcholine (DOPC). A good accumulation at tumor site was achieved due to enhanced permeability and retention (EPR) effect after intravenous injection of CLT@DP. Responsive to the high H2O2 levels and acidic aqueous conditions of TME, LT can be oxidized to produce 1O2via CRET, and the CaO2 can be decomposed to supply H2O2 and O2. Additionally, the presence of DOPC helps to enhance the permeability of the micelle shell under the oxidation of 1O2, thereby accelerating the release of H2O2 and O2. Our proposed nanoparticles exhibit excellent performance in eradicating in situ tumor cells and inhibiting metastasis by simultaneously enhancing self-luminous PDT and alleviating oxygen depletion in TME.

Dual Enzyme-Encapsulated Materials for Biological Cascade Chemistry and Synergistic Tumor Starvation.

Framework and polymeric nanoreactors (NRs) have distinct advantages in improving chemical reaction efficiency in the tumor microenvironment (TME). Nanoreactor-loaded oxidoreductase enzyme is activated by tumor acidity to produce H2O2 by increasing tumor oxidative stress. High levels of H2O2 induce self-destruction of the vesicles by releasing quinone methide to deplete glutathione and suppress the antioxidant potential of cancer cells. Therefore, the synergistic effect of the enzyme-loaded nanoreactors results in efficient tumor ablation via suppressing cancer-cell metabolism. The main driving force would be to take advantage of the distinct metabolic properties of cancer cells along with the high peroxidase-like activity of metalloenzyme/metalloprotein. A cascade strategy of dual enzymes such as glucose oxidase (GOx) and nitroreductase (NTR) wherein the former acts as an O2-consuming agent such as overexpression of NTR and further amplified NTR-catalyzed release for antitumor therapy. The design of cascade bioreductive hypoxia-responsive drug delivery via GOx regulates NTR upregulation and NTR-responsive nanoparticles. Herein, we discuss tumor hypoxia, reactive oxygen species (ROS) formation, and the effectiveness of these therapies. Nanoclusters in cascaded enzymes along with chemo-radiotherapy with synergistic therapy are illustrated. Finally, we outline the role of the nanoreactor strategy of cascading enzymes along with self-synergistic tumor therapy.

H2O2-Induced Oxidative Stress Responses in Eriocheir sinensis: Antioxidant Defense and Immune Gene Expression Dynamics.

Eriocheir sinensis, a key species in China's freshwater aquaculture, is threatened by various diseases, which were verified to be closely associated with oxidative stress. This study aimed to investigate the response of E. sinensis to hydrogen peroxide (H2O2)-induced oxidative stress to understand the biological processes behind these diseases. Crabs were exposed to different concentrations of H2O2 and their antioxidant enzyme activities and gene expressions for defense and immunity were measured. Results showed that activities of antioxidant enzymes-specificallysuperoxide dismutase (SOD), catalase (CAT), total antioxidant capacity(T-AOC), glutathione (GSH), and glutathione peroxidase (GSH-Px)-varied with exposure concentration and duration, initially increasing then decreasing. Notably, SOD, GSH-Px, and T-AOC activities dropped below control levels at 96 h. Concurrently, oxidative damage markers, including malondialdehyde (MDA), H2O2, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, increased with exposure duration. The mRNA expression of SOD, CAT, and GSH-Px also showed an initial increase followed by a decrease, peaking at 72 h. The upregulation of phenoloxidaseloxidase (proPO) and peroxinectin (PX) was also detected, but proPO was suppressed under high levels of H2O2. Heat shock protein 70 (HSP70) expression gradually increased with higher H2O2 concentrations, whereas induced nitrogen monoxide synthase (iNOS) was upregulated but decreased at 96 h. These findings emphasize H2O2's significant impact on the crab's oxidative and immune responses, highlighting the importance of understanding cellular stress responses for disease prevention and therapy development.

Activatable near-infrared fluorescence and chemical exchange saturation transfer MRI multimodal imaging probe for tumor detection in vitro and in vivo

Multimodal imaging has emerged as a powerful tool in biomedical research and clinical diagnostics. Ideally, it combines multiple imaging techniques to provide complementary anatomical and molecular information in living subjects. Particularly desirable are multimodal imaging probes capable of providing differential diagnostic signals upon interaction with specific molecular targets. Hydrogen peroxide (H2O2) is a key target in this regard, since it is typically overexpressed in cancer cells. In this study, we present a small-molecule probe that not only selectively detects endogenous H2O2 through multimodal imaging, with a significant H2O2-triggered 15-fold fluorescence enhancement but also turns “on” a chemical exchange saturation transfer (CEST) magnetic resonance (MR) response with 60-fold signal enhancement at pH 7.4. Excellent selectivity against various other biologically relevant species is seen. Using this probe, we observed 3.4–4.5-fold and 2.8–5.8-fold higher H2O2 levels in cancerous cell lines and tumor tissues compared to normal cell lines and tissues, respectively. Time-dependent in vivo fluorescence and CEST imaging in a HeLa (Henrietta Lacks) tumor xenograft mouse model revealed probe-dependent tumor detection by fluorescence and CEST MRI contrast in the tumor area. These observations are attributed to the relatively high endogenous H2O2 levels produced during mitosis. This newly developed probe holds promise for advancing our understanding of H2O2-related biology and for cancer detection both in vitro and in vivo.

Photosynthetic Costs and Impact on Epidemiological Parameters Associated with Ht Resistance Genes in Maize Lines Infected with Exserohilum turcicum.

Northern corn leaf blight, caused by Exserohilum turcicum, is mainly controlled by the use of resistant cultivars. Maize lines carrying individual resistance genes B37Ht1, B37Ht2, B37Ht3, and B37Htn1 express different defense symptoms having an impact on the photosynthetic activity, the accumulation of reactive oxygen species, and epidemiological parameters. Plants were inoculated with a race 0 isolate of E.turcicum conferring a compatible interaction with B37 and incompatible interactions with plants carrying resistance genes. Five days postinoculation (dpi), the resistant lines displayed a reduction in leaf CO2 assimilation of 30 to 80% compared with healthy plants. At 14 dpi, inoculated plants of B37Ht1 showed a significant decrease in leaf CO2 assimilation, similar to B37 (up to 94%). The instantaneous carboxylation efficiency was significantly reduced on inoculated plants of the lines B37Ht2, B37Ht3, and B37Htn1 (54 to 81%) at 5 dpi. Curiously, the reduction in carboxylation efficiency for B37 and B37Ht1 (up to 95%) was higher at 14 dpi than at 5 dpi (up to 81%). At 6 dpi, low levels of H2O2 were detected in B37Ht1, in contrast to B37Htn1, where a high H2O2 level and peroxidase activity were observed. The sporulation rate on B37Ht1, B37Ht3, and B37Htn1 decreased by 92% compared with the susceptible control, whereas strong sporulation occurred in lesions on line B37Ht2. The resistance in maize to E. turcicum conferred by Ht resistance genes is associated with photosynthetic costs and may have quite contrasting effects on host physiology and major epidemiological parameters, such as sporulation, which contributes inoculum for secondary infections.