Target Cell Extraction and Spectrum-Effect Relationship Coupled with BP Neural Network Classification for Screening Potential Bioactive Components in Ginseng Extract with a Protective Effect against Myocardial Damage.

Cardiovascular disease has become a common ailment that endangers human health, having garnered widespread attention due to its high prevalence, recurrence rate, and sudden death risk. Ginseng possesses functions such as invigorating vital energy, enhancing vein recovery, promoting body fluid and blood nourishment, calming the nerves, and improving cognitive function. It is widely utilized in the treatment of various heart conditions, including palpitations, chest pain, heart failure, and other ailments. Although numerous research reports have investigated the cardiovascular activity of single ginsenoside, there remains a lack of systematic research on the specific components group that predominantly contribute to cardiovascular efficacy in ginseng medicinal materials. In this research, the spectrum-effect relationship, target cell extraction, and BP neural network classification were used to establish a rapid screening system for potential active substances. The results show that red ginseng extract (RGE) can improve the decrease in cell viability and ATP content and inhibit the increase in ROS production and LDH release in OGD-induced H9c2 cells. A total of 70 ginsenosides were identified in RGE using HPLC-Q-TOF-MS/MS analysis. Chromatographic fingerprints were established for 12 batches of RGE by high-performance liquid chromatography (HPLC). A total of 36 common ingredients were found in 12 batches of RGE. The cell viability, ATP, ROS, and LDH of 12 batches RGE were tested to establish gray relationship analysis (GRA) and partial least squares discrimination analysis (PLS-DA). BP neural network classification and target cell extraction were used to narrow down the scope of Spectral efficiency analysis and screen the potential active components. According to the cell experiments, RGE can improve the cell viability and ATP content and reduce the oxidative damage. Then, seven active ingredients, namely, Ginsenoside Rg1, Rg2, Rg3, Rb1, Rd, Re, and Ro, were screened out, and their cardiovascular activity was confirmed in the OGD model. The seven ginsenosides were the main active substances of red ginseng in treating myocardial injury. This study offers a reference for quality control in red ginseng and preparations containing red ginseng for the management of cardiovascular diseases. It also provides ideas for screening active ingredients of the same type of multi-pharmacologically active traditional Chinese medicines.

Polyhedral {Ag12} and {Ag16} Clusters: Synthesis, Structural Characterization and Third-Order Nonlinear Optical Properties.

Two polyhedral silver-thiolate clusters, [S@Ag16(Tab)10(MeCN)8](PF6)14 (Ag16) and [Ag12(Tab)6(DMF)12](PF6)12 (Ag12), were synthesized by using electroneutral Tab species as protective ligands (Tab = 4-(trimethylammonio)benzenethiolate, DMF = N,N-dimethylformamide, MeCN = acetonitrile). Ag16 has a decahedral shape composed of eight pentagon {Ag5} units and two square {Ag4} units. The structure of Ag12 is a cuboctahedron, a classical Archimedean structure composed of six triangular faces and eight square faces. The former configuration is discovered in silver-thiolate cluster for the first time, possibly benefited from the more flexible coordination between the Tab ligand and Ag+ facilitated by the electropositive -N(CH3)3 substituent group. Third-order nonlinear optical studies show that both clusters in DMF exhibit reverse saturate absorption response under the irradiation of 532 nm laser.

Ent-eudesmane sesquiterpenoids with anti-neuroinflammatory activity from the marine-derived fungus Eutypella sp. F0219.

In this study, twenty-three ent-eudesmane sesquiterpenoids (1-23) including fifteen previously undescribed ones, named eutypelides A-O (1-15) were isolated from the marine-derived fungus Eutypella sp. F0219. Their planar structures and relative configurations were established by HR-ESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of the previously undescribed compounds were determined by single-crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Structurally, eutypelide A (1) is a rare 1,10-seco-ent-eudesmane, whereas 2-15 are typically ent-eudesmanes with 6/6/-fused bicyclic carbon nucleus. The anti-neuroinflammatory activity of all isolated compounds (1-23) was accessed based on their ability to NO production in LPS-stimulated BV2 microglia cells. Compound 16 emerged as the most potent inhibitor. Further mechanistic investigation revealed that compound 16 modulated the inflammatory response by decreasing the protein levels of iNOS and increasing ARG 1 levels, thereby altering the iNOS/ARG 1 ratio and inhibiting macrophage polarization. qRT-PCR analysis showed that compound 16 reversed the LPS-induced upregulation of pro-inflammatory cytokines, including iNOS, TNF-α, IL-6, and IL-1ß, at both the transcriptional and translational levels. These effects were linked to the inhibition of the NF-κB pathway, a key regulator of inflammation. Our findings suggest that compound 16 may be a potential structure basis for developing neuroinflammation-related disease therapeutic agents.

DIRMC: a database of immunotherapy-related molecular characteristics.

Cancer immunotherapy has brought about a revolutionary breakthrough in the field of cancer treatment. Immunotherapy has changed the treatment landscape for a variety of solid and hematologic malignancies. To assist researchers in efficiently uncovering valuable information related to cancer immunotherapy, we have presented a manually curated comprehensive database called DIRMC, which focuses on molecular features involved in cancer immunotherapy. All the content was collected manually from published literature, authoritative clinical trial data submitted by clinicians, some databases for drug target prediction such as DrugBank, and some experimentally confirmed high-throughput data sets for the characterization of immune-related molecular interactions in cancer, such as a curated database of T-cell receptor sequences with known antigen specificity (VDJdb), a pathology-associated TCR database (McPAS-TCR) et al. By constructing a fully connected functional network, ranging from cancer-related gene mutations to target genes to translated target proteins to protein regions or sites that may specifically affect protein function, we aim to comprehensively characterize molecular features related to cancer immunotherapy. We have developed the scoring criteria to assess the reliability of each MHC-peptide-T-cell receptor (TCR) interaction item to provide a reference for users. The database provides a user-friendly interface to browse and retrieve data by genes, target proteins, diseases and more. DIRMC also provides a download and submission page for researchers to access data of interest for further investigation or submit new interactions related to cancer immunotherapy targets. Furthermore, DIRMC provides a graphical interface to help users predict the binding affinity between their own peptide of interest and MHC or TCR. This database will provide researchers with a one-stop resource to understand cancer immunotherapy-related targets as well as data on MHC-peptide-TCR interactions. It aims to offer reliable molecular characteristics support for both the analysis of the current status of cancer immunotherapy and the development of new immunotherapy. DIRMC is available at http://www.dirmc.tech/. Database URL: http://www.dirmc.tech/.

Effects of Intrinsic Defects in Pt-Based Carbon Supports on Alkaline Hydrogen Evolution Reaction.

Carbon material has widely been utilized in the synthesis of efficient carbon-supported Pt (Pt/C) catalysts, in which the structural properties greatly influence the electrocatalytic performances of Pt/C catalysts. However, the effects of intrinsic defects in carbon supports on the performance of the alkaline hydrogen evolution reaction (HER) have not been systematically investigated. Herein, porous carbon supports with different degrees of intrinsic defects were prepared by a simple template-assisted strategy, and the resulting samples were systematically studied by various analytical methods. The results suggested that the presence of abundant intrinsic defects (vacancy and topological defects) in the carbon support was advantageous in terms of favoring the dispersion and anchoring of Pt species, promoting electron transfer between Pt atoms and the carbon support, and tuning the electronic states of Pt species. These features improved the HER performance of Pt/C catalysts. Compared to the nontemplate-assisted carbon-supported Pt catalyst (Pt/NTC) with an overpotential of 178 mV, the optimized template-assisted carbon-supported Pt catalyst (Pt/TC) exhibited a lower overpotential of 58 mV at 10 mA cm-2. Besides, the Pt/TC catalyst displayed better HER durability than the Pt/NTC catalyst owing to its strong metal-support interaction. The DFT calculations confirmed the important role played by intrinsic defects (vacancy and topological defects) in stabilizing Pt atoms, with Pt-C3 coordination identified as the most favorable structure for improving the HER performance of Pt. Overall, novel insights on the significant contribution of intrinsic defects in porous carbon supports on the HER performances of Pt/C catalysts were provided, useful for future design and fabrication of advanced carbon-supported catalysts or other carbon-based electrode materials.

Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3ß-Nrf2 pathways in Alzheimer's disease.

Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer's disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3ß-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer's disease.

Preventive and Therapeutic Potential of Streptococcus cristatus CA119 in Experimental Periodontitis in Rats.

Periodontitis is an inflammatory condition of the oral cavity caused by a mixed infection of various bacteria, which not only severely affects the alveolar bone and connective tissues but also displays potential correlations with distal intestinal inflammation. In this study, we aimed to elucidate the therapeutic effects of Streptococcus cristatus CA119 on experimental periodontitis in rats and its impact on intestinal morphology. The results demonstrate that CA119 is capable of colonizing the oral cavity and exerting antagonistic effects on Porphyromonas gingivalis and Fusobacterium nucleatum, thus leading to a significant reduction in the oral pathogen load. Following CA119 intervention, there was a significant alleviation of weight loss in rats induced by periodontitis (P < 0.001). CA119 also regulated the expression of IL-6 (P < 0.05), IL-1ß (P < 0.001), IL-18 (P < 0.001), COX-2 (P < 0.001), iNOS (P < 0.001), and MCP-1 (P < 0.01) in the gingival tissue. Additionally, CA119 reduced oxidative stress levels in rats and enhanced their antioxidant capacity. Microcomputed tomography (micro-CT) and histological analysis revealed that CA119 significantly reduced alveolar bone loss and reversed the downregulation of OPG/RANKL (P < 0.001). Furthermore, CA119 exhibited a significant protective effect against intestinal inflammation induced by periodontal disease and improved the colonic morphology in rats. In conclusion, this study demonstrates the role of CA119 as a potential oral probiotic in the prevention and treatment of experimental periodontitis, underscoring the potential of probiotics as a complementary approach to traditional periodontal care.

STING agonist diABZI enhances the cytotoxicity of T cell towards cancer cells.

Antigen-specific T cell receptor-engineered T cell (TCR-T) based immunotherapy has proven to be an effective method to combat cancer. In recent years, cross-talk between the innate and adaptive immune systems may be requisite to optimize sustained antigen-specific immunity, and the stimulator of interferon genes (STING) is a promising therapeutic target for cancer immunotherapy. The level of expression or presentation of antigen in tumor cells affects the recognition and killing of tumor cells by TCR-T. This study aimed at investigating the potential of innate immune stimulation of T cells and engineered T cells to enhance immunotherapy for low-expression antigen cancer cells. We systematically investigated the function and mechanism of cross-talk between STING agonist diABZI and adaptive immune systems. We established NY-ESO-1 full knockout Mel526 cells for this research and found that diABZI activated STING media and TCR signaling pathways. In addition, the results of flow cytometry showed that antigens presentation from cancer cells induced by STING agonist diABZI also improved the affinity of TCR-T cells function against tumor cells in vitro and in vivo. Our findings revealed that diABZI enhanced the immunotherapy efficacy of TCR-T by activating STING media and TCR signaling pathways, improving interferon-γ expression, and increasing antigens presentation of tumor cells. This indicates that STING agonist could be used as a strategy to promote TCR-T cancer immunotherapy.

Divergence in regulatory mechanisms of GR-RBP genes in different plants under abiotic stress.

The IVa subfamily of glycine-rich proteins (GRPs) comprises a group of glycine-rich RNA binding proteins referred to as GR-RBPa here. Previous studies have demonstrated functions of GR-RBPa proteins in regulating stress response in plants. However, the mechanisms responsible for the differential regulatory functions of GR-RBPa proteins in different plant species have not been fully elucidated. In this study, we identified and comprehensively studied a total of 34 GR-RBPa proteins from five plant species. Our analysis revealed that GR-RBPa proteins were further classified into two branches, with proteins in branch I being relatively more conserved than those in branch II. When subjected to identical stresses, these genes exhibited intensive and differential expression regulation in different plant species, corresponding to the enrichment of cis-acting regulatory elements involving in environmental and internal signaling in these genes. Unexpectedly, all GR-RBPa genes in branch I underwent intensive alternative splicing (AS) regulation, while almost all genes in branch II were only constitutively spliced, despite having more introns. This study highlights the complex and divergent regulations of a group of conserved RNA binding proteins in different plants when exposed to identical stress conditions. These species-specific regulations may have implications for stress responses and adaptations in different plant species.

Diagnostic value of one-step nucleic acid amplification for sentinel lymph node metastasis in cytokeratin 19-positive tumors: evidence from bioinformatics and meta-analysis.

Background: The status of the sentinel lymph nodes (SLNs) was an important prognostic factor in varies cancers. A one-step nucleic acid amplification (OSNA) assay, a molecular-based whole-node analysis method based on CK19 mRNA copy number, was developed to diagnose lymph node metastases. We aimed to evaluate the value of OSNA for the diagnosis of sentinel lymph node metastasis in CK19 positive cancers. CK19 mRNA and protein expression for pan-caner analysis were obtained from TCGA and the Human protein atlas database. Methods: Two researchers independently searched the PubMed, Cochrane Library and Web of Science databases for qualified articles published before December 1, 2023. A meta-analysis was performed using MetaDisc and STATA. Risk bias and quality assessments of the included studies were evaluated, and a subgroup analysis was performed. Ten cancer types were found to be CK19 positively expressed and 7 of 10 had been reported to use OSNA for SLN detection. Results: After literature review, there were 61 articles included in the meta-analysis, which consisted of 7115 patients with 18007 sentinel lymph nodes. The pooled sensitivity and specificity of OSNA were 0.87 and 0.95 in overall patients. Moreover, we found the background CK19 expression in normal tissue affected the diagnostic accuracy of OSNA. In breast cancer, we performed subgroup analysis. OSNA exhibited to be a stable method across different population groups and various medical centers. In addition, when 250 copies/µl was chosen as the cutoff point of CK19 mRNA, there were a relatively higher sensitivity and AUC in detecting SLN micro-metastasis than 5000 copies/µl. Discussion: OSNA can predict the occurrence of SLN metastasis accurately in CK19 positive cancers, especially in breast cancer, colorectal cancer, lung cancer, gastric cancer and endometrial cancer. Our study warrants future studies investigating the clinical application of OSNA in pancreatic, ovarian and bladder cancers.

Using machine learning to develop a five-item short form of the children's depression inventory.

BACKGROUND: Many adolescents experience depression that often goes undetected and untreated. Identifying children and adolescents at a high risk of depression in a timely manner is an urgent concern. While the Children's Depression Inventory (CDI) is widely utilized in China, it lacks a localized revision or simplified version. With its 27 items requiring professional administration, the original CDI proves to be a time-consuming method for predicting children and adolescents with high depression risk. Hence, this study aimed to develop a shortened version of the CDI to predict high depression risk, thereby enhancing the efficiency of prediction and intervention. METHODS: Initially, backward elimination is conducted to identify various version of the short-form scales (e.g., three-item and five-item versions). Subsequently, the performance of five machine learning (ML) algorithms on these versions is evaluated using the area under the ROC curve (AUC) to determine the best algorithm. The chosen algorithm is then utilized to model the short-form scales, facilitating the identification of the optimal short-form scale based on predefined evaluation metrics. Following this, evaluation metrics are computed for all potential decision thresholds of the optimal short-form scale, and the threshold value is determined. Finally, the reliability and validity of the optimal short-form scale are assessed using a new sample. RESULTS: The study identified a five-item short-form CDI with a decision threshold of 4 as the most appropriate scale considering all assessment indicators. The scale had 81.48% fewer items than the original version, indicating good predictive performance (AUC = 0.81, Accuracy = 0.83, Recall = 0.76, Precision = 0.71). Based on the test of 315 middle school students, the results showed that the five-item CDI had good measurement indexes (Cronbach's alpha = 0.72, criterion-related validity = 0.77). CONCLUSIONS: This five-item short-form CDI is the first shortened and revised version of the CDI in China based on large local data samples.

Recent advances in potential targets for myocardial ischemia reperfusion injury: Role of macrophages.

Myocardial ischemia-reperfusion injury (MIRI) is a complex process that occurs when blood flow is restored after myocardium infarction (MI) with exacerbated tissue damage. Macrophages, essential cell type of the immune response, play an important role in MIRI. Macrophage subpopulations, namely M1 and M2, are distinguished by distinct phenotypes and functions. In MIRI, macrophages infiltrate in infarcted area, shaping the inflammatory response and influencing tissue healing. Resident cardiac macrophages interact with monocyte-derived macrophages in MIRI, and influence injury progression. Key factors including chemokines, cytokines, and toll-like receptors modulate macrophage behavior in MIRI. This review aims to address recent findings on the classification and the roles of macrophages in the myocardium, spanning from MI to subsequent MIRI, and highlights various signaling pathways implicated in macrophage polarization underlining the complexity of MIRI. This article will shed light on developing advanced therapeutic strategies for MIRI management.

Dynamic pressure surface deformation measurement based on a chromatic confocal sensor: erratum.

This erratum corrects errors in Fig. 4 of the original paper, Appl. Opt.62, 1467 (2023)APOPAI0003-693510.1364/AO.482808.

Transcription and splicing variations of SR genes accompany with genome-wide accumulation of long-introns in pine.

Most of mRNAs in Eukaryote were matured after the removal of introns in their pre-mRNA transcripts. Serine/arginine-rich (SR) proteins are a group of splicing regulators regulating the splicing processes globally. Expressions of SR proteins themselves were extensively regulated, at both transcription and splicing levels, under different environmental conditions, specially heat stress conditions. The pine genome is characterized by super-long and easily methylated introns in a large number of genes that derived from the extensive accumulation of transposons (TEs). Here, we identified and analyzed the phylogenetic characteristics of 24 SR proteins and their encoding genes from the pine genome. Then we explored transcription and pre-mRNA splicing expression patterns of SR genes in P. massoniana seedlings under normal and heat stress temperature conditions. Our results showed that the transcription patterns of SR genes in pine exhibited significant changes compared to other plant species, and these changes were not strictly correlated with the intron length and DNA methylation intensity of the SR genes. Interestingly, none of the long introns of SR genes underwent alternative splicing (AS) in our experiment. Furthermore, the intensity of AS regulation may be related to the potential DNA methylation intensity of SR genes. Taken together, this study explores for the first time the characteristics of significant variations in the transcription and splicing patterns of SR proteins in a plant species with an over-accumulation of super-long introns.

Application of dental pulp stem cells for bone regeneration.

Bone defects resulting from severe trauma, tumors, inflammation, and other factors are increasingly prevalent. Stem cell-based therapies have emerged as a promising alternative. Dental pulp stem cells (DPSCs), sourced from dental pulp, have garnered significant attention owing to their ready accessibility and minimal collection-associated risks. Ongoing investigations into DPSCs have revealed their potential to undergo osteogenic differentiation and their capacity to secrete a diverse array of ontogenetic components, such as extracellular vesicles and cell lysates. This comprehensive review article aims to provide an in-depth analysis of DPSCs and their secretory components, emphasizing extraction techniques and utilization while elucidating the intricate mechanisms governing bone regeneration. Furthermore, we explore the merits and demerits of cell and cell-free therapeutic modalities, as well as discuss the potential prospects, opportunities, and inherent challenges associated with DPSC therapy and cell-free therapies in the context of bone regeneration.

BASALT refines binning from metagenomic data and increases resolution of genome-resolved metagenomic analysis.

Metagenomic binning is an essential technique for genome-resolved characterization of uncultured microorganisms in various ecosystems but hampered by the low efficiency of binning tools in adequately recovering metagenome-assembled genomes (MAGs). Here, we introduce BASALT (Binning Across a Series of Assemblies Toolkit) for binning and refinement of short- and long-read sequencing data. BASALT employs multiple binners with multiple thresholds to produce initial bins, then utilizes neural networks to identify core sequences to remove redundant bins and refine non-redundant bins. Using the same assemblies generated from Critical Assessment of Metagenome Interpretation (CAMI) datasets, BASALT produces up to twice as many MAGs as VAMB, DASTool, or metaWRAP. Processing assemblies from a lake sediment dataset, BASALT produces ~30% more MAGs than metaWRAP, including 21 unique class-level prokaryotic lineages. Functional annotations reveal that BASALT can retrieve 47.6% more non-redundant opening-reading frames than metaWRAP. These results highlight the robust handling of metagenomic sequencing data of BASALT.

Single-cell profile reveals the landscape of cardiac immunity and identifies a cardio-protective Ym-1hi neutrophil in myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) is a major hindrance to the success of cardiac reperfusion therapy. Although increased neutrophil infiltration is a hallmark of MIRI, the subtypes and alterations of neutrophils in this process remain unclear. Here, we performed single-cell sequencing of cardiac CD45+ cells isolated from the murine myocardium subjected to MIRI at six-time points. We identified diverse types of infiltrating immune cells and their dynamic changes during MIRI. Cardiac neutrophils showed the most immediate response and largest changes and featured with functionally heterogeneous subpopulations, including Ccl3hi Neu and Ym-1hi Neu, which were increased at 6 h and 1 d after reperfusion, respectively. Ym-1hi Neu selectively expressed genes with protective effects and was, therefore, identified as a novel specific type of cardiac cell in the injured heart. Further analysis indicated that neutrophils and their subtypes orchestrated subsequent immune responses in the cardiac tissues, especially instructing the response of macrophages. The abundance of Ym-1hi Neu was closely correlated with the therapeutic efficacy of MIRI when neutrophils were specifically targeted by anti-Lymphocyte antigen 6 complex locus G6D (Ly6G) or anti-Intercellular cell adhesion molecule-1 (ICAM-1) neutralizing antibodies. In addition, a neutrophil subtype with the same phenotype as Ym-1hi Neu was detected in clinical samples and correlated with prognosis. Ym-1 inhibition exacerbated myocardial injury, whereas Ym-1 supplementation significantly ameliorated injury in MIRI mice, which was attributed to the tilt of Ym-1 on the polarization of macrophages toward the repair phenotype in myocardial tissue. Overall, our findings reveal the anti-inflammatory phenotype of Ym-1hi Neu and highlight its critical role in myocardial protection during the early stages of MIRI.

NY-ESO-1-specific T cell receptor-engineered T cells and Tranilast, a TRPV2 antagonist bivalent treatment enhances the killing of esophageal cancer: a dual-targeted cancer therapeutic route.

BACKGROUND: Esophageal cancer (EC) is a global canker notorious for causing high mortality due to its relentless incidence rate, convoluted with unyielding recurrence and metastasis. However, these intricacies of EC are associated with an immoderate expression of NY-ESO-1 antigen, presenting a lifeline for adoptive T cell therapy. We hypothesized that naturally isolated higher-affinity T cell receptors (TCRs) that bind to NY-ESO-1 would allow T lymphocytes to target EC with a pronounced antitumor response efficacy. Also, targeting TRPV2, which is associated with tumorigenesis in EC, creates an avenue for dual-targeted therapy. We exploited the dual-targeting antitumor efficacy against EC. METHODS: We isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells. RESULTS: Our study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157-165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast. CONCLUSION: Our findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.

The combination of Tanshinone IIA and Astragaloside IV attenuates myocardial ischemia-reperfusion injury by inhibiting the STING pathway.

BACKGROUND: Astragaloside IV (As-IV) and Tanshinone IIA (Ta-IIA) are the main ingredients of traditional Chinese medicinal Astragalus membranaceus (Fisch.) Bunge and Salvia miltiorrhiza Bunge, respectively, both of which have been employed in the treatment of cardiovascular diseases. Nevertheless, the efficacy of the combination (Co) of Ta-IIA and As-IV for cardiovascular diseases remain unclear and warrant further investigation. This study aimed to investigate the efficacy and the underlying molecular mechanism of Co in treating myocardial ischemia-reperfusion injury (MIRI). METHODS: In order to assess the efficacy of Co, an in vivo MIRI mouse model was created by temporarily blocking the coronary arteries for 30 min and then releasing the blockage. Parameters such as blood myocardial enzymes, infarct size, and ventricular function were measured. Additionally, in vitro experiments were conducted using HL1 cells in both hypoxia-reoxygenation model and oxidative stress models. The apoptosis rate, expression levels of apoptosis-related proteins, oxidative stress indexes, and release of inflammatory factors were detected. Furthermore, molecular docking was applied to examine the binding properties of Ta-IIA and As-IV to STING, and western blotting was performed to analyze protein expression of the STING pathway. Additionally, the protective effect of Ta-IIA, As-IV and Co via inhibiting STING was further confirmed in models of knockdown STING by siRNA and adding STING agonist. RESULTS: Both in vitro and in vivo data demonstrated that, compared to Ta-IIA or As-IV alone, the Co exhibited superior efficacy in reducing the area of myocardial infarction, lowering myocardial enzyme levels, and promoting the recovery of myocardial contractility. Furthermore, the Co showed more potent anti-apoptosis, antioxidant, and anti-inflammation effects. Additionally, the Co enhanced the inhibitory effects of Ta-IIA and As-IV on STING phosphorylation and the activation of STING signaling pathway. However, the administration of a STING agonist attenuated the protective effects of the Co, Ta-IIA, and As-IV by compromising their anti-apoptotic, antioxidant, and anti-inflammatory effects in MIRI. CONCLUSION: Compared to the individual administration of Ta-IIA or As-IV, the combined treatment demonstrated more potent ability in inhibiting apoptosis, oxidative stress, inflammation, and the STING signaling pathway in the context of MIRI, indicating a more powerful protective effect against MIRI.