Superparamagnetic iron oxide nanoparticles (SPIONs) are promising contrast agents for imaging-guided cancer therapies. However, challenges such as the requirement for a high alternating magnetic field (AMF), dosage limitations, and suboptimal imaging contrast have hindered their practical applications. Methods: First, the optimal doping ratio of Mn and Zn in MnxZn1-xFe2O4 nanoparticles synthesized using a modified high-temperature thermal decomposition method (mHTTD) was determined. Then, the magnetic and physical properties of the optimal 7-nm Mn0.5Zn0.5Fe2O4 SPIONs were systematically and comprehensively characterized via hysteresis measurements, dynamic light scattering (DLS), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray absorption fine structure (XAFS) spectroscopy, and X-ray absorption near edge structure (XANES) spectroscopy. Next, the stability, biosafety, biocompatibility, and theranostic performance of 7-nm Mn0.5Zn0.5Fe2O4 SPIONs in magnetic hyperthermia therapy (MHT) were evaluated by in vivo and in vitro studies involving mouse models, magnetic resonance imaging (MRI), and bioassays. The results were then compared with those for conventional SPIONs. Results: Under an AMF of 140 Oe at 100 kHz, 7-nm Mn0.5Zn0.5Fe2O4 SPIONs demonstrated significantly higher heat production than conventional SPIONs. Following surface modification with methoxy-PEG-silane, PEGylated 7-nm Mn0.5Zn0.5Fe2O4 SPIONs showed excellent monodispersity and magnetic properties, with an exceptionally high T2 relaxivity (r2). Conclusions: The high in vitro and in vivo theranostic performance of PEGylated 7-nm Mn0.5Zn0.5Fe2O4 SPIONs as efficient and stable contrast agents for treating glioblastoma, encompassing strengthened magnetic hyperthermia, activated anti-tumor immunity, and remarkable T2 contrast enhancement, underscores the potential of precisely designed ferrites to concurrently enhance the T2 contrast and magnetocaloric properties for optimal theranostic outcomes. Our study provides a compelling rationale for the development of tailored magnetic nanoprobes for improved glioblastoma theranostics.
© The author(s).

Colorectal cancer (CRC) has traditionally been treated with genotoxic chemotherapy to activate pro-apoptotic proteins to induce anticancer effects. However, cancer cells develop resistance to apoptosis, which leads to recurrence and poor prognosis. Moreover, this kind of therapy has been shown to be highly toxic to healthy tissues and, therefore, to patients. To overcome this issue, we developed a self-assembly tumor-targeted nanoparticle, T22-DITOX-H6, that incorporates the T22 peptide (a CXCR4 ligand) to selectively target cells overexpressing CXCR4, fused to the catalytic domain of diphtheria toxin, that exhibits a potent cytotoxic effect on these CXCR4+ cancer cells that exhibits potent cytotoxic effects on CXCR4-overexpressing cancer cells through the activation of pyroptosis, an immunogenic type of cell death.
Colorectal CXCR4-expressing tumor cells (CT26-CXCR4+) were implanted subcutaneously into immunocompetent mice to study the effects of T22-DITOX-H6 treatment on tumor growth, cell death and innate immune cell recruitment to the tumor.
Here, we demonstrated that the T22-DITOX-H6 nanoparticle selectively activated pyroptosis, an immunogenic cell death that differs from apoptosis, leading to cell death in CXCR4-expressing cells, without affecting the viability of CXCR4-lacking cells. In addition, the nanoparticle administered to tumor-bearing mice induced a local antitumor effect due to the selective activation of pyroptosis in CXCR4+ targeted cancer cells. Biochemical analysis of plasma and histological analysis of non-tumor tissues revealed no differences between the groups. Remarkably, pyroptosis activation stimulates eosinophil infiltration into the tumor microenvironment, an effect recently reported to have an anti-tumorigenic function.
These results highlight the dual role of CXCR4-targeted cytotoxic nanoparticle in eliminating cancer cells and boosting the self-immune response without compromising healthy organs.
© 2025 Carrasco-Díaz et al.

The existing anticancer drugs in clinical practice show poor efficacy in cervical cancer patients and are associated with multiple side effects. Our previous study demonstrated the strong antineoplastic activity of crude extract prepared from the stem bark of Azadirachta indica (Neem) against cervical cancer. However, the active phytoconstituents of neem stem bark extract and its underlying anticancer mechanism are yet to be investigated. Thus, the present study aimed to identify the active fraction from crude neem stem bark extract to further dissect its anticancer mechanism and determine the active components.
Dichloromethane (DCM) extract from neem stem bark was prepared and fractionated using thin-layer chromatography. The fractions obtained were screened against HeLa and ME-180 cervical cancer cell lines to identify the most active fraction, which was then selected for further studies. Clonogenic assay, cell cycle analysis, apoptosis assay, and reactive oxygen species (ROS) assay were performed to determine the cytotoxicity of the active fraction. Gene expression was analyzed using real-time PCR and western blot to determine the mechanism. Additionally, the HeLa cells-derived 3D spheroid model was used to determine the antitumor efficacy of the active fraction. Electrospray ionization-mass spectrometry, Fourier-transform infrared spectroscopy, and proton nuclear magnetic resonance were used to identify the phytoconstituents of the fraction.
Initial screening revealed fraction 2 (F2) as the most active fraction. Additionally, F2 showed the least cytotoxic effect on normal human fibroblast cells. Mechanistically, F2 induced cell cycle arrest and apoptosis in cervical cancer cells. F2 increased ROS levels, induced ER stress, and activated cell survival pathway. Treatment with N-acetyl cysteine revealed that F2 induced ROS-independent ER stress and apoptosis. 3D spheroid viability and growth delay experiments demonstrated the strong antitumor potential of F2. Finally, six compounds, including one flavonoid (nicotiflorin) and five limonoids, were identified in the F2 fraction.
This is the first study to identify the active fraction and its phytoconstituents from neem stem bark and demonstrate the anticancer mechanism against cervical cancer. Our study highlights the importance of investigating neem stem bark-derived limonoids and nicotiflorin as a potential source to develop new anticancer therapeutic agents.
© 2025. The Author(s).

Generation of reactive oxygen species is an important part of the innate immune response. Generating microbicidal levels of reactive oxygen species (ROS) requires adaptation of mucosal barriers. High tolerance of ROS provides improved innate immune defenses against pathogens, whereas low tolerance renders host cells prone to chronic toxicity and mutagenesis, which can promote inflammation (e.g., in asthma and Crohn’s disease) and cancerogenesis. The mechanisms that sense and mediate host tolerance to ROS are little understood. In this study, we discover an unexpected role for the redox-sensitive, chemokine-like lipid 5-oxo-eicosatetraenoic acid (5-KETE) in redox adaptation. 5-KETE is known to attract leukocytes to damaged/infected mucosal barriers by signaling through its receptor, OXER1. Suggestive of a distinct non-immune function, we here report that the loss of the OXER1 ortholog Hcar1-4 causes barrier defects and baseline inflammation in the intestine of live zebrafish larvae. In zebrafish and cultured human cells, OXER1 signaling protects against oxidative nucleotide lesions by inducing DNA-protective Nudix hydrolases. Our data reveal the oxoeicosanoid pathway as a conserved ROS resilience mechanism that fortifies pathogen-exposed mucosal linings against increased oxidative stress in vivo .

Acute liver failure is a serious, life-threatening disease. Although the gut microbiota has been considered to play a role in liver failure, the extent to which it is involved in the pathogenesis of this disease has not been fully elucidated to date. Therefore, we here analyzed the importance of the presence of intestinal microbiota in the pathogenesis of acute liver injury, using D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-treated mice, which is a widely used experimental model of acute liver injury. First, administration of the antibiotic polymyxin B markedly alleviated liver injury. Liver injury was also reduced in germ-free mice, leading to the conclusion that the presence of intestinal microbiota aggravates D-GalN/LPS-induced liver injury. The amount of bacteria and LPS transferred from the gut to the blood was not increased by D-GalN/LPS, suggesting that the worsening of liver injury was not simply owing to the entry of bacteria into the circulation. In conclusion, acute liver injury in polymyxin B-pretreated or germ-free mice was ameliorated by modulation of the gut microbiota. Modification of the gut microbiota using polymyxin B may hence have the potential to alleviate acute liver injury in human patients.
© 2024 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.