Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes.

Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8+ T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8+ thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells.

Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response.

Cell fate decisions during early B cell activation determine the outcome of responses to pathogens and vaccines. We examined the early B cell response to T-dependent antigen in mice by single-cell RNA sequencing. Early after immunization, a homogeneous population of activated precursors (APs) gave rise to a transient wave of plasmablasts (PBs), followed a day later by the emergence of germinal center B cells (GCBCs). Most APs rapidly exited the cell cycle, giving rise to non-GC-derived early memory B cells (eMBCs) that retained an AP-like transcriptional profile. Rapid decline of antigen availability controlled these events; provision of excess antigen precluded cell cycle exit and induced a new wave of PBs. Fate mapping revealed a prominent contribution of eMBCs to the MBC pool. Quiescent cells with an MBC phenotype dominated the early response to immunization in primates. A reservoir of APs/eMBCs may enable rapid readjustment of the immune response when failure to contain a threat is manifested by increased antigen availability.

Intelligent Identification of Cerebrospinal Fluid for the Diagnosis of Parkinson's Disease.

Cerebrospinal fluid (CSF) biomarkers are more sensitive than the Movement Disorder Society (MDS) criteria for detecting prodromal Parkinson's disease (PD). Early detection of PD provides the best chance for successful implementation of disease-modifying treatments, making it crucial to effectively identify CSF extracted from PD patients or normal individuals. In this study, an intelligent sensor array was built by using three metal-organic frameworks (MOFs) that exhibited varying catalytic kinetics after reacting with potential protein markers. Machine learning algorithms were used to process fingerprint response patterns, allowing for qualitative and quantitative assessment of the proteins. The results were robust and capable of discriminating between PD and non-PD patients via CSF detection. The k-nearest neighbor regression algorithm was used to predict MDS scores with a minimum mean square error of 38.88. The intelligent MOF sensor array is expected to promote the detection of CSF biomarkers due to its ability to identify multiple targets and could be used in conjunction with MDS criteria and other techniques to diagnose PD more sensitively and selectively.

Hydrogen-Bonded Organic Frameworks Chelated Manganese for Precise Magnetic Resonance Imaging Diagnosis of Cancers.

Magnetic resonance imaging (MRI) is an important tool in the diagnosis of many cancers. However, clinical gadolinium (Gd)-based MRI contrast agents have limitations, such as large doses and potential side effects. To address these issues, we developed a hydrogen-bonded organic framework-based MRI contrast agent (PFC-73-Mn). Due to the hydrogen-bonded interaction of water molecules and the restricted rotation of manganese ions, PFC-73-Mn exhibits high longitudinal relaxation r1 (5.03 mM-1 s-1) under a 3.0 T clinical MRI scanner. A smaller intravenous dose (8 µmol of Mn/kg) of PFC-73-Mn can provide strong contrast and accurate diagnosis in multiple kinds of cancers, including breast tumor and ultrasmall orthotopic glioma. PFC-73-Mn represents a prospective new approach in tumor imaging, especially in early-stage cancer.

Cleavage of Homonuclear Chalcogen-Chalcogen Bonds in a Hybrid Platform in Response to X-Ray Radiation Potentiates Tumor Radiochemotherapy.

Chalcogens are used as sensitive redox-responsive reagents in tumor therapy. However, chalcogen bonds triggered by external ionizing radiation, rather than by internal environmental stimuli, enable site-directed and real-time drug degradation in target lesions. This approach helps to bypass chemoresistance and global systemic toxicity, presenting a significant advancement over traditional chemoradiotherapy. In this study, we fabricated a hybrid monodisperse organosilica nanoprodrug based on homonuclear single bonds (disulfide bonds (S-S, approximately 240 kJ/mol), diselenium bonds (Se-Se, approximately 172 kJ/mol), and tellurium bonds (Te-Te, 126 kJ/mol)), including ditelluride-bond-bridged MONs (DTeMSNs), diselenide-bond-bridged MONs (DSeMSNs) and disulfide-bond-bridged MONs (DSMSNs). The results demonstrated that differences in electronegativities and atomic radii influenced their oxidation sensitivities and reactivities. Tellurium, with the lowest electronegativity, showed the highest sensitivity, followed by selenium and sulfur. DTeMSNs exhibited highly responsive cleavage upon exposure to X-rays, resulting in oxidation to TeO3 2-. Furthermore, chalcogen-hybridized organosilica was loaded with manganese ions (Mn2+) to enhance the release of Mn2+ during radiotherapy, thereby activating the the stimulator of interferon genes (STING) pathway and enhancing the tumor immune response to inhibit tumor growth. This investigation of hybrid organosilica deepens our understanding of chalcogens response characteristics to radiotherapy and enriches the design principles for nanomedicine based on prodrugs.

Magnetic Resonance Diagnosis of Early Triple-Negative Breast Cancer Based on the Ionic Covalent Organic Framework with High Relaxivity and Long Retention Time.

Patients with triple-negative breast cancer (TNBC) have dismal prognoses due to the lack of therapeutic targets and susceptibility to lymph node (LN) metastasis. Therefore, it is essential to develop more effective approaches to identify early TNBC tissues and LNs. In this work, a magnetic resonance imaging (MRI) contrast agent (Mn-iCOF) was constructed based on the Mn(II)-chelated ionic covalent organic framework (iCOF). Because of the porous structure and hydrophilicity, the Mn-iCOF has a high longitudinal relaxivity (r1) of 8.02 mM-1 s-1 at 3.0 T. For the tumor-bearing mice, a lower dose (0.02 mmol [Mn]/kg) of Mn-iCOF demonstrated a higher signal-to-noise ratio (SNR) value (1.8) and longer retention time (2 h) compared to a 10-fold dose of commercial Gd-DOTA (0.2 mmol [Gd]/kg). Moreover, the Mn-iCOF can provide continuous and significant MR contrast for the popliteal LNs within 24 h, allowing for accurate evaluation and dissection of LNs. These excellent MRI properties of the Mn-iCOF may open new avenues for designing more biocompatible MRI contrast agents with higher resolutions, particularly in the diagnosis of TNBC.

Photoactivatable aggregation-induced emission luminogens based on photodehydrogenation reactions for biomedical applications.

The development of photoactivatable aggregation-induced emission (AIE) probes is one of the hotspots for bioimaging and imaging-guided precise disease therapy due to the distinct advantages of high spatiotemporal resolution, precise spatiotemporal controllability, and noninvasiveness of light. To design and develop novel photoactivatable AIE probes, functional groups based on photodehydrogenation reaction mechanisms are combined with the AIE-active skeleton. Here, the recent progress in biomedical applications of photoactivatable AIE probes based on photocyclodehydrogenation and photo-oxidative dehydrogenation reactions are summarized briefly. Moreover, the outlook for photoactivatable AIE probes is discussed to aim at promoting innovative research in biomedical applications.

Facile synthesis of near-infrared responsive on-demand oxygen releasing nanoplatform for precise MRI-guided theranostics of hypoxia-induced tumor chemoresistance and metastasis in triple negative breast cancer.

BACKGROUND: Hypoxia is an important factor that contributes to chemoresistance and metastasis in triple negative breast cancer (TNBC), and alleviating hypoxia microenvironment can enhance the anti-tumor efficacy and also inhibit tumor invasion. METHODS: A near-infrared (NIR) responsive on-demand oxygen releasing nanoplatform (O2-PPSiI) was successfully synthesized by a two-stage self-assembly process to overcome the hypoxia-induced tumor chemoresistance and metastasis. We embedded drug-loaded poly (lactic-co-glycolic acid) cores into an ultrathin silica shell attached with paramagnetic Gd-DTPA to develop a Magnetic Resonance Imaging (MRI)-guided NIR-responsive on-demand drug releasing nanosystem, where indocyanine green was used as a photothermal converter to trigger the oxygen and drug release under NIR irradiation. RESULTS: The near-infrared responsive on-demand oxygen releasing nanoplatform O2-PPSiI was chemically synthesized in this study by a two-stage self-assembly process, which could deliver oxygen and release it under NIR irradiation to relieve hypoxia, improving the therapeutic effect of chemotherapy and suppressed tumor metastasis. This smart design achieves the following advantages: (i) the O2 in this nanosystem can be precisely released by an NIR-responsive silica shell rupture; (ii) the dynamic biodistribution process of O2-PPSiI was monitored in real-time and quantitatively analyzed via sensitive MR imaging of the tumor; (iii) O2-PPSiI could alleviate tumor hypoxia by releasing O2 within the tumor upon NIR laser excitation; (iv) The migration and invasion abilities of the TNBC tumor were weakened by inhibiting the process of EMT as a result of the synergistic therapy of NIR-triggered O2-PPSiI. CONCLUSIONS: Our work proposes a smart tactic guided by MRI and presents a valid approach for the reasonable design of NIR-responsive on-demand drug-releasing nanomedicine systems for precise theranostics in TNBC.

Discovery of novel VEGFR-2 inhibitors embedding 6,7-dimethoxyquinazoline and diarylamide fragments.

VEGF/VEGFR-2 signaling plays a critical part in tumor angiogenesis. Inhibition of this pathway has been considered as a promising approach for cancer treatment. In this work, a series of 6,7-dimethoxy-4-anilinoquinazoline derivatives bearing diarylamide moiety were designed, synthesized and evaluated as potent inhibitors of VEGFR-2 kinase. Their in vitro antiproliferation activities against two human cancer cell lines Hep-G2 and MCF-7 have also been determined. Among them, compound 14b exhibited the most potent inhibitory activity against VEGFR-2 with IC50 value of 0.016 ± 0.002 µM and it showed the most potent antiproliferative effect against Hep-G2 and MCF-7 with IC50 values at low-micromolar range. Molecular docking studies revealed that these compounds represented by the most potent compound 14b could bind well to the ATP-binding site of VEGFR-2, which suggested that compound 14b could be a potential anticancer agent targeting VEGFR-2.

Glutaredoxin 1 up-regulates deglutathionylation of α4 integrin and thereby restricts neutrophil mobilization from bone marrow.

α4 integrin plays a crucial role in retention and release of neutrophils from bone marrow. Although α4 integrin is known to be a potential target of reactive oxygen species (ROS)-induced cysteine glutathionylation, the physiological significance and underlying regulatory mechanism of this event remain elusive. Here, using in vitro and in vivo biochemical and cell biology approaches, we show that physiological ROS-induced glutathionylation of α4 integrin in neutrophils increases the binding of neutrophil-associated α4 integrin to vascular cell adhesion molecule 1 (VCAM-1) on human endothelial cells. This enhanced binding was reversed by extracellular glutaredoxin 1 (Grx1), a thiol disulfide oxidoreductase promoting protein deglutathionylation. Furthermore, in a murine inflammation model, Grx1 disruption dramatically elevated α4 glutathionylation and subsequently enhanced neutrophil egress from the bone marrow. Corroborating this observation, intravenous injection of recombinant Grx1 into mice inhibited α4 glutathionylation and thereby suppressed inflammation-induced neutrophil mobilization from the bone marrow. Taken together, our results establish ROS-elicited glutathionylation and its modulation by Grx1 as pivotal regulatory mechanisms controlling α4 integrin affinity and neutrophil mobilization from the bone marrow under physiological conditions.

Cancer-Targeting Functionalization of Selenium-Containing Ruthenium Conjugate with Tumor Microenvironment-Responsive Property to Enhance Theranostic Effects.

A mutifunctional ruthenium-based conjugate Ru-BSe was designed and synthesized. The Ru complex with favorable bioimaging function was covalently linked with a cancer-targeted molecule that could be effectively internalized by the tumor to realize enhanced theranostic effects. The pH-response of the Ru conjugate in tumor acidic microenvironment causes ligand substitution and release of therapeutic complex. This activated complex remains inert to the reducing biomolecule-glutathione and terminally locates in mitochondria, in which it triggers oxidative stress, and activates intrinsic apoptosis. Real-time monitoring reveals that this Ru conjugate could selectively accumulate in tumor tissue in vivo, which significantly suppresses tumor progression and alleviate the damage to normal organs, realizing the precise cancer theranosis.

Lead Neurotoxicity on Human Neuroblastoma Cell Line SH-SY5Y is Mediated via Transcription Factor EGR1/Zif268 Induced Disrupted in Scherophernia-1 Activation.

Lead (Pb2+) is a well-known type of neurotoxin and chronic exposure to Pb2+ induces cognition dysfunction. In this work, the potential role of early growth response gene 1 (EGR1) in the linkage of Pb2+ exposure and disrupted in scherophernia-1 (DISC1) activity was investigated. Human neuroblastoma cell line SH-SY5Y was subjected to different concentrations of lead acetate (PbAc) to determine the effect of Pb2+ exposure on the cell viability, apoptosis, and activity of EGR1 and DISC1. Then the expression of EGR1 in SH-SY5Y cells was knocked down with specific siRNA to assess the function of EGR1 in Pb2+ induced activation of DISC1. The interaction between EGR1 and DISC1 was further validated with dual luciferase assay, Supershift electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP)-PCR. Administration of PbAc decreased cell viability and induced apoptosis in SH-SY5Y cells in a dose-dependent manner. Additionally, exposure to PbAc also up-regulated expression of EGR1 and DISC1 at all concentrations. Knockdown of EGR1 blocked the effect of PbAc on SH-SY5Y cells, indicating the central role of EGR1 in the function of Pb2+ on activity of DISC1. Based on the results of dual luciferase assay, Supershift EMSA, and ChIP-PCR, EGR1 mediated the effect of Pb2+ on DISC1 by directly bound to the promoter region of DISC1 gene. The current study elaborated the mechanism involved in the effect of Pb2+ exposure on expression of DISC1 for the first time: EGR1 activated by Pb2+ substitution of zinc triggered the transcription of DISC1 gene by directly binding to its promoter.

A cancer-targeted nanosystem for delivery of gold(III) complexes: enhanced selectivity and apoptosis-inducing efficacy of a gold(III) porphyrin complex.

Construction of delivery systems for anticancer gold complexes to decrease their toxicity while maintaining efficacy is a key strategy to optimize and develop anticancer gold medicines. Herein, we describe cancer-targeted mesoporous silica nanoparticles (MSN) for delivery of a gold(III) porphyrin complex (Au-1 a@MSN(R)) to enhance its anticancer efficacy and selectivity between cancer and normal cells. Encapsulation of Au-1 a within mesoporous silica nanoparticles amplifies its inhibitory effects on thioredoxin reductase (TrxR), resulting in a loss of redox balance and overproduction of reactive oxygen species (ROS). Elevated cellular oxidative stress activates diversified downstream ROS-mediated signaling pathways, leading to enhanced apoptosis-inducing efficacy.

Activatable fluorescent probes for atherosclerosis theranostics.

The onset of atherosclerosis (AS) is insidious, and early stage patients have atypical clinical symptoms. After being diagnosed in late stage, it is often prone to sudden and fatal cardiovascular events. Therefore, it is highly desirable to develop precise and efficient diagnosis and therapy strategies of AS. Benefiting from high signal-to-noise ratio, low detection limit, high specificity and sensitivity, a series of activatable fluorescent probes based on atherosclerotic microenvironment have emerged for identification and treatment of AS. In this review, we focus on the atherosclerotic microenvironment and briefly summarize the correlation between the structural transformation and fluorescence signal changes of mono-/double-activatable fluorescent probes upon biomarkers stimulation. Moreover, their cutting-edge progress for AS theranostics is described. Finally, the outlook for activatable theranostic probes based on atherosclerotic microenvironment is discussed to aim at promoting innovative research in imaging-guided precise AS therapy.

Dual-/multi-organelle-targeted AIE probes associated with oxidative stress for biomedical applications.

In situ monitoring of biological processes between different organelles upon oxidative stress is one of the most important research hotspots. Fluorescence imaging is especially suitable for biomedical applications due to its distinct advantages of high spatiotemporal resolution, high sensitivity, non-invasiveness, and in situ monitoring capabilities. However, most fluorescent probes can only achieve light-up imaging of single organelles, thus the combined use of two or more probes is usually required for monitoring biological processes between organelles, which can suffer from tedious staining and washing procedures, increased cytotoxicity and poor photostability. Exogenetic oxidants can affect broad-spectrum subcellular organelles, which are not conducive to in situ monitoring of biological processes between specific organelles. To tackle these challenges, a series of dual-/multi-organelle-targeted aggregation-induced emission (AIE) probes associated with oxidative stress have been designed and developed in the past few years. Herein, the recent progress of these AIE probes is summarized in biomedical applications, such as apoptosis monitoring, interplay between organelles, microenvironmental changes of organelles, organelle morphology tracking, precise cancer therapy, and so forth. Moreover, the further outlook for dual-/multi-organelle-targeted AIE probes is discussed, aiming to promote innovative research in biomedical applications.

Ultrasound-triggered functional hydrogel promotes multistage bone regeneration.

The dysfunction of bone mesenchymal stem cells (BMSCs), caused by the physical and chemical properties of the inflammatory and repair phases of bone regeneration, contributes to the failure of bone regeneration. To meet the spatiotemporal needs of BMSCs in different phases, designing biocompatible materials that respond to external stimuli, improve migration in the inflammatory phase, reduce apoptosis in the proliferative phase, and clear the hurdle in the differentiation phase of BMSCs is an effective strategy for multistage repair of bone defects. In this study, we designed a cascade-response functional composite hydrogel (Gel@Eb/HA) to regulate BMSCs dysfunction in vitro and in vivo. Gel@Eb/HA improved the migration of BMSCs by upregulating the expression of chemokine (C-C motif) ligand 5 (CCL5) during the inflammatory phase. Ultrasound (US) triggered the rapid release of Ebselen (Eb), eliminating the accumulation of reactive oxygen species (ROS) in BMSCs, and reversing apoptosis under oxidative stress. Continued US treatment accelerated the degradation of the materials, thereby providing Ca2+ for the osteogenic differentiation of BMSCs. Altogether, our study highlights the prospects of US-controlled intelligent system, that provides a novel strategy for addressing the complexities of multistage bone repair.

SNPs Give LACTB Oncogene-Like Functions and Prompt Tumor Progression via Dual-Regulating p53.

LACTB is identified as a tumor suppressor in several tumors. However, preliminary study reveals that LACTB is overexpressed in osteosarcoma and indicates poor prognosis. Two missense mutations (rs34317102 and rs2729835) exist simultaneously in 92.31% of osteosarcoma patients and cause M5L and R469K double mutations in LACTB, suggesting the biologic function of LACTB protein may be altered in osteosarcoma. Moreover, LACTBM5L+R469K overexpression can promote malignant progression in different tumors, which suggests that the M5L and R469K mutations confer oncogene-like functions to LACTB. Mechanistically, LACTBM5L+R469K not only reduces the wild type p53 via enhancing PSMB7 catalytic activity, but also protects p53R156P protein from lysosomal degradation, which suggesting LACTBM5L+R469K is a dual-regulator for wt-p53 and mutant p53, and derive oncogene-like functions. More importantly, clavulanate potassium, a bacterial ß-lactamase inhibitor, can inhibit osteosarcoma proliferation and sensitize osteosarcoma to cisplatin by binding and blocking LACTBM5L+R469K. These findings revealed that the M5L and R469K double mutations can diminish the tumor suppressive ability of wild type LACTB and provide oncogene-like functions to LACTB. Inhibiting LACTBM5L+R469K can suppress the progression of osteosarcoma harbouring wild-type or mutant p53. Clavulanate potassium is a promising drug by targeting LACTBM5L+R469K-p53 pathway for the treatment of osteosarcoma patients.

A homologous membrane-camouflaged self-assembled nanodrug for synergistic antitumor therapy.

Limited success has been achieved in ferroptosis-induced cancer treatment due to the challenges related to low production of toxic reactive oxygen species (ROS) and inherent ROS resistance in cancer cells. To address this issue, a self-assembled nanodrug have been investigated that enhances ferroptosis therapy by increasing ROS production and reducing ROS inhibition. The nanodrug is constructed by allowing doxorubicin (DOX) to interact with Fe2+ through coordination interactions, forming a stable DOX-Fe2+ chelate, and this chelate further interacts with sorafenib (SRF), resulting in a stable and uniform nanoparticle. In tumor cells, overexpressed glutathione (GSH) triggers the disassembly of nanodrug, thereby activating the drug release. Interestingly, the released DOX not only activates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) to produce abundant H2O2 production for enhanced ROS production, but also acts as a chemotherapeutics agent, synergizing with ferroptosis. To enhance tumor selectivity and improve the blood clearance, the nanodrug is coated with a related cancer cell membrane, which enhances the selective inhibition of tumor growth and metastasis in a B16F10 mice model. Our findings provide valuable insights into the rational design of self-assembled nanodrug for enhanced ferroptosis therapy in cancer treatment. STATEMENT OF SIGNIFICANCE: Ferroptosis is a non-apoptotic form of cell death induced by the iron-regulated lipid peroxides (LPOs), offering a promising potential for effective and safe anti-cancer treatment. However, two significant challenges hinder its clinical application: 1) The easily oxidized nature of Fe2+ and the low concentration of H2O2 leads to a low efficiency of intracellular Fenton reaction, resulting in poor therapeutic efficacy; 2) The instinctive ROS resistance of cancer cells induce drug resistance. Therefore, we developed a simple and high-efficiency nanodrug composed of self-assembling by Fe2+ sources, H2O2 inducer and ROS resistance inhibitors. This nanodrug can effectively deliver the Fe2+ sources into tumor tissue, enhance intracellular concentration of H2O2, and reduce ROS resistance, achieving a high-efficiency, precise and safe ferroptosis therapy.

Thermoresponsive hydrogel for transcatheter arterial chemoembolization of hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is one of the most commonly used treatments for hepatocellular carcinoma (HCC); however, the poor stability of emulsified chemotherapy drugs by iodinated oil always leads to serious systemic cytotoxicity. Herein, a composite hydrogel Epi/Etpoil@MC/XG was proposed by stably distributing ethiodized poppyseed oil (Etpoil) and epirubicin (Epi) in the blend hydrogel of methylcellulose (MC) and xanthan gum (XG). Benefiting from its adjusted thermo-responsive and injectable properties, the Epi/Etpoil@MC/XG has been successfully applied in the embolization of the feeding artery for a VX2 tumor model.

Biomimetic Epigallocatechin Gallate-Cerium Assemblies for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease that is so far incurable with long-term health risks. The high doses and frequent administration for the available RA drug always lead to adverse side effects. Aiming at the obstacles to achieving effective RA treatment, we prepared macrophage cell membrane-camouflaged nanoparticles (M-EC), which were assembled from epigallocatechin gallate (EGCG) and cerium(IV) ions. Due to its geometrical similarity to the active metal sites of a natural antioxidant enzyme, the EC possessed a high scavenge efficiency to various types of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The macrophage cell membrane assisted M-EC in escaping from the immune system, being uptaken by inflammatory cells, and specifically binding IL-1ß. After tail vein injection to the collagen-induced arthritis (CIA) mouse model, the M-EC accumulated at inflamed joints and effectively repaired the bone erosion and cartilage damage of rheumatoid arthritis by relieving synovial inflammation and cartilage erosion. It is expected that the M-EC can not only pave a new way for designing metal-phenolic networks with better biological activity but also provide a more biocompatible therapeutic strategy for effective treatment of RA.