Tumor microenvironment-activated theranostic nanoreactor for NIR-II Photoacoustic imaging-guided tumor-specific photothermal therapy.

Theranostic agents that can be sensitively and specifically activated by the tumor microenvironment (TME) have recently attracted considerable attention. In this study, TME-activatable 3,3',5,5'-tetramethylbenzidine (TMB)-copper peroxide (CuO2)@poly(lactic-co-glycolic acid) (PLGA)@red blood cell membrane (RBCM) (TCPR) nanoparticles (NPs) for second near-infrared photoacoustic imaging-guided tumor-specific photothermal therapy were developed by co-loading CuO2 NPs and TMB into PLGA camouflaged by RBCMs. As an efficient H2O2 supplier, once exposed to a proton-rich TME, CuO2 NPs can generate H2O2 and Cu2+, which are further reduced to Cu+ by endogenous glutathione. Subsequently, the Cu+-mediated Fenton-like reaction produces cytotoxic ·OH to kill the cancer cells and induce TMB-mediated photoacoustic and photothermal effects. Combined with the RBCM modification-prolonged blood circulation, TCPR NPs display excellent specificity and efficiency in suppressing tumor growth, paving the way for more accurate, safe, and efficient cancer theranostics.

Characterization and toxicological potential of Alternaria alternata associated with post-harvest fruit rot of Prunus avium in China.

Post-harvest fruit rot caused by Alternaria species is one of the most important threats to the fruit industry. Post-harvest rot on sweet cherry (Prunus avium) fruit was observed in the fruit markets of the Haidian district of Beijing, China. The fungal isolates obtained from the infected sweet cherry fruits matched the descriptions of Alternaria alternata based on the morphology and multi-gene (ITS, endo-PG, and Alta1) sequence analysis. Pathogenicity tests indicated that ACT-3 was the most virulent isolate, exhibiting typical post-harvest fruit rot symptoms. Physiological studies revealed that the optimal conditions for the growth of ACT-3 were temperature of 28°C, water activity of 0.999, and pH of 8 with 87, 85, and 86 mm radial growth of ACT-3 on a potato dextrose agar (PDA) medium, respectively, at 12 days post-inoculation (dpi). Moreover, the fungus showed the highest growth on a Martin agar medium (MAM) modified (85 mm) and a PDA medium (84 mm) at 12 dpi. The proliferation of the fungus was visualized inside the fruit tissues by confocal and scanning electron microscope (SEM), revealing the invasion and destruction of fruit tissues. Alternaria mycotoxins, tenuazonic acid (TeA), and alternariol (AOH) were detected in five representative isolates by HPLC analysis. The highest concentrations of TeA (313 µg/mL) and AOH (8.9 µg/mL) were observed in ACT-6 and ACT-3 isolates, respectively. This study is the first to present a detailed report on the characteristics and proliferation of A. alternata associated with sweet cherry fruit rot and the detection of toxic metabolites.

Thiourea-Cu(OTf)2/NIS-synergistically promoted stereoselective glycoside formation with 2-azidoselenoglycosides or thioglycosides as donors.

A novel promoter system for glycosylation is described. A catalytic amount of thiourea and Cu(OTf)2 together with a slight excess of N-iodosuccinimide synergistically promotes glycosylation at room temperature. The combination of reagents applies to some 2-azidoselenoglycoside and thioglycoside donors. A wide range of alcoholic acceptors underwent smooth conversion to O-(2-azido)glycosides with good stereoselectivities. In addition, the value of this method has been highlighted by its convenient operation and outstanding functional group compatibility.

P7C3-A20 treats traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.

Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain. 3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine (P7C3-A20) can be neuroprotective in various diseases, including ischemic stroke and neurodegenerative diseases. However, whether P7C3-A20 has a therapeutic effect on traumatic brain injury and its possible molecular mechanisms are unclear. Therefore, in the present study, we investigated the therapeutic effects of P7C3-A20 on traumatic brain injury and explored the putative underlying molecular mechanisms. We established a traumatic brain injury rat model using a modified weight drop method. P7C3-A20 or vehicle was injected intraperitoneally after traumatic brain injury. Severe neurological deficits were found in rats after traumatic brain injury, with deterioration in balance, walking function, and learning memory. Furthermore, hematoxylin and eosin staining showed significant neuronal cell damage, while terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining indicated a high rate of apoptosis. The presence of autolysosomes was observed using transmission electron microscope. P7C3-A20 treatment reversed these pathological features. Western blotting showed that P7C3-A20 treatment reduced microtubule-associated protein 1 light chain 3-II (LC3-II) autophagy protein, apoptosis-related proteins (namely, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 [BNIP3], and Bcl-2 associated x protein [Bax]), and elevated ubiquitin-binding protein p62 (p62) autophagy protein expression. Thus, P7C3-A20 can treat traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.

A preliminary study on the pathology and molecular mechanism of fumonisin B1 nephrotoxicity in young quails.

Fumonisin B1 (FB1) is a widely present mycotoxin that accumulates in biological systems and poses a health risk to animals. However, few studies have reported the molecular mechanism by which FB1 induces nephrotoxicity. The aim of this study was to assess the extent of nephrotoxicity during FB1 exposure and the possible molecular mechanisms behind it. Therefore, 180 young quails were equally divided into two groups. The control group was fed typical quail food, while the experimental group was fed quail food containing 30 mg·kg-1 FB1. Various parameters were assessed, which included histopathological, ultrastructural changes, levels of biochemical parameters, oxidative indicators, inflammatory factors, possible target organelles mitochondrial and endoplasmic reticulum (ER)-related factors, nuclear xenobiotic receptors (NXR) response, and cytochrome P450 system (CYP450s)-related factors in the kidneys on days 14, 28, and 42. The results showed that FB1 can induce oxidative stress through NXR response and disorder of the CYP450s system, leading to mitochondrial dysfunction and ER stress, promoting the expression of inflammatory factors (including IL-1ß, IL-6, and IL-8) and causing kidney damage. This study elucidated the possible molecular mechanism by which FB1 induces nephrotoxicity in young quails.

Correction: A H2O2 self-sufficient nanoplatform with domino effects for thermal-responsive enhanced chemodynamic therapy.

[This corrects the article DOI: 10.1039/C9SC05506A.].

Selenium-rich yeast counteracts the inhibitory effect of nanoaluminum on the formation of porcine neutrophil extracellular traps.

Aluminum is widely used in daily life due to its excellent properties. However, aluminum exposure to the environment severely threatens animal and human health. Conversely, selenium (Se) contributes to maintaining the balance of the immune system. Neutrophils exert immune actions in several ways, including neutrophil extracellular traps (NETs) that localize and capture exogenous substances. Despite the recent investigations on the toxic effects of aluminum and its molecular mechanisms, the immunotoxicity of aluminum nanoparticles on pigs and the antagonistic effect of selenium on aluminum toxicity are poorly understood. Here, we treated porcine peripheral blood neutrophils with zymosan for 3 h to induce NETs formation. Then, we investigated the effect of nanoaluminum on NETs formation in pigs and its possible molecular mechanisms. Microscopy observations revealed that NETs formation was inhibited by nanoaluminum. Using a multifunctional microplate reader, the production of extracellular DNA and the burst of reactive oxygen species (ROS) in porcine neutrophils were inhibited by nanoaluminum. Western blot analyses showed that nanoaluminum caused changes in amounts of cellular selenoproteins. After Se supplementation, the production of porcine NETs, the burst of ROS, and selenoprotein levels were restored. This study indicated that nanoaluminum inhibited the zymosan-induced burst of ROS and release of NETs from porcine neutrophils, possibly through the selenoprotein signaling pathway. In contrast, Se supplementation reduced the toxic effects of nanoaluminum and restored NETs formation.

Biocontrol potential of lipopeptides produced by the novel Bacillus subtilis strain Y17B against postharvest Alternaria fruit rot of cherry.

The use of synthetic fungicides against postharvest Alternaria rot adversely affects human health and the environment. In this study, as a safe alternative to fungicides, Bacillus subtilis strain Y17B isolated from soil exhibited significant antifungal activity against Alternaria alternata. Y17B was identified as B. subtilis based on phenotypic identification and 16S rRNA sequence analysis. To reveal the antimicrobial activity of this strain, a PCR-based study detected the presence of antifungal lipopeptide (LP) biosynthetic genes from genomic DNA. UPLC Q TOF mass spectrometry analysis detected the LPs surfactin (m/z 994.64, 1022.68, and 1026.62), iturin (m/z 1043.56), and fengycin (m/z 1491.85) in the extracted LP crude of B. subtilis Y17B. In vitro antagonistic study demonstrated the efficiency of LPs in inhibiting A. alternata growth. Microscopy (SEM and TEM) studies showed the alteration of the morphology of A. alternata in the interaction with LPs. In vivo test results revealed the efficiency of LPs in reducing the growth of the A. alternata pathogen. The overall results highlight the biocontrol potential of LPs produced by B. subtilis Y17B as an effective biological control agent against A. alternata fruit rot of cherry.

Acute Aluminum Sulfate Triggers Inflammation and Oxidative Stress, Inducing Tissue Damage in the Kidney of the Chick.

In this study, a total of 20 7-day-old chicks were randomly divided into an experimental group and a control group. The experimental group was administered aluminum sulfate (Al2(SO4)3) once by gavage, and the control group was sacrificed after 24 h of fasting with distilled water. Serum and kidney tissue samples from both groups were collected and compared using hematoxylin-eosin staining (H&E) and microscopy. The Paller scores increased (p < 0.01) for biochemical kidney function, redox-related indicators, and mRNA expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) downstream related genes. The results showed that in the kidneys of the experimental group, renal tubular epithelial cells appeared to swell, and there was necrosis and shedding; the blood urea nitrogen (BUN) and uric acid (UA) decreased, serum creatinine (CREA) increased; nitric oxide (NO), glutathione (GSH), and malondialdehyde (MDA) contents increased; NO synthase (NOS), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) enzyme activities increased; tumor necrosis factor alpha (TNF-α), tumor necrosis factor receptor 1 (TNF-R1), tumor necrosis factor receptor 2 (TNF -R2), cyclooxygenase-2 (COX-2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and heme oxygenase-1 (HO-1) mRNA expression levels increased (p < 0.05 or p < 0.01); Nrf2, glutathione S-transferase A3 (GSTA3), glutathione-S-transferase mu-1 (GSTM1), glutathione synthetase (GSS), glutamate cysteine ligase (GCLC and GCLM), quinone oxidoreductase 1 (NQO1), and Kelch-like ECH-associated protein 1 (Keap1) mRNA expression levels decreased (p < 0.05 or p < 0.01) compared to the control group. Acute aluminum poisoning can cause obvious pathological changes in the structure of the kidney tissue of the chick, resulting in damage to the kidney function, as well as triggering inflammation and oxidative stress in the kidney.

The mechanisms of aluminum-induced immunotoxicity in chicks.

Aluminum (Al) is a ubiquitous environmental pollutant representing a significant global health hazard to human and animal health, including chicks. Al toxicity causes oxidative stress, leading to tissue injury, and consequently causes various diseases. NRF2 signaling is vital for protecting cells against oxidative stress. Nuclear xenobiotic receptors are activated by exogenous toxins, thereby inducing the transcription of cytochrome P450 enzyme systems (CYP450s) isoforms involved in xenobiotic metabolism and transport. However, little is known about Al-induced oxidative stress, nuclear xenobiotic receptors and fibrosis in chicks and the mechanisms involved. In this study, male chicks were treated with 0 mg/kg and 500 mg/kg Al2(SO4)3 to evaluate the mechanisms for Al-induced immunotoxicity. Histopathology revealed pathological injury, fibrin aggregation, disruption of the Nuclear Xenobiotic Receptors, and alteration of CYP450s homeostasis in Al-treated chicks due to oxidative stress. Notably, regulation of the NRF2 pathway and CYP450s and fibrosis-related genes was found to play a vital role in inhibiting immunotoxicity. This study provides new insights regarding the mechanisms of Al-induced immunotoxicity, including activation of the nuclear xenobiotic receptors, triggering oxidative stress, and altering the homeostasis of CYP450s in chicks. Further, it provides a theoretical basis for controlling Al exposure and highlights the importance of further studying its mechanisms to provide additional information for formulating preventive measures.

Modulating the Electronic Structures of Dual-Atom Catalysts via Coordination Environment Engineering for Boosting CO2 Electroreduction.

Dual-atom catalysts (DACs) have emerged as efficient electrocatalysts for CO2 reduction owing to the synergistic effect between the binary metal sites. However, rationally modulating the electronic structure of DACs to optimize the catalytic performance remains a great challenge. Herein, we report the electronic structure modulation of three Ni2 DACs (namely, Ni2 -N7 , Ni2 -N5 C2 and Ni2 -N3 C4 ) by the regulation of the coordination environments around the dual-atom Ni2 centres. As a result, Ni2 -N3 C4 exhibits significantly improved electrocatalytic activity for CO2 reduction, not only better than the corresponding single-atom Ni catalyst (Ni-N2 C2 ), but also higher than Ni2 -N7 and Ni2 -N5 C2 DACs. Density functional theory (DFT) calculations revealed that the high electrocatalytic activity of Ni2 -N3 C4 for CO2 reduction could be attributed to the electronic structure modulation to the Ni centre and the resulted proper binding energies to COOH* and CO* intermediates.

Fumonisin B1 promotes germ cells apoptosis associated with oxidative stress-related Nrf2 signaling in mice testes.

Fumonisins (FBs) are widespread Fusarium toxins commonly found in corn. This study aimed to establish the mechanism of oxidative stress via the Nrf2 signaling pathway associated with FB1-induced toxicity in mice testis. Male mice were fed with 5 mg/kg FB1 diet for 21 or 42 days, the expression of inflammatory related genes, apoptosis related genes and Nrf2 pathway genes were detected by RT-qPCR, Western blot and immunohistochemical. Furthermore, Sertoli cell was treatment with FB1. Cell viability was measured by CCK8 assay, ROS level and apoptosis related genes were detected by immunofluorescence staining. The results showed that FB1 had toxic effects on testis, which could increase the ROS level of Sertoli cells, affect the Keap1-Nrf2 pathway related factors, destroy the oxidative balance of testis, lead to the occurrence of inflammation and the initiation of apoptosis, and finally destroy the testicular tissue structure and affect the formation of sperm.

Antagonistic Effect of Selenium on Fumonisin B1 Promotes Neutrophil Extracellular Traps Formation in Chicken Neutrophils.

Neutrophils are an important component of the innate immune system, and one of their defense mechanisms, neutrophil extracellular traps (NETs), is a hot topic of the current research. This study explored the effects of fumonisin B1 (FB1) on chicken neutrophil production of NETs and its possible molecular mechanism of action. Scanning electron microscopy and fluorescence microscopy were used to observe morphological changes in neutrophils, and a fluorescence microplate reader was used to detect reactive oxygen species (ROS) and extracellular DNA release from neutrophils. Quantitative PCR (qPCR) and western blot were used to determine the expression levels of selenoproteins. The results indicate that FB1 inhibited the zymosan-induced formation of NETs in chicken neutrophils by preventing ROS burst and histone H3 (H3) and neutrophil elastase (NE) release. Moreover, the mRNA expression levels of glutathione peroxidase (GPX), thioredoxin reductase (TXNRD), and deiodinase (DIO) were downregulated in the FB1 group. The protein expression levels of GPX1, GPX2, GPX3, DIO3, and TXNRD1 were consistent with the changes in their gene expressions, suggesting an abnormal selenoprotein expression in response to the toxic effects of FB1. Conversely, selenium (Se) supplementation reduced the toxic effects of FB1 and restored the NETs formation, indicating that Se can be used as a potential drug to prevent and control FB1 toxicity in livestock farming.

Starvation, Ferroptosis, and Prodrug Therapy Synergistically Enabled by a Cytochrome c Oxidase like Nanozyme.

Nanozymes, which are inorganic nanomaterials mimicking natural enzyme activities, are bringing enormous opportunities to theranostics. Herein, a cytochrome c oxidase-like nanozyme (copper-silver alloy nanoparticle, Cu-Ag NP) is demonstrated for nanocatalytic cancer therapy. Loaded with bioreductive predrug (AQ4N), this Cu-Ag nanozyme unprecedentedly enables simultaneous starvation, ferroptosis, and chemical therapy with high specificity, and is able to totally eliminate tumor and greatly prolong the survival rate for 4T1-tumor-bearing mice. The underlying working mechanism is revealed both experimentally and theoretically.

POD Nanozyme optimized by charge separation engineering for light/pH activated bacteria catalytic/photodynamic therapy.

The current feasibility of nanocatalysts in clinical anti-infection therapy, especially for drug-resistant bacteria infection is extremely restrained because of the insufficient reactive oxygen generation. Herein, a novel Ag/Bi2MoO6 (Ag/BMO) nanozyme optimized by charge separation engineering with photoactivated sustainable peroxidase-mimicking activities and NIR-II photodynamic performance was synthesized by solvothermal reaction and photoreduction. The Ag/BMO nanozyme held satisfactory bactericidal performance against methicillin-resistant Staphylococcus aureus (MRSA) (~99.9%). The excellent antibacterial performance of Ag/BMO NPs was ascribed to the corporation of peroxidase-like activity, NIR-II photodynamic behavior, and acidity-enhanced release of Ag+. As revealed by theoretical calculations, the introduction of Ag to BMO made it easier to separate photo-triggered electron-hole pairs for ROS production. And the conduction and valence band potentials of Ag/BMO NPs were favorable for the reduction of O2 to ·O2-. Under 1064 nm laser irradiation, the electron transfer to BMO was beneficial to the reversible change of Mo5+/Mo6+, further improving the peroxidase-like catalytic activity and NIR-II photodynamic performance based on the Russell mechanism. In vivo, the Ag/BMO NPs exhibited promising therapeutic effects towards MRSA-infected wounds. This study enriches the nanozyme research and proves that nanozymes can be rationally optimized by charge separation engineering strategy.

Recent advances of cancer chemodynamic therapy based on Fenton/Fenton-like chemistry.

Applying Fenton chemistry in the tumor microenvironment (TME) for cancer therapy is the most significant feature of chemodynamic therapy (CDT). Owing to the mild acid and overexpressed H2O2 in TME, more cytotoxic hydroxyl radicals (˙OH) are generated in tumor cells via Fenton and Fenton-like reactions. Without external stimulus and drug resistance generation, reactive oxygen species (ROS)-mediated CDT exhibits a specific and desirable anticancer effect and has been seen as a promising strategy for cancer therapy. However, optimizing the treatment efficiency of CDT in TME is still challenging because of the limited catalytic efficiency of CDT agents and the strong cancer antioxidant capacity in TME. Hence, scientists are trying their best to design and fabricate many more CDT agents with excellent catalytic activity and remodeling TME for optimal CDT. In this perspective, the latest progress of CDT is discussed, with some representative examples presented. Consequently, promising strategies for further optimizing the efficiency of CDT guided by Fenton chemistry are provided. Most importantly, several feasible ways of developing CDT in the future are offered for reference.

Fumonisin B1 induces hepatotoxicity in mice through the activation of oxidative stress, apoptosis and fibrosis.

Fumonisin B1 (FB1) is a harmful environmental pollutant that induces hepatotoxicity, but the mechanism is still poorly understood. Therefore, the aim of this work was to investigate the effects of FB1 on the liver of mice and discover the underlying molecular mechanisms. A total of 40 male mice were exposed to 0 or 5 mg/kg FB1 for 42 days, and then, they were sacrificed, and the liver and blood were collected. Besides, AML12 cells were exposed to FB1. Biochemical and liver related indexes as well morphological changes, redox, apoptosis and fibrosis related markers were measured in liver and AML12 cells. The results showed that the liver function and biochemical indexes in the blood were changes, and the histopathological analysis indicated that FB1 exposure caused hepatic sinusoid atrophy, hemosiderosis, hepatocyte steatosis and fibrosis, finally inducing liver injury. Notably, a significant increase in the intracellular antioxidant enzymes SOD1, SOD2, NF-κB (p65), H2O2 and NO was found in FB1 exposed AML12 cells and liver tissues. In addition, TUNEL staining showed many apoptotic cells, and western blotting revealed a significant increase in the pro-apoptosis proteins. FB1 also induced liver fibrosis by triggering TGF-ß1/α-SMA/collagen/MMP signaling in the hepatocytes. Our results provide a novel explanation of the toxicological mechanism of action of FB1, which provoked oxidative stress, apoptosis and fibrosis in mice liver.

Fe3 O4 /Ag/Bi2 MoO6 Photoactivatable Nanozyme for Self-Replenishing and Sustainable Cascaded Nanocatalytic Cancer Therapy.

Catalytic cancer therapy based on nanozymes has recently attracted much interest. However, the types of the current nanozymes are limited and their efficiency is usually compromised and not sustainable in the tumor microenvironment (TME). Therefore, combination therapy involving additional therapeutics is often necessary and the resulting complication may jeopardize the practical feasibility. Herein, an unprecedented "all-in-one" Fe3 O4 /Ag/Bi2 MoO6 nanoparticle (FAB NP) is rationally devised to achieve synergistic chemodynamic, photodynamic, photothermal therapy with guidance by magnetic resonance, photoacoustic, and photothermal imaging. Based on its manifold nanozyme activities (mimicking peroxidase, catalase, superoxide dismutase, glutathione oxidase) and photodynamic property, cascaded nanocatalytic reactions are enabled and sustained in TME for outstanding therapeutic outcomes. The working mechanisms underlying the intraparticulate interactions, sustainability, and self-replenishment arising from the coupling between the nanocatalytic reactions and nanozyme activities are carefully revealed, providing new insights into the design of novel nanozymes for nanocatalytic therapy with high efficiency, good specificity, and low side effects.