Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer.

The immune checkpoint blockade (ICB) response in human cancers is closely linked to the gut microbiota. Here, we report that the abundance of commensal Lactobacillus johnsonii is positively correlated with the responsiveness of ICB. Supplementation with Lactobacillus johnsonii or tryptophan-derived metabolite indole-3-propionic acid (IPA) enhances the efficacy of CD8+ T cell-mediated αPD-1 immunotherapy. Mechanistically, Lactobacillus johnsonii collaborates with Clostridium sporogenes to produce IPA. IPA modulates the stemness program of CD8+ T cells and facilitates the generation of progenitor exhausted CD8+ T cells (Tpex) by increasing H3K27 acetylation at the super-enhancer region of Tcf7. IPA improves ICB responsiveness at the pan-cancer level, including melanoma, breast cancer, and colorectal cancer. Collectively, our findings identify a microbial metabolite-immune regulatory pathway and suggest a potential microbial-based adjuvant approach to improve the responsiveness of immunotherapy.

Unusual Janus Bi2TeSe2 Topological Insulators Displaying Second-Harmonic Generation, Linear-in-Temperature Resistivity, and Weak Antilocalization.

Well-established knowledge about inversion-symmetric Bi2TexSe3-x topological insulators characterizes the promising new-generation quantum device. Noticeably, the inversion asymmetric phase containing different surface electronic structures may create an extra topological phenomenon pointing to a new device paradigm. Herein, Janus Bi2TeSe2 single-crystal nanosheets with an unconventional stacking sequence of Se-Bi-Se-Bi-Te are realized via chemical vapor deposition growth, which is clarified by atomically resolved AC-STEM and elemental mapping. An obvious polarization-dependent second-harmonic generation with a representative 6-fold rotational symmetry is detected due to the broken out-of-plane mirror symmetry in this system. Low-temperature transport measurements display a strange metal-like linear-in-temperature resistivity. Anomalous conductance peaks under low magnetic fields induced by the weak antilocalization effect of topological surface states and the two-dimensional transport-dominated anisotropic magnetoresistance are revealed. These findings correlate the Janus Bi2TeSe2 phase with emerging physics topics, which would inspire fresh thoughts in well-developed Bi3TexSe3-x topological insulators and open up opportunities for exploring hybrid nonlinear optoelectronic topological devices.

Nuclear-Targeting Lipid PtIV Prodrug Amphiphile Cooperates with siRNA for Enhanced Cancer Immunochemotherapy by Amplifying Pt-DNA Adducts and Reducing Phosphatidylserine Exposure.

Patients treated with Pt-based anticancer drugs (PtII) often experience severe side effects and are susceptible to cancer recurrence due to the limited bioavailability of PtII and tumor-induced immunosuppression. The exposure of phosphatidylserine on the cell's outer surface induced by PtII results in profound immunosuppression through the binding of phosphatidylserine to its receptors on immune cells. Here, we report a novel approach for enhanced cancer chemoimmunotherapy, where a novel nuclear-targeting lipid PtIV prodrug amphiphile was used to deliver a small interfering RNA (siXkr8) to simultaneously amplify Pt-DNA adducts and reduce the level of exposure of phosphatidylserine. This drug delivery vehicle is engineered by integrating the PtIV prodrug with self-assembly performance and siXkr8 into a lipid nanoparticle, which shows tumor accumulation, cancer cell nucleus targeting, and activatable in a reduced microenvironment. It is demonstrated that nuclear-targeting lipid PtIV prodrug increases the DNA cross-linking, resulting in increased Pt-DNA adduct formation. The synergistic effects of the PtIV prodrug and siXkr8 contribute to the improvement of the tumor immune microenvironment. Consequently, the increased Pt-DNA adducts and immunogenicity effectively inhibit primary tumor growth and prevent tumor recurrence. These results underscore the potential of utilizing the nuclear-targeting lipid PtIV prodrug amphiphile to enhance Pt-DNA adduct formation and employing siXkr8 to alleviate immunosuppression during chemotherapy.

Nitrogen-Anchored Boridene Enables Mg-CO2 Batteries with High Reversibility.

Nanoscale defect engineering plays a crucial role in incorporating extraordinary catalytic properties in two-dimensional materials by varying the surface groups or site interactions. Herein, we synthesized high-loaded nitrogen-doped Boridene (N-Boridene (Mo4/3(BnN1-n)2-mTz), N-doped concentration up to 26.78 at %) nanosheets by chemical exfoliation followed by cyanamide intercalation. Three different nitrogen sites are observed in N-Boridene, wherein the site of boron vacancy substitution mainly accounts for its high chemical activity. Attractively, as a cathode for Mg-CO2 batteries, it delivers a long-term lifetime (305 cycles), high-energy efficiency (93.6%), and ultralow overpotential (∼0.09 V) at a high current of 200 mA g-1, which overwhelms all Mg-CO2 batteries reported so far. Experimental and computational studies suggest that N-Boridene can remarkably change the adsorption energy of the reaction products and lower the energy barrier of the rate-determining step (*MgCO2 → *MgCO3·xH2O), resulting in the rapid reversible formation/decomposition of new MgCO3·5H2O products. The surging Boridene materials with defects provide substantial opportunities to develop other heterogeneous catalysts for efficient capture and converting of CO2.

Single-cell analysis of Crohn's disease: Unveiling heterogeneity and evaluating ustekinumab outcomes.

BACKGROUND: The present study aimed to dissect the cellular complexity of Crohn's disease (CD) using single-cell RNA sequencing, focusing on identifying key cell populations and their transcriptional profiles in inflamed tissue. METHODS: We applied scRNA-sequencing to compare the cellular composition of CD patients with healthy controls, utilizing Seurat for clustering and annotation. Differential gene expression analysis and protein-protein interaction networks were constructed to identify crucial genes and pathways. RESULTS: Our study identified eight distinct cell types in CD, highlighting crucial fibroblast and T cell interactions. The analysis revealed key cellular communications and identified significant genes and pathways involved in the disease's pathology. The role of fibroblasts was underscored by elevated expression in diseased samples, offering insights into disease mechanisms and potential therapeutic targets, including responses to ustekinumab treatment, thus enriching our understanding of CD at a molecular level. CONCLUSIONS: Our findings highlight the complex cellular and molecular interplay in CD, suggesting new biomarkers and therapeutic targets, offering insights into disease mechanisms and treatment implications.

Programmed Cascade Polydopamine Nanoclusters for Pyroptosis-Based Tumor Immunotherapy.

Pyroptosis, an inflammatory cell death, plays a pivotal role in activating inflammatory response, reversing immunosuppression and enhancing anti-tumor immunity. However, challenges remain regarding how to induce pyroptosis efficiently and precisely in tumor cells to amplify anti-tumor immunotherapy. Herein, a pH-responsive polydopamine (PDA) nanocluster, perfluorocarbon (PFC)@octo-arginine (R8)-1-Hexadecylamine (He)-porphyrin (Por)@PDA-gambogic acid (GA)-cRGD (R-P@PDA-GC), is rationally design to augment phototherapy-induced pyroptosis and boost anti-tumor immunity through a two-input programmed cascade therapy. Briefly, oxygen doner PFC is encapsulated within R8 linked photosensitizer Por and He micelles as the core, followed by incorporation of GA and cRGD peptides modified PDA shell, yielding the ultimate R-P@PDA-GC nanoplatforms (NPs). The pH-responsive NPs effectively alleviate hypoxia by delivering oxygen via PFC and mitigate heat resistance in tumor cells through GA. Upon two-input programmed irradiation, R-P@PDA-GC NPs significantly enhance reactive oxygen species production within tumor cells, triggering pyroptosis via the Caspase-1/GSDMD pathway and releasing numerous inflammatory factors into the TME. This leads to the maturation of dendritic cells, robust infiltration of cytotoxic CD8+ T and NK cells, and diminution of immune suppressor Treg cells, thereby amplifying anti-tumor immunity.

N-Decorated Main-Group MgAl2O4 Spinel: Unlocking Exceptional Oxygen Reduction Activity for Zn-Air Batteries.

The development of economical and efficient oxygen reduction reaction (ORR) catalysts is crucial to accelerate the widespread application rhythm of aqueous rechargeable zinc-air batteries (ZABs). Here, a strategy is reported that the modification of the binding energy for reaction intermediates by the axial N-group converts the inactive spinel MgAl2O4 into the active motif of MgAl2O4-N. It is found that the introduction of N species can effectively optimize the electronic configuration of MgAl2O4, thereby significantly reducing the adsorption strength of *OH and boosting the reaction process. This main-group MgAl2O4-N catalyst exhibits a high ORR activity in a broad pH range from acidic and alkaline environments. The aqueous ZABs assembled with MgAl2O4-N shows a peak power density of 158.5 mW cm-2, the long-term cyclability over 2000 h and the high stability in the temperature range from -10 to 50 °C, outperforming the commercial Pt/C in terms of activity and stability. This work not only serves as a significant candidate for the robust ORR electrocatalysts of aqueous ZABs, but also paves a new route for the effective reutilization of waste Mg alloys.

A facile Immunoregulatory Constructional Design by Proanthocyanidin Optimizing Directional Chitosan Microchannel.

Improving the interconnected structure and bioregulatory function of natural chitosan is beneficial for optimizing its performance in bone regeneration. Here, a facile immunoregulatory constructional design is proposed for developing instructive chitosan by directional freezing and alkaline salting out. The molecular dynamics simulation confirmed the assembly kinetics and structural features of various polyphenols and chitosan molecules. Along with the in vitro anti-inflammatory, antioxidative, promoting bone mesenchymal stem cell (BMSC) adhesion and proliferation performance, proanthocyanidin optimizing chitosan (ChiO) scaffold presented an optimal immunoregulatory structure with the directional microchannel. Transcriptome analysis in vitro further revealed the cytoskeleton- and immune-regulation effect of ChiO are the key mechanism of action on BMSC. The rabbit cranial defect model (Φ = 10 mm) after 12 weeks of implantation confirmed the significantly enhanced bone reconstitution. This facile immunoregulatory directional microchannel design provides effective guidance for developing inducible chitosan scaffolds.

Nonreciprocal toroidal dipole resonance and one-way quasi-bound state in the continuum.

Bound states in the continuum (BICs) provide an alternative way of trapping light at nanoscale. Although the last 10 years have witnessed tremendous progress on BICs from fundamentals to applications, nonreciprocal BICs and their potential applications have not been fully exploited yet. In this study, we demonstrated a one-way quasi-BIC by leveraging an all-dielectric magneto-optical (MO) metasurface. We show that the key point for achieving a one-way quasi-BIC is to excite a magnetization-induced leaky resonance. Here we adopt the longitudinal toroidal dipole (TD) resonance characterized by a vortex distribution of head-to-tail magnetic dipoles parallel to the plane of the MO metasurface. We show that, by breaking the time-reversal symmetry, at critical conditions, the TD resonance can be enhanced in the forward channel and perfectly canceled in the time-reversed channel, resulting in a one-way quasi-BIC. The demonstrated phenomena hold significant promise for practical applications such as magnetic field optical sensing, nonreciprocal optical switching, isolation, and modulation.

Chirality-dependent topological edge states in photonic metacrystal.

Topological edge state, a unique mode for manipulating electromagnetic waves (EMs), has been extensively studied in both fundamental and applied physics. Up to now, the work on topological edge states has focused on manipulating linearly polarized waves. Here, we realize chirality-dependent topological edge states in one-dimensional photonic crystals (1DPCs) to manipulate circularly polarized waves. By introducing the magneto-electric coupling term (chirality), the degeneracy Dirac point (DP) is opened in PCs with symmetric unit cells. The topological properties of the upper and lower bands are different in the cases of left circularly polarized (LCP) and right circularly polarized (RCP) waves by calculating the Zak phase. Moreover, mapping explicitly 1D Maxwell's equations to the Dirac equation, we demonstrate that the introduction of chirality can lead to different topological properties of bandgaps for RCP and LCP waves. Based on this chirality-dependent topology, we can further realize chirality-dependent topological edge states in photonic heterostructures composed of two kinds of PCs. Finally, we propose a realistic structure for the chirality-dependent topological edge states by placing metallic helixes in host media. Our work provides a method for manipulating topological edge states for circularly polarized waves, which has a broad range of potential applications in designing optical devices including polarizers, filters, and sensors with robustness against disorder.

The lncRNA LINC01605 promotes the progression of pancreatic ductal adenocarcinoma by activating the mTOR signaling pathway.

BACKGROUND: This study investigated the molecular mechanism of long intergenic non-protein coding RNA 1605 (LINC01605) in the process of tumor growth and liver metastasis of pancreatic ductal adenocarcinoma (PDAC). METHODS: LINC01605 was filtered out with specificity through TCGA datasets (related to DFS) and our RNA-sequencing data of PDAC tissue samples from Renji Hospital. The expression level and clinical relevance of LINC01605 were then verified in clinical cohorts and samples by immunohistochemical staining assay and survival analysis. Loss- and gain-of-function experiments were performed to estimate the regulatory effects of LINC01605 in vitro. RNA-seq of LINC01605-knockdown PDAC cells and subsequent inhibitor-based cellular function, western blotting, immunofluorescence and rescue experiments were conducted to explore the mechanisms by which LINC01605 regulates the behaviors of PDAC tumor cells. Subcutaneous xenograft models and intrasplenic liver metastasis models were employed to study its role in PDAC tumor growth and liver metastasis in vivo. RESULTS: LINC01605 expression is upregulated in both PDAC primary tumor and liver metastasis tissues and correlates with poor clinical prognosis. Loss and gain of function experiments in cells demonstrated that LINC01605 promotes the proliferation and migration of PDAC cells in vitro. In subsequent verification experiments, we found that LINC01605 contributes to PDAC progression through cholesterol metabolism regulation in a LIN28B-interacting manner by activating the mTOR signaling pathway. Furthermore, the animal models showed that LINC01605 facilitates the proliferation and metastatic invasion of PDAC cells in vivo. CONCLUSIONS: Our results indicate that the upregulated lncRNA LINC01605 promotes PDAC tumor cell proliferation and migration by regulating cholesterol metabolism via activation of the mTOR signaling pathway in a LIN28B-interacting manner. These findings provide new insight into the role of LINC01605 in PDAC tumor growth and liver metastasis as well as its value for clinical approaches as a metabolic therapeutic target in PDAC.

Realization of Gapped and Ungapped Photonic Topological Anderson Insulators.

It is commonly believed that topologically nontrivial one-dimensional systems support edge states rather than bulk states at zero energy. In this work, we find an unanticipated case of topological Anderson insulator (TAI) phase where two bulk modes are degenerate at zero energy, in addition to degenerate edge modes. We term this "ungapped TAI" to distinguish it from the previously known gapped TAIs. Our experimental realization of both gapped and ungapped TAIs relies on coupled photonic resonators, in which the disorder in coupling is judiciously engineered by adjusting the spacing between the resonators. By measuring the local density of states both in the bulk and at the edges, we demonstrate the existence of these two types of TAIs, together forming a TAI plateau in the phase diagram. Our experimental findings are well supported by theoretical analysis. In the ungapped TAI phase, we observe stable coexistence of topological edge states and localized bulk states at zero energy, highlighting the distinction between TAIs and traditional topological insulators.

Transcriptomic and genomic characteristics of intrahepatic metastases of primary liver cancer.

BACKGROUND: Patients with primary multifocal hepatocellular carcinoma (HCC) have a poor prognosis and often experience a high rate of treatment failure. Multifocal HCC is mainly caused by intrahepatic metastasis (IM), and though portal vein tumor thrombosis (PVTT) is considered a hallmark of IM, the molecular mechanism by which primary HCC cells invade the portal veins remains unclear. Therefore, it is necessary to recognize the early signs of metastasis of HCC to arrange better treatment for patients. RESULTS: To determine the differential molecular features between primary HCC with and without phenotype of metastasis, we used the CIBERSORTx software to deconvolute cell types from bulk RNA-Seq based on a single-cell transcriptomic dataset. According to the relative abundance of tumorigenic and metastatic hepatoma cells, VEGFA+ macrophages, effector memory T cells, and natural killer cells, HCC samples were divided into five groups: Pro-T, Mix, Pro-Meta, NKC, and MemT, and the transcriptomic and genomic features of the first three groups were analyzed. We found that the Pro-T group appeared to retain native hepatic metabolic activity, whereas the Pro-Meta group underwent dedifferentiation. Genes highly expressed in the group Pro-Meta often signify a worse outcome. CONCLUSIONS: The HCC cohort can be well-typed and prognosis predicted according to tumor microenvironment components. Primary hepatocellular carcinoma may have obtained corresponding molecular features before metastasis occurred.

Construction of a Multifunctional Upconversion Nanoplatform Based on Autophagy Inhibition and Photodynamic Therapy Combined with Chemotherapy for Antitumor Therapy.

Inhibition of autophagy increases the sensitivity of tumor cells to radiotherapy and chemotherapy and improves the therapeutic effect on tumors. Recently, photodynamic therapy (PDT) combined with chemotherapy has been proven to further improve the efficiency of cancer treatment. As such, combining autophagy inhibition with PDT and chemotherapy may represent a potentially effective new strategy for cancer treatment. However, currently widely studied autophagy inhibitors inevitably produce various toxic side effects due to their inherent pharmacological activity. To overcome this constraint, in this study, we designed an ideal multifunctional upconversion nanoplatform, UCNP-Ce6-EPI@mPPA + NIR (MUCEN). Control, UCNP-EPI@mPPA (MUE), UCNP-EPI@mPPA + NIR (MUEN), Ce6-EPI@mPPA (MCE), Ce6-EPI@mPPA + NIR (MCEN), and UCNP-Ce6-EPI@mPPA (MUCE) groups were set up separately as controls. Based on a combination of autophagy inhibition and PDT, the average particle size of MUCEN was 197 nm, which can simultaneously achieve the double encapsulation of chlorine e6 (Ce6) and epirubicin (EPI). In vitro tests revealed that MUCE was efficiently endocytosed by 4T1 cells under near-infrared light irradiation. Further, in vivo tests revealed that MUCE dramatically inhibited tumor growth. Immunohistochemistry results indicated that MUCE efficiently increased the expression of autophagy inhibitors p62 and LC3 in tumor tissues. The synergistic effect of autophagy inhibition and PDT with MUCE exhibited superior tumor suppression, providing an innovative approach to cancer treatment.

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

Long daytime napping: A silent danger for hypertensive individuals.

BACKGROUND AND PURPOSE: Hypertension significantly contributes to stroke. Previous research has indicated a connection between daytime napping and stroke. Research on the connection between daytime napping duration and first stroke in hypertensive individuals is lacking nevertheless. METHODS: This research, which ran from 24 August 2013 to 31 December 2022, recruited 11,252 individuals with hypertension and without a history of stroke from the China Stroke Primary Prevention Trial. To determine the relationship between daytime napping duration and stroke onset in hypertensive individuals, we conducted analyses for threshold effects, multivariate-adjusted Cox proportional hazard regression models, and Kaplan-Meier survival curves. RESULTS: The duration of daytime napping (<75 min) was positively correlated with stroke risk; beyond 75 min, the risk did not increase further. When compared to hypertensive individuals who napped for 1-30 min, daytime napping 31-60 min (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 1.06-1.53) and >60 min (HR = 1.37, 95% CI = 1.14-1.65) were substantially related with a greater risk of first stroke. Additionally, this correlation was absent in cases of hemorrhagic stroke, but present in cases of ischemic stroke, specifically for hypertensive individuals who napped for 31-60 min or >60 min (p < 0.05). Kaplan-Meier survival curves displayed that hypertensive individuals who extended daytime napping had an elevated incidence of stroke. CONCLUSIONS: Hypertensive individuals who take longer daytime naps (>30 min) are at an elevated risk of stroke onset, particularly ischemic stroke, irrespective of other factors.

A pH-responsive nanoplatform with dual-modality imaging for enhanced cancer phototherapy and diagnosis of lung metastasis.

To address the limitations of traditional photothermal therapy (PTT)/ photodynamic therapy (PDT) and real-time cancer metastasis detection, a pH-responsive nanoplatform (NP) with dual-modality imaging capability was rationally designed. Herein, 1 H,1 H-undecafluorohexylamine (PFC), served as both an oxygen carrier and a 19F magnetic resonance imaging (MRI) probe, and photosensitizer indocyanine green (ICG) were grafted onto the pH-responsive peptide hexahistidine (H6) to form H6-PFC-ICG (HPI). Subsequently, the heat shock protein 90 inhibitor, gambogic acid (GA), was incorporated into hyaluronic acid (HA) modified HPI (HHPI), yielding the ultimate HHPI@GA NPs. Upon self-assembly, HHPI@GA NPs passively accumulated in tumor tissues, facilitating oxygen release and HA-mediated cell uptake. Once phagocytosed by lysosomes, protonation of H6 was triggered due to the low pH, resulting in the release of GA. With near-infrared laser irradiation, GA-mediated decreased HSP90 expression and PFC-mediated increased ROS generation amplified the PTT/PDT effect of HHPI@GA, leading to excellent in vitro and in vivo anticancer efficacies. Additionally, the fluorescence and 19F MRI dual-imaging capabilities of HHPI@GA NPs enabled effective real-time primary cancer and lung metastasis monitoring. This work offers a novel approach for enhanced cancer phototherapy, as well as precise cancer diagnosis.

Secreted frizzled-related protein 5 overexpression reverses oxLDL-induced lipid accumulation in human vascular smooth muscle cells.

Atherosclerosis (AS) is the major cause of multiple cardiovascular diseases. In addition, the lipid accumulation of human vascular smooth muscle cells (HVSMCs) can cause the occurrence of AS. Secreted frizzled-related protein 5 (Sfrp5) was known to be downregulated in AS; however, the detailed function of Sfrp5 in HVSMCs remains unclear. Specifically, we found that Sfrp5 expression in oxLDL-treated HVSMCs was downregulated. Sfrp5 overexpression inhibited the viability of HVSMCs induced by oxLDL. In addition, oxLDL-induced proliferation and migration in HVSMCs were abolished by Sfrp5 overexpression. Sfrp5 overexpression reduced oxLDL-caused oxidative stress, lipid accumulation, and inflammation in HVSMCs. Meanwhile, oxLDL treatment increased the expressions of Wnt5a, c-Myc, and ß-catenin in HVSMCs, while this phenomenon was rescued by Sfrp5 overexpression. Furthermore, the inhibitory effect of Sfrp5 upregulation on the viability and migration of HVSMCs was reversed by R-spondin 1. These results indicate that Sfrp5 overexpression could reverse oxLDL-induced lipid accumulation in HVSMCs through inactivating Wnt5a/ß-catenin signaling pathway.

Factors Influencing Time to First Medical Contact in Patients with Acute ST-Segment Elevation Myocardial Infarction: A Retrospective Analysis.

BACKGROUND Exploring the factors that impact the time from symptom onset to first medical contact (S2FMC) is crucial for improving outcomes in elderly patients diagnosed with acute ST-segment elevation myocardial infarction (STEMI). This study conducted a retrospective analysis on 282 patients who underwent emergency percutaneous coronary intervention (PCI) or percutaneous transluminal coronary angioplasty (PTCA) in Guangzhou City District to identify significant factors affecting S2FMC. MATERIAL AND METHODS A retrospective analysis was conducted on 282 patients with STEMI who underwent emergency percutaneous coronary intervention (PCI). Descriptive statistics, univariate and multivariate Cox regression analyses were used to identify significant factors affecting S2FMC. Additionally, interactions between risk factors were examined using multivariate logistic regression and the structural equation model (SEM). RESULTS Age (HR=0.984, 95% CI: 0.975-0.993), nature of chest pain (HR=2.561, 95% CI: 1.900-3.458), admission mode (HR=1.805, 95% CI: 1.358-2.400), and vascular characteristics (HR=1.246, 95% CI: 1.069-1.451) were independent influencing factors for S2FMC. Persistent chest tightness/pain, EMS admission, and vascular characteristics (RCADL or LCADL) played a protective role in S2FMC. Among the influencing factors, vascular characteristics (OR=1.072, 95% CI: 1.008-1.141) had an independent effect on the nature of chest pain. Meanwhile, the nature of chest pain (OR=1.148, 95% CI: 1.015-1.298) was an independent influencing factor in the admission mode. CONCLUSIONS Patients with persistent chest tightness/pain, EMS admission, and vascular characteristics (RCADL or LCADL) experienced shorter S2FMC and higher compliance rate (S2FMC ≤180 min). At the same time, age and other vascular features played an inverse role. This study proposes enhancing follow-up and monitoring measures, and shows the consequences of intermittent chest pain should not be disregarded.

Network pharmacology analysis and molecular docking using the Chinese herbal agent WYHX formula (according to Yan Dexin): Management of coronary artery disease.

BACKGROUND: The therapeutic impact of the Wenyang Huoxue (WYXH) formula on coronary atherosclerotic heart disease (CHD) is well established, yet the precise mechanisms are currently not fully understood. This study provides preliminary insights into the potential mechanisms underlying the therapeutic effects of the formula on CHD by utilizing network pharmacology and molecular docking technology. MATERIALS AND METHODS: The primary active constituents and their corresponding action targets for the formula were retrieved from the TCMSP database. Utilizing Cytoscape 3.9.1 software, a network linking the components of the formula to their respective targets was constructed. Information was collected from Genecards, OMIM, TTD, and DrugBank databases to identify targets related to CHD. The common targets shared by the formula and CHD were then imported into the STRING database to create a protein-protein interaction (PPI) network. Following this, enrichment analyses were performed on the shared targets using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, molecular docking was conducted on the primary active compounds and the core targets. RESULTS: The network encompassing the components and targets of the formula comprises a total of 311 nodes and 895 edges. Compounds exhibiting higher degree centrality consist of quercetin, ß-sitosterol, and kaempferol. In the PPI network, proteins with elevated degree centrality are protein kinase B (AKT1), epidermal growth factor receptor (EGFR), and mitogen-activated protein kinase 3 (MAPK3). The results of GO and KEGG enrichment analyses reveal that the biological processes associated with the efficacy of the formula in treating CHD primarily involve positive regulation of gene expression, hypoxia response, and lipopolysaccharide response, among others. The signaling pathways primarily involved include phosphatidylinositol 3-kinase and protein kinase B (PI3K-AKT), MAPK3, tumor necrosis factor (TNF), and so on. Molecular docking results demonstrate a strong affinity between quercetin, ß-sitosterol, and kaempferol with AKT1, EGFR, and MAPK3. CONCLUSION: We showed for the first time that AKT1, EGFR, and MAPK3 are potential targets influenced by the WYHX formula in CHD treatment. The therapeutic effects could possibly involve signaling pathways such as the PI3K-AKT, MAPK, TNF, and AGE-RAGE pathways.