Zinc-Iron Bimetallic Peroxides Modulate the Tumor Stromal Microenvironment and Enhance Cell Immunogenicity for Enhanced Breast Cancer Immunotherapy Therapy.

Immunotherapy has emerged as a potential approach for breast cancer treatment. However, the rigid stromal microenvironment and low immunogenicity of breast tumors strongly reduce sensitivity to immunotherapy. To sensitize patients to breast cancer immunotherapy, hyaluronic acid-modified zinc peroxide-iron nanocomposites (Fe-ZnO2@HA, abbreviated FZOH) were synthesized to remodel the stromal microenvironment and increase tumor immunogenicity. The constructed FZOH spontaneously generated highly oxidative hydroxyl radicals (·OH) that degrade hyaluronic acid (HA) in the tumor extracellular matrix (ECM), thereby reshaping the tumor stromal microenvironment and enhancing blood perfusion, drug penetration, and immune cell infiltration. Furthermore, FZOH not only triggers pyroptosis through the activation of the caspase-1/GSDMD-dependent pathway but also induces ferroptosis through various mechanisms, including increasing the levels of Fe2+ in the intracellular iron pool, downregulating the expression of FPN1 to inhibit iron efflux, and activating the p53 signaling pathway to cause the failure of the SLC7A11-GSH-GPX4 signaling axis. Upon treatment with FZOH, 4T1 cancer cells undergo both ferroptosis and pyroptosis, exhibiting a strong immunogenic response. The remodeling of the tumor stromal microenvironment and the immunogenic response of the cells induced by FZOH collectively compensate for the limitations of cancer immunotherapy and significantly enhance the antitumor immune response to the immune checkpoint inhibitor αPD-1. This study proposes a perspective for enhancing immune therapy for breast cancer.

Characterization, Structural Analysis, and Thermal Stability Mutation of a New Zearalenone-Degrading Enzyme Mined from Bacillus subtilis.

Zearalenone (ZEN) is a widespread mycotoxin that causes serious damage to animal husbandry and poses a threat to human health. A screen of ZEN-degrading soil bacteria yielded Bacillus subtilis YT-4, which yielded 80% ZEN degradation after 6 h and 95% after 36 h. The gene sequence encoding the degradative enzyme ZENY was mined from the genome of YT-4 and expressed in yeast. ZENY is an α/ß-hydrolase with an optimal enzyme activity at 37 °C and pH 8. By breaking the lactone ring of ZEN, it produces ZENY-C18H24O5 with a molecular weight of 320.16 g/mol. Sequence comparison and molecular docking analyses identified the catalytic ZENY triad 99S-245H-123E and the primary ZEN-binding mode within the hydrophobic pocket of the enzyme. To improve the thermal stability of the enzyme for industrial applications, we introduced a mutation at the N-terminus, specifically replacing the fifth residue N with V, and achieved a 25% improvement in stability at 45 °C. These findings aim to achieve ZEN biodegradation and provide insight into the structure and function of ZEN hydrolases.

Buffer solution induced highly crystalline sodium-rich Prussian blue for sodium storage.

In this work, we have developed an efficient method to synthesize Prussian blue by self-decomposition of sodium ferrocyanide in acetic acid-sodium acetate buffer solution. This buffer solution-based proton pool provides a relatively low and stable concentration of protons for the slow decomposition of sodium ferrocyanide to get highly crystalline and sodium rich Prussian blue, which can be used as the cathode for high-performance sodium-ion batteries.

Mechanism of inactivation of Aspergillus flavus spores by dielectric barrier discharge plasma.

Dielectric barrier discharge plasma (DBDP) displays strong against fungal spores, while its precise mechanism of spore inactivation remains inadequately understood. In this study, we applied morphological, in vivo and in vitro experiments, transcriptomics, and physicochemical detection to unveil the potential molecular pathways underlying the inactivation of Aspergillus flavus spores by DBDP. Our findings suggested that mycelium growth was inhibited as observed by SEM after 30 s treatment at 70 kV, meanwhile spore germination ceased and clustering occurred. It led to the release of cellular contents and subsequent spore demise by disrupting the integrity of spore membrane. Additionally, based on the transcriptomic data, we hypothesized that the induction of spore inactivation by DBDP might be associated with downregulation of genes related to cell membranes, organelles (mitochondria), oxidative phosphorylation, and the tricarboxylic acid cycle. Subsequently, we validated our transcriptomic findings by measuring the levels of relevant enzymes in metabolic pathways, such as superoxide dismutase, acetyl-CoA, total dehydrogenase, and ATP. These physicochemical indicators revealed that DBDP treatment resulted in mitochondrial dysfunction, redox imbalance, and inhibited energy metabolism pathways. These findings were consistent with the transcriptomic results. Hence, we concluded that DBDP accelerated spore rupture and death via ROS-mediated mitochondrial dysfunction, which does not depend on cell membranes.

Activation of Intestinal HIF2α Ameliorates Iron-Refractory Anemia.

In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG-4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin-activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5-fluorouracil-induced anemia, which can not be rescued by FG-4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia-related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.

Mining Lactonase Gene from Aflatoxin B1-Degrading Strain Bacillus megaterium and Degrading Properties of the Recombinant Enzyme.

Mycotoxins are toxic secondary metabolites mainly produced by filamentous fungal species that commonly contaminate food and feed. Aflatoxin B1 (AFB1) is extremely toxic and seriously threatens the health of humans and animals. In this work, the Bacillus megaterium HNGD-A6 was obtained and showed a 94.66% removal ability of AFB1 by employing extracellular enzymes as the degrading active substance. The degradation products were P1 (AFD1, C16H14O5) and P2 (C14H16N2O2), and their toxicity was greatly reduced compared to that of AFB1. The AttM gene was mined by BlastP comparison and successfully expressed in Escherichia coli BL21. AttM could degrade 86.78% of AFB1 at pH 8.5 and 80 °C, as well as 81.32% of ochratoxin A and 67.82% of zearalenone. The ability of AttM to degrade a wide range of toxins and its resistance to high temperatures offer the possibility of its use in food or feed applications.

Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis.

Given the rapidly aging population, aging-related diseases are becoming an excessive burden on the global healthcare system. Metformin has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. During the aging process, kidney function progressively declines. Currently, whether and how metformin protects the kidney remains unclear. In this study, among longevity drugs, including metformin, nicotinamide, resveratrol, rapamycin, and senolytics, we unexpectedly found that metformin, even at low doses, exacerbated experimentally-induced acute kidney injury (AKI) and increased mortality in mice. By single-cell transcriptomics analysis, we found that death of renal parenchymal cells together with an expansion of neutrophils occurs upon metformin treatment after AKI. We identified programmed cell death by ferroptosis in renal parenchymal cells and blocking ferroptosis, or depleting neutrophils protects against metformin-induced nephrotoxicity. Mechanistically, upon induction of AKI, ferroptosis in renal parenchymal cells initiates the migration of neutrophils to the site of injury via the surface receptor CXCR4-bound to metformin-iron-NGAL complex, which results in NETosis aggravated AKI. Finally, we demonstrated that reducing iron showed protective effects on kidney injury, which supports the notion that iron plays an important role in metformin-triggered AKI. Taken together, these findings delineate a novel mechanism underlying metformin-aggravated nephropathy and highlight the mechanistic relationship between iron, ferroptosis, and NETosis in the resulting AKI.

Targeting ferroptosis opens new avenues for the development of novel therapeutics.

Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, diseases involving tissue and/or organ injury, and inflammatory and infectious diseases. Although the precise regulatory networks that underlie ferroptosis are largely unknown, particularly with respect to the initiation and progression of various diseases, ferroptosis is recognized as a bona fide target for the further development of treatment and prevention strategies. Over the past decade, considerable progress has been made in developing pharmacological agonists and antagonists for the treatment of these ferroptosis-related conditions. Here, we provide a detailed overview of our current knowledge regarding ferroptosis, its pathological roles, and its regulation during disease progression. Focusing on the use of chemical tools that target ferroptosis in preclinical studies, we also summarize recent advances in targeting ferroptosis across the growing spectrum of ferroptosis-associated pathogenic conditions. Finally, we discuss new challenges and opportunities for targeting ferroptosis as a potential strategy for treating ferroptosis-related diseases.

Porous Graphitic phase carbon nitride/graphene oxide hydrogel microspheres for efficient and recyclable degradation of aflatoxin B1 in peanut oil.

Removal of aflatoxin is an urgent issue in agricultural products. A porous graphitic carbon nitride/graphene oxide hydrogel microsphere (CN/GO/SA) was synthesized and used to degrade AFB1 in peanut oil. CN/GO/SA was characterized by scanning electron micrograph (SEM), X-ray diffraction (XRD) and FT-IR. The introduction of GO significantly improved the adsorption capacity and visible light activity of photocatalysts. About 98.4% AFB1 in peanut oil was removed by 20% CN/GO/SA under visible light for 120 min. ‧O2- and h+ were the main active species during photoreaction, and five degradation products were identified by UPLC-Q-Orbitrap MS analysis. At the same time, the quality of treated peanut oil was still acceptable. More importantly, CN/GO/SA showed excellent cycle stability, and the degradation rate of AFB1 in peanut oil remained above 95% after five-time recycling. This work provides a practical way for developing efficient and sustainable photocatalysts to degrade mycotoxins in edible oil.

Polar Electrocatalysts for Preventing Polysulfide Migration and Accelerating Redox Kinetics in Room-Temperature Sodium-Sulfur Batteries.

Due to the high theoretical energy density, low cost, and rich abundance of sodium and sulfur, room-temperature sodium-sulfur (RT Na-S) batteries are investigated as the promising energy storage system. However, the inherent insulation of the S8 , the dissolution and shuttle of the intermediate sodium polysulfides (NaPSs), and especially the sluggish conversion kinetics, restrict the commercial application of the RT Na-S batteries. To address these issues, various catalysts are developed to immobilize the soluble NaPSs and accelerate the conversion kinetics. Among them, the polar catalysts display impressive performance. Polar catalysts not only can significantly accelerate (or alter) the redox process, but also can adsorb polar NaPSs through polar-polar interaction because of their intrinsic polarity, thus inhibiting the notorious shuttle effect. Herein, the recent advances in the electrocatalytic effect of polar catalysts on the manipulation of S speciation pathways in RT Na-S batteries are reviewed. Furthermore, challenges and research directions to realize rapid and reversible sulfur conversion are put forward to promote the practical application of RT Na-S batteries.

Delayed feeding of a high-sucrose diet led to increased body weight by affecting the circadian rhythm of body temperature and hepatic lipid-metabolism genes in rats.

Skipping breakfast is an irregular feeding behavior, typically in young people. In our previous study, we established a 4 h-delayed feeding protocol for rats as a breakfast-skipping model and showed that the 4 h-delayed feeding of a high-fat diet led to body weight gain in rats. Excess sucrose induces metabolic syndrome and fatty liver. Recently, excess sucrose intake has received increased attention. Young people generally consume more sugar than adults do. In the present study, we investigated whether a 4 h-delayed feeding promoted high-sucrose diet-induced abnormalities in lipid metabolism, such as fatty liver and obesity in rats. The 4 h-delayed feeding rats showed increased body weight gain, although it did not induce fatty liver and hyperlipidemia compared to normal feeding rats. Serum insulin concentration during the feeding period was higher than in the control rats, suggesting that slight insulin resistance was induced by the 4 h-delayed feeding. The surge in body temperature was also delayed by 4 h in response to the 4 h-delayed feeding. This delay would result in less energy expenditure to increase body weight. The oscillations of hepatic lipid and glucose metabolism-related gene expression were delayed by almost 2-4 h, and the clock genes were delayed by approximately 2 h. The 4 h-delayed feeding induced weight gain by affecting body temperature, insulin resistance, and circadian oscillation of lipid metabolism-related genes in rats fed a high-sucrose diet, suggesting that a high sucrose intake with breakfast skipping leads to obesity.

Research progress of ochratoxin a bio-detoxification.

Ochratoxins (OTs) is an extremely toxic mycotoxin in which Ochratoxin A (OTA) is the most toxic and prevalent in the ochratoxin family. OTA is among the five most critical mycotoxins that are subject to legal regulations. Animals and humans may be exposed to OTA through dietary intake, inhalation, and dermal contact. OTA is considered nephrotoxic, genotoxic, cytotoxic, teratogenic, carcinogenic, mutagenic, immunotoxic, and myelotoxic. So, intake of OTA contaminated foods and feeds can impact the productivity of animals and health of people. According to this review, several studies have reported on the approaches that have been established for OTA removal. This review focused on the control approaches to mitigate OTA contamination, OTA bio-detoxification materials and their applicable techniques, recombinant strains for OTA bio-detoxification, and their detoxification effects, recombinant OTA-degrading enzymes and their sources, recombinant fusion enzymes for OTA, ZEN and AFB1 mycotoxins detoxification, as well as the current application and commercialized OTA bio-detoxification products. However, there is no single technique that has been approved to detoxify OTA by 100% to date. Some preferred current strategies for OTA bio-detoxification have been recombinant degrading enzymes and genetic engineering technology due to their efficiency and safety. Therefore, prospective studies should focus on standardizing pure enzymes from genetically engineered microbial strains that have great potential for OTA detoxification.

Formation, structure and stability of high internal phase Pickering emulsions stabilized by BSPI-C3G covalent complexes.

Food-grade high internal phase Pickering emulsions (HIPPEs) are stabilized by protein-based particles, which have attracted extensive attention due to their good gel-like structure. The black soybean isolate protein/cyanidin-3-O-glucoside (BSPI-C3G) covalent particles were used as a particulate emulsifier to form stable HIPPEs with oil phase fractions (74 % v/v) and low particle concentrations (0.5 %-3 % w/v) The particle size distribution and microstructure demonstrated that the BSPI-C3G covalent particles acted as an interfacial layer and surrounded the oil droplets. As the concentration of BSPI-C3G particles increased from 0.5 % to 3 %, the droplet size, elasticity, antioxidant capacity of the heated or stored HIPPEs more stable. So, the HIPPEs had the best stability with the BSPI-C3G particle at 3 % (w/v) concentration. These findings may extend the application of BSPI and C3G in foods and provide the guidelines for the rational design of food-grade HIPPEs stabilized by protein/anthocyanin complexes.

Treatment dependent sodium-rich Prussian blue as a cathode material for sodium-ion batteries.

In the preparation of Prussian blue analogs (PBAs), Na+ loss and Fe2+ oxidation take place when washing with water. Sodium-rich PBAs were prepared with sodium ascorbate aqueous solution as the washing solution, which can suppress the Na+ loss and Fe2+ oxidation. As the cathode of sodium-ion batteries, it exhibited excellent electrochemical performance.

Skipping breakfast regimen induces an increase in body weight and a decrease in muscle weight with a shifted circadian rhythm in peripheral tissues of mice.

Meal timing is a key factor in synchronising the circadian clock in peripheral tissues. Circadian disorders are associated with the metabolic syndrome. Previously, we demonstrated that a skipping breakfast regimen (SBR) with a high-fat diet increased body weight gain in rats. In this study, we investigated whether SBR with a normal diet led to abnormal lipid metabolism and muscle metabolism in mice. Male C57BL/6 mice were fed during zeitgeber time (ZT) 12-24 in the control group and ZT 16-24 in the SBR group for 2 weeks. SBR mice showed increased body weight gain and perirenal adipose tissue weight. The plantar muscle weight was decreased in the SBR group compared with that in the control group. Furthermore, SBR delayed the circadian oscillations in clock gene expression in peripheral tissues, such as the liver, adipose tissue and muscle, as well as the oscillations in the expression of lipid metabolism-related genes in the liver and adipose tissue. These results suggest that skipping breakfast over a long period of time is associated with a risk of obesity, the metabolic syndrome and muscle loss, such as sarcopenia.

Rapid Detection of Cysticercus cellulosae by an Up-Converting Phosphor Technology-Based Lateral-Flow Assay.

Cysticercosis is a neglected tropical disease caused by the larvae of Taenia solium in pigs and humans. The current diagnosis of porcine cysticercosis is difficult, and traditional pathological tests cannot meet the needs of detection. This study established a UPT-LF assay for the detection of Cysticercus cellulosae. UCP particles were bound to two antigens, TSOL18 and GP50; samples were captured, and the signal from the UCP particles was converted into a detectable signal for analysis using a biosensor. Compared to ELISA, UPT-LF has higher sensitivity and specificity, with a sensitivity of 93.59% and 97.44%, respectively, in the case of TSOL18 and GP50 antigens and a specificity of 100% for both. Given its rapidness, small volume, high sensitivity and specificity, and good stability and reproducibility, this method could be used in the diagnosis of cysticercosis.

PROTEOMIC ANALYSIS OF TAENIA SOLIUM CYST FLUID BY SHOTGUN LC-MS/MS.

Taenia solium cysts were collected from pig skeletal muscle and analyzed via a shotgun proteomic approach to identify known proteins in the cyst fluid and to explore host-parasite interactions. Cyst fluid was aseptically collected and analyzed with shotgun liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene alignment and annotation were performed using Blast2GO software followed by gene ontology analysis of the annotated proteins. The pathways were further analyzed with the Kyoto Encyclopedia of Genes and Genomes (KEGG), and a protein-protein interaction (PPI) network map was generated using STRING software. A total of 158 known proteins were identified, most of which were low-molecular-mass proteins. These proteins were mainly involved in cellular and metabolic processes, and their molecular functions were predominantly related to catalytic activity and binding functions. The pathway enrichment analysis revealed that the known proteins were mainly enriched in the PI3K-Akt and glycolysis/gluconeogenesis signaling pathways. The nodes in the PPI network mainly consisted of enzymes involved in sugar metabolism. The cyst fluid proteins screened in this study may play important roles in the interaction between the cysticerci and the host. The shotgun LC-MS/MS, gene ontology, KEGG, and PPI network map data will be used to identify and analyze the cyst fluid proteome of cysticerci, which will provide a basis for further exploration of the invasion and activities of T. solium.

Regulation of DNA methylation on key parasitism genes of Cysticercus cellulosae revealed by integrative epigenomic-transcriptomic analyses.

BACKGROUND: The life cycle of Taenia solium is characterized by different stages of development, requiring various kinds of hosts that can appropriately harbor the eggs (proglottids), the oncospheres, the larvae and the adults. Similar to other metazoan pathogens, T. solium undergoes transcriptional and developmental regulation via epigenetics during its complex lifecycle and host interactions. RESULT: In the present study, we integrated whole-genome bisulfite sequencing and RNA-seq technologies to characterize the genome-wide DNA methylation and its effect on transcription of Cysticercus cellulosae of T. solium. We confirm that the T. solium genome in the cysticercus stage is epigenetically modified by DNA methylation in a pattern similar to that of other invertebrate genomes, i.e., sparsely or moderately methylated. We also observed an enrichment of non-CpG methylation in defined genetic elements of the T. solium genome. Furthermore, an integrative analysis of both the transcriptome and the DNA methylome indicated a strong correlation between these two datasets, suggesting that gene expression might be tightly regulated by DNA methylation. Importantly, our data suggested that DNA methylation might play an important role in repressing key parasitism-related genes, including genes encoding excretion-secretion proteins, thereby raising the possibility of targeting DNA methylation processes as a useful strategy in therapeutics of cysticercosis.