Lanthanide complexes with an azo-dye chromophore ligand: syntheses, crystal structures, and near-infrared luminescence by long-wavelength excitation.

Near-infrared (NIR) emissive probes are becoming increasingly popular in biological sensing and imaging due to the advantages of non-invasiveness and deep tissue-penetrating ability. Herein, a series of complexes of trivalent lanthanide ions (Ln = Yb, Er, and Gd) with the commercially available azo dye chromophore 2R (Na2H2C2R) as ligand and featuring respectively H2O and dimethylsulfoxide (DMSO) as ancillary ligands have been prepared. Formulated as [Ln2(HC2R)2(H2O)10]·8H2O (1-3, Ln = Yb, Er, Gd) and [Ln2(HC2R)2(DMSO)10]·2DMSO (4-6, Ln = Yb, Er, Gd), their structures have been determined by single-crystal X-ray diffraction studies. Photophysical property studies revealed NIR emissions of the DMSO complexes characteristic of Yb(III) and Er(III), effectively sensitized by the dye ligand arising mainly from the π-π* transition of the chromophore. The long-wavelength excitation of the complexes, covering the whole visible-light range and extending into the NIR region, portends the potential applications of such complexes for flexible bioimaging and sensing.

Impact of guideline-directed medical therapy on systolic blood pressure and cardiovascular outcomes in patients with heart failure and low blood pressure: A systematic review and meta-analysis.

AIMS: Existing research indicates that patients with heart failure (HF) may have restricted access to guideline-directed medical therapy (GDMT) when their blood pressure (BP) is comparatively low. However, recent clinical trials suggest that HF patients with low BP could still benefit from certain HF medications, which have a minimal impact on BP. This systematic review and meta-analysis was conducted to determine whether this applies to all GDMT. METHODS AND RESULTS: A systematic search of MEDLINE and EMBASE was conducted for studies published from inception to 10 January 2024. Randomized controlled trials were selected if they reported on the longitudinal change of systolic BP (SBP) due to GDMT, or the risks of cardiovascular events in HF patients based on SBP categories. Weighted mean difference (WMD), hazard ratio or relative risk, and corresponding 95% confidence intervals (CI) were pooled for meta-analysis where possible. Data from 20 studies, encompassing information on 84 782 individuals, were analysed. Overall, GDMT is associated with lower SBP (WMD, -2.16; 95% CI -2.86 to -1.46), with no significant difference between baseline low and non-low BP subgroups (interaction p = 0.810). However, SBP of the treatment group increased by 5.8 mmHg from baseline in the low SBP subgroup during follow-up, while it decreased by 4.0 mmHg in the baseline non-low SBP subgroup. GDMT demonstrated similar cardiovascular benefits and risk of hypotension between low and non-low SBP subgroups (interaction p = 0.318 and 0.903, respectively). CONCLUSIONS: Guideline-directed medical therapy is associated with a negligible decrease in SBP, but can provide similar cardiovascular benefits in both low and non-low SBP HF patients, with no significant interaction with SBP as to hypotension. Therefore, GDMT should be initiated and maintained in HF patients with low BP.

In Situ Visualization of RNA-Specific Sialylation on Living Cell Membranes to Explore N-Glycosylation Sites.

The small RNAs on living cell membranes were recently found to be N-glycosylated and terminated with sialic acids, although the glycosylation sites and potential functions remain unclear. Herein, we designed a second-generation hierarchical coding strategy (HieCo 2) for in situ visualization of cell surface RNA-specific sialylation. After covalently binding DNA codes to sialic acids and then binding a DNA code to a target RNA via sequence specificity, cascade decoding processes were performed with subsequent signal amplification that enabled sensitive in situ visualization of low-abundance Y5 RNA-specific sialic acids on living cell membranes. The proposed strategy unveils the number of glycosylation sites on a single RNA and reveals the binding preference of glycosylated RNAs to different sialic acid binding-immunoglobulin lectin-type receptors, demonstrating a new route for exploration of the glycosylated RNA-related biological and pathological processes.

In situ SERS imaging of protein-specific glycan oxidation on living cells to quantitatively visualize pathogen-cell interactions.

Glycan oxidation on the cell surface occurs in many specific life processes including pathogen-cell interactions. This work develops a surface-enhanced Raman scattering (SERS) imaging strategy for in situ quantitative monitoring of protein-specific glycan oxidation mediated pathogen-cell interactions by utilizing Raman reporter DTNB and aptamer co-assembled platinum shelled gold nanoparticles (Au@Pt-DTNB/Apt). Using Fusarium graminearum (FG) and MCF-7 cells as models, Au@Pt-DTNB/Apt can specifically bind to MUC1 protein on the cell surface containing heavy galactose (Gal) and N-acetylgalactosamine (GalNAc) modification. When FG interacts with cells, the secreted galactose oxidase (GO) can oxidize Gal/GalNAc, and the generated reactive oxygen species (ROS) further oxidizes DTNB to produce TNB for greatly enhancing the SERS signal. This strategy can quantitatively visualize for the first time both the protein-specific glycan oxidation and the mediated pathogen-cell interactions, thus providing key quantitative information to distinguish and explore the pathogen-resistance and pharmacological mechanisms of different drugs.

In Situ Glycan Analysis and Editing in Living Systems.

Besides proteins and nucleic acids, carbohydrates are also ubiquitous building blocks of living systems. Approximately 70% of mammalian proteins are glycosylated. Glycans not only provide structural support for living systems but also act as crucial regulators of cellular functions. As a result, they are considered essential pieces of the life science puzzle. However, research on glycans has lagged far behind that on proteins and nucleic acids. The main reason is that glycans are not direct products of gene coding, and their synthesis is nontemplated. In addition, the diversity of monosaccharide species and their linkage patterns contribute to the complexity of the glycan structures, which is the molecular basis for their diverse functions. Research in glycobiology is extremely challenging, especially for the in situ elucidation of glycan structures and functions. There is an urgent need to develop highly specific glycan labeling tools and imaging methods and devise glycan editing strategies. This Perspective focuses on the challenges of in situ analysis of glycans in living systems at three spatial levels (i.e., cell, tissue, and in vivo) and highlights recent advances and directions in glycan labeling, imaging, and editing tools. We believe that examining the current development landscape and the existing bottlenecks can drive the evolution of in situ glycan analysis and intervention strategies and provide glycan-based insights for clinical diagnosis and therapeutics.

Ultra-Galactocation to Sialic Acid on Tumor Cells with A Penta-Functional Dendritic Probe for Enhanced Immune-Killing.

Glycans on tumor cell surface have significant impacts in the immune-killing process. Here an ultra-galactocation to sialic acid (Sia) strategy is designed to hugely introduce galactose (Gal) to Sia and on tumor cells in vivo by using a penta-functional dendritic probe (Den@5F), which efficiently enhances the immune-killing of tumor cells. The Den@5F contains five different kinds of functional groups, including Gal, Cy5, amino, phenylboronic acid (PBA) and 4-(4-(hydroxymethyl)-2-methoxy-5-nitrophenoxy) butanoate (mNB), which can be conveniently prepared through a two-step reaction. After injecting into the tumor-bearing mouse, Den@5F can efficiently block Sia through the specific recognition between PBA and Sia on tumor cells and hugely introduce Gal through the subsequent photo-crosslinking between mNB and amino groups to multiply conjugate excessive Den@5Fs. The comprehensively blocked Sia can prevent the immune escape, and the hugely introduced Gal can promote the immune stimulation of the immune cells, which lead to an efficient enhancement of the immune-killing. The proposed strategy provides a significant and promising tool to promote the clinical immunotherapy of tumor.

Triply Enhanced Immunotherapy via Dual Glycan Reforming Integrated with Perforation.

The enhancement of immunotherapy is an emerging direction to develop highly effective and practical cancer therapeutic methods. Here a triply enhanced immunotherapy drug (TEID) is designed for ingeniously integrating in situ dual glycan reforming with perforation on cell membrane. The TEID is composed of galactose and neuraminidase conjugated streptolysin O (SLO-Gal and SLO-NEU), which are encapsulated in a hyaluronic acid (HA) shell for targeted recognition to tumor tissue via cell surface CD44. After targeted delivery and HAase-mediated degradation in the tumor region, the TEID releases SLO-Gal and SLO-NEU, which can easily anchor Gal and NEU on the tumor cell membrane via the perforation of SLO to perform dual glycan reforming for the introduction of Gal and the cleavage of sialic acid. The former can activate immune cells to secret cytokines for immune-killing, and the latter can weaken the immune inhibition to improve the immunotherapeutic efficacy. Meanwhile, the perforation of SLO can promote the delivery of cytokines into the tumor cells to further enhance the efficacy. The designed triply enhanced immunotherapy strategy opens a significant and promising route to promote clinical immunotherapy of cancer.

Aitongping patch could alleviate cancer pain via suppressing microglia activation and modulating the miR-150-5p/CXCL12 signaling.

PURPOSE: We aimed to investigate the pharmacological effects and mechanisms of the Aitongping formula for treating cancer pain. METHODS: We enrolled 60 cancer patients with Numeric Rating Scale above 4 and grouped them randomly as a Control group (N = 30) and a Patch group (N = 30). We also established bone cancer mice models via tumor implantation. And the animal groups were established as a Sham group, a tumor cell implantation (TCI) group, a TCI + Patch group, and a Patch group. RESULTS: After the validation of successful tumor implantation, we identified candidate miRNAs and genes that were dysregulated in TCI mice and compared their expressions between different mice groups. We also observed the effect of Aitongping patch in vitro in mice primary microglia. The time to disease progression and cancer stability were prolonged by Aitongping patch in cancer patients. And the daily morphine dose was lower, and patients' quality of life was improved in the Patch group. Moreover, Aitongping patch alleviated cancer pain and inhibited microglia activation after the successful implantation of bone tumor in TCI mice. We also observed the dysregulation of miR-150-5p and chemokine CXC motif ligand 12 (CXCL12) mRNA in TCI mice. And CXCL12 was found to be targeted by miR-150-5p. Aitongping patch was found to upregulate miR-150-5p and downregulate CXCL12 in vivo and in vitro. CONCLUSION: Aitongping patch could alleviate cancer pain via suppressing microglia activation, and the downregulation of miR-150-5p, as well as the upregulation of CXCL12 mRNA and protein, induced by tumor implantation or lipopolysaccharide stimulation, was restored by Aitongping treatment.

Rapid conversion of porcine pluripotent stem cells into macrophages with chemically defined conditions.

A renewable source of porcine macrophages derived from pluripotent stem cells (PSCs) would be a valuable alternative to primary porcine alveolar macrophages (PAMs) in the research of host-pathogen interaction mechanisms. We developed an efficient and rapid protocol, within 11 days, to derive macrophages from porcine PSCs (pPSCs). The pPSC-derived macrophages (pPSCdMs) exhibited molecular and functional characteristics of primary macrophages. The pPSCdMs showed macrophage-specific surface protein expression and macrophage-specific transcription factors, similar to PAMs. The pPSCdMs also exhibited the functional characteristics of macrophages, such as endocytosis, phagocytosis, porcine respiratory and reproductive syndrome virus infection and the response to lipopolysaccharide stimulation. Furthermore, we performed transcriptome sequencing of the whole differentiation process to track the fate transitions of porcine PSCs involved in the signaling pathway. The activation of transforming growth factor beta signaling was required for the formation of mesoderm and the inhibition of the transforming growth factor beta signaling pathway at the hematopoietic endothelium stage could enhance the fate transformation of hematopoiesis. In summary, we developed an efficient and rapid protocol to generate pPSCdMs that showed aspects of functional maturity comparable with PAMs. pPSCdMs could provide a broad prospect for the platforms of host-pathogen interaction mechanisms.

Surface-enhanced Raman scattering sensing for detection and mapping of key cellular biomarkers.

Cellular biomarkers mainly contain proteins, nucleic acids, glycans and many small molecules including small biomolecule metabolites, reactive oxygen species and other cellular chemical entities. The detection and mapping of the key cellular biomarkers can effectively help us to understand important cellular mechanisms associated with physiological and pathological processes, which greatly promote the development of clinical diagnosis and disease treatment. Surface-enhanced Raman scattering (SERS) possesses high sensitivity and is free from the influence of strong self-fluorescence in living systems as well as the photobleaching of the dyes. It exhibits rich and narrow chemical fingerprint spectra for multiplexed detection, and has become a powerful tool to detect and map cellular biomarkers. In this review, we present an overview of recent advances in the detection and mapping of different classes of cellular biomarkers based on SERS sensing. These advances fully confirm that the SERS-based sensors and sensing methods have great potential for the exploration of biological mechanisms and clinical applications. Additionally, we also discuss the limitations of present research and the future developments of the SERS technology in this field.

Multifactor analysis of the technique in total laparoscopic gastric cancer.

BACKGROUND: Esophageal gastric anastomosis is a common surgical technique used to treat patients with gastric cancer who undergo total gastrectomy. However, using simple anastomosis techniques alone may not meet the needs of patients in some cases and can lead to complications such as anastomotic stenosis and ulceration. In order to overcome these issues and improve patient prognosis, muscle flap reconstruction technique has emerged. Muscle flap reconstruction is a method of improving gastric-esophageal anastomosis by transplanting muscle tissue. By covering the anastomotic site with muscle tissue, it not only enhances the stability of the anastomosis site but also increases blood supply, promoting healing and recovery of the anastomosis. Therefore, the use of muscle flap reconstruction technique in esophageal gastric anastomosis during total gastrectomy for gastric cancer is increasingly widely applied. AIM: To determine the effectiveness of esophagogastric anastomosis using the muscle flap reconstruction technology in total abdominal gastrectomy for gastric cancer and perform follow-up experiments to understand the factors affecting patients' prognosis. METHODS: The study subjects were 60 patients with gastric cancer who were admitted to our hospital between October 2018 and January 2022. All patients underwent esophagogastric anastomosis using the double muscle flap reconstruction technology in total abdominal gastrectomy. Perioperative indicators were determined, and patients were followed up for 1 year. Furthermore, patient outcomes were observed within 1 year, followed by patient classification based on different outcomes. Moreover, clinicopathological parameters were observed and relevant factors affecting patient prognosis were analyzed. RESULTS: The operation time was 318 ± 43 min, the formation time of esophageal double muscle flap anastomosis was 110 ± 13 min, the number of lymph node dissections was 26 ± 6, the incision length was 3 ± 0.6 cm, intraoperative bleeding volume was 48 ± 15 mL, first anal exhaust time was 5.3 ± 1.8 d, first meal time was 6.0 ± 1.6 d, length of hospital stay was 11.8 ± 2.5, and treatment cost was 5.8 ± 0.7 thousand yuan. The patient experienced three postoperative complications: 2 cases of pulmonary infection and 1 case of respiratory discomfort. During 1-year follow-up, 50 patients survived and 10 died. Univariate analysis revealed that histological types, tumor size, tumor-node-metastasis staging, vascular invasion, and postoperative adjuvant radiotherapy and chemotherapy were the main factors affecting the prognosis of surviving patients. Furthermore, Cox regression analysis revealed that postoperative adjuvant radiotherapy and chemotherapy were the main factors affecting patient prognosis. The survival time of the survival group was significantly higher than that of the death group (P < 0.05). CONCLUSION: Esophagogastric anastomotic using muscle flap reconstruction exhibits good effects on patients who undergo total abdominal gastrectomy for cancer. Postoperative adjuvant radiotherapy and chemotherapy are the main factors affecting patient prognosis.

Exploration of molecular mechanism underlying protective effect of astragaloside IV against radiation-induced lung injury by suppressing ferroptosis.

In this study, we aimed to investigate the pharmacological effects and underlying mechanisms of astragaloside IV (AS IV) against radiation-induced lung injury. We established experimental models of radiation-induced lung injury and observed the effect of AS IV on cell viability, cell death, inflammatory responses and ferroptosis. Accordingly, we found that AS IV restored the suppressed cell viability and promoted cell death induced by X-ray irradiation. Moreover, radiation-induced up-regulation of lactate dehydrogenase (LDH) release, ferroptosis, reactive oxygen species (ROS) and inflammatory responses were also restored by AS IV in a dose-dependent manner. Besides, in radiation-induced lung injury C57BL/6 mice, AS IV evidently alleviated lung injury and promoted the survival rate of lung-injured mice. And the ferroptosis level in mice lung tissues were also alleviated by the administration of AS IV in a dose-dependent manner. As a conclusion, by comparing the changes of ferroptosis, ROS and inflammatory responses in the experimental models, we validated that AS IV could inhibit inflammatory responses and cell injury in the treatment of radiation-induced lung injury by suppressing ferroptosis. This finding not only find potentially effective treatments to mitigate radiation-induced lung injury, but also provides supporting evidence for clinical application of AS IV to improve the management of radiation-treated patients and minimize the associated lung complications or other adverse effects. Moreover, as inflammation and ROS are key contributors to tissue damage in various diseases, our study suggested the potential application of AS IV in the treatments for other diseases.

In situ evaluation of in vivo sialylation with a dual-color imaging strategy.

This work designs a functional dendrimer probe to conveniently identify newly generated sialic acid groups in vivo with a dual-color imaging strategy, which achieves in situ semiquantitative evaluation of the sialylation difference between tumor and normal tissues to reveal sialylation-related biological events and promote clinical tumor diagnosis.

Revealing the mechanism underlying the effects of γ-aminobutyric acid-dioscorin interactions on dioscorin structure and emulsifying properties by molecular dynamic simulations.

Many studies have shown that γ-aminobutyric acid (GABA) exhibits various beneficial biological activities, including gut-modulating, neuro-stimulating, and cardio-protecting activities. Naturally, GABA exists in small amounts in yam, which is primarily synthesized by the decarboxylation of L-glutamic acid in the presence of glutamate decarboxylase. Dioscorin, the major tuber storage protein of yam, has been shown to have good solubility and emulsifying activity. However, how GABA interacts with dioscorin and affects their properties has yet to be clarified. In this research, the physicochemical and emulsifying properties of GABA-fortified dioscorin, which was dried by spray drying and freeze drying, were studied. As results, the freeze-dried (FD) dioscorin produced more stable emulsions, while the spray-dried (SD) dioscorin adsorbed more rapidly to oil/water (O/W) interface. The fluorescence spectroscopy, ultraviolet spectroscopy and circular dichroism spectroscopy showed that GABA changed the structure of dioscorin, by exposing its hydrophobic groups. The addition of GABA significantly promoted the adsorption of dioscorin to the O/W interface and prevented droplets coalescence. The results of molecular dynamics simulation (MD) showed that GABA destroyed the H-bond network between dioscorin and water, increased surface hydrophobicity and finally improved the emulsifying properties of dioscorin.

Biomimetic Nanoparticles Loaded with Ulinastatin for the Targeted Treatment of Acute Pancreatitis.

Ulinastatin is commonly used in the clinic to treat acute pancreatitis (AP), but its therapeutic effect was limited by the presence of the blood-pancreas barrier (BPB) and low specificity. Here, we prepared a macrophage biomimetic nanoparticle (MU) that delivered ulinastatin to address the above issues. Macrophage membrane was used as a shell for a mixture of PEG-PLGA and ulinastatin. It was found that MU showed good stability and biocompatibility in vitro and in vivo. According to in vivo fluorescence imaging, MU displayed a great inflammation targeting effect both in a subcutaneous inflammation model and in situ pancreatitis mouse model, which was ascribed to the presence of adhesion proteins. In vitro and in vivo results demonstrated that MU have a superior AP treatment effect by inhibiting pro-inflammatory factors and keeping cells viability. It was suggested the MU could provide a new strategy for targeted AP treatment.

Signal-On Mass Spectrometric Biosensing of Multiplex Matrix Metalloproteinases with a Phospholipid-Structured Mass-Encoded Microplate.

The detection of matrix metalloproteinases (MMPs) is of great importance for diagnosis and staging of cancer. This work proposed a signal-on mass spectrometric biosensing strategy with a phospholipid-structured mass-encoded microplate for assessment of multiplex MMP activities. The designed substrate and internal standard peptides were subsequently labeled with the reagents of isobaric tags for relative and absolute quantification (iTRAQ), and DSPE-PEG(2000)maleimide was embedded on the surface of a 96-well glass bottom plate to fabricate the phospholipid-structured mass-encoded microplate, which offered a simulated environment of the extracellular space for enzyme reactions between MMPs and the substrates. The strategy achieved multiplex MMP activity assays by dropping the sample in the well for enzyme cleavages, followed by adding trypsin to release the coding regions for ultrahigh performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) analysis. The peak area ratios of released coding regions and their respective internal standard (IS) peptides exhibited satisfied linear ranges of 0.05-50, 0.1-250, and 0.1-100 ng mL-1 with the detection limits of 0.017, 0.046, and 0.032 ng mL-1 for MMP-2, MMP-7, and MMP-3, respectively. The proposed strategy demonstrated good practicability in inhibition analysis and detections of multiplex MMP activities in serum samples. It is of great potential for clinical applications and can be expanded for multiplex enzyme assays.

Tumor identification via in vivo portable Raman detection of sialic acid with a dual gold nanoprobe system.

A dual gold nanoprobe system was designed for in vivo portable Raman detection of sialic acid (SA) for tumor identification. The dual gold nanoprobe system contained two gold nanoprobes, Au10-DTTC/PEG-PBA and Au40-PEG-SA. Au10-DTTC/PEG-PBA was constructed on a 10 nm gold nanoparticle modified with 3,3'-diethylthia tricarbocyanine iodide (DTTCI) as the Raman reporter and 3-aminophenylboronic acid (APBA) through a thiol PEG succinimidyl carboxymethyl ester (HS-PEG-NHS) linker for specific recognition of SA. Au40-PEG-SA was constructed on a 40 nm gold nanoparticle modified with SA through HS-PEG-NHS. For in vivo detection of SA, Au10-DTTC/PEG-PBA and Au40-PEG-SA were subsequently injected into tumor xenografted mice with optimal interval and retention times. Through the specific recognition between PBA and SA, the conjugates of Au10-DTTC/PEG-PBA and Au40-PEG-SA formed in the tumor region emitted strong SERS signals of DTTC, which could be detected by a portable Raman detector. This work provides a convenient and portable method to detect SA in tumor xenografted mice, which is useful for family-stay identification and clinical cleavage of tumors.

Fluorine-doped BiVO4 photocatalyst: Preferential cleavage of C-N bond for green degradation of glyphosate.

With increasing concerns on the environment and human health, the degradation of glyphosate through the formation of less toxic intermediates is of great importance. Among the developed methods for the degradation of glyphosate, photodegradation is a clean and efficient strategy. In this work, we report a new photocatalyst by doping F ion on BiVO4 that can efficiently degrade glyphosate and reduce the toxic emissions of aminomethylphosphonic acid (AMPA) through the selective (P)-C-N cleavage in comparison of BiVO4 catalyst. The results demonstrate that the best suppression of AMPA formation was achieved by the catalyst of 0.3F@BiVO4 at pH = 9 (AMPA formation below 10%). In situ attenuated total reflectance Fourier transforms infrared (ATR-FTIR) spectroscopy indicates that the adsorption sites of glyphosate on BiVO4 and 0.3F@BiVO4 are altered due to the difference in electrostatic interactions. Such an absorption alteration leads to the preferential cleavage of the C-N bond on the N-C-P skeleton, thereby inhibiting the formation of toxic AMPA. These results improve our understanding of the photodegradation process of glyphosate catalyzed by BiVO4-based catalysts and pave a safe way for abiotic degradation of glyphosate.