2-ethylhexyl diphenyl phosphate exposure induces duodenal inflammatory injury through oxidative stress in chickens.

2-ethylhexyl diphenyl phosphate (EHDPHP) is a widely used organophosphorus flame retardant and plasticizer, which is commonly found in the environment. EHDPHP not only potentially harms the environment but also causes different degrees of damage to the organism. In this study, the duodenum of chicks was selected as the potential toxic target organ to explore the mechanism of duodenal injury induced by EHDPHP exposure. Ninety one-day-old healthy male chicks were selected and randomly divided into C1(control group), C2(solvent control group), L(800 mg/kg), M(1600 mg/kg), H(3200 mg/kg) according to different doses of EHDPHP after one week of environmental adaptation. The chicks were given continuous gavage for 14 d, 28 d, and 42 d. It was found that constant exposure to EHDPHP caused an increase in duodenal MDA content, a decrease in P-gp, SOD, GSH-Px activities, and a decrease in duodenal mucosal immune factor (sIgA, GSH-Px). The expression of sIgM and mucosal link proteins (CLDN, OCLN, ZO-1, JAM) decreased, and the expression of the inflammatory protein (NF-κB, COX2) in duodenal tissues was up-regulated. The results showed that continuous exposure to EHDPHP could cause duodenal oxidative stress, inflammation, and mucosal barrier damage in chicks, which provided a basis for studying the mechanism of toxic damage caused by EHDPHP in poultry.

Real-time detection and resection of sentinel lymph node metastasis in breast cancer through a rare earth nanoprobe based NIR-IIb fluorescence imaging.

Sentinel lymph node (SLN) biopsy is a commonly employed procedure for the routine assessment of axillary involvement in patients with breast cancer. Nevertheless, conventional SLN mapping cannot reliably distinguish the presence and absence of metastatic disease. Additionally, the complex anatomical structures and lymphatic drainage patterns surrounding tumor sites pose challenges to the sensitivity of the near-infrared fluorescence imaging with subcutaneously injected probes. To identifying the SLN metastases, we developed a novel nanoprobe for in vivo fluorescence imaging within the second near-infrared (NIR-II) range. This nanoprobe utilizes rare-earth nanoparticles (RENPs) to emit bright fluorescence at 1525 nm and is conjugated with tumor-targeted hyaluronic acid (HA) to facilitate the detection of metastatic SLN. Upon intravenous administration, RENPs@HA effectively migrated to SLNs and selectively entered metastatic breast tumor cells through CD44-mediated endocytosis. The RENPs@HA nanoprobes exhibited rapid accumulation in metastatic inguinal lymph nodes in mouse model, displaying a 5.8-fold-stronger fluorescence intensity to that observed in normal SLNs. Consequently, these nanoprobes effectively differentiate metastatic SLNs from normal SLNs. Importantly, the probes accurately detected micrometastases. These findings underscore the potential of RENPs@HA for real-time visualization and screening of SLNs metastasis.

Untethered Microgrippers for Biopsy in the Upper Urinary Tract.

Untethered microrobots offer the possibility to perform medical interventions in anatomically complex and small regions in the body. Presently, it is necessary to access the upper urinary tract to diagnose and treat Upper Tract Urothelial Carcinoma (UTUC). Diagnostic and treatment challenges include ensuring adequate tissue sampling, accurately grading the disease, achieving completeness in endoscopic treatment, and consistently delivering medications to targeted sites. This work introduces microgrippers (µ-grippers) that are autonomously triggered by physiological temperature for biopsy in the upper urinary tract. The experiments demonstrated that µ-grippers can be deployed using standard ureteral catheters and maneuvered using an external magnetic field. The µ-grippers successfully biopsied tissue samples from ex vivo pig ureters, indicating that the thin-film bilayer springs' autonomous, physiologically triggered actuation exerts enough force to retrieve urinary tract tissue. The quality of these biopsy samples is sufficient for histopathological examination, including hematoxylin and eosin (H&E) and GATA3 immunohistochemical staining. Beyond biopsy applications, the µ-grippers' small size, wafer-scale fabrication, and multifunctionality suggest their potential for statistical sampling in the urinary tract. Experimental data and clinical reports underscore this potential through statistical simulations that compare the efficacy of µ-grippers with conventional tools, such as ureteroscopic forceps and baskets.

Miniaturized Hyperspectral Imager Utilizing a Reconfigurable Filter Array for Both High Spatial and Spectral Resolutions.

Miniaturized hyperspectral imaging based on filter arrays has attracted much attention in consumer applications, such as food safety and biomedical applications. In this Letter, we demonstrate a miniaturized hyperspectral imager using a reconfigurable filter array to tackle the existing trade-off issue between the spectral and spatial resolutions. Utilizing tens of intermediate states of a vanadium dioxide cavity, we increase the total number of physical spectral channels by tens of times from a 2 × 2 mosaic filter unit, providing both high spatial and spectral resolutions for spectral imaging. The reconfigurable filter has a good spectral resolvability of 10 nm in the visible range with a wavelength inaccuracy of less than 2.1 nm. Hyperspectral imaging is demonstrated with a frame rate of 4.5 Hz.

Light-Activated In Situ Vaccine with Enhanced Cytotoxic T Lymphocyte Infiltration and Function for Potent Cancer Immunotherapy.

In situ cancer vaccination is an attractive strategy that stimulates protective antitumor immunity. Cytotoxic T lymphocytes (CTLs) are major mediators of the adaptive immune defenses, with critical roles in antitumor immune response and establishing immune memory, and are consequently extremely important for in situ vaccines to generate systemic and lasting antitumor efficacy. However, the dense extracellular matrix and hypoxia in solid tumors severely impede the infiltration and function of CTLs, ultimately compromising the efficacy of in situ cancer vaccines. To address this issue, a robust in situ cancer vaccine, Au@MnO2 nanoparticles (AMOPs), based on a gold nanoparticle core coated with a manganese dioxide shell is developed. The AMOPs modulated the unfavorable tumor microenvironment (TME) to restore CTLs infiltration and function and efficiently induced immunogenic cell death. The Mn2+-mediated stimulator of the interferon genes pathway can be activated to further augment the therapeutic efficacy of the AMOPs. Thus, the AMOPs vaccine successfully elicited long-lasting antitumor immunity to considerably inhibit primary, recurrent, and metastatic tumors. This study not only highlights the importance of revitalizing CTLs efficacy against solid tumors but also makes progress toward overcoming TME barriers for sustained antitumor immunity.

TGF-ß/SMAD Pathway Mediates Cadmium Poisoning-Induced Chicken Liver Fibrosis and Epithelial-Mesenchymal Transition.

Cadmium(Cd) is a toxic heavy metal widely present in the environment, capable of accumulating in the liver and causing liver damage. In this study, the mechanism of cadmium-induced liver fibrosis in chickens was investigated from the perspective of hepatocyte epithelial-mesenchymal transition (EMT) based on the establishment of a model of chicken cadmium toxicity and a model of cadmium-stained cells in a chicken hepatocellular carcinoma cell line (LMH). The 7-day-old chickens were randomly divided into the regular group (C group) and cadmium poisoning group (Cd group), and the entire test cycle was 60 days. Three sampling time points of 20 days, 40 days, and 60 days were established. By testing the liver coefficient, histopathological and ultrastructural changes in chicken livers were observed. The enzyme activities of liver function and the expression changes of fibrosis markers (COL1A1, Fibronectin), epithelial-mesenchymal transition markers (E-cadherin, Vimentin, and α-SMA), and the critical factors of the TGF-ß/SMAD signaling pathway (TGF-ß1, SMAD 2, and SMAD 3) were detected in the liver expression changes. The results showed that at the same sampling time point, the chicken liver coefficient in group Cd was significantly higher than that in control group (P < 0.01); the activities of the liver function enzymes ALT and AST in chickens in the Cd group were significantly higher than those in the C group (P < 0.01); liver hepatocytes degenerated and necrotic, the number of erythrocytes in the blood vessels was increased, and inflammatory cells infiltrated in the sinusoidal gap; the perisinusoidal gap of the liver was enlarged, and there was an apparent aggregation of collagen fibers in the intervening period as seen by transmission electron microscopy. The results of Masson staining showed that the percentage of fiber area was significantly higher in the chickens' livers of the Cd group. The fiber area percentage was significantly higher. The results of real-time fluorescence quantitative PCR and Western Blot showed that the expression of E-cadherin in the livers of chickens in the Cd group was significantly lower than that in the C group (P < 0.01). The expression of α-SMA, Vimentin, COL1A1, Fibronectin, TGF-ß1, SMAD 2, and SMAD 3 was significantly higher than that in the C group (P < 0.01). The results of in vitro assays showed that in the LMH cell model established by adding trimethylamine N-oxide, an activator of the TGF-ß/SMAD signaling pathway, and oxidized picric acid, an inhibitor of the TGF-ß/SMAD signaling pathway, the expression of E-cadherin was significantly reduced in cadmium-stained LMH cells (P < 0.01). The expression of α-SMA, Vimentin, COL1A1, Fibronectin, TGF-ß, SMAD 2, and SMAD 3 was significantly elevated (P < 0.01). Cadmium and Trimethylamine N-oxide, an activator of the TGF-ß/SMAD signaling pathway, promoted the expression of these factors. In contrast, the inhibitor of the TGF-ß/SMAD signaling pathway, Oxymatrine, a TGF-ß/SMAD signaling pathway inhibitor, significantly slowed down these changes. These results suggest that cadmium induces hepatic epithelial-mesenchymal transition by activating the TGF-ß/SMAD signaling pathway in chicken hepatocytes, promoting hepatic fibrosis.

Heat-shock transcription factor HsfA8a regulates heat stress response in Sorbus pohuashanensis.

MAIN CONCLUSION: The SpHsfA8a upregulated expression can induce the expression of multiple heat-tolerance genes, and increase the tolerance of Arabidopsis thaliana to high-temperature stress. Sorbus pohuashanensis is an ornamental tree used in courtyards. However, given its poor thermotolerance, the leaves experience sunburn owing to high temperatures in summer, severely affecting its ornamental value. Heat-shock transcription factors play a critical regulatory role in the plant response to heat stress. To explore the heat-tolerance-related genes of S. pohuashanensis to increase the tree's high-temperature tolerance, the SpHsfA8a gene was cloned from S. pohuashanensis, and its structure and expression patterns in different tissues and under abiotic stress were analyzed, as well as its function in heat tolerance, was determined via overexpression in Arabidopsis thaliana. The results showed that SpHsfA8a encodes 416 amino acids with a predicted molecular weight of 47.18 kDa and an isoelectric point of 4.63. SpHsfA8a is a hydrophilic protein without a signal peptide and multiple phosphorylation sites. It also contains a typical DNA-binding domain and is similar to MdHsfA8a in Malus domestica and PbHsfA8 in Pyrus bretschneideri. In S. pohuashanensis, SpHsfA8a is highly expressed in the roots and fruits and is strongly induced under high-temperature stress in leaves. The heterologous expression of SpHsfA8a in A. thaliana resulted in a considerably stronger growth status than that of the wild type after 6 h of treatment at 45 °C. Its proline content, catalase and peroxidase activities also significantly increased, indicating that the SpHsfA8a gene increased the tolerance of A. thaliana to high-temperature stress. SpHsfA8a could induce the expression of multiple heat-tolerance genes in A. thaliana, indicating that SpHsfA8a could strengthen the tolerance of A. thaliana to high-temperature stress through a complex regulatory network. The results of this study lay the foundation for further elucidation of the regulatory mechanism of SpHsfA8a in response of S. pohuashanensis to high-temperature stress.

Subthalamic and pallidal oscillations and their couplings reflect dystonia severity and improvements by deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) targeting the globus pallidus internus (GPi) and subthalamic nucleus (STN) is employed for the treatment of dystonia. Pallidal low-frequency oscillations have been proposed as a pathophysiological marker for dystonia. However, the role of subthalamic oscillations and STN-GPi coupling in relation to dystonia remains unclear. OBJECTIVE: We aimed to explore oscillatory activities within the STN-GPi circuit and their correlation with the severity of dystonia and efficacy achieved by DBS treatment. METHODS: Local field potentials were recorded simultaneously from the STN and GPi from 13 dystonia patients. Spectral power analysis was conducted for selected frequency bands from both nuclei, while power correlation and the weighted phase lag index were used to evaluate power and phase couplings between these two nuclei, respectively. These features were incorporated into generalized linear models to assess their associations with dystonia severity and DBS efficacy. RESULTS: The results revealed that pallidal theta power, subthalamic beta power and subthalamic-pallidal theta phase coupling and beta power coupling all correlated with clinical severity. The model incorporating all selected features predicts empirical clinical scores and DBS-induced improvements, whereas the model relying solely on pallidal theta power failed to demonstrate significant correlations. CONCLUSIONS: Beyond pallidal theta power, subthalamic beta power, STN-GPi couplings in theta and beta bands, play a crucial role in understanding the pathophysiological mechanism of dystonia and developing optimal strategies for DBS.

A Dual-Cascade Activatable Near-Infrared Fluorescent Probe for Precise Intraoperative Imaging of Tumor.

Accurate intraoperative tumor delineation is critical to achieving successful surgical outcomes. However, conventional techniques typically suffer from poor specificity and low sensitivity and are time-consuming, which greatly affects intraoperative decision-making. Here, we report a cascade activatable near-infrared fluorescent (NIRF) probe IR780SS@CaP that can sequentially respond to tumor acidity and elevated glutathione levels for accurate intraoperative tumor localization. Compared with nonactivatable and single-factor activatable probes, IR780SS@CaP with a cascade strategy can minimize nonspecific activation and false positive signals in a complicated biological environment, affording a superior tumor-to-normal tissue ratio to facilitate the delineation of abdominal metastases. Small metastatic lesions that were less than 1 mm in diameter can be precisely identified by IR780SS@CaP and completely excised under NIRF imaging guidance. This study could benefit tumor diagnosis and image-guided tumor surgery by providing real-time information and reliable decision support, thus reducing the risk of both recurrence and complications to improve patient outcomes.

Cerebrospinal fluid CXCL13 concentration for diagnosis of neurosyphilis: a systematic review and meta-analysis.

OBJECTIVE: To systematically assess the diagnostic accuracy of CXCL13 testing of cerebrospinal fluid (CSF) for neurosyphilis diagnosing. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Cochrane Library and Web of Science databases from their inception until 1 May 2023. ELIGIBILITY CRITERIA: Both cross-sectional and case-control diagnostic test studies evaluating the diagnostic value of CSF CXCL13 in diagnosing neurosyphilis were included, with no language restrictions. DATA EXTRACTION AND SYNTHESIS: Two researchers extracted data independently from all finally included articles. The updated Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the quality of the included studies. Quantitative synthesis was done using a bivariate random-effects model. RESULTS: This meta-analysis included seven eligible studies involving a total of 1152 patients with syphilis and 430 patients with neurosyphilis. The pooled sensitivity, specificity and summary area under the curve (AUC) of CSF CXCL13 testing for the diagnosis of neurosyphilis were 0.76 (95% CI 0.64 to 0.85; I2=82%), 0.83 (95% CI 0.80 to 0.85; I2=32.29%) and 0.84 (95% CI 0.81 to 0.87), respectively. Sensitivity analysis confirmed the stability of the combined results. Meta-regression analysis revealed that the heterogeneity of pooled sensitivity was related to different study regions; subgroup analysis indicated that the diagnostic value of CSF CXCL13 testing reported in studies from China was superior to that reported in non-Chinese studies (pooled sensitivity, specificity and summary AUC values were 0.84 (I2=0) vs 0.64 (I2=79.53%), 0.83 (I2=42.03%) vs 0.83 (I2=32.87%) and 0.87 vs 0.83, respectively). The diagnostic value reported in studies with a sample size ≥200, unclassified neurosyphilis and HIV-negative subgroups was superior to the total combined value. CONCLUSIONS: This meta-analysis has demonstrated a reasonable level of accuracy for diagnosis of neurosyphilis with CSF CXCL13 testing. Further multicentre, prospective diagnostic studies, especially in asymptomatic neurosyphilis and HIV-infected patients, are needed to provide more evidence for evaluation before clinical application. PROSPERO REGISTRATION NUMBER: CRD42023414212.

ADAMTS5 Promotes Permeability of the Blood-Brain Barrier during Treponema pallidum Subspecies pallidum Invading the Central Nervous System.

The pathogenesis of neurosyphilis remains unclear. A previous study found a noteworthy up-regulation of a disintegrin and metalloproteinase with thrombospondin type 1 motif 5 (ADAMTS5) gene in human brain microvascular endothelial cells cocultured with Treponema pallidum subspecies pallidum (Tp). To investigate the ADAMTS5 role in Tp invading the central nervous system (CNS), we conducted relevant experiments. Our study revealed that Tp caused an increase in human cortical microvascular endothelial cell/D3 (hCMEC/D3) barrier permeability and significantly enhanced ADAMTS5 expression. The heightened permeability of the hCMEC/D3 barrier was effectively mitigated by inhibiting ADAMTS5. During this process, Tp promoted interleukin-1ß production, which, in turn, facilitated ADAMTS5 expression. Furthermore, Tp significantly reduced the glycocalyx on the surface of hCMEC/D3 cells, which was also ameliorated by inhibiting ADAMTS5. Additionally, ADAMTS5 and endothelial glycocalyx components notably increased in the cerebrospinal fluid of HIV-negative neurosyphilis patients. This research provided the first demonstration of the ADAMTS5 role in Tp invading the CNS and offered new insight into neurosyphilis pathogenesis.

Genetically engineered macrophages as living cell drug carriers for targeted cancer therapy.

Precise targeting is a major prerequisite for effective cancer therapy because it ensures a sufficient therapeutic dosage in tumors while minimizing off-target side effects. Herein, we report a live-macrophage-based therapeutic system for high-efficiency tumor therapy. As a proof of concept, anti-human epidermal growth factor receptor-2 (HER2) affibodies were genetically engineered onto the extracellular membrane of macrophages (AE-Mφ), which further internalized doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) nanoparticles (NPs) to produce a macrophage-based therapeutic system armed with anti-HER2 affibodies. NPs(DOX)@AE-Mφ were able to target HER2+ cancer cells and specifically elicit affibody-mediated cell therapy. Most importantly, the superior HER2 + -targeting capability of NPs(DOX)@AE-Mφ greatly guaranteed high accumulation at the tumor site for improved chemotherapy, which acted synergistically with cell therapy to significantly enhance anti-tumor efficacy. This study suggests that NPs(DOX)@AE-Mφ could be utilized as an innovative 'living targeted drug' platform for combining both macrophage-mediated cell therapy and targeted chemotherapy for the individualized treatment of solid tumors.

Prognostic value of oxidative stress-related genes in colorectal cancer and its correlation with tumor immunity.

Oxidative stress (OS) plays an essential role in chronic diseases such as colorectal cancer (CRC). In this study, we aimed to explore the relation between oxidative stress-related genes and CRC prognosis and their involvement in the immune microenvironment. Totally 101 OS-related genes were selected from the MsigDB database. Then, univariate Cox regression was used to explore the prognostic value of the selected genes correlated with the CRC patient survival in the TCGA database. A total of 9 prognostic OS-related genes in CRC were identified. Based on consensus clustering, CRC patients were then categorized into two molecular subtypes. A prognostic risk model containing 8 genes was established using Lasso regression, and CRC patients were divided into high or low-risk groups based on the median risk scores. The predictive value of the 8 genes in CRC prognosis was validated using ROC curves, which indicate that CTNNB1, STK25, RNF112, SFPQ, MMP3, and NOL3 were promising prognostic biomarkers in CRC. Furthermore, the immune cell infiltration levels in different risk groups or CRC subtypes were analyzed. We found that the high-risk or C1 subtype had immunosuppressive microenvironment, which might explain the unfavorable prognosis in the two groups of CRC patients. Additionally, functional experiments were conducted to investigate the effects of OS-related genes on CRC cell proliferation, stemness, and apoptosis. We found that CTNNB1, HSPB1, MMP3, and NOL3 were upregulated in CRC tissues and cells. Knockdown of CTNNB1, HSPB1, MMP3, and NOL3 significantly suppressed CRC cell proliferation, stemness and facilitated CRC cell apoptosis. In conclusion, we established prognostic CRC subtypes and an eight-gene risk model, which may provide novel prognostic indicators and benefit the design of individualized therapeutic strategies for CRC patients.

A multi-omics approach to unravelling the coupling mechanism of nitrogen metabolism and phenanthrene biodegradation in soil amended with biochar.

The presence of polycyclic aromatic hydrocarbons (PAHs) in soil negatively affects the environment and the degradation of these contaminants is influenced by nitrogen metabolism. However, the mechanisms underlying the interrelationships between the functional genes involved in nitrogen metabolism and phenanthrene (PHE) biodegradation, as well as the effects of biochar on these mechanisms, require further study. Therefore, this study utilised metabolomic and metagenomic analysis to investigate primary nitrogen processes, associated functional soil enzymes and functional genes, and differential soil metabolites in PHE-contaminated soil with and without biochar amendment over a 45-day incubation period. Results showed that dissimilatory nitrate reduction to ammonium (DNRA) and denitrification were the dominant nitrogen metabolism processes in PHE-contaminated soil. The addition of biochar enhanced nitrogen modules, exhibiting discernible temporal fluctuations in denitrification and DNRA proportions. Co-occurrence networks and correlation heatmap analysis revealed potential interactions among functional genes and enzymes responsible for PHE biodegradation and nitrogen metabolism. Notably, enzymes associated with denitrification and DNRA displayed significant positive correlation with enzymes involved in downstream phenanthrene degradation. Of particular interest was stronger correlation observed with the addition of biochar. However, biochar amendment inhibited the 9-phenanthrol degradation pathway, resulting in elevated levels of glutathione (GSH) in response to environmental stress. These findings provide new insights into the interactions between nitrogen metabolism and PHE biodegradation in soil and highlight the dual effects of biochar on these processes.

In Situ Constructing Ultrafast Ion Channel for Promoting High-Rate Cycle Stability of Nano-Na3V2(PO4)3 Cathode.

Encapsulating nanomaterials in carbon is one of the main ways to increase the cathode stability, but it is difficult to simultaneously optimize the rate capacity and enhance durability derived from the insufficient ion transport channels and deficient ion adsorption sites that constipate the ion transport and pseudocapacitive reaction. Herein, we develop the ligand-confined growth strategy to encapsulate the nano-Na3V2(PO4)3 cathode material in various carbon channels (microporous, mesoporous, and macroporous) to discriminate the optimal carbon channels for synchronously improving rate capacity and holding the high-rate cycle stability. Benefiting from the unobstructed ion/charge transport channels and flexible maskant created by the interconnected mesoporous carbon channels, the prepared Na3V2(PO4)3 nanoparticles confined in mesoporous carbon channel (Mes-NVP/C) achieve a discharge-specific capacity of 70 mAh g-1 even at the ultrahigh rate of 100 C, higher than those of the Na3V2(PO4)3 nanoparticles confined in microporous and macroporous carbon channel (Micr-NVP/C and Macr-NVP/C), respectively. Significantly, the capacity retention rate of Mes-NVP/C after 5000 cycles at 20 C is as high as 90.48%, exceeding most of the reported work. These findings hold great promise for traditional cathode materials to synergistically realize fast charging ability and long cycle life.

Untethered shape-changing devices in the gastrointestinal tract.

INTRODUCTION: Advances in microfabrication, automation, and computer engineering seek to revolutionize small-scale devices and machines. Emerging trends in medicine point to smart devices that emulate the motility, biosensing abilities, and intelligence of cells and pathogens that inhabit the human body. Two important characteristics of smart medical devices are the capability to be deployed in small conduits, which necessitates being untethered, and the capacity to perform mechanized functions, which requires autonomous shape-changing. AREAS COVERED: We motivate the need for untethered shape-changing devices in the gastrointestinal tract for drug delivery, diagnosis, and targeted treatment. We survey existing structures and devices designed and utilized across length scales from the macro to the sub-millimeter. These devices range from triggerable pre-stressed thin film microgrippers and spring-loaded devices to shape-memory and differentially swelling structures. EXPERT OPINION: Recent studies demonstrate that when fully enabled, tether-free and shape-changing devices, especially at sub-mm scales, could significantly advance the diagnosis and treatment of GI diseases ranging from cancer and inflammatory bowel disease (IBD) to irritable bowel syndrome (IBS) by improving treatment efficacy, reducing costs, and increasing medication compliance. We discuss the challenges and possibilities associated with ensuring safe, reliable, and autonomous operation of these smart devices.

An Activatable Near-Infrared Fluorescent Probe for Precise Detection of the Pulmonary Metastatic Tumors: A Traditional Molecule Having a Stunning Turn.

An accurate detection of lung metastasis is of great significance for making better treatment choices and improving cancer prognosis, but remains a big challenge in clinical practice. In this study, we propose a reinventing strategy to develop a pH-activatable near-infrared (NIR) fluorescent nanoprobe, pulmonary metastasis tracer (denoted as PMT), based on assembly of NIR dye IR780 and calcium phosphate (CaP). By delicately tuning the intermolecular interactions during the assembly process and dye doping content, as well as the synthetic condition of probe, the fluorescence of PMT could be finely adjusted via the tumor acidity-triggered disassembly. Notably, the selected PMT9 could sharply convert subtle pH variations into a distinct fluorescence signal to generate high fluorescence ON/OFF contrast, dramatically reducing the background signals. Benefiting from such preferable features, PMT9 is able to precisely identify not only the tumor sites in orthotopic lung cancer models but also the pulmonary metastases in mice with remarkable signal-to-background ratio (SBR). This study provides a unique strategy to turn shortcomings of traditional dye IR780 during in vivo imaging into advantages and further expand the application of fluorescent probe to image lung associated tumor lesions.

Dendritic Cell-Derived Exosomes Stimulated by Treponema pallidum Induce Endothelial Cell Inflammatory Response through the TLR4/MyD88/NF-κB Signaling Pathway.

Exosomes have been implicated in vascular damage in recent research. The influence of dendritic cell-derived exosomes generated by Treponema pallidum (T. pallidum) on the inflammatory process of vascular cells was examined in this study. Human umbilical vein endothelial cells (HUVECs) were cocultured with exosomes isolated from dendritic cells induced by T. pallidum. Western blot and reverse transcription-quantitative real-time polymerase chain reaction were used to assess toll-like receptor 4 (TLR4) expression and the quantity of proinflammatory cytokines. The findings showed that the expression of TLR4 was considerably upregulated, and TLR4 knockdown dramatically reduced interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) production in exosome-treated HUVECs. Furthermore, TLR4 silencing reduced myeloid differentiation primary response protein 88 (MyD88) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) levels in exosome-treated HUVECs. Additionally, suppression of the activity of NF-κB with BAY11-7082, an NF-κB inhibitor, also reduced the exosome-treated inflammatory response. Our results suggested that dendritic cell-derived exosomes stimulated by T. pallidum induced endothelial cell inflammation, and the TLR4/MyD88/NF-κB signal axis was activated, significantly increasing IL-1ß, IL-6, and TNF-α expression. This may have a significant role in the vascular inflammatory response in syphilis, which would contribute to the understanding of the pathogenesis of syphilis and the host immunological response to T. pallidum.

Protective effects of maternal administration of total saponins of Codonopsis pilosula in the mice offspring following diarrhea: role of immune function, antioxidant function, and intestinal inflammatory injury.

Total saponins of Codonopsis (TSC) are a kind of critical bioactive substances in Codonopsis, which have anti-inflammatory, antioxidant, anti-ulcer, immunomodulatory effects, and protective effects on ulcerative enteritis. In this study, TSC (3.75 mL/kg, gavage) was administered once a day to 13-day gestation Kunming mice for 5 days. On day 13 of birth, the offspring were given Escherichia coli solution (0.15 mL/mouse, intraperitoneal injection) and senna leaf decoction (0.15 mL/mouse, gavage) once a day for 6 days. The results showed that gestation maternal administration of TSC effectively reduced the diarrhea index, increased the content of sIgA, IgG, SOD, and GSH, inhibited the TLR4/MyD88/NF-κB pathway in the intestine, reduced the expression of inflammatory factors, and alleviated intestinal injury in the littermates. The results provided a critical reference for the clinical application of TSC to control diarrhea in animal offspring.

Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination.

BACKGROUND: Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and has significant scope for improvement. Moreover, current nanomedicine studies mainly use disulfide-thiol exchange to deplete glutathione (GSH) for GPX4 inactivation, which is unsatisfactory because of the compensatory effect of continuous GSH synthesis. METHODS: In this study, we design a two-in-one ferroptosis-inducing nanoplatform using iron-based metal-organic framework (MOF) that combines iron supply and GPX4 deactivation by loading the small molecule buthionine sulfoxide amine (BSO) to block de novo GSH biosynthesis, which can achieve sustainable GSH elimination and dual ferroptosis amplification. A coated lipid bilayer (L) can increase the stability of the nanoparticles and a modified tumor-homing peptide comprising arginine-glycine-aspartic acid (RGD/R) can achieve tumor-specific therapies. Moreover, as a decrease in GSH can alleviate resistance of cancer cells to chemotherapy drugs, oxaliplatin (OXA) was also loaded to obtain BSO&OXA@MOF-LR for enhanced cancer chemo-ferrotherapy in vivo. RESULTS: BSO&OXA@MOF-LR shows a robust tumor suppression effect and significantly improved the survival rate in 4T1 tumor xenograft mice, indicating a combined effect of dual amplified ferroptosis and GSH elimination sensitized apoptosis. CONCLUSION: BSO&OXA@MOF-LR is proven to be an efficient ferroptosis/apoptosis hybrid anti-cancer agent. This study is of great significance for the clinical development of novel drugs based on ferroptosis and apoptosis for enhanced cancer chemo-ferrotherapy.