A Two-Pronged Nanostrategy of Iron Metabolism Disruption to Synergize Tumor Therapy by Triggering the Paraptosis-Apoptosis Hybrid Pathway.

Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of "reprogramming" and "interfering" iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical "Trojan horse", mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis-apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.

Characterization, Mechanism, and Application of Dipeptidyl Peptidase III: An Aflatoxin B1-Degrading Enzyme from Aspergillus terreus HNGD-TM15.

Aflatoxin B1 is a notorious mycotoxin with mutagenicity and carcinogenicity, posing a serious hazard to human and animal health. In this study, an AFB1-degrading dipeptidyl-peptidase III mining from Aspergillus terreus HNGD-TM15 (ADPP III) with a molecular weight of 79 kDa was identified. ADPP III exhibited optimal activity toward AFB1 at 40 °C and pH 7.0, maintaining over 80% relative activity at 80 °C. The key amino acid residues that affected enzyme activity were identified as H450, E451, H455, and E509 via bioinformatic analysis and site-directed mutagenesis. The degradation product of ADPP III toward AFB1 was verified to be AFD1. The zebrafish hepatotoxicity assay verified the toxicity of the AFB1 degradation product was significantly weaker than that of AFB1. The result of this study proved that ADPP III presented a promising prospect for industrial application in food and feed detoxification.

Fluorinated Titanium Oxide (TiO2-xFx) Nanospindles as Ultrasound-Triggered Pyroptosis Inducers to Boost Sonodynamic Immunotherapy.

Pyroptosis is an inflammatory form of programmed cell death associated with the immune system that can be induced by reactive oxygen species (ROS). As a therapeutic strategy with better penetration depth, sonodynamic therapy (SDT) is expected to induce pyroptosis of cancer cells and boost the immune response. However, it is still a limited problem to precisely adjust the structure of sonosensitizers to exhibit satisfactory sono-catalytic properties. Herein, fluorinated titanium oxide (TiO2-xFx) sonosensitizers were developed to induce pyroptosis under ultrasound (US) to boost antitumor immune responses, enabling highly effective SDT. On the one hand, the introduction of F atoms significantly reduced the adsorption energy of TiO2-xFx for oxygen and water, which is conducive to the occurrence of sono-catalytic reactions. On the other hand, the process of F replacing O increased the oxygen vacancies of the sonosensitizer and shortened the band gap, which enabled powerful ROS generation ability under US stimulation. In this case, large amounts of ROS could effectively kill cancer cells by inducing mitochondrial damage and disrupting oxidative homeostasis, leading to significant cell pyroptosis. Moreover, SDT treatment with TiO2-xFx not only suppressed tumor proliferation but also elicited robust immune memory effects and hindered tumor recurrence. This work highlighted the importance of precisely regulating the structure of sonosensitizers to achieve efficient ROS generation for inducing pyroptosis, which sets the stage for the further development of SDT-immunotherapy.

Turning Waste into Wealth: A Potent Sono-Immune Strategy Based on Microcystis.

Currently, sonodynamic therapy (SDT) has limited therapeutic outcomes and immune responses, highlighting the urgent need for enhanced strategies that can stimulate robust and long-lasting antitumor effects. Microcystis, a notorious microalga, reveals the possibility of mediating SDT owing to the presence of gas vesicles (GVs) and phycocyanin (PC). Herein, a nontoxic strain of Microcystis elabens (labeled Me) is developed as a novel agent for SDT because it generates O2 under red light (RL) illumination, while GVs and PC act as cavitation nuclei and sonosensitizers, respectively. Moreover, algal debris is released after ultrasound (US) irradiation, which primes the Toll-like receptor pathway to initiate a cascade of immune responses. This sono-immune strategy inhibits CT26 colon tumor growth largely by promoting dendritic cell (DC) maturation and cytotoxic T-cell activation. After combination with the immune checkpoint blockade (ICB), the therapeutic outcome is further amplified, accompanied by satisfactory abscopal and immune memory effects; the similar potency is proven in the "cold" 4T1 triple-negative breast tumor. In addition, Me exhibits good biosafety without significant acute or chronic toxicity. Briefly, this study turns waste into wealth by introducing sono-immunotherapy based on Microcystis that achieved encouraging therapeutic effects on cancer, which is expected to be translated into the clinic.

Thermo-Alkali-Tolerant Recombinant Laccase from Bacillus swezeyi and Its Degradation Potential against Zearalenone and Aflatoxin B1.

The enzymatic biodegradation of mycotoxins in food and feed has attracted the most interest in recent years. In this paper, the laccase gene from Bacillus swezeyi was cloned and expressed in Escherichia coli BL 21(D3). The sequence analysis indicated that the gene consisted of 1533 bp. The purified B. swezeyi laccase was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis -12% with an estimated molecular weight of 56.7 kDa. The enzyme is thermo-alkali-tolerant, displaying the optimal degradation of zearalenone (ZEN) and aflatoxin B1 (AFB1) at pH 8 and 9, with incubation temperatures of 55 and 50 °C, respectively, within 24 h. The degradation potentials of the 50 µg of the enzyme against ZEN (5.0 µg/mL) and AFB1 (2.5 µg/mL) were 99.60 and 96.73%, respectively, within 24 h. To the best of our knowledge, this is the first study revealing the recombinant production of laccase from B. swezeyi, its biochemical properties, and potential use in ZEN and AFB1 degradation in vitro and in vivo.

Magnesium implants with alternating magnetic field-enhanced hydrogen release and proton depletion for anti-infection treatment and tissue repair.

Implant-related osteomyelitis is a formidable hurdle in the clinical setting and is characterized by inflammation, infection, and consequential bone destruction. Therefore, effective reactive oxygen species (ROS) scavenging, bacterial killing, and subsequent bone tissue repair are urgently needed for the treatment of difficult-to-heal osteomyelitis. Herein, we utilized the eddy-thermal effect of magnesium (Mg) implants under an alternating magnetic field (AMF) for the controlled release of H2 gas and ions (OH- and Mg2+) for the treatment of osteomyelitis. H2 released by Mg rods under AMFs effectively scavenged cytotoxic ROS, exhibiting anti-inflammatory effects and consequently disrupting the environment of bacterial infections. In addition, the OH- hindered the energy metabolism of bacteria by effectively neutralizing protons within the microenvironment. Moreover, H2 impaired the permeability of bacterial membranes and expedited the damage induced by OH-. This synergistic AMF-induced H2 and proton depletion treatment approach not only killed both gram-negative and gram-positive bacteria but also effectively treated bacterial infections (abscesses and osteomyelitis). Moreover, Mg2+ released from the Mg rods enhanced and accelerated the process of bone osteogenesis. Overall, our work cleverly exploited the eddy-thermal effect and chemical activity of Mg implants under AMFs, aiming to eliminate the inflammatory environment and combat bacterial infections by the simultaneous release of H2, OH-, and Mg2+, thereby facilitating tissue regeneration. This therapeutic strategy achieved multiple benefits in one, thus presenting a promising avenue for clinical application.

Development and evaluation of time-resolved rapid immunofluorescence test for detection of TSOL18 specific antibody in porcine cysticercosis infections.

BACKGROUND: Porcine cysticercosis, a serious zoonotic parasitic disease, is caused by the larvae of Taenia solium and has been acknowledged by the World Organization for Animal Health. The current detection methods of Cysticercus cellulosae cannot meet the needs of large-scale and rapid detection in the field. We hypothesized that the immunofluorescence chromatography test strip (ICS) for detecting Cysticercus cellulosae, according to optimization of a series of reaction systems was conducted, and sensitivity, specificity, and stability testing, and was finally compared with ELISA. This method utilizes Eu3+-labeled time-resolved fluorescent microspheres (TRFM) coupled with TSOL18 antigen to detect TSOL18 antibodies in infected pig sera. RESULTS: ICS and autopsy have highly consistent diagnostic results (n = 133), as determined by Cohen's κ analysis (κ = 0.925). And the results showed that the proposed ICS are high sensitivity (0.9459) with specificity (0.9792). The ICS was unable to detect positive samples of other parasites. It can be stored for at least six months at 4℃. CONCLUSIONS: In summary, we established a TRFM-ICS method with higher sensitivity and specificity than indirect ELISA. Results obtained from serum samples can be read within 10 min, indicating a rapid, user-friendly test suitable for large-scale field detection.

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.

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.

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.