Search

Abstract Chest pain, a common initial symptom in hypertrophic cardiomyopathy (HCM) patients, is closely linked to myocardial ischemia, despite the absence of significant coronary artery stenosis. This study explored microvascular dysfunction in HCM patients by employing angiography-derived microcirculatory resistance (AMR) as a novel tool for comprehensive assessment. This retrospective analysis included HCM patients with chest pain as the primary symptom and control patients without cardiac hypertrophy during the same period. The AMR was computed through angiography, providing a wire-free and adenosine-free index for evaluating microcirculatory function. Propensity score matching ensured balanced demographics between groups. This study also investigated the correlation between the AMR and clinical outcomes by utilizing echocardiography and follow-up data. After matching, 76 HCM patients and 152 controls were analyzed. While there was no significant difference in the incidence of epicardial coronary stenosis, the AMR of three epicardial coronary arteries was markedly greater in HCM patients. The criterion of an AMR ≥ 250 mmHg*s/m was that 65.7% of HCM patients experienced coronary microvascular dysfunction (CMD). Independent risk factors for CMD included increased left ventricular (LV) wall thickness (OR = 1.209, 95% CI 1.013–1.443, p = 0.036). Furthermore, an AMR_LAD ≥ 250 mmHg*s/m had an increased cumulative risk of the endpoint (log-rank p = 0.023) and was an independent risk factor for the endpoint (HR = 11.64, 95% CI 1.13–120.03, p = 0.039), providing valuable prognostic insights.

Background This study endeavored to develop a nicotinamide adenine dinucleotide (NAD+) metabolism-related biomarkers in gastric cancer (GC), which could provide a theoretical foundation for prognosis and therapy of GC patients. Methods In this study, differentially expressed genes (DEGs1) between GC and paraneoplastic tissues were overlapped with NAD+ metabolism-related genes (NMRGs) to identify differentially expressed NMRGs (DE-NMRGs). Then, GC patients were divided into high and low score groups by gene set variation analysis (GSVA) algorithm for differential expression analysis to obtain DEGs2, which was overlapped with DEGs1 for identification of intersection genes. These genes were further analyzed using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses to obtain prognostic genes for constructing a risk model. Enrichment and immune infiltration analyses further investigated investigate the different risk groups, and qRT-PCR validated the prognostic genes. Results Initially, we identified DE-NMRGs involved in NAD biosynthesis, with seven (DNAJB13, CST2, THPO, CIDEA, ONECUT1, UPK1B and SNCG) showing prognostic significance in GC. Subsequent, a prognostic model was constructed in which the risk score, derived from the expression profiles of these genes, along with gender, emerged as robust independent predictors of patient outcomes in GC. Enrichment analysis linked high-risk patients to synaptic membrane pathways and low-risk to the CMG complex pathway. Tumor immune infiltration analysis revealed correlations between risk scores and immune cell abundance, suggesting a relationship between NAD+ metabolism and immune response in GC. The prognostic significance of our identified genes was validated by qRT-PCR, which confirmed their upregulated expression in GC tissue samples. Conclusion In this study, seven NAD+ metabolism-related markers were established, which is of great significance for the development of prognostic molecular biomarkers and clinical prognosis prediction for gastric cancer patients.

Abstract The role of ATP6AP1 in colorectal cancer (CRC) remains elusive despite its observed upregulation in pan-cancer. Therefore, the current study aimed to assess the clinical significance of ATP6AP1 and its relationship with the immune infiltration in CRC. Transcriptome data of CRC were obtained from The Cancer Genome Atlas (TCGA) database and analyzed using the combination of R packages and tumor-related databases, including TIMER2, TISIDB, cBioPortal, and MethSurv. The tissue arrays and immunohistochemical staining were performed to verify the expression and clinical characteristics of ATP6AP1. The results revealed that ATP6AP1 expression was significantly elevated in CRC and associated with poor clinicopathological characteristics and prognosis. Furthermore, the analysis demonstrated ATP6AP1 expression was correlated with the infiltration of immune cells and cancer-associated fibroblasts in the microenvironment of CRC. Moreover, ATP6AP1 was found to be linked to various immune checkpoints and chemokines, with enrichment of cytoplasmic vesicle lumen, endopeptidase regulator activity, and endopeptidase inhibitor activity observed in the high ATP6AP1 expressional group. In conclusion, the findings of this study suggest that ATP6AP1 upregulation may serve as a biomarker for poor diagnosis in CRC and offer a potential target for immunotherapy in CRC.

Abstract Gasdermin-E (GSDME), the executioner of pyroptosis when cleaved by caspase 3, plays a crucial role in tumor defense and the response to chemotherapy drugs in cells. So far, there are poorly known mechanisms for the expression regulation of GSDME during cell death. Here, we identify the transcription factor Sp1 (Specificity protein 1) as a positive regulator of GSDME-mediated pyroptosis. Sp1 directly interacts with the GSDME promoter at −36 ~ −28 site and promotes GSDME gene transcription. Further, Sp1 knockdown or inhibition suppresses GSDME expression, thus reducing chemotherapy drugs (topotecan, etoposide, doxorubicin, sorafinib and cisplatin) induced cell pyroptosis. The regulation process synergizes with STAT3 (Signal transducer and activator of transcription 3) activity and antagonizes with DNA methylation but barely affects GSDMD-mediated pyroptosis or TNF-induced necroptosis. Our current finding reveals a new regulating mechanism of GSDME expression, which may be a viable target for the intervention of GSDME-dependent inflammatory diseases and cancer therapy.

Compute‐in‐memory (CIM) is a pioneering approach using parallel data processing to eliminate traditional data transmission bottlenecks for faster, energy‐efficient data handling. Crossbar arrays with two‐terminal devices such as memristors and phase‐change memory are commonly employed in CIM, but they encounter challenges such as leakage current and increased power usage. Three‐terminal transistor arrays have potential solutions, yet large‐scale electrolyte‐gated transistors (EGTs) demonstrations are uncommon due to compatibility issues with existing photolithography processes. Herein, a 20 × 20 EGTs array is designed using indium‐gallium‐zinc‐oxide as the semiconductor channel and polyacrylonitrile (PAN) doped with C2F6LiNO4S2 as the electrolyte. Each transistor unit in the array can serve as a synapse, exhibiting a large conductance range, low energy consumption (6.984 fJ) for read–write operations, excellent repeatability, and quasilinear update characteristics. It has been confirmed that the EGTs array not only enables precise device programming but also virtually eliminates signal interference between neighboring devices during the programming process. Using 54 transistors in the EGTs array, unsupervised learning with a winner‐takes‐all neural network is successfully demonstrated. After 50 training iterations, the neural network achieves perfect 100% accuracy in classifying test‐set letters. The work demonstrates the potential of EGTs for constructing large‐scale integration synaptic array toward efficient computing architectures.

Abstract Parkinson’s disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases, including inflammatory bowel disease and neurodegenerative diseases; however, its precise role in PD remains unclear. Here, we investigated the neuroprotective role of MLKL inhibition or ablation against primary neuronal cells and human iPSC-derived midbrain organoids induced by toxic α-Synuclein preformed fibrils (PFFs). Using a mouse model (Tg-Mlkl −/− ) generated by crossbreeding the SNCA A53T synuclein transgenic mice with MLKL knockout (KO)mice, we assessed the impact of MLKL deficiency on the progression of Parkinsonian traits. Our findings demonstrate that Tg-Mlkl −/− mice exhibited a significant improvement in motor symptoms and reduced phosphorylated α-synuclein expression compared to the classic A53T transgenic mice. Furthermore, MLKL deficiency alleviated tyrosine hydroxylase (TH)-positive neuron loss and attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Single-cell RNA-seq (scRNA-seq) analysis of the SN of Tg-Mlkl −/− mice revealed a unique cell type-specific transcriptome profile, including downregulated prostaglandin D synthase (PTGDS) expression, indicating reduced microglial cells and dampened neuron death. Thus, MLKL represents a critical therapeutic target for reducing neuroinflammation and preventing motor deficits in PD.

BackgroundDifferences in border zone contribute to different outcomes post-infarction, such as left ventricular aneurysm (LVA) and myocardial infarction (MI). LVA usually forms within 24 h of the onset of MI and may cause heart rupture; however, LVA surgery is best performed 3 months after MI. Few studies have investigated the LVA model, the differences in border zones between LVA and MI, and the mechanism in the border zone.MethodsThe LVA, MI, and SHAM mouse models were used. Echocardiography, Masson’s trichrome staining, and immunofluorescence staining were performed, and RNA sequencing of the border zone was conducted. The adipocyte-conditioned medium-treated hypoxic macrophage cell line and LVA and MI mouse models were employed to determine the effects of the hub gene, adiponectin (ADPN), on macrophages. Quantitative polymerase chain reaction (qPCR), Western blot analysis, transmission electron microscopy, and chromatin immunoprecipitation (ChIP) assays were conducted to elucidate the mechanism in the border zone. Human subepicardial adipose tissue and blood samples were collected to validate the effects of ADPN.ResultsA novel, simple, consistent, and low-cost LVA mouse model was constructed. LVA caused a greater reduction in contractile functions than MI owing to reduced wall thickness and edema in the border zone. ADPN impeded cardiac edema and promoted lymphangiogenesis by increasing macrophage infiltration post-infarction. Adipocyte-derived ADPN promoted M2 polarization and sustained mitochondrial quality via the ADPN/AdipoR2/HMGB1 axis. Mechanistically, ADPN impeded macrophage HMGB1 inflammation and decreased interleukin-6 (IL6) and HMGB1 secretion. The secretion of IL6 and HMGB1 increased ADPN expression via STAT3 and the co-transcription factor, YAP, in adipocytes. Based on ChIP and Dual-Glo luciferase experiments, STAT3 promoted ADPN transcription by binding to its promoter in adipocytes. In vivo, ADPN promoted lymphangiogenesis and decreased myocardial injury after MI. These phenotypes were rescued by macrophage depletion or HMGB1 knockdown in macrophages. Supplying adipocytes overexpressing STAT3 decreased collagen disposition, increased lymphangiogenesis, and impaired myocardial injury. However, these effects were rescued after HMGB1 knockdown in macrophages. Overall, the IL6/ADPN/HMGB1 axis was validated using human subepicardial tissue and blood samples. This axis could serve as an independent factor in overweight MI patients who need coronary artery bypass grafting (CABG) treatment.ConclusionThe IL6/ADPN/HMGB1 loop between adipocytes and macrophages in the border zone contributes to different clinical outcomes post-infarction. Thus, targeting the IL6/ADPN/HMGB1 loop may be a novel therapeutic approach for cardiac lymphatic regulation and reduction of cell senescence post-infarction.

Abstract Introduction The relationship between relative hyperglycemia and ventricular arrhythmia (VA) in critically ill patients admitted to intensive care units (ICU) remains unclear. This study aims to investigate the association between stress hyperglycemia ratio (SHR) and VA in this population. Methods This retrospective and observational study analyzed data from 4324 critically ill patients admitted to the ICU, obtained from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The SHR was calculated as the highest blood glucose level during the first 24 h of ICU admission divided by the admission blood glucose level. Based on the optimal cut-off values under the receiver operating characteristic curve, patients were stratified into high SHR (≥ 1.31) and low SHR (

IntroductionThromboembolic events associated with extracorporeal membrane oxygenation (ECMO) in clinical treatment are typical. Heparin coating has been widely employed as a surface modification strategy for ECMO tubes. However, its clinical application is often accompanied by unavoidable complications due to its mechanism of action. As a direct thrombin inhibitor with a single target, Bivalirudin (BV) has exhibited a lower incidence of adverse events and superior pharmacokinetic performance compared to heparin.MethodsA gelatin methacrylate hydrogel (GelMA) coating layer with BV was successfully synthesized on polyvinyl chloride, and the drug release ratio was close to complete release within 7 days.Results and discussionSimulated extracorporeal circulation experiments using roller pumps in vitro and jugular arteriovenous bypass experiments in rabbits demonstrated its outstanding anticoagulant efficacy. The systemic anticoagulant assay proved that BV hydrogel coating does not affect the coagulation level, and reduces the risk of complications such as systemic bleeding compared to intravenous injection. BV-Coating GelMA hydrogel tube has exhibited good biocompatibility and significantly improved anticoagulant performance, making it an optimal choice for surface materials used in blood-contacting medical devices.

Abstract Background Colorectal cancer (CRC), ranking third in cancer prevalence and second in mortality worldwide, is mainly derived from colorectal adenoma (CRA). CRA is a common benign disease in the intestine with rapidly increasing incidence and malignant potential. Therefore, this study aimed to recognize significant biomarkers and original pathogenesis in CRA. Methods Transcriptome data of GSE8671, GSE37364, and GSE15960 were downloaded from the Gene Expression Omnibus (GEO) datasets, and differentially expressed genes (DEGs) were screened. Functional pathways enrichment, protein–protein interaction (PPI) network, stem-correlation analysis, CIBERSORT, risk score and survival analyses were performed. RT-qPCR and immunohistochemical staining were applied to verify our results. Results Screening for significant DEGs in each dataset, we identified 230 robust DEGs, including 127 upregulated and 103 downregulated genes. Functional pathways enrichment showed that these DEGs were distinctly enriched in various tumor-associated pathways, such as growth factor activity, extracellular structure organization, neutrophil activation, and inflammatory response. We filtered out two hub genes via STRING and Modules analysis, including CA2 and HSD11B2. Stem-correlation analysis displayed that hub genes were negatively associated with stem-related genes (Olfm4, CD44, CCND1 and MYC). The CIBERSORT algorithm indicated that Macrophage2, activated mast cells, and Neutrophils promoted CRA progression through inflammation. Survival analysis showed that CA2 and HSD11B2 were positively associated with survival outcomes in CRC. Conclusion Our study has successfully identified the critical role of two core genes in the development and oncogenesis of CRA, which provides novel insight into the underlying pathogenesis, potential biomarkers and therapeutic targets.

Crystal structures of M. tuberculosis elongation factors EF-Tu and EF-Ts in complex and GDP-bound Ef-Tu reveal the molecular basis of EF-Tu’s representative recycling and inactive forms in protein translation.

BackgroundThis study aims to compare the potential short-term effects of non-pharmacological interventions (NPIs) on prehypertensive people, and provide evidence for intervention models with potential in future community-based management.MethodsIn this Bayesian network meta-analysis, Pubmed, Embase, and Web of science were screened up to 16 October 2021. Prehypertensive patients (systolic blood pressure, SBP 120–139 mmHg/diastolic blood pressure, DBP 80–89 mmHg) with a follow-up period longer than 4 weeks were targeted. Sixteen NPIs were identified during the scope review and categorized into five groups. Reduction in SBP and DBP was selected as outcome variables and the effect sizes were compared using consistency models among interventions and intervention groups. Grade approach was used to assess the certainty of evidence.ResultsThirty-nine studies with 8,279 participants were included. For SBP, strengthen exercises were the most advantageous intervention group when compared with usual care (mean difference = −6.02 mmHg, 95% CI −8.16 to −3.87), and combination exercise, isometric exercise, and aerobic exercise were the three most effective specific interventions. For DBP, relaxation was the most advantageous intervention group when compared with usual care (mean difference = −4.99 mmHg, 95% CI −7.03 to −2.96), and acupuncture, meditation, and combination exercise were the three most effective specific interventions. No inconsistency was found between indirect and direct evidence. However, heterogeneity was detected in some studies.ConclusionNPIs can bring short-term BP reduction benefits for prehypertensive patients, especially exercise and relaxation. NPIs could potentially be included in community-based disease management for prehypertensive population once long-term real-world effectiveness and cost-effectiveness are proven.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=151518, identifier: CRD42020151518.

Background: Atherosclerosis can impact cancer progression due to the cholesterol and calcium metabolism, illustrating the links between atherosclerosis and cancer metastasis. Tetraspanin 4 (TSPAN4) may help understand migrasomes in diseases and provide novel targets for treatment.Methods: TSPAN4 expression in atherosclerosis Gene Expression Omnibus (EO) dataset and multiple omics data were explored, such as enriched pathways analysis, protein-protein interaction analysis, immune subtypes as well as diagnostic and prognostic value in pan-cancer. The relationship between Glioblastoma multiforme (GBM) and TSPAN4 was further investigated.Results: Compared to control, TSPAN4 expression was upregulated in foam cells from patients with atherosclerosis and survival analysis demonstrated high TSPAN4 expression contributes to poor prognosis. TSPAN4 expression differs significantly in immune subtypes of cancers, which can be a diagnostic and prognostic target of cancers due to the high accuracy. Overall survival analysis of subgroups demonstrated that higher TSPAN4 expression had a worse prognosis and the univariate analysis and multivariate analysis demonstrated age, TSPAN4 expression, WHO grade, IDH status and histological types were independent risk factors of Glioblastoma multiforme.Conclusion: The TSPAN4 expression was associated with atherosclerosis progression and pan-cancer, especially in Glioblastoma multiforme and GBMLGG. Therefore, TSPAN4 may serve as a potential biomarker and the crosstalk between atherosclerosis and tumor progression. The results are not fully validated and further studies are still needed to validate in vivo and in vitro.

Thromboembolism caused by the use of extracorporeal membrane oxygenation (ECMO) remains common among patients with existing heart diseases and contributes to significant morbidity and mortality during the COVID-19 pandemic. Various surface modification strategies have been proposed, showing that the methacrylated alginate (MA-SA) hydrogel layer is transparent, which aids the observation of the thromboembolism from the inner wall of the tubing. In the combined dynamic and static blood of ECMO tubing inner surface in vitro experiments, it was also demonstrated that the adhesion of blood clots to the surface of vessels was remarkably reduced, and the MA-SA-based hydrogel coating could significantly prolong the activated partial thrombin time and block the endogenous coagulation. The favorable properties of natural polysaccharides of hydrogel coatings make them the best surface material choices to be applied for blood-contacting medical devices and significantly improve anticoagulant performance.

BackgroundObesity plays an important role in type 2 diabetes mellitus (T2DM) and myocardial infarction (MI). Ferroptosis and ferritinophagy are related to metabolic pathways, such as fatty acid metabolism and mitochondrial respiration. We aimed to investigate the ferroptosis- and autophagy-related differentially expressed genes (DEGs) that might be potential targets for MI progression.MethodsGSE116250 was analyzed to obtain DEGs. A Venn diagram was used to obtain the overlapping ferroptosis- and autophagy-related DEGs. The enrichment pathway analysis was performed and the hub genes were obtained. Pivotal miRNAs, transcription factors, and drugs with the hub genes interactions were also predicted. The MI mice model was constructed, and qPCR analysis and single-cell sequencing were used to validate the hub genes.ResultsUtilizing the limma package and the Venn diagram, 26 ferroptosis-related and 29 autophagy-related DEGs were obtained. The list of ferroptosis-related DEGs was analyzed, which were involved in the cellular response to a toxic substance, cellular oxidant detoxification, and the IL-17 signaling pathway. The list of autophagy-related DEGs was involved in the regulation of autophagy, the regulation of JAK-STAT signaling pathway, and the regulation of MAPK cascade. In the protein-protein interaction network, the hub DEGs, such as IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, were obtained. After validation using qPCR analysis in the MI mice model and single-cell sequencing, the 10 hub genes can be the potential targets for MI deterioration.ConclusionThe screened hub genes, IL-6, PTGS2, JUN, NQO1, NOS3, LEPR, NAMPT, CDKN2A, CDKN1A, and Snai1, may be therapeutic targets for patients with MI and may prevent adverse cardiovascular events.

BackgroundThe macrophages are involved in all stages of cardiovascular diseases, demonstrating the correlation between inflammation, atherosclerosis, and myocardial infarction (MI). Here, we aim to investigate macrophages-related genes in the deterioration of atherosclerosis.MethodsGSE41571 was downloaded and the abundance of immune cells was estimated by utilizing the xCell. By utilizing the limma test and correlation analysis, differentially expressed macrophages-related genes (DEMRGs) were documented. The functional pathways and the protein–protein interaction (PPI) network were analyzed and the hub DEMRGs were obtained. The hub DEMRGs and their interactions were analyzed using NetworkAnalyst 3.0 and for validation, the expressions of hub DEMRGs were analyzed using the GSE135055 and GSE116250 datasets as well as atherosclerosis and MI mice model.ResultsA total of 509 differentially expressed genes (DEGs) were correlated with the abundance of macrophages and were identified as DEMRGs (Pearson correlation coefficients (PCC) > 0.6), which were mainly enriched in extracellular structure organization, lysosomal membrane, MHC protein complex binding, and so on. After screening out, 28 hub DEMRGs were obtained with degrees ≥20, including GNAI1 (degree = 113), MRPS2 (degree = 56), HCK (degree = 45), SOCS3 (degree = 40), NET1 (degree = 28), and so on. After validating using Gene Expression Omnibus (GEO) datasets and the atherosclerosis and MI mice model, eight proteins were validated using ApoE-/- and C57 mice. The expression levels of proteins, including SYNJ2, NET1, FZD7, LCP2, HCK, GNB2, and PPP4C were positively correlated to left ventricular ejection fraction (LVEF), while that of EIF4EBP1 was negatively correlated to LVEF.ConclusionThe screened hub DEMRGs, SYNJ2, NET1, FZD7, LCP2, HCK, GNB2, EIF4EBP1, and PPP4C, may be therapeutic targets for treatment and prediction in the patients with plaque progression and MI recurrent events. The kit of the eight hub DEMRGs may test plaque progression and MI recurrent events and help in the diagnosis and treatment of MI-induced heart failure (HF), thus decreasing mortality and morbidity.

Hydrogen peroxide (H2O2) and glucose play a key role in many cellular signaling pathways. The efficient and accurate in situ detection of H2O2 released from living cells has attracted extensive research interests. Herein, a new porphyrin-based porous covalent organic framework (TAP-COF) was fabricated via one-step condensation of 1,6,7,12-tetrachloroperylene tetracarboxylic acid dianhydride and 5,10,15,20-tetrakis (4-aminophenyl)porphyrin iron(III). The obtained TAP-COF has high surface areas, abundant surface catalytic active sites, and highly effective electron transport due to its precisely controllable donor–acceptor arrangement and 3D porous structure. Then, the new TAP-COF exhibited excellent peroxidase-like catalytic activity, which could effectively catalyze oxidation of the substrate 3,3′,5,5′-tetramethylbenzidine by H2O2 to produce a typical blue-colored reaction. On this basis, simple, rapid and selective colorimetric methods for in situ H2O2 detection were developed with the detection limit of 2.6 nM in the wide range of 0.01 to 200 μM. The colorimetric approach also could be used for in situ detection of H2O2 released from living MCF-7 cells. This portable sensor based on a COF nanozyme not only opens a new path for point-of-care testing, but also has potential applications in the field of cell biology and clinical diagnosis.

Background: Salvia miltiorrhiza is used extensively to treat cardiovascular diseases. SAA is a major bioactive component in Salvia miltiorrhiza and mediates myocardial ischemia (MI). However, the industrial production of SAA is limited due to low yields. In addition, the direct targets of SAA are unknown. Here we explore cardioprotective mechanisms and targets of SAA in the cardiovascular system. Methods: Transgelin and actin were identified as targets of SAA using a chemical biology method and were validated by Biacore analysis, microscale thermophoresis and single-molecule imaging. Studies of transgelin (−/−) knockout mice further verify the target. Cardioprotective mechanisms and targets of SAA were studied in cultured vascular smooth muscle cells and transgenic mice. Findings: In WT mice, SAA targeted transgelin and had a protective effect on myocardium but did not have the same protective effect on transgelin (−/−) mice. SAA stabilizes the transgelin-actin complex, modulates the reorganization of the actin cytoskeleton, facilitates F-actin bundling, further enhances the contractility and blood flows of coronary arteries, and improves outcomes of myocardial ischemia. Based on the target, a more active SAA derivative offering myocardial protection, SAA-30, was obtained. Interpretation: We report on the direct targets of SAA and mechanisms of myocardial ischemia treatment. We also find that transgelin may act as a novel therapeutic target of myocardial ischemia. Furthermore, a more effective derivative of SAA provides the basis for further clinical translational research. Keywords: Transgelin, Actin, SAA, Vascular smooth muscle cell, Myocardial ischemia

Background. Young patients with type 2 diabetes mellitus (DM) and acute myocardial infarction (AMI) have high long-term all-cause and cardiovascular mortality rates. We aimed to investigate the differentially expressed genes (DEGs) that might be potential targets for DM patients with AMI. Methods. Gene datasets GSE775, GSE19322, and GSE97494 were meta-analyzed to obtain DEGs of the left ventricle myocardium in infarcted mice. Gene datasets including GSE3313, GSE10617, and GSE136948 were meta-analyzed to identify DEGs in diabetes mice. A Venn diagram was used to obtain the overlapping DEGs. KEGG and GO pathway analyses were performed, and hub genes were obtained. Pivotal miRNAs were predicted and validated using the miRNA dataset in GSE114695. To investigate the cardiac function of the screened genes, a MI mouse model was constructed; echocardiogram, qPCR, and ELISA of hub genes were performed; ELISA of hub genes in human blood samples was also utilized. Results. A total of 67 DEGs were identified, which may be potential biomarkers for patients with DM and AMI. GO and KEGG pathway analyses were performed, which were mainly enriched in response to organic cyclic compound and PI3K-Akt signaling pathway. The expression of PIK3R1 and SPNB2 increased in the MI group and was negatively correlated to left ventricular ejection fraction (LVEF), whereas that of CRYAB decreased and was positively correlated to LVEF. Patients with high CRYAB expression demonstrated a short hospital stay and the area under the curves of the three protein levels before and after treatment were 0.964, 0.982, and 0.918, suggesting that PIK3R1, SPNB2, and CRYAB may be diagnostic and prognostic biomarkers for the diabetes patients with AMI. Conclusion. The screened hub genes, PIK3R1, SPNB2, and CRYAB, were validated as credible molecular biomarkers and may provide a novel therapy for diabetic cardiac diseases with increased proteotoxic stress.

Background: Elevated left ventricular mass index contributes to morbidity and mortality induced by heart failure and M2 macrophages play a critical role in left ventricular remodeling. Here, our aim was to investigate the roles of M2 macrophage-related genes in heart failure. Methods: GSE10161 was downloaded and the abundance of immune cells were estimated utilizing the CIBERSORT algorithm. Using the limma test and correlation analysis, differentially expressed plasm B cells and M2 macrophages-related genes (DEBRGs and DEMRGs) were documented. Functional pathways and the protein-protein interaction network were analyzed and the hub DEMRGs were obtained. The hub DEMRGs and their interactions were analyzed using NetworkAnalyst 3.0 and for validation, the hub DEMRGs expressions were analyzed using the GSE135055, GSE116250 and GSE74144 datasets. Results: 103 differentially expressed genes were correlated with the abundance of M2 Macrophages and were identified as DEMRGs (PCC >0.4), which were mainly enriched in extracellular matrix organization, cell adhesion molecule binding and postsynaptic membrane. After screening out, 5 hub DEMRGs were obtained, including FN1 (degree = 21), COL3A1 (degree = 13), COL1A2 (degree = 13), FBN1 (degree = 12), and MMP2 (degree = 11). However, no hub DEBRGs were obtained in the network. The expression patterns of the screened DEMRGs were further validated in the patients with heart failure, dilated cardiomyopathy, ischemic cardiomyopathy or hypertension. Conclusions: The results can improve our understanding of the macrophages-associated molecular mechanisms in heart failure induced by dilated cardiomyopathy, ischemic cardiomyopathy or hypertension and 5 hub DEMRGs may help prevent the adverse left ventricular remodeling to decrease mortality and morbidity.

Abstract RNA helicase DDX21 plays vital roles in ribosomal RNA biogenesis, transcription, and the regulation of host innate immunity during virus infection. How DDX21 recognizes and unwinds RNA and how DDX21 interacts with virus remain poorly understood. Here, crystal structures of human DDX21 determined in three distinct states are reported, including the apo‐state, the AMPPNP plus single‐stranded RNA (ssRNA) bound pre‐hydrolysis state, and the ADP‐bound post‐hydrolysis state, revealing an open to closed conformational change upon RNA binding and unwinding. The core of the RNA unwinding machinery of DDX21 includes one wedge helix, one sensor motif V and the DEVD box, which links the binding pockets of ATP and ssRNA. The mutant D339H/E340G dramatically increases RNA binding activity. Moreover, Hill coefficient analysis reveals that DDX21 unwinds double‐stranded RNA (dsRNA) in a cooperative manner. Besides, the nonstructural (NS1) protein of influenza A inhibits the ATPase and unwinding activity of DDX21 via small RNAs, which cooperatively assemble with DDX21 and NS1. The structures illustrate the dynamic process of ATP hydrolysis and RNA unwinding for RNA helicases, and the RNA modulated interaction between NS1 and DDX21 generates a fresh perspective toward the virus–host interface. It would benefit in developing therapeutics to combat the influenza virus infection.

The configuration designs of the laser diode (LD) side-pumping laser rods focus on how to solve the space conflict between the pump and heat-removal devices because both want to use the larger lateral surface of the laser rod. The conflict is better balanced in the three different side-pumping geometries: the segmented circular LD array side-pumping configuration, the annular liquid-cooling structure, and the compensated semicircular LD array side-pumping arrangement. The temperature distributions and thermo-optic effects of the laser rod in the segmented circular LD array side-pumping configuration are analyzed in contrast with those in the other arrangements. The numerical results indicate that the periodical segment-pumping scheme provides higher beam quality than the compensated semicircular side-pumping scheme, enabling removal of the complex liquid cooling system in medium-power applications, thus showing the potential to be used in compact and miniature laser systems.

In this article we describe a new methodology for the total synthesis of 3,4-unsubstituted coumarins from commercially available starting materials. Six examples were prepared, including five naturally occurring coumarins—7-hydroxy-6,8-dimethoxy-coumarin (isofraxidin), 7-hydroxy-6-methoxycoumarin (scopoletin), 6,7,8-trimethoxy-coumarin, 6,7-dimethoxycoumarin (scoparone), and 7,8-dihydroxycoumarin (daphnetin) and one synthetic coumarin, 7-hydroxy-6-ethoxycoumarin. Moreover, five important o-hydroxybenzaldehyde intermediates were also obtained, namely 2,4-dihydroxy-3,5-dimethoxybenzaldehyde, 2,4-dihydroxy-5-methoxybenzaldehyde, 5-ethoxy-2,4-dihydroxy-benzaldehyde, 2-hydroxy-3,4,5-trimethoxybenzaldehyde, and 2-hydroxy-4,5-dimethoxy-benzaldehyde. The method developed herein involves just three or four steps and allows for the rapid synthesis of these important molecules in excellent yields. This is the first synthesis of 6,7,8-trimethoxycoumarin and 7-hydroxy-6-ethoxycoumarin.

Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types. To further elucidate the enzymatic role of G9a in cancer, we describe herein the biological activities of a novel peptide-competitive histone methyltransferase inhibitor, A-366, that selectively inhibits G9a and the closely related GLP (EHMT1), but not other histone methyltransferases. A-366 has significantly less cytotoxic effects on the growth of tumor cell lines compared to other known G9a/GLP small molecule inhibitors despite equivalent cellular activity on methylation of H3K9me2. Additionally, the selectivity profile of A-366 has aided in the discovery of a potentially important role for G9a/GLP in maintenance of leukemia. Treatment of various leukemia cell lines in vitro resulted in marked differentiation and morphological changes of these tumor cell lines. Furthermore, treatment of a flank xenograft leukemia model with A-366 resulted in growth inhibition in vivo consistent with the profile of H3K9me2 reduction observed. In summary, A-366 is a novel and highly selective inhibitor of G9a/GLP that has enabled the discovery of a role for G9a/GLP enzymatic activity in the growth and differentiation status of leukemia cells.

Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV.

The function of ribosome binding protein 1 (RRBP1) is regulating the transportation and secretion of some intracellular proteins in mammalian cells. Transcription of RRBP1 is induced by various cytokines. However, few studies focused on the process of RRPB1 mRNA translation. The RRBP1 mRNA has a long 5′ untranslated region that potentially formed a stable secondary structure. In this study, we show that the 5′ UTR of RRBP1 mRNA contains an internal ribosome entry site (IRES). Moreover, the RRBP1 expression is induced by chemotherapeutic drug paclitaxel or adriamycin in human hepatocellular carcinoma cells and accompanied with the increased expression of La autoantigen (La), which binds to RRBP1 IRES element and facilitates translation initiation. Interestingly, we found IRES-mediated RRBP1 translation is also activated during serum-starvation condition which can induce cytoplasmic localization of La. After mapping the entire RRBP1 5′ UTR, we determine the core IRES activity is located between nt-237 and -58. Furthermore, two apical GARR loops within the functional RRBP1 IRES elements may be important for La binding. These results strongly suggest an important role for IRES-dependent translation of RRBP1 mRNA in hepatocellular carcinoma cells during cellular stress conditions.

Although new cell-based research suggests a link between PPFIA4 and colon adenocarcinoma cancer, there is currently no pan-cancer study available. Using The Cancer Genome Atlas datasets, we firstly investigated the possible oncogenic function of PPFIA4 in 33 tumors. We discovered that PPFIA4 is substantially expressed in most malignancies and is associated with tumor patient prognosis. Furthermore, missense mutation and amplification of the PPFIA4 gene were the most common types of genetic change. In contrast to lung squamous cell carcinoma, tumor purity in prostate adenocarcinoma was strongly negatively connected with PPFIA4 expression and considerably positively correlated with the amount of infiltration of cluster of differentiation 8+ T cells, dendritic cells, macrophages, cluster of differentiation 4+ T cells, B cells and neutrophils in the tumor microenvironment. PPFIA4 expression in bladder cancer and lung squamous cell carcinoma is a strong correlation with the expression levels of tumor microenvironment, M1 and M2 macrophages, which are seen in the majority of monocyte marker groups. Furthermore, the functional mechanisms of PPFIA4 were influenced by chemical synaptic transmission as well as the development of the nervous system. In summary, our work provided essential insights into PPFIA4 dysregulation in pan-cancer and prompted potential molecular mechanisms in the progression of cancer, which highlight its potential therapeutic target for patients. [ABSTRACT FROM AUTHOR]