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.

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.

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.

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.

In Situ Ratiometric Determination of Cerebral Ascorbic Acid after Ischemia Reperfusion.

Ascorbic acid (AA) is significant in protecting the brain from further damage and maintaining brain homeostasis after ischemia stroke (IS); however, the dynamic change of cerebral AA content after different degrees of ischemic stroke is still unclear. Herein, carboxylated single-walled carbon nanotube (CNT-COOH)- and polyethylenedioxythiophene (PEDOT)-modified carbon fiber microelectrodes (CFEs) were proposed to detect in situ cerebral AA with sensitivity, selectivity, and stability. Under differential pulse voltammetry scanning, the CFE/CNT-COOH/PEDOT gave a ratiometric, electrochemically responsive signal. The internal standard peak at -310 mV was from the reversible peak of O2 reduction and the deprotonation and protonation of quinone groups, while AA was oxidized at -70 mV. In vivo experimental results indicated that the cerebral AA level gradually increased with the ischemic time increasing in different middle cerebral artery occlusion (MCAO) model mice. This work implies that the increasing cerebral AA level may be highly related to the glutamate excitotoxicity and ROS-led cell apoptosis and paves a new way for further understanding the release and metabolic mechanisms of AA during ischemia reperfusion and IS.

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.

Safety and immunogenicity of human rabies vaccine for the Chinese population after PEP: A systematic review and meta-analysis.

AIM: To evaluate the safety and immunogenicity of rabies vaccine for human use after post-exposure in China. METHODS: A systematic search was performed from PubMed, EMBASE, CNKI and Cochrane Library database, supplemented by manual retrieval. According to the inclusion and exclusion criteria, a meta-analysis was performed using Stata 16.0 software after independent literature screening, data extraction and quality assessment by two evaluators. RESULTS: A total of 32 studies were included. It was found that rabies vaccination after PEP could induce the body to produce sufficient RVNA. Both Essen and Zagreb regimens showed good immunogenicity, with no significant difference in systemic events and local events after PEP, but a relatively high incidence of local and systemic events after PEP under the Zagreb regimen. CONCLUSION: For the Chinese population, rabies vaccination after PEP has shown relatively a good immune efficacy and acceptable safety for preventing human rabies. The survey also found that the Zagreb regimen was comparable to the Essen regimen in terms of rabies prophylaxis with an acceptable safety profile.

Attribution of streamflow changes across the globe based on the Budyko framework.

Differentiating and clarifying the driving factors behind streamflow changes are critical for highlighting hydrological responses to changing environments. However, due to the limited number of hydrological stations, the dominant factor controlling global observed streamflow change remains unclear and intensely debated. Here, we revisit this scientific issue by using the most comprehensive dataset to attribute the observed global streamflow changes during 1960-2014. The results suggest that other factors than precipitation (P) and potential evaporation (E0) are the most important contributors to global observed streamflow changes, which dominate streamflow change for 48.9-50.9% of the stations. In contrast, the dominant factor translated into P in 72.3-72.9% of stations when using reconstructed streamflow datasets, in agreement with most previous global assessments. These differences indicate that streamflow attributions using reconstructed streamflow might overestimate the effects of P while underestimating the roles of other factors, such as the vegetation and human impact. At the global scale, the other factors affected by many catchment characteristics and their impacts on streamflow change have remarkable regional differences. This study highlights the necessity to apply the observed data in streamflow attribution to avoid biased conclusions regarding the dominant factor of streamflow changes.

Designing intelligent nano-bomb with on-demand site-specific drug burst release to synergize with high-intensity focused ultrasound cancer ablation.

High intensity focused ultrasound (HIFU) has been widely used in clinical treatment of cervical cancer for its non-invasiveness and sharp treatment margins with very low complication rates. However, how to intensify the therapeutic efficacy of HIFU by specifically focusing the ultrasound energy on targeting pathological tissues is still a bottleneck for it to realize successful cancer ablation. Herein, a multifunctional organic-inorganic hybrid nanovesicles, by coating ultrathin silica shell on the surface of poly (lactic-co-glycolic acid) (PLGA) loaded with perfluorocarbon (PFOB), hydrophobic antitumor ruthenium complex (RuPOP) and superparamagnetic Fe3O4, has been designed to achieve synchronous ultrasound (US)/magnetic resonance imaging (MR) dual mode imaging-guided HIFU-triggered chemotherapy. The introduction of PFOB in this nanosystem could cause phase transition and make it gasification to cause collapse of the outer ultrathin silicon shell under HIFU irradiation, which results in enhanced intensive mechanical stress during blasting and enhanced therapeutic effect. The blasting behavior of this nanosystem triggered by HIFU also induced the on-demand RuPOP burst release in tumor site, thus maximizing the inhibition on residual tumor induced by inhomogeneous HIFU ablation. Taken together, this treatment strategy could overcome the inevitable tumor recurrence and significantly reduces systemic side effects of HIFU, thus could be further developed for noninvasive cancer therapy.