Human neutralizing antibodies target a conserved lateral patch on H7N9 hemagglutinin head.

Avian influenza A virus H7N9 causes severe human infections with >30% fatality. Currently, there is no H7N9-specific prevention or treatment for humans. Here, from a 2013 H7N9 convalescent case in Hong Kong, we isolate four hemagglutinin (HA)-reactive monoclonal antibodies (mAbs), with three directed to the globular head domain (HA1) and one to the stalk domain (HA2). Two clonally related HA1-directed mAbs, H7.HK1 and H7.HK2, potently neutralize H7N9 and protect female mice from lethal H7N9/AH1 challenge. Cryo-EM structures reveal that H7.HK1 and H7.HK2 bind to a ß14-centered surface and disrupt the 220-loop that makes hydrophobic contacts with sialic acid on an adjacent protomer, thereby blocking viral entry. Sequence analysis indicates the lateral patch targeted by H7.HK1 and H7.HK2 to be conserved among influenza subtypes. Both H7.HK1 and H7.HK2 retain HA1 binding and neutralization capacity to later H7N9 isolates from 2016-2017, consistent with structural data showing that the antigenic mutations during this timeframe occur at their epitope peripheries. The HA2-directed mAb H7.HK4 lacks neutralizing activity but when used in combination with H7.HK2 moderately augments female mouse protection. Overall, our data reveal antibodies to a conserved lateral HA1 supersite that confer neutralization, and when combined with a HA2-directed non-neutralizing mAb, augment protection.

A Combined Measure of the Triglyceride Glucose Index and Trimethylamine N-Oxide in Risk Stratification of ST-Segment Elevation Myocardial Infarction Patients with High-Risk Plaque Features Defined by Optical Coherence Tomography: A Substudy of the OCTAMI Registry Study.

Background and Aim: An elevated triglyceride-glucose (TyG) level is associated with increased risk of mortality in patients with CAD. Trimethylamine N-oxide (TMAO) has mechanistic links to atherosclerotic coronary artery disease (CAD) pathogenesis and is correlated with adverse outcomes. However, the incremental prognostic value of TMAO and TyG in the cohort of optical coherence tomography (OCT)-defined high-risk ST-segment elevation myocardial infarction (STEMI) patients is unknown. Methods: We studied 274 consecutive aged ≥18 years patients with evidence of STEMI and detected on pre-intervention OCT imaging of culprit lesions between March 2017 and March 2019. Outcomes: There were 22 (22.68%), 27 (27.84%), 26 (26.80%), and 22 (22.68%) patients in groups A-D, respectively. The baseline characteristics according to the level of TMAO and TyG showed that patients with higher level in both indicators were more likely to have higher triglycerides (p < 0.001), fasting glucose (p < 0.001) and higher incidence of diabetes (p = 0.008). The group with TMAO > median and TyG ≤ median was associated with higher rates of MACEs significantly (p = 0.009) in fully adjusted analyses. During a median follow-up of 2.027 years, 20 (20.6%) patients experienced MACEs. To evaluate the diagnostic value of the TyG index combined with TMAO, the area under the receiver operating characteristic curve for predicting MACEs after full adjustment was 0.815 (95% confidence interval, 0.723-0.887; sensitivity, 85.00%; specificity, 72.73%; cut-off level, 0.577). Among the group of patients with TMAO > median and TyG ≤ median, there was a significantly higher incidence of MACEs (p=0.033). A similar tendency was found in the cohort with hyperlipidemia (p=0.016) and diabetes mellitus (p=0.036). Conclusion: This study demonstrated the usefulness of combined measures of the TyG index and TMAO in enhancing risk stratification in STEMI patients with OCT-defined high-risk plaque characteristics. Trial Registration: This study was registered at ClinicalTrials.gov as NCT03593928.

Investigation of the Nanoparticulation Method and Cell-Killing Effect following the Mitochondrial Delivery of Hydrophobic Porphyrin-Based Photosensitizers.

Photodynamic therapy is expected to be a less invasive treatment, and strategies for targeting mitochondria, the main sources of singlet oxygen, are attracting attention to increase the efficacy of photodynamic therapy and reduce its side effects. To date, we have succeeded in encapsulating the photosensitizer rTPA into MITO-Porter (MP), a mitochondria-targeted Drug Delivery System (DDS), aimed at mitochondrial delivery of the photosensitizer while maintaining its activity. In this study, we report the results of our studies to alleviate rTPA aggregation in an effort to improve drug efficacy and assess the usefulness of modifying the rTPA side chain to improve the mitochondrial retention of MITO-Porter, which exhibits high therapeutic efficacy. Conventional rTPA with anionic side chains and two rTPA analogs with side chains that were converted to neutral or cationic side chains were encapsulated into MITO-Porter. Low-MP (MITO-Porter with Low Drug/Lipid) exhibited high drug efficacy for all three types of rTPA, and in Low-MP, charged rTPA-encapsulated MP exhibited high drug efficacy. The cellular uptake and mitochondrial translocation capacities were similar for all particles, suggesting that differences in aggregation rates during the incorporation of rTPA into MITO-Porter resulted in differences in drug efficacy.

Characterizing fitness and immune escape of SARS-CoV-2 EG.5 sublineage using elderly serum and nasal organoid.

SARS-CoV-2 Omicron variant has evolved into sublineages. Here, we compared the neutralization susceptibility and viral fitness of EG.5.1 and XBB.1.9.1. Serum neutralization antibody titer against EG.5.1 was 1.71-fold lower than that for XBB.1.9.1. However, there was no significant difference in virus replication between EG.5.1 and XBB.1.9.1 in human nasal organoids and TMPRSS2/ACE2 over-expressing A549 cells. No significant difference was observed in competitive fitness and cytokine/chemokine response between EG.5.1 and XBB.1.9.1. Both EG.5.1 and XBB.1.9.1 replicated more robustly in the nasal organoid from a younger adult than that from an older adult. Our findings suggest that enhanced immune escape contributes to the dominance of EG.5.1 over earlier sublineages. The combination of population serum susceptibility testing and viral fitness evaluation with nasal organoids may hold promise in risk assessment of upcoming variants. Utilization of serum specimens and nasal organoid derived from older adults provides a targeted risk assessment for this vulnerable population.

Prospect of research on anti-atherosclerosis effect of main components of traditional Chinese medicine Yiqi Huoxue Huatan recipe through gut microbiota: A review.

The incidence and mortality rates of cardiovascular diseases are on the rise globally, posing a severe threat to human health. Atherosclerosis (AS) is considered a multi-factorial inflammatory disease and the main pathological basis of cardiovascular and cerebrovascular diseases, as well as the leading cause of death. Dysbiosis of the gut microbiota can induce and exacerbate inflammatory reactions, accelerate metabolic disorders and immune function decline, and affect the progression and prognosis of AS-related diseases. The Chinese herbal medicine clinicians frequently utilize Yiqi Huoxue Huatan recipe, an effective therapeutic approach for the management of AS. This article reviews the correlation between the main components of Yiqi Huoxue Huatan recipe and the gut microbiota and AS to provide new directions and a theoretical basis for the prevention and treatment of AS.

Lipid Content Distribution and its Clinical Implication in Patients with Acute Myocardial Infarction-Plaque Erosion: Results from the Prospective OCTAMI Study.

AIMS: Plaque erosion (PE) is one of the main plaque phenotypes of acute coronary syndrome (ACS). However, the underlying plaque component and distribution have not been systematically analysed. This study aims to investigate the distribution of lipid and calcium content in culprit lesions assessed by optical coherence tomography (OCT) in patients with PE and explore its relationship with prognosis in a cohort of ST segment elevation myocardial infarction (STEMI) patients. METHODS: A prospective cohort of 576 patients with STEMI was enrolled in our study. After exclusion, 152 PE patients with clear underlying plaque components were ultimately analysed. The culprit lesion was divided into the border zone, external erosion zone and erosion site in the longitudinal view. Each pullback of the culprit lesions was assessed by 3 independent investigators frame-by-frame, and the quantity and distribution of lipid and calcium components were recorded. RESULTS: Of the 152 PE patients, lipid and calcium contents were more likely to exist in the external erosion zone than in the other regions. In particular, a high level of lipid content proximal to the erosion site was significantly associated with plaque vulnerability and a higher incidence of MACEs. CONCLUSION: This study revealed that high level of lipid content in the proximal external erosion zone was related to high-risk plaque characteristics and poor prognosis, which provided a novel method for risk stratification and precise management in patients with plaque erosion.

Atherosclerotic Autoantigen ALDH4A1 as a Novel Immunological Indicator for Plaque Erosion in Patients with ST Segment Elevated Myocardial Infarction.

OBJECTIVE: Aldehyde dehydrogenase 4A1 (ALDH4A1) was recently reported to be a novel autoantigen of atherosclerosis. However, its role in different phenotypes of acute coronary syndrome remains unclear. Herein, we planned to explore the circulating and regional expression of ALDH4A1 in patients with plaque rupture (PR) and plaque erosion (PE) determined by optical coherence tomography (OCT). METHODS AND RESULTS: After applying the inclusion and exclusion criteria, a prospective series of 312 patients with ST segment elevated myocardial infarction (STEMI), including 161 patients with PR and 151 patients with PE determined by OCT, were enrolled for plasma ALDH4A1 testing. In addition, ALDH4A1 was quantified using immunofluorescence in aspirated coronary thrombus samples obtained from 31 patients with PR and 25 patients with PE. In addition, we established an atherosclerosis mouse model and analyzed the distribution of ALDH4A1 expression in different mouse organs. Furthermore, we compared the level of ALDH4A1 in the spleen and carotid artery between Apoe-/- and C57 mice. The results showed that the plasma level of ALDH4A1 was significantly higher in STEMI patients with PE than in those with PR (4.6 ng/mL [2.2-8.7] vs. 3.5 ng/mL [1.6-5.6] p = 0.005). The expression of ALDH4A1 in aspirated coronary thrombi was also significantly higher in patients with PE than in those with PR (mean gray value: 32.0 [23.6-40.6] vs. 16.8 [14.0-24.5], p < 0.001). In animal models, the expression of ALDH4A1 is much higher in the spleen than in other organs, and the level of ALDH4A1 is significantly elevated in the spleen and carotid artery of Apoe-/- mice compared with C57 mice. CONCLUSION: The high levels of ALDH4A1 in the plasma and aspirated coronary thrombi independently correlated with PE in patients with STEMI. These results suggested that ALDH4A1 is involved in the mechanism of PE and serves as a promising biomarker and treatment target for patients with PE.

Allosteric Neutralization by Human H7N9 Antibodies.

The avian influenza A virus H7N9 causes severe human infections with more than 30% fatality despite the use of neuraminidase inhibitors. Currently there is no H7N9-specific prevention or treatment for humans. From a 2013 H7N9 convalescent case occurred in Hong Kong, we isolated four H7 hemagglutinin (HA)-reactive monoclonal antibodies (mAbs) by single B cell cloning, with three mAbs directed to the HA globular head domain (HA1) and one to the HA stem region (HA2). Two clonally related HA1-directed mAbs, H7.HK1 and H7.HK2, potently neutralized H7N9 and protected mice from a lethal H7N9/AH1 challenge. Cryo-EM structures revealed that H7.HK1 and H7.HK2 bind to a ß14-centered surface partially overlapping with the antigenic site D of HA1 and disrupt the 220-loop that makes hydrophobic contacts with sialic acid on the adjacent protomer, thus affectively blocking viral entry. The more potent mAb H7.HK2 retained full HA1 binding and neutralization capacity to later H7N9 isolates from 2016-2017, which is consistent with structural data showing that the antigenic mutations of 2016-2017 from the 2013 H7N9 only occurred at the periphery of the mAb epitope. The HA2-directed mAb H7.HK4 lacked neutralizing activity but protected mice from the lethal H7N9/AH1 challenge when engineered to mouse IgG2a enabling Fc effector function in mice. Used in combination with H7.HK2 at a suboptimal dose, H7.HK4 augmented mouse protection. Our data demonstrated an allosteric mechanism of mAb neutralization and augmented protection against H7N9 when a HA1-directed neutralizing mAb and a HA2-directed non-neutralizing mAb were combined.

Ozone Pollution and Acute Exacerbation of Asthma in Residents of China: An Ecological Study.

Purpose: The evidence for a causal relationship between high-level ozone (O3) exposure and acute exacerbation of asthma among adults is limited, and the conclusions are less definitive. Patients and methods: Here we collected the daily data on asthma cases, O3 exposure, and meteorological factors from 2010 to 2016 in Shijiazhuang, China. We investigated the risk of asthma exacerbation associated with high-level ozone exposure using a polynomial distributed lag model (PDLM). Using a generalized additive model (GAM), we estimated the interactive effects between O3 and other pollutants as well as meteorological factors on asthma exacerbation. Results: A total of 7270 patients with asthma were enrolled from 22 governmental hospitals in 13 counties. Each 10 µg/m3 increase in O3 concentration on the exacerbation of asthma was associated with a 1.92% (95% CI = 0.80-3.03%) higher risk of asthma exacerbation on day lag 7. The cumulative risk of O3 on asthma exacerbation increased by 18.9% (95% CI = 12.8-25.4%) on the 14th day. High consecutive levels of O3 increase the risk of asthma exacerbation, and the interactive effect of O3 and sulfur dioxide (SO2) appears before the exacerbation onset. Conclusion: These findings suggested that O3 should be an important risk factor for asthma exacerbation, and health benefits in reducing asthma exacerbation risk would be gained with continued efforts to improve the air quality in China.

Mechanism of Yiqi Huoxue Huatan recipe in the treatment of coronary atherosclerotic disease through network pharmacology and experiments.

In recent years, with population aging and economic development, morbidity and mortality of atherosclerotic cardiovascular disease associated with atherosclerosis (AS) have gradually increased. In this study, a combination of network pharmacology and experimental verification was used to systematically explore the action mechanism of Yiqi Huoxue Huatan Recipe (YHHR) in the treatment of coronary atherosclerotic heart disease (CAD). We searched and screened the active ingredients of Coptis chinensis, Astragalus membranaceus, Salvia miltiorrhiza, and Hirudo. We also searched multiple databases for related target genes corresponding to the compounds and CAD. STRING was used to construct the protein-protein interaction (PPI) network of genes. Metascape was used to perform gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for common targets to analyze the main pathways, and finally, the molecular docking and main possible pathways were verified by experimental studies. Firstly, a total of 1480 predicted target points were obtained through the Swiss Target Prediction database. After screening, merging, and deleting duplicate values, a total of 768 targets were obtained. Secondly, "Coronary atherosclerotic heart disease" was searched in databases such as the OMIM, GeneCards, and TTD. 1844 disease-related targets were obtained. Among PPI network diagram of YHHR-CAD, SRC had the highest degree value, followed by AKT1, TP53, hsp90aa1 and mapk3. The KEGG pathway bubble diagram was drawn using Chiplot, the Signal pathways such as NF kappa B signaling pathway, Lipid and AS, and Apelin signaling pathway are closely related to the occurrence of CAD. The PCR and Western blot methods were used to detect the expression of NF-κB p65. When compared with that in the model group, the expression of NF-κB p65mRNA decreased in the low-concentration YHHR group, with P < .05, while the expression of NF-κB p65mRNA decreased significantly in the high-concentration YHHR group, with P < .01. On the other hand, when compared with that in the model group, the expression of NF-κB p65 decreased in the low-concentration YHHR group, but was not statistically significant, while the expression of NF-κB p65 was significant in the high-concentration YHHR group, and has statistical significance with P < .05. YHHR has been shown to resist inflammation and AS through the SRC/NF-κB signaling pathway.

Long-term effects of SARS-CoV-2 infection on human brain and memory.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have caused several waves of outbreaks. From the ancestral strain to Omicron variant, SARS-CoV-2 has evolved with the high transmissibility and increased immune escape against vaccines. Because of the multiple basic amino acids in the S1-S2 junction of spike protein, the widespread distribution of angiotensin-converting enzyme 2 (ACE2) receptor in human body and the high transmissibility, SARS-CoV-2 can infect multiple organs and has led to over 0.7 billion infectious cases. Studies showed that SARS-CoV-2 infection can cause more than 10% patients with the Long-COVID syndrome, including pathological changes in brains. This review mainly provides the molecular foundations for understanding the mechanism of SARS-CoV-2 invading human brain and the molecular basis of SARS-CoV-2 infection interfering with human brain and memory, which are associated with the immune dysfunction, syncytia-induced cell death, the persistence of SARS-CoV-2 infection, microclots and biopsychosocial aspects. We also discuss the strategies for reducing the Long-COVID syndrome. Further studies and analysis of shared researches will allow for further clarity regarding the long-term health consequences.

Prognostic impacts of diabetes status and lipoprotein(a) levels in patients with ST-segment elevation myocardial infarction: a prospective cohort study.

OBJECTS: This study aimed to investigate the impact of lipoprotein(a) [Lp(a)] levels on the prognosis of Chinese patients with ST-segment elevation myocardial infarction (STEMI), and to explore if the impact may differ in the diabetes mellitus (DM) and nonDM groups. METHODS: Between March 2017 and January 2020, 1543 patients with STEMI who underwent emergency percutaneous coronary intervention (PCI) were prospectively recruited. The primary outcome was a composite of all-cause death, MI recurrence (reMI), and stroke, known as major adverse cardiovascular events (MACE). Analyses involving the Kaplan-Meier curve, Cox regression, and restricted cubic spline (RCS) were conducted. RESULTS: During the 1446-day follow-up period, 275 patients (17.8%) experienced MACEs, including 141 with DM (20.8%) and 134 (15.5%) without DM. As for the DM group, patients with Lp(a) ≥ 50 mg/dL showed an apparently higher MACE risk compared to those with Lp(a) < 10 mg/dL (adjusted hazard ratio [HR]: 1.85, 95% confidence interval [CI]:1.10-3.11, P = 0.021). The RCS curve indicates that the HR for MACE appeared to increase linearly with Lp(a) levels exceeding 16.9 mg/dL. However, no similar associations were obtained in the nonDM group, with an adjusted HR value of 0.57 (Lp(a) ≥ 50 mg/dL vs. < 10 mg/dL: 95% CI 0.32-1.05, P = 0.071). Besides, compared to patients without DM and Lp(a) ≥ 30 mg/dL, the MACE risk of patients in the other three groups (nonDM with Lp(a) < 30 mg/dL, DM with Lp(a) < 30 mg/dL, and DM with Lp(a) ≥ 30 mg/dL) increased to 1.67-fold (95% CI 1.11-2.50, P = 0.013), 1.53-fold (95% CI 1.02-2.31, P = 0.041), and 2.08-fold (95% CI 1.33-3.26, P = 0.001), respectively. CONCLUSIONS: In this contemporary STEMI population, high Lp(a) levels were linked to an increased MACE risk, and very high Lp(a) levels (≥ 50 mg/dL) significantly indicated poor outcomes in patients with DM, while not for those without DM. TRIAL REGISTRATION: clinicaltrials.gov NCT: 03593928.

Prognostic significance of serial N-terminal pro-B-type natriuretic peptide levels in patients with acute myocardial infarction: A prospective study.

OBJECTS: This study aimed to investigate the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at different sampling times and prognosis in patients with acute myocardial infarction (AMI) undergoing emergency percutaneous coronary intervention (PCI). METHODS AND RESULTS: Between March 2017 and January 2020, 1,105 patients with AMI who underwent emergency PCI were included. NT-proBNP levels were measured on days 0, 1, 2, 3, and 7. A composite of all-cause death, MI recurrence (reMI), and rehospitalization due to heart failure, known as major adverse cardiovascular events (MACE), was recorded. During the 36.8-month follow-up, 175 patients (15.8%) experienced MACEs. When patients were grouped based on quartiles of NT-proBNP levels on days 0 and 7, the results demonstrated that patients in quartile 4 showed a substantially increased MACE risk compared to those in quartile 1 (hazard ratio [HR] 2.27, 95% confidence interval [CI]:1.27-4.08, P = .006; HR 2.20, 95%CI:1.23-3.94, P = .008). There were U-shaped relationships between the HR for MACE and NT-proBNP levels on days 2, 3, and 7, as well as peak NT-proBNP (P for nonlinearity = .007, .006, .004, and .009, respectively). A similar relationship was observed in the HR for reMI and NT-proBNP levels on days 2 and 3. For MACE at 3 years, serial NT-proBNP levels improved the predictive accuracy of the Global Registry of Acute Coronary Events (GRACE) risk score (concordance index [C-index]: 0.711; continuous net reclassification improvement [NRI]: 0.192, 95% CI: 0.022-0.445; integrated discrimination improvement [IDI]: 0.034, 95% CI: 0.016-0.064). For all-cause death at 3 years, the combination of NT-proBNP and GRACE score showed excellent performance, with C-index, continuous NRI, and IDI values of 0.801, 0.373 (95%CI: 0.072-0.853), and 0.051 (95%CI: 0.025-0.091), respectively. CONCLUSIONS: Early and sequential measurement of NT-proBNP levels could assist in predicting MACE risk. Moreover, the relationship between MACE risk and NT-proBNP levels was U-shaped. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT: 03593928.

ANGPTL4 suppresses the profibrogenic functions of atrial fibroblasts induced by angiotensin II by up-regulating PPARγ.

Objectives: The present study's objective was to investigate the association between angiopoietin-like 4 (ANGPTL4) levels and the prognosis of Atrial fibrillation (AF), the causative effect in angiotensin II- (Ang II) induced AF, and its underlying mechanisms. Materials and Methods: Baseline serum ANGPTL-4 concentrations were measured in 130 patients with AF. Rat atrial fibroblasts were isolated from 14-day-old SD rats and transfected with Ang II treatment. Transfected cells were divided into: The control group, ANGPTL4-OE group, Ang II group, and Ang II+ANGPTL4-OE group. Transfected cells were used to analyze fibroblasts' proliferation, migration, and collagen production at the cellular level. RT-qPCR and western blotting evaluated the ANGPTL4-targeted gene and PPARγ-Akt pathway. Results: In patients with AF, serum ANGPTL4 concentrations decreased significantly compared with the healthy group. ANGPTL4 mRNA and protein expressions were significantly down-regulated in Ang II-induced cardiac fibroblasts. ANGPTL4 overexpression potentially attenuated Ang IIinduced fibroblast proliferation, migration, and collagen production in atrial tissue. ANGPTL4 inhibited the signaling proteins, such as PPARγ, α-SMA, and Akt. Conclusion: Our experimental data speculate that ANGPTL4 is a key factor in regulating AF progression. Therefore, increasing ANGPTL4 expression could be an effective strategy for AF treatment.

Effect of Triglyceride-Glucose Indices and Circulating PCSK9-Associated Cardiovascular Risk in STEMI Patients with Primary Percutaneous Coronary Artery Disease: A Prospective Cohort Study.

Background and Aims: This study aimed to determine whether convertase subtilisin/kexin type 9 (PCSK9)-associated cardiovascular risk is modulated by triglyceride-glucose (TyG) in ST-segment elevation myocardial infarction (STEMI) patients with primary percutaneous coronary disease (PCI). Methods: A total of 1541 patients with STEMI (aged ≥18 years) undergoing primary PCI were consecutively enrolled between March 2017 and March 2019. Outcomes: When stratifying the overall population according to TyG indices less than or greater than the median (TyG median = 9.07) as well as according to quartiles of PCSK9 levels, higher TyG index levels were significantly associated with all-cause mortality only when TyG levels were 9.07 or higher (ie, relative to quartile 1 [Q1], the adjusted HR for all-cause mortality was 3.20 [95% CI, 0.54-18.80] for Q2, p = 0.199; 7.89 [95% CI, 1.56-40.89] for Q3, p = 0.013; and 5.61 [95% CI, 1.04-30.30] for Q4, p = 0.045. During a median follow-up period of 1.96 years, the HR for all-cause mortality was higher in the subset of patients with TyG ≥median and PCSK9 ≥median (p for trend = 0.023) among those with type 2 diabetes mellitus (T2DM). However, there were no statistically significant differences among the subgroups. Among T2DM patients with a TyG index greater than the median, the Kaplan-Meier curve showed that patients with the highest PCSK9 levels had an increased risk of all-cause mortality (log-rank p = 0.017) and cardiac-cause mortality (log-rank p = 0.037) compared with lower PCSK9 quartile levels. Conclusion: Elevated PCSK9 levels are related to all-cause mortality and cardiac-related mortality when TyG levels are greater than the median, but not when levels are less than the median. This suggests a potential benefit of lowering circulating PCSK9 levels in STEMI patients with insulin resistance.

Interleukin-11 Is Elevated in Patients with Atrial Fibrillation, Correlates with Serum Fibrosis Markers, and Represents a Therapeutic Target for Atrial Fibrosis.

INTRODUCTION: Inflammatory cytokines are closely associated with developing cardiac fibrosis. This research aimed to explore the significant role of IL-11 in atrial fibrosis progression and potential therapeutic targets. METHODS: 207 AF patients and 160 healthy subjects were included in the case-control study. Blood samples were analyzed for the level of IL-11 by enzyme-linked immunosorbent assay (ELISA). Angiotensin II (Ang II)-treated fibrosis mouse models were generated, and expression of IL-11 mRNA and protein was detected by RT-qPCR and Western blot. IL-11 antagonist was used to evaluating atrial fibrosis-related markers. RESULTS: The persistent atrial fibrillation patients (n = 76) had significantly larger left atrial size, higher serum levels of hypertrophic protein BNP, proinflammatory cytokine high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) compared to paroxysmal atrial fibrillation patients (n = 131), and healthy subjects (all p < 0.05). Pearson correlation analysis revealed significant positive correlation between serum IL-11 and cardiac fibrosis markers BNP (r = 0.394, p < 0.001), CTX-I (r = 0.418, p < 0.001), PICP (r = 0.306, p < 0.001), PIIINP (r = 0.335, p < 0.001), and TGF-ß1 (r = 0.273, p < 0.001). In the fibrosis mouse model, Ang II infusion significantly upregulated IL-11 mRNA and protein expression in the left atrium of mice (p < 0.05), as well as staining intensity of Masson trichrome, the intensity of α-SMA, and it increased mRNA expression of collagen I and III in atrial tissue. IL-11 antagonist treatment significantly attenuated Masson trichrome, number of α-SMA-positive myofibroblasts in atrial tissue. Also, it significantly reduced the p-ERK1/2 in atrial tissue of mice infused with Ang II (p < 0.05). CONCLUSIONS: IL-11 is upregulated in the serum of AF patients, and IL-11 inhibitor significantly inhibited Ang II-induced atrial fibrosis, a key pathological feature of AF. Therefore, IL-11 could be a potential therapeutic target for AF.

Prognostic impacts of Lipoxin A4 in patients with acute myocardial infarction: A prospective cohort study.

Lipoxin A4 (LXA4) is one of the specialized pro-resolving lipid mediators proved to suppress the progression of atherosclerosis in vivo, but its clinical impacts in atherosclerotic patients is unclear. In this study, we assessed the prognostic impacts of LXA4 in patients with acute myocardial infarction (AMI). A total of 1569 consecutive AMI patients were prospectively recruited from March 2017 to January 2020. Plasma samples of AMI patients were collected, and LXA4 levels were determined using enzyme-linked immunosorbent assay. The primary outcome was major adverse cardiovascular event (MACE), a composite of all-cause death, recurrent MI, ischemic stroke, or ischemia-driven revascularization. Cox regression was used to assess associations between LXA4 and clinical outcomes. Overall, the median level of LXA4 was 5.637 (3.047-9.014) ng/mL for AMI patients. During a median follow-up of 786 (726-1108) days, high LXA4 (≥ 5.637 ng/mL) was associated with lower risk of MACE (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.60-0.89, P = 0.002), which was sustained in propensity score matching (HR: 0.73, 95% CI: 0.60-0.90, P = 0.004) and inverse probability weighting analysis (HR: 0.74, 95% CI: 0.61-0.90, P = 0.002). Combined with pro-inflammatory biomarker, patients with high levels of LXA4 (≥ 5.637 ng/mL) but low levels of high-sensitivity C-reactive protein (< 5.7 mg/L) acquired the lowest risk of MACE (HR: 0.68, 95% CI: 0.51-0.92, P = 0.012). In sum, high levels of LXA4 were associated with lower risk of recurrent ischemic events for AMI patients, which could serve as new therapeutic target to tackle cardiovascular inflammation.

Associations Between Resolvin D1 and Culprit Plaque Morphologies: An Optical Coherence Tomography Study in Patients with ST-Segment Elevation Myocardial Infarction.

Background: As a specialized pro-resolving lipid mediator, resolvin D1 (RvD1) inhibits atherosclerosis progression in vivo by reducing regional oxidative stress and chronic inflammation. However, it is unclear how RvD1 is involved in human coronary artery disease. This study aims to investigate the association between plasma levels of RvD1 and culprit-plaque characteristics in patients with ST-segment elevation myocardial infarction (STEMI). Methods: A total of 240 STEMI patients undergoing optical coherence tomography (OCT) examination were analyzed. RvD1 levels were measured in patient plasma samples using an enzyme-linked immunosorbent assay. Logistic regression was performed to assess the association between RvD1 levels and various culprit plaque morphologies, and the receiver operating curve was used to search for an optimal cutoff threshold to predict certain pathological features. Results: The median RvD1 level was 129.7 (56.6-297.8) pg/mL. According to multivariable logistic regression, high RvD1 was associated with plaque rupture (≥111.5 pg/mL, odds ratio [OR]: 2.09, 95% confidence interval [CI]: 1.20-3.66, P = 0.010), healed plaques (≥246.4 pg/mL, OR: 2.17, 95% CI: 1.11-4.24, P = 0.023), and calcification (≥293.38 pg/mL, OR: 2.10, 95% CI: 1.21-3.66, P = 0.008) at culprit lesions. Conclusion: Increased levels of RvD1 were associated with higher instability of coronary atherosclerotic plaques in STEMI patients.

Endosomal Escapable and Nuclear Localizing Cationic Polyaspartate-Based CRISPR Activation System for Preventing Respiratory Virus Infection by Specifically Inducing Interferon-λ.

Global pandemics caused by viruses cause widespread panic and economic losses. The lack of specific antivirals and vaccines increases the spreading of viral diseases worldwide. Thus, alternative strategies are required to manage viral outbreaks. Here, we develop a CRISPR activation (CRISPRa) system based on polymeric carriers to prevent respiratory virus infection in a mouse model. A polyaspartate grafted with 2-(diisopropylamino) ethylamine (DIP) and nuclear localization signal peptides (NLS-MTAS fusion peptide) was complexed with plasmid DNA (pDNA) encoding dCas9-VPR and sgRNA targeting IFN-λ. The pH-sensitive DIP and NLS-MTAS groups were favor of endo-lysosomal escape and nuclear localization of pDNA, respectively. They synergistically improved gene transfection efficiency, resulting in significant reporter gene expression and IFN-λ upregulation in lung tissue. In vitro and in vivo prophylactic experiments showed that the non-viral CRISPRa system could prevent infection caused by H1N1 viruses with minimal inflammatory responses, presenting a promising prophylactic approach against respiratory virus infections.