Excess Peroxide Research Articles

AQP3 Promotes the Invasion and Metastasis in Cervical Cancer by Regulating NOX4-derived H2O2 Activation of Syk/PI3K/Akt Signaling Axis.

Unrestrained chronic inflammation leads to the abnormal activity of NOX4 and the subsequent production of excessive hydrogen peroxide (H2O2). Excessive H2O2 signaling triggered by prolonged inflammation is thought to be one of the important reasons for the progression of some types of cancer including cervical cancer. Aquaporin 3 (AQP3) is a member of the water channel protein family, and it remains unknown whether AQP3 can regulate the transmembrane transport of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)-derived H2O2 induced by the stimulation of inflammatory factors to facilitate the malignant progression in cervical cancer. In this study, cervical cancer HeLa cell line was respectively treated with diphenyleneiodonium (DPI), N-Acetylcysteine (NAC) or lentivirus-shRNA- AQP3. Plate cloning, cell migration or transwell invasion assays, etc. were performed to detect the invasive and migration ability of the cells. Western blot and CO-IP were used to analyze the mechanism of AQP3 regulating H2O2 conduction. Finally, in vivo assays were performed for validation in nude mice. AQP3 Knockdown, DPI or NAC treatments all reduced intracellular H2O2 influx, and the activation of Syk/PI3K/Akt signal axis was inhibited, the migration and invasive ability of the cells was attenuated. In vivo assays confirmed that the excessive H2O2 transport through AQP3 enhanced the infiltration and metastasis of cervical cancer. These results suggest that AQP3 activates H2O2/Syk/PI3K/Akt signaling axis through regulating NOX4-derived H2O2 transport to contribute to the progression of cervical cancer, and AQP3 may be a potential target for the clinical treatment of advanced cervical cancer.

Umbelliferone and Its Synthetic Derivatives as Suitable Molecules for the Development of Agents with Biological Activities: A Review of Their Pharmacological and Therapeutic Potential.

Umbelliferone (UMB), known as 7-hydroxycoumarin, hydrangine, or skimmetine, is a naturally occurring coumarin in the plant kingdom, mainly from the Umbelliferae family that possesses a wide variety of pharmacological properties. In addition, the use of nanoparticles containing umbelliferone may improve anti-inflammatory or anticancer therapy. Also, its derivatives are endowed with great potential for therapeutic applications due to their broad spectrum of biological activities such as anti-inflammatory, antioxidant, neuroprotective, antipsychotic, antiepileptic, antidiabetic, antimicrobial, antiviral, and antiproliferative effects. Moreover, 7-hydroxycoumarin ligands have been implemented to develop 7-hydroxycoumarin-based metal complexes with improved pharmacological activity. Besides therapeutic applications, umbelliferone analogues have been designed as fluorescent probes for the detection of biologically important species, such as enzymes, lysosomes, and endosomes, or for monitoring cell processes and protein functions as well various diseases caused by an excess of hydrogen peroxide. Furthermore, 7-hydroxy-based chemosensors may serve as a highly selective tool for Al3+ and Hg2+ detection in biological systems. This review is devoted to a summary of the research on umbelliferone and its synthetic derivatives in terms of biological and pharmaceutical properties, especially those reported in the literature during the period of 2017-2023. Future potential applications of umbelliferone and its synthetic derivatives are presented.

Comparative Study of Organics Removal from Refinery Wastewater by Photocatalytic Fenton Reaction Coupled with Visible Light and Ultraviolet Irradiation

The study investigates photocatalytic advanced oxidation processes using iron-doped zeolite catalysts in heterogeneous Fenton reactions to degrade organic contents as chemical oxygen demand. The research revealed that the heterogenous photocatalytic Fenton process was the most successful treatment method under acidic circumstances and generated a greater rate of chemical oxygen demand degradation in a concise amount of radiation time. Compared to the heterogenous Fenton process with ultraviolet irradiation, it increased oxidation and was affected by catalyst load, power of hydrogen pH, hydrogen peroxide amounts, and temperature. The findings showed that the iron-doped zeolite catalyst, pH, and temperature significantly degraded the chemical oxygen demand. The experiment determined that the optimal conditions were obtained at a catalyst load of 0.07 g, pH of 3, with 20% excess of hydrogen peroxide, 40 °C in 2 hours for the ultraviolet/ iron-doped zeolite/hydrogen peroxide system that gave 99.84 % of the removal of the chemical oxygen demand. The heterogeneous photocatalytic Fenton method accompanied the reactions by hydroxyl radical production, which quickly reached its maximal reduction.

Palladium-based multifunctional nanoparticles for combined chemodynamic/photothermal and calcium overload therapy of tumors.

Due to the high mortality and incidence rates associated with tumors and the specificity of the tumor microenvironment (TME), it is difficult to achieve a complete cure for tumors using a single therapy. In this study, calcium carbonate-modified palladium hydride nanoparticles (PdH@CaCO3) were prepared and utilized for the combined treatment of tumors through chemodynamic therapy (CDT)/photothermal therapy (PTT) and calcium overload therapy. After entering tumor cells, PdH@CaCO3 releases calcium ions (Ca2+) and PdH once it reaches the TME due to the pH reactivity of the calcium carbonate coating. The mitochondrial membrane potential is lowered by the Ca2+, leading to irreversible cell damage. Meanwhile, PdH reacts with excessive hydrogen peroxide (H2O2) in the TME via the Fenton reaction, generating hydroxyl radicals (·OH). Moreover, PdH is an excellent photothermal agent that can kill tumor cells under laser irradiation, leading to significant anti-tumor effects. In vitro and in vivo studies have demonstrated that PdH@CaCO3 could combine CDT/PTT and calcium overload therapy, exhibiting great clinical potential in the treatment of tumors.

Beneficial Effect of Acetic Acid on the Formation of FeIII(OOH) Species and on the Catalytic Activity of Bioinspired Nonheme FeII Complexes.

AbstractThree new amine/pyridine FeII complexes bearing pentadentate ligand with one, two or three electron enriched 4‐methoxy‐3,5‐dimethylpyridine were used as catalysts for the oxidation of small organic molecules by hydrogen peroxide. The distribution of products formed suggests that these ligands are not enough electron donating to promote the O−O heterolytic cleavage of the oxidant in order to generate selective FeV(O) species. Using acetic acid in the reaction mixtures results in a significant increase of the efficiency of these catalytic systems. Our investigations show that the use of AcOH leads to the protonation/dissociation of a pyridyl moiety and the formation of (N4)FeII(OAc)(OH) species. These complexes readily react with excess hydrogen peroxide to yield (N4)FeIII(OAc)(OOH) intermediates. These latter intermediates are proposed to evolve into (N4)FeIV(OAc)(O), which are more efficient than the usual (N4)FeIV(O) and (N5)FeIV(O).

Tetrahydrobiopterin as a Trigger for Vitiligo: Phototransformation during UV Irradiation.

Vitiligo is a type of hypomelanosis. Tetrahydrobiopterin (H4Bip), the coenzyme of the initial stage of melanogenesis, appears to be a trigger for vitiligo. H4Bip is present in vitiligo in 3-5-fold excess and causes oxidative stress by triggering an autocatalytic cycle of excess hydrogen peroxide synthesis. Using quantum-chemical calculations, we have evaluated the possibility of H4Bip reactions occurring in the dark and under ultraviolet (UV) irradiation, including the formation of dihydropterin dimers. In order to simulate the oxidative stress, oxidative modification of human serum albumin (HSA) has been carried out in the presence of excessive H4Bip using the fluorescence method. The fraction of oxidized protein (FOP) has been calculated. It has been established that there is a strong oxidative modification of amino acids chromophores (tryptophan and tyrosine) in the protein (FOP 0.64). Under UV irradiation of the system (HSA + H4Bip), FOP is reduced to 0.39. Apparently, a part of H4Bip transforms into dihydropterin dimers and does not participate in the oxidative modification of the protein. The data on oxidative modification of HSA are consistent with dynamic light scattering: H4Bip promotes HSA aggregation with the formation of particles with a hydrodynamic radius Rh ≥ 2000 nm, which can become immunogenic.

Stability and kinetics of iron‐terephthalate MOFs with diverse structures in aqueous pollutant degradation

AbstractSynthesized iron‐terephthalate metal–organic frameworks (MOFs), MIL‐101 and MOF‐235, with contrasting morphologies are examined to elucidate the role of structural arrangement in catalytic aqueous pollutant degradation. MIL‐101 demonstrates a larger pseudo‐first order rate constant than MOF‐235 (3.5 ± 0.2 molFe−1·s−1 vs. 0.84 ± 0.07 molFe−1·s−1) toward oxidation of methylene blue (MB) dye with excess hydrogen peroxide at ambient temperature, likely due to intrinsic differences in ligand coordination at their metal nodes. However, despite continued activity upon reuse, both MOFs undergo structural alterations resulting in formation of leached species active for MB degradation that have been obfuscated in previous studies. Detailed stability testing and ex situ characterization of recovered catalyst, examinations that remain underreported in Fe‐MOF studies for pollutant oxidation, indicate that water plays a prominent role in the breakdown of these frameworks. Collectively, this work informs the interpretation and use of common Fe‐MOFs for aqueous applications, relating material changes to observed reaction phenomena.

Tumor-targeted bioactive nanoprobes visualizing of hydrogen peroxide for forecasting chemotherapy-exacerbated malignant prognosis.

Introduction: Fluorescent visualization of hydrogen peroxide in the tumor microenvironment (TME) is conducive to predicting malignant prognosis after chemotherapy. Two photon microscopy has been employed for in vivo hydrogen peroxide detection owing to its advantages of deep penetration and low phototoxicity. Methods: In this study, a two-photon fluorescent probe (TPFP) was protected by mesoporous silica nanoparticles (MSNs) and masked by cloaking the cancer cell membranes (CM), forming a tumor-targeted bioactive nanoprobe, termed MSN@TPFP@CM. Results: This multifunctional nanoprobe allowed for the effective and selective detection of excessive hydrogen peroxide production in chemotherapeutic Etoposide (VP-16)-challenged tumor cells using two-photon microscopy. After specific accumulation in tumors, VP-16-MSN@TPFP@CM monitored tumor-specific hydrogen peroxide levels and revealed a positive correlation between oxidative stress in the TME and chemotherapy-exacerbated malignant prognosis. Discussion: Given the recent translation of fluorescent imaging into early clinical trials and the high biocompatibility of bioactive nanoprobes, our approach may pave the way for specific imaging of oxidative stress in solid tumors after treatment and provide a promising technology for malignant prognosis predictions.

FRIENDLY is required for efficient dark-induced mitophagy and controlled senescence in Arabidopsis.

Mitochondria play essential roles in plant metabolism, supporting both development and stress responses. To maintain a healthy pool of mitochondria, several quality control systems are in place. Selected degradation of mitochondria by autophagy -mitophagy- has been extensively studied in yeast and animals, but information on mitophagy components in plants is limited. The 'Friendly Mitochondria' (FRIENDLY; FMT) protein, homologous to 'clustered mitochondria protein homolog' CLU in animals, was recently suggested to mediate mitophagy of depolarized mitochondria. In this study, we evaluated the role of FMT in carbon starvation- and dark senescence-induced mitophagy in Arabidopsis. Using mitophagy flux assays, we show that loss of FMT results in decreased mitophagy during dark-induced senescence. Mitophagy induced by inhibition of Target of Rapamycin (TOR) signalling is also partially impaired in fmt mutants. The FMT protein is mostly localised in the cytosol, but we show that during darkness FMT is redistributed into speckles, some of which associate with mitochondria. Fmt mutants were initially identified for their abnormal mitochondrial morphology, with mitochondria often forming clusters. We found that dark senescence strongly increases the number and size of mitochondrial clusters in fmt mutants. In agreement with a role for FMT in mitophagy, we show that fmt mutants show accelerated senescence phenotypes comparable to autophagy 11 (atg11) mutants, but less prominent than in atg5 mutants. Furthermore, FMT prevents excessive dark-induced cell death and hydrogen peroxide production, and supports mitophagy and greening in etiolated seedlings. Our findings thus indicate that FMT contributes to mitophagy and provide evidence that mitophagy is required for controlled senescence and prevention of accelerated cell death. We propose that FMT mediates efficient mitophagy by preventing mitochondrial clustering, thereby allowing mitochondria to be captured more effectively by autophagosomes, rather than by acting as a direct mitophagy receptor.

The role of the distal cavity in carbon monoxide stabilization in the coproheme decarboxylase enzyme from C. diphtheriae

This work focuses on the carbon monoxide adducts of the wild-type and selected variants of the coproheme decarboxylase from actinobacterial Corynebacterium diphtheriae complexed with coproheme, monovinyl monopropionyl deuteroheme (MMD), and heme b. The UV − vis and resonance Raman spectroscopies together with the molecular dynamics simulations clearly show that the wild-type coproheme-CO adduct is characterized by two CO conformers, one hydrogen-bonded to the distal H118 residue and the other showing a weak polar interaction with the distal cavity. Instead, upon conversion to heme b, i.e. after decarboxylation of propionates 2 and 4 and rotation by 90o of the porphyrin ring inside the cavity, CO probes a less polar environment. In the absence of the H118 residue, both coproheme and heme b complexes form only the non-H-bonded CO species. The unrotated MMD-CO adduct as observed in the H118F variant, confirms that decarboxylation of propionate 2 only, does not affect the heme cavity. The rupture of both the H-bonds involving propionates 2 and 4 destabilizes the porphyrin inside the cavity with the subsequent formation of a CO adduct in an open conformation. In addition, in this work we present data on CO binding to reversed heme b, obtained by hemin reconstitution of the H118A variant, and to heme d, obtained by addition of an excess of hydrogen peroxide. The results will be discussed and compared with those reported for the representatives of the firmicute clade.

Colorimetric and fluorescent dual-signals probes for naked-eye detection of hydrogen peroxide and applications in milk samples and in vivo

Excessive residual hydrogen peroxide (H2O2) disinfectant in food is harmful to human health. Therefore, it is necessary to develop efficient detection methods for H2O2 detection. In this work, we designed and synthesized five D-A molecules 3a-3e by introducing electron-donor substituents (–OCH3 and –CH3) to the electron-acceptor dicyanoisophorone skeleton in order to find out the suitable probes for H2O2 detection. Among them, two promising probes, 3a and 3c, are screened out according to structure-property relationships. Based on the principle of intramolecular charge transfer (ICT), 3a and 3c express colorimetric and fluorescent dual-signals towards H2O2 with low detection limits (0.20 μM and 0.14 μM) and rapid response (within 20 mins). The reaction mechanism between probes and H2O2 is determined by 1H NMR and HRMS. Density functional theory (DFT) calculations are measured to study the regulation mechanism of structure adjustment on probs performance. Furthermore, a smartphone RGB analysis is utilized as a portable platform for the quantitative detection of H2O2 without complicated instruments, indicating a high efficiency and on-site detection method for H2O2. In addition, probes are applied to detect H2O2 in milk samples, HepG-2 cells and zebrafish, suggesting the promising applications in food samples and physiological systems.

Evaluating the grafting of Maleic anhydride with Poly(lactic acid) (PLA) and Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) via batch compounding

Maleic anhydride (MA) was grafted to Poly(lactic acid) (PLA) and Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) at twelve different content ratios by batch compounding method. The rheology, morphology and grafting possibilities of blend components were analysed. It was found that excessive peroxide content can cause chain scission and chain shortening in the blend which produces a porous structure with inferior mechanical properties. The addition of MA increases the degradation rate of the blend. MA increased the dispersity and interfacial adhesion of PHBV phase within PLA phase.

Large-Scale Qualitative and Quantitative Assessment of Dityrosine Crosslinking Omics in Response to Endogenous and Exogenous Hydrogen Peroxide in Escherichia coli.

Excessive hydrogen peroxide causes oxidative stress in cells. The oxidation of two tyrosine residues in proteins can generate o,o'-dityrosine, a putative biomarker for protein oxidation, which plays critical roles in a variety of organisms. Thus far, few studies have investigated dityrosine crosslinking under endogenous or exogenous oxidative conditions at the proteome level, and its physiological function remains largely unknown. In this study, to investigate qualitative and quantitative dityrosine crosslinking, two mutant Escherichia coli strains and one mutant strain supplemented with H2O2 were used as models for endogenous and exogenous oxidative stress, respectively. By integrating high-resolution liquid chromatography-mass spectrometry and bioinformatic analysis, we created the largest dityrosine crosslinking dataset in E. coli to date, identifying 71 dityrosine crosslinks and 410 dityrosine loop links on 352 proteins. The dityrosine-linked proteins are mainly involved in taurine and hypotaurine metabolism, citrate cycle, glyoxylate, dicarboxylate metabolism, carbon metabolism, etc., suggesting that dityrosine crosslinking may play a critical role in regulating the metabolic pathways in response to oxidative stress. In conclusion, we have reported the most comprehensive dityrosine crosslinking in E. coli for the first time, which is of great significance in revealing its function in oxidative stress.

Design of a highly efficient Cu-based catalyst with two functional areas: The role of Cu0 and oxygen vacancies in Fenton-like system

In Fenton process, excess hydrogen peroxide (H2O2) was usually input into reaction systems to achieve high reaction efficiency, which has become one of the development bottlenecks for applications. Herein, a novel strategy for designing Cu catalyst (G-Cu) with two functional regions (zero-valent copper (Cu0) and oxygen vacancies (OVs)) was proposed to mitigate this problem. Experimental results and DFT calculation results collaboratively verified that Cu0 sites were able to produce H2O2 in situ through activating dissolved oxygen (DO), thereby reducing the input of H2O2. Meanwhile, the presence of OVs could improve the electron transfer capability of material and lengthen the O-O bond of H2O2, thus promoting the activation of H2O2 over catalyst surface. As a result, G-Cu achieved higher oxytetracycline (OTC) degradation efficiency (89.2%) than unmodified Cu catalyst (28.29%) at a small dosage of H2O2 (5 mM), in which OH, O2−, and 1O2 were involved in the degradation process. Meanwhile, this system could operate well in a broad pH range (3–11), which had a certain possibility in practical application. In a word, this work offers a valuable strategy for reducing the input of H2O2 in Fenton process.

NO and GSH Alleviate the Inhibition of Low-Temperature Stress on Cowpea Seedlings.

Low-temperature stress in early spring seriously affects the growth and development of cowpea seedlings. To study the alleviative effect of the exogenous substances nitric oxide (NO) and glutathione (GSH) on cowpea (Vigna unguiculata (Linn.) Walp.) seedlings under 8 °C low-temperature stress, 200 μmol·L-1 NO and 5 mmol·L-1 GSH were sprayed on cowpea seedlings whose second true leaf was about to unfold to enhance the tolerance of cowpea seedlings to low temperature. Spraying NO and GSH can eliminate excess superoxide radicals (O2-) and hydrogen peroxide (H2O2) to varying degrees, reduce the content of malondialdehyde and relative conductivity, delay the degradation of photosynthetic pigments, increase the content of osmotic regulating substances such as soluble sugar, soluble protein, and proline, and improve the activity of antioxidant enzymes such as superoxide dismutase, peroxidase, catalase, ascorbate peroxidase, dehydroascorbate reductase, and monodehydroascorbate reductase. This study revealed that the mixed use of NO and GSH played an important role in alleviating low temperature stress, and the effect of spraying NO alone was better than that of spraying GSH.

The Novel Chiral 2(5H)-Furanone Sulfones Possessing Terpene Moiety: Synthesis and Biological Activity.

Over the past decades, 2(5H)-furanone derivatives have been extensively studied because of their promising ability to prevent the biofilm formation by various pathogenic bacteria. Here, we report the synthesis of a series of optically active sulfur-containing 2(5H)-furanone derivatives and characterize their biological activity. Novel thioethers were obtained by an interaction of stereochemically pure 5-(l)-menthyloxy- or 5-(l)-bornyloxy-2(5H)-furanones with aromatic thiols under basic conditions. Subsequent thioethers oxidation by an excess of hydrogen peroxide in acetic acid resulted in the formation of the corresponding chiral 2(5H)-furanone sulfones. The structure of synthesized compounds was confirmed by IR and NMR spectroscopy, HRMS, and single crystal X-ray diffraction. The leading compound, 26, possessing the sulfonyl group and l-borneol moiety, exhibited the prominent activity against Staphylococcus aureus and Bacillus subtilis with MICs of 8 μg/mL. Furthermore, at concentrations of 0.4-0.5 μg/mL, the sulfone 26 increased two-fold the efficacy of aminoglycosides gentamicin and amikacin against S. aureus. The treatment of the model-infected skin wound in the rat with a combination of gentamicin and sulfone 26 speeded up the bacterial decontamination and improved the healing of the wound. The presented results provide valuable new insights into the chemistry of 2(5H)-furanone derivatives and associated biological activities.

Mitochondrial Hydrogen Peroxide Activates PTEN and Inactivates Akt Leading to Autophagy Inhibition-Dependent Cell Death in Neuronal Models of Parkinson's Disease.

Defective autophagy relates to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. Our recent study has demonstrated that PD toxins (6-OHDA, MPP+, or rotenone) induce neuronal apoptosis by impeding the AMPK/Akt-mTOR signaling. Here, we show that treatment with 6-OHDA, MPP+, or rotenone triggered decreases of ATG5/LC3-II and autophagosome formation with a concomitant increase of p62 in PC12, SH-SY5Y cells, and primary neurons, suggesting inhibition of autophagy. Interestingly, overexpression of wild-type ATG5 attenuated the inhibitory effect of PD toxins on autophagy, reducing neuronal apoptosis. The effects of PD toxins on autophagy and apoptosis were found to be associated with activation of PTEN and inactivation of Akt. Overexpression of dominant negative PTEN, constitutively active Akt and/or pretreatment with rapamycin rescued the cells from PD toxins-induced downregulation of ATG5/LC3-II and upregulation of p62, as well as consequential autophagosome diminishment and apoptosis in the cells. The effects of PD toxins on autophagy and apoptosis linked to excessive intracellular and mitochondrial hydrogen peroxide (H2O2) production, as evidenced by using a H2O2-scavenging enzyme catalase, a mitochondrial superoxide indicator MitoSOX and a mitochondria-selective superoxide scavenger Mito-TEMPO. Furthermore, we observed that treatment with PD toxins reduced the protein level of Parkin in the cells. Knockdown of Parkin alleviated the effects of PD toxins on H2O2 production, PTEN/Akt activity, autophagy, and apoptosis in the cells, whereas overexpression of wild-type Parkin exacerbated these effects of PD toxins, implying the involvement of Parkin in the PD toxins-induced oxidative stress. Taken together, the results indicate that PD toxins can elicit mitochondrial H2O2, which can activate PTEN and inactivate Akt leading to autophagy inhibition-dependent neuronal apoptosis, and Parkin plays a critical role in this process. Our findings suggest that co-manipulation of the PTEN/Akt/autophagy signaling by antioxidants may be exploited for the prevention of neuronal loss in PD.

Genome-wide analysis of Catalase gene family reveal insights into abiotic stress response mechanism in Brassica juncea and B. rapa.

Environmental stresses affect the yield and productivity of Brassica crops. Catalases are important antioxidant enzymes involved in reducing excess hydrogen peroxide produced by environmental stresses. In the present study, nine and seven CAT family members in two oilseed Brassica species (B. juncea and B. rapa) were identified with complete characterization based on gene and protein structure. Phylogenetic classification categorized CAT proteins into three classes and differentiated the monocot and dicot-specific CAT proteins. Further, the gene and protein characterizations revealed a high degree of conservation across the CAT family members. Differences were observed in the CAT-HEME binding affinity in CAT1, CAT2, and CAT3 isozymes, which could suggest their differential enzyme activities in different conditions. Furthermore, protein-protein interaction with other antioxidant proteins suggested their coordinated role in ROS scavenging mechanisms. Notably, the differential gene expression of BjuCATs and BraCATs and CAT enzyme activities suggested their crucial roles in major abiotic stresses faced by Brassica species. Promoter analysis in BjuCATs and BraCATs suggested the presence of abiotic-stress responsive cis-regulatory elements. Gene regulatory network analysis suggested miRNA and TF mediated stress response in BjuCATs and BraCATs. CAT family screening and characterization in Brassica sp. has established a basic ground for further functional validation in abiotic and heavy-metal stresses which can help in developing stress tolerant crops.

Implantable 3D Printed Hydrogel Scaffolds Loading Copper-Doxorubicin Complexes for Postoperative Chemo/Chemodynamic Therapy

Biomaterial-based implants hold great potential for postoperative cancer treatment due to the enhanced drug dosage at the disease site and decreased systemic toxicity. However, the elaborate design of implants to avoid complicated chemical modification and burst release remains challenging. Herein, we report a three-dimensional (3D) printed hydrogel scaffold to enable sustained release of drugs for postoperative synergistic cancer therapy. The hydrogel scaffold is composed of Pluronic F127 and sodium alginate (SA) as well as doxorubicin (DOX) and copper ions (F127-SA/Cu-DOX hydrogel scaffold). Benefiting from the coordination of Cu(II) with both SA and DOX, burst release of DOX can be overcome, and prolonged release time can be achieved. The therapeutic efficiency can be adjusted by altering the amount of DOX and Cu(II) in the scaffolds. Moreover, apoptosis and ferroptosis of cancer cells can be induced through the combination of chemotherapy and chemodynamic therapy. In addition, DOX supplies excess hydrogen peroxide to enhance the efficiency of Cu-based chemodynamic therapy. When implanted in the resection site, hydrogel scaffolds effectively inhibit tumor growth. Overall, this study may offer a new strategy for fabricating local implants with synergistic therapeutic performance for preventing postoperative cancer recurrence.

Intelligent manganese dioxide nanocomposites induce tumor immunogenic cell death and remould tumor microenvironment

The solid tumor often has unique structure and microenvironment that quite different with normal tissue. The tumor microenvironment (TME) of solid tumor is often characterized by mild acid, high glutathione (GSH) level, excessive hydrogen peroxide (H2O2) and hypoxia. These characteristics not only accelerate tumor progression, angiogenesis and metastasis, but also lead to drug resistance and treatment failure. To regulate these adverse factors in TME plays vital roles in improving tumor response to various treatments. In this study, a silk fibroin-cRGDfk-Ce6 conjugate-based MnO2 nanocomposite (SRCM) was fabricated, and its modulation potentials of these adverse factors, enhanced immune cell activation and infiltration in TME were systematically studied in vitro and in vivo. After administration in vivo, the synthesized SRCM quickly targeted to acidic TME, reduced to ultra-small nanosheets and Mn2+, triggered the endogenous H2O2 decomposition and oxygen generation, and converted GSH into GSSG. Therefore, to modulate the adverse factors in TME, while Mn2+ simultaneously enhanced the magnetic resonance imaging (MRI) capability. Together with photodynamic therapy (PDT) and photothermal therapy (PTT), the SRCM effectively induced immunogenic cell death (ICD), antigen-presenting cell (APC) activation, and improved immune-competent cell infiltration. The results demonstrated that the SRCM not only alleviated hypoxia in TME, enhanced PDT efficacy, but also efficiently induced the IDC of tumor cells, corrected the adverse physical, chemical and biological factors in TME, thereby effectively reducing the tumor burden in animal model.