The Study of Endothelial-Mesenchymal Transition in an Atrial Fibrillation Rat Model.

Background: Activated fibroblasts are reported partly of endothelial origin, derived through endothelial-mesenchymal transition (EndMT). Few studies have investigated EndMT in atrial fibrillation (AF), which may have a potential effect on cardiac fibrosis. Objective: To investigate whether EndMT occurs in an animal model of AF. Methods: A total of 80 Sprague‒Dawley rats (8 weeks, male, 200-250 g) were randomly divided into two groups: the control group and the AF group (n = 40 in each group). Rats in the AF group received a daily intravenous injection of acetylcholine-calcium chloride for seven days to establish an AF model, and rats in the control rats were injected with saline in the same way. At different time points (Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, and Day 17), we observed changes in EndMT-related indexes (CD31, VE-cadherin, FSP-1, TGF-ß1 and collagen) and HIF-1α in the rat atria of two groups, as well as immunofluorescence co-expression of CD31/FSP-1 and VE-cadherin/FSP-1 in the endocardial endocardium of the atria. Results: In the AF group, atrial EndMT was observed and enhanced with time. Compared with the control group, the levels of CD31 and VE-cadherin in the AF group decreased, while mesenchymal marker (FSP-1) and EndMT inducer (TGF-ß1) were dynamically increased after Day 3. The co-expression of CD31/FSP-1 and VE-cadherin/FSP-1 was observed from Day 3 to the end of observation time Day 17 by immunofluorescence in AF rat hearts, indicating the existence of EndMT. In addition, the level of HIF-1α in the hearts of AF rats was increased. Conclusion: As far as we know, this is the first study to explore the dynamic process of EndMT in an AF rat model. The presence of EndMT was verified in the atria of the AF rat model, and Day 7-Day 17 was the best observation time point for the model. This may lead to a better understanding of the pathological changes and mechanisms in AF with a short modeling cycle.

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.

Single-cell RNA sequencing of mouse left ventricle reveals cellular diversity and intercommunication.

Previous studies have revealed the diversity of the whole cardiac cellulome but not refined the left ventricle, which was essential for finding therapeutic targets. Here, we characterized single-cell transcriptional profiles of the mouse left ventricular cellular landscape using single-cell RNA sequencing (10× Genomics). Detailed t-distributed stochastic neighbor embedding (tSNE) analysis revealed the cell types of left ventricle with gene markers. Left ventricular cellulome contained cardiomyocytes highly expressed Trdn, endothelial cells highly expressed Pcdh17, fibroblast highly expressed Lama2, and macrophages highly expressed Hpgds, also proved by in situ hybridization. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analysis (ListHits > 2, P < 0.05) were employed with the DAVID database to investigate subtypes of each cell type with the underlying functions of differentially expressed genes (DEGs). Endothelial cells included 5 subtypes, fibroblasts comprising 7 subtypes, and macrophages contained 11 subtypes. The key representative DEGs (P < 0.001) were Gja4 and Gja5 in cluster 3 of endothelial cells, Aqp2 and Thbs4 in cluster 2 of fibroblasts, and Clec4e and Trem-1 in cluster 3 of macrophages perhaps involved in the occurrence of atherosclerosis, heart failure, and acute myocardial infarction proved by literature review. We also revealed extensive networks of intercellular communication in left ventricle. We suggested possible therapeutic targets for cardiovascular disease and autocrine and paracrine signaling underpins left ventricular homeostasis. This study provided new insights into the structure and function of the mammalian left ventricular cellulome and offers an important resource that will stimulate studies in cardiovascular research.

Inhibition of Src improves cardiac fibrosis in AngII-induced hypertrophy by regulating the expression of galectin-3.

BACKGROUND: The expression of Src is upregulated in the vasculature associated with cardiac hypertrophy events. Here, we aimed to explore the underlying mechanism of Src in angiotensin II (AngII)-mediated cardiac fibrosis and hypertrophy. METHODS: The heart conditional Src knockout mouse model was established and administrated with AngII. The effects of Src on the AngII-mediated cardiac hypertrophy were assessed by Hematoxylin and Eosin (HE), Masson's trichrome, immunohistochemical staining, Annexin V-FITC/PI apoptosis detection assay and Western blot analysis. RESULTS: The expression levels of galectin-3, Src and the hypertrophy marker brain natriuretic peptide (BNP), as well as the phosphorylation of Src were all elevated in heart tissues of mice with AngII-induced cardiac hypertrophy and fibrosis. Heart conditional Src knockout attenuated AngII-activated cardiac fibrosis and hypertrophy in mice. Consistently, AngII could promote the expression of Src in a dose-dependent manner and the knockout of Src impaired Ang II-mediated apoptosis and fibrosis in the cardiomyocytes. In addition, Src inhibition suppressed the expression of galectin-3 in vivo and in vitro. Specifically, AngII could upregulate the expression of galectin-3, and knockdown of galectin-3 (Gal-3) remarkably inhibited AngII-enhanced apoptosis and fibrosis in the cardiomyocytes. Furthermore, overexpression of galectin-3 reinforced Ang II-induced cell apoptosis and fibrosis that was attenuated by knockout of Src. CONCLUSIONS: Our findings indicate that Src and Gal-3 play an important role in AngII-mediated cardiac structural remodeling. Src and galectin-3 might serve as potential targets for the treatment of AngII-induced cardiac fibrosis and hypertrophy.

LOXL2 Inhibitor Attenuates Angiotensin II-Induced Atrial Fibrosis and Vulnerability to Atrial Fibrillation through Inhibition of Transforming Growth Factor Beta-1 Smad2/3 Pathway.

OBJECTIVES: Angiotensin II (Ang II)-induced atrial fibrosis plays a vital role in the development of atrial fibrillation (AF). Lysyl oxidase-like 2 (LOXL2) plays an essential role in matrix remodeling and fibrogenesis, indicating it may involve fibrosis-associated diseases. This study aims to elucidate the role of LOXL2 in AF, and its specific inhibitor can suppress Ang II-induced inflammatory atrial fibrosis and attenuate the enhanced vulnerability to AF. METHODS: Male mice C57BL/6 were subcutaneously infused with either saline or Ang II (2 mg/kg/day) for 4 weeks. DMSO or LOXL2 inhibitor LOXL2-IN-1 hydrochloride (LOXL2-IN-1) at a dose of 100 µg/kg/day were intraperitoneally injected once daily for 4 weeks. Morphological, histological, and biochemical analyses were performed. AF was induced by transesophageal burst pacing in vivo. RESULTS: Expression of LOXL2 was increased in serum of AF patients and Ang II-treated mice. LOXL2-IN-1 significantly attenuated Ang II-induced AF vulnerability, cardiac hypertrophy, atrial inflammation, and fibrosis. LOXL2-IN-1 suppressed Ang II-induced expression of transforming growth factor beta-1 (TGF-ß1) and collagen I and phosphorylation of Smad2/3 in atrial tissue. CONCLUSIONS: LOXL2 is a target of AF, and its inhibitor prevents atrial fibrosis and attenuated enhanced vulnerability to AF potentially through the TGF-ß/Smad pathway.

Identification of an Epigenetic Signature for Coronary Heart Disease in Postmenopausal Women's PBMC DNA.

Menopause is accompanied with an increased risk of cardiovascular disease. DNA methylation may have a significant impact on postmenopausal women's development of coronary heart disease. DNA methylation alterations in peripheral blood mononuclear cells (PBMCs) from women with coronary heart disease and healthy controls were detected using the Illumina Infinium MethylationEPIC BeadChip platform in this work. We employed Sangerbox technology and the GO and KEGG databases to further study the pathogenesis of coronary heart disease in postmenopausal women. After that, we used functional epigenetic module analysis and Cytoscape to remove the hub genes from the protein-protein interaction networks. Five genes (FOXA2, PTRD, CREB1, CTNAP2, and FBN2) were the hub genes. Lipid accumulation, endothelial cell failure, inflammatory responses, monocyte recruitment and aggregation, and other critical biological processes were all influenced by these genes. Finally, we employed methylation-specific PCR to demonstrate that FOXA2 was methylated at a high level in postmenopausal women with coronary heart disease. To better understand coronary heart disease in postmenopausal women's molecular mechanisms, our study examine the major factors contributing to the state of DNA methylation modification, which will help discover novel diagnostic tools and treatment options.

Urinary cadmium in relation to bone damage: Cadmium exposure threshold dose and health-based guidance value estimation.

Cadmium (Cd) is a widespread heavy metal with osteotoxicity, and bone mineral density (BMD) is often used as an early sensitive biomarker of bone damage. This study retrieved worldwide epidemiological studies to conduct a systematic meta-analysis to explore the association between Cd exposure and bone damage. A random effect model was used to establish the relationship between urinary Cd (U-Cd) and BMD and explore the influence of covariate factors. The benchmark dose method was used to calculate the safety threshold of U-Cd when the BMD decrease within an acceptable range. Toxicokinetic (TK) model was used to estimate the health-based guidance value (HBGV) of dietary Cd exposure based on the U-Cd threshold. The 95% lower confidence interval of benchmark dose of U-Cd derived in this study was 1.71 µg/g Cr, and the HBGV of dietary Cd exposure was determined to be 0.64 µg/kg bw/day. Gender had the greatest influence on BMD, followed by body mass index (BMI), age, and race. This study conducted a comprehensive systematic analysis of global research and was the first exploration to quantify the decreased BMD caused by Cd exposure in a large-scale population. The results provided reference for the risk assessment of Cd exposure and the formulation of dietary exposure standards.

[Progress in the Treatment of Tachyarrhythmia by Pulsed Electric Field Ablation Catheter Ablation].

Pulsed electric field(PEF) provides high-energy instantaneous pulse and release energy to myocardial cell membrane, resulting in irreversible electroporation and causes myocardial cell contents leakage, destruction of intracellular homeostasis, cell death, and slight inflammatory response. PEF as non-thermal energy promotes the design and application of arrhythmia ablation catheter to enter a new stage. There are currently limited clinical studies that have proved the safety and effectieness of Farawave PEF catheter, PVAC GOLD PEF catheter, Lattice-tip Sphere-9 PEF and radiofrequency (RF) catheter used for atrial fibrillation ablation, but still need further discussion. The research of atrial fibrillation ablation with PEF is under study in China. In this paper, the design and application of PEF ablation for tachyarrhythmia are reviewed.

Intermedin alleviates pathological cardiac remodeling by upregulating klotho.

Cardiac remodeling is accompanied by cardiac hypertrophy, fibrosis, dysfunction, and eventually leading to heart failure. Intermedin (IMD), as a paracrine/autocrine peptide, has a protective effect in cardiovascular diseases. In this study, we elucidated the role and the underlying mechanism of IMD in pathological remodeling. Pathological remodeling mouse models were induced by abdominal aorta constriction for 4 weeks or angiotensin II (Ang II) infusion for 2 weeks in wildtype, IMD-overexpression, IMD-knockout and klotho-knockdown mice. Western blot, real-time PCR, histological staining, echocardiography and hemodynamics were used to detect the role of IMD in cardiac remodeling. Cardiac hypertrophy, fibrosis and dysfunction were significantly aggravated in IMD-knockout mice versus wildtype mice, and the expression of klotho was downregulated. Conversely, cardiac remodeling was alleviated in IMD-overexpression mice, and the expression of klotho was upregulated. Hypertension induced by Ang II infusion rather than abdominal aorta constriction was mitigated by IMD. However, the cardioprotective effect of IMD was blocked in klotho-knockdown mice. Similar results were found in cultured neonatal rat cardiomyocytes, which was pretreated with IMD before Ang II stimulation. Mechanistically, IMD inhibited the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the activity of calcineurin to protect against cardiac hypertrophy through upregulating klotho in vivo and in vitro. Furthermore, peroxisome proliferator-activated receptor γ (PPARγ) might mediate IMD upregulating klotho. In conclusion, pathological remodeling may be alleviated by endogenous IMD, which inhibits the expression of calcineurin and p-CaMKII by upregulating klotho via the PPARγ pathway. It suggested that IMD might be a therapeutic target for heart disease.

UBE3A alleviates isoproterenol-induced cardiac hypertrophy through the inhibition of the TLR4/MMP-9 signaling pathway.

Cardiac hypertrophy is considered to be a leading factor in heart function-related deaths. In this study, we explored the potential mechanism underlying cardiac hypertrophy induced by isoproterenol. Our results showed that isoproterenol induced cardiac hypertrophy in AC16 cells, as reflected by the increased cell surface area and increased hypertrophic markers, which was accompanied by increased ubiquitin-protein ligase E3a (UBE3A) expression. Moreover, UBE3A knockdown by siRNAs accelerated cardiac hypertrophy, suggesting that increased UBE3A expression induced by isoproterenol might be a protective response and UBE3A might be a protective factor against cardiac hypertrophy. Our study also revealed that UBE3A knockdown increased the protein expression of the TLR4/MMP-9 pathway that has been shown to be associated with cardiac hypertrophy, which suggested that UBE3A-mediated protection is likely to be associated with the blockade of the TLR4/MMP-9 signaling pathway. UBE3A might be thus a potential target gene for the treatment of cardiac hypertrophy.

Hypoxia induces hypomethylation of the HMGB1 promoter via the MAPK/DNMT1/HMGB1 pathway in cardiac progenitor cells.

Apoptosis is involved in the death of cardiac progenitor cells (CPCs) after myocardial infarction (MI) in the heart. The loss of CPCs results in infarct scar and further deterioration of the heart function. Though stem cell-based therapy provides an effective approach for heart function recovery after MI, the retention of CPCs in the infarcted area of the heart is the main barrier that limits its promising therapy. Therefore, the underlying mechanisms of CPC apoptosis in hypoxia are important for the development of new therapeutic targets for MI patients. In this work, we found that the expression of high-mobility group box 1(HMGB1) was upregulated in CPCs under hypoxia conditions. Further study demonstrated that HMGB1 was regulated by DNA methyltransferases 1 (DNMT1) via changing the methylation state of CpGs in the promoter of HMGB1 in CPCs during hypoxia process. Additionally, mitogen-activated protein kinase (MAPK) signaling pathway was found to be involved in regulating DNMT1/HMGB1-mediated CPC apoptosis in hypoxia process. In conclusion, our findings demonstrate a novel regulatory mechanism for CPC apoptosis and proliferation under hypoxia conditions, which may provide a new therapeutic approach for MI patients.

Atorvastatin protects cardiac progenitor cells from hypoxia-induced cell growth inhibition via MEG3/miR-22/HMGB1 pathway.

Heart failure (HF) induced by ischemia myocardial infarction (MI) is one of the major causes of morbidity and mortality all around the world. Atorvastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, has been demonstrated to benefit patients with ischemic or non-ischemic-induced HF, but the mechanism is still poorly understood. Increasing evidence indicates that lncRNAs play important role in variety of human disease. However, the role and underlying molecular mechanisms remain largely unclear. In our work, we applied 0.5% O2 to generate a hypoxia cardiac progenitor cell (CPC) model. Then, CCK8 and EdU assays were employed to investigate the role of atorvastatin in hypoxia CPC cell model. We found that hypoxia inhibits CPC viability and proliferation through modulating MEG3 expression, while atorvastatin application can protect CPCs from hypoxia-induced injury through inhibiting MEG3 expression. Then, we demonstrated that repression of MEG3 inhibited the hypoxia-induced injury of CPCs and overexpression of MEG3 inhibited the protective effect of atorvastatin in the hypoxia-induced injury of CPCs. Furthermore, our study illustrated that atorvastatin played its role in CPC viability and proliferation by modulating the expression of HMGB1 through the MEG3/miR-22 pathway. Our study, for the first time, uncovered the molecular mechanism of atorvastatin's protective role in cardiomyocytes under hypoxia condition, which may provide an exploitable target in developing effective therapy drugs for MI patients.

Multidetector Computed Tomography Angiography Combined with Intravascular Ultrasound for the Evaluation of Coronary Veins for Percutaneous Mitral Annulus Repair Using Transcoronary Sinus Devices.

BACKGROUND: Multidetector computed tomography angiography (MDCTA) can be used to evaluate the target location of transcoronary sinus devices. This study aimed to assess the accuracy of MDCTA in evaluating the target location of transcoronary sinus devices compared with intravascular ultrasound (IVUS). MATERIALS AND METHODS: Forty-two patients planned to undergo mitral valve repair (MVR) were prospectively enrolled at Zhoupu Hospital (China) including 15 with secondary mitral regurgitation (MR) grade ≥3. MDCTA was performed to measure the diameters of coronary sinus ostium (CSO) and proximal anterior interventricular vein (PAIV) and the distance between them. RESULTS: During MVR, these parameters were measured using IVUS before electrode insertion. There was a strong linear correlation between the diameter of CSO measured by MDCTA and IVUS (r = 0.967, P < 0.001), as well as for PAIV (r = 0.954, P < 0.001) and the distance between them (r = 0.986, P < 0.001). No significant differences were found between the results measured by MDCTA and IVUS. The patients with secondary MR grade ≥3 had significantly larger CSO and PAIV measured by IVUS (P = 0.003 and P = 0.017, respectively), as well as by MDCTA (P = 0.010 and P = 0.008, respectively). CONCLUSION: Dual-source MDCTA might allow the quantitative evaluation of the target location of transcoronary sinus devices with a good accuracy. It may be a good choice for guiding the selection of transcoronary sinus devices.

SLIT3 promotes cardiac fibrosis and differentiation of cardiac fibroblasts by RhoA/ROCK1 signaling pathway.

Objectives: Slit guidance ligand 3 (SLIT3) has been identified as a potential therapeutic regulator against fibroblast activity and fibrillary collagen production in an autocrine manner. However, this research aims to investigate the potential role of SLIT3 in cardiac fibrosis and fibroblast differentiation and its underlying mechanism. Materials and Methods: C57BL/6 mice (male, 8-10 weeks, n=47) were subcutaneously infused with Ang II (2.0 mg/kg/day) for 4 weeks. One to two-day-old Sprague-Dawley (SD) rats were anesthetized by intraperitoneal injection of 1% pentobarbital sodium (60 mg/kg) and ketamine (50 mg/kg) and the cardiac fibroblast was isolated aseptically. The mRNA and protein expression were analyzed using RT-qPCR and Western blotting. Results: The SLIT3 expression level was increased in Ang II-induced mice models and cardiac fibroblasts. SLIT3 significantly increased migrated cells and α-smooth muscle actin (α-SMA) expression in cardiac fibroblasts. Ang II-induced increases in mRNA expression of collagen I (COL1A1), and collagen III (COL3A1) was attenuated by SLIT3 inhibition. SLIT3 knockdown attenuated the Ang II-induced increase in mRNA expression of ACTA2 (α-SMA), Fibronectin, and CTGF. SLIT3 suppression potentially reduced DHE expression and decreased malondialdehyde (MDA) content, and the superoxide dismutase (SOD) and catalase (CAT) levels were significantly increased in cardiac fibroblasts. Additionally, SLIT3 inhibition markedly decreased RhoA and ROCK1 protein expression, whereas ROCK inhibitor Y-27632 (10 µM) markedly attenuated the migration of cardiac fibroblasts stimulated by Ang II and SLIT3. Conclusion: The results speculate that SLIT3 could significantly regulate cardiac fibrosis and fibroblast differentiation via the RhoA/ROCK1 signaling pathway.

Corilagin inhibits angiotensin II-induced atrial fibrosis and fibrillation in mice through the PI3K-Akt pathway.

Objectives: Corilagin (Cor) is reported as beiing hepatoprotective, anti-inflammatory, antibacterial, and anti-oxidant, while the effect on atrial fibrosis remains unknown. Therefore, we investigated the protective effect of Cor in angiotensin II (Ang II)-induced atrial fibrosis and atrial fibrillation (AF). Materials and Methods: C57BL/6 mice (male, 8-10 weeks, n = 40) were subcutaneously infused either with saline or Ang II (2.0 mg/kg/day) and Cor (30 mg/kg) intraperitoneally injected 2 hr before Ang II infusion for 4 weeks. Mice were grouped into the control group (n=8), Cor group (n=8), Ang II group (n=8), and Ang II + Cor group (n=8). Morphological, histological, and biochemical examinations were performed. In vivo, transesophageal burst pacing was used to generate AF. Results: Cor treatment markedly reduced Ang II-induced AF development in mice. Ang II + Cor therapy potentially decreased the atrial fibrotic area. It significantly decreased the increase in smooth muscle alpha-actin (α-SMA), CTGF, Collagen I, and Collagen III expressions brought on by Ang II treatment. Moreover, Ang II + Cor treatment remarkably decreased the malondialdehyde (MDA) content, whereas superoxide dismutase (SOD) and catalase (CAT) activities were potentially increased (all, P<0.001). In addition, Ang II + Cor significantly reduced Ang II-induced interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) concentrations in atrial tissues. Furthermore, Cor significantly inhibited Ang II-induced p-PI3K, p-Akt, and NF-κB p-p65 protein expression in atrial tissues. Conclusion: Our data speculated that Cor could have a protective effect against Ang II-induced atrial fibrosis and AF via down-regulation of the PI3K-Akt pathway.

Astragaloside IV inhibits angiotensin II-induced atrial fibrosis and atrial fibrillation by SIRT1/PGC-1α/FNDC5 pathway.

Aims and objectives: Astragaloside IV (AS-IV) has been found to possess anti-oxidative, anti-inflammatory, and anti-apoptotic properties, but its effect on atrial fibrosis is yet to be determined. This research investigates the protective role of AS-IV in angiotensin II (Ang II)-induced atrial fibrosis and atrial fibrillation (AF). Methods: C57BL/6 male mice aged 8-10 weeks (n = 40) were subcutaneously administered Ang II (2.0 mg/kg/day) or saline, with AS-IV (80 mg/kg) intraperitoneally administered 2 h before Ang II infusion for 4 weeks. Biochemical, histological, and morphological analyses were carried out. Using transesophageal burst pacing, AF was generated in vivo. Results: Here, we report that AS-IV treatment inhibited Ang II-induced AF development in mice (58 ± 5.86 vs 15.13 ± 2.16 %, p < 0.001). Ang II + AS-IV therapy was effective in reducing the atrial fibrotic area and decreasing the increase in smooth muscle alpha-actin (α-SMA)-positive myofibroblasts brought on by Ang II treatment (fibrotic area: 26.25 ± 3.81 vs 8.62 ± 1.83 %, p < 0.001 and α-SMA: 65.62 ± 10.63 vs 17.25 ± 1.78 %, p < 0.001). The reactive oxygen species (ROS) production was reduced by pretreatment with Ang II + AS-IV (9.20 ± 0.92 vs 2.63 ± 0.22 %/sec, p < 0.001). In addition, Ang II + AS-IV treatment suppressed oxidative stress in Ang II-induced atrial fibrosis (malondialdehyde: 701.78 ± 85.01 vs 504.07 ± 25.62 pmol/mg protein, p < 0.001; superoxide dismutase: 13.82 ± 1.25 vs 29.54 ± 2.45 U/mg protein, p < 0.001 and catalase: 11.43 ± 1.19 vs 20.83 ± 3.29 U/mg protein, p < 0.001, respectively). Moreover, Ang II + AS-IV decreased the expression of α-SMA, collagen III and collagen I (3.32 ± 0.53 vs 1.41 ± 0.20 fold, p < 0.001; 3.41 ± 0.55 vs 1.48 ± 0.18 fold, p < 0.001; 2.34 ± 0.55 vs 0.99 ± 0.17 fold, p < 0.001, respectively) while increasing the protein expression of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), and fibronectin type III domain-containing protein 5 (FNDC5) in Ang II-treated mice (0.22 ± 0.02 vs 0.57 ± 0.08 fold, p < 0.001; 0.28 ± 0.04 vs 0.72 ± 0.05 fold, p < 0.001; 0.38 ± 0.03 vs 0.68 ± 0.06 fold, p < 0.001, respectively). Conclusion: Our data led us to speculate that AS-IV may protect against Ang II-induced atrial fibrosis and AF via upregulation of the SIRT1/PGC-1α/FNDC5 pathway.

Salidroside attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin-II through inhibition of LOXL2-TGF-ß1-Smad2/3 pathway.

Aims and objectives: Salidroside (SAL), an active component isolated from the Chinese plant Rose Rhodiola, has anti-inflammatory, antioxidant, anti-cancer, neuroprotective, and renal protective properties. Atrial fibrosis developed due to angiotensin II (Ang II) plays a crucial function in developing atrial fibrillation (AF). This research investigates the involvement of SAL in AF, its vulnerability to AF, and Ang II-induced inflammatory atrial fibrosis. Methods: Ang II (2 mg/kg/day) was infused underneath the skin into male C57BL/6 mice (8-10 weeks old, n = 40) for four weeks to create the AF model. SAL (50 mg/kg/day) was given intraperitoneally once per day for 28 days. Analyses of morphology, histology, and biochemical were carried out. Transesophageal burst pacing was used in vivo to induce AF. Results: Ang II injection increased mice's heart rate and systolic blood pressure (SBP), whereas SAL treatment was significantly reduced. Ang II infusion increased left atrial diameter (LAD) in mice, which was attenuated after SAL treatment. SAL alone did not affect AF inducibility, but SAL therapy markedly decreased Ang II-induced AF inducibility. Additionally, the expression levels of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were inhibited with SAL therapy in mice. Compared to the Ang II group, Ang II infusion raised malondialdehyde (MDA) levels and reduced superoxide dismutase (SOD) and catalase (CAT) activity, but SAL therapy altered all of these effects. SAL treatment significantly reduced LOXL2, TGF-ß1, p-Smad2 and p-Smad3 protein expression than the Ang II group mice. Conclusion: SAL inhibits atrial fibrosis and potentially attenuates increased susceptibility to AF by suppressing the LOXL2-TGF-ß1-Smad2/3 pathway.

Temporary COVID-19 Specialized Hospital: Management Strategies for Public Health Emergencies.

During the coronavirus disease 2019 (COVID-19) outbreak in Shanghai with the Omicron variant in March 2022, locally accessible hospitals and healthcare centres encountered difficulties quickly responding to a demand for hospitals that were rapidly increasing, optimizing clinical results and controlling the infection. In this commentary, we summarize the management strategies of patients in a temporary COVID-19 specialized hospital during the outbreak in Shanghai, China. The present commentary was considered eight characteristics of management system, including general idea, infection prevention team, and efficient time management, and preventive and protective measures management, strategies for the management of infected patients, disinfection management, drug supply management strategies, and medical waste management. Following eight characteristics, the temporary COVID-19 specialized hospital operated effectively for 21 days. A total of 9674 patients were admitted, 7127 cases (73.67%) were cured and discharged, and 36 were transferred to designate hospitals for better treatment. Twenty-five management staff, 1130 medical, nursing staff, 565 logistics staff, and 15 volunteers participated in the temporary COVID-19 specialized hospital, and no infection prevention team member was infected. We speculated that these management strategies could be potential references for public health emergencies.

Echinacoside ameliorates 5-fluorouracil-induced endothelial injury and senescence through SIRT1 activation.

Echinacoside (ECH) is a natural bioactive component with antioxidant, anti-inflammatory, anti-apoptosis, and anti-tumor properties. In the current study, we explore the ECH-mediated protective effect and underlying mechanism of 5-fluorouracil (5-FU)-induced endothelial injury and senescence in the Human umbilical vein endothelial cells (HUVECs). In HUVECs, Cell viability, Apoptosis and Senescence assays evaluated 5-fluorouracil-induced endothelial injury and senescence. Protein expressions were assessed using RT-qPCR and Western blotting. Our results showed that 5-FU-induced endothelial injury and endothelial cell senescence could be improved when treated with ECH in HUVECs. ECH treatment potentially attenuated oxidative stress and ROS production in HUVECs. In addition, the effect of ECH on autophagy markedly reduced the percentage of HUVECs with LC3-II dots and suppressed the Beclin-1 and ATG7 mRNA expression but enhanced the p62 mRNA expression. Besides, ECH treatment significantly increased migrated cells and suppressed the adhesion of THP-1 monocytes in HUVECs. Furthermore, ECH treatment activated the SIRT1 pathway, and its related proteins (SIRT1, p-AMPK and eNOS) expression increased. Nicotinamide (NAM), an inhibitor of SIRT1, significantly attenuated the ECH-induced decrease in the apoptotic rate, increased SA-ß-gal-positive cells and significantly reversed the ECH-induced reduction of endothelial senescence. Our results demonstrated that ECH employed endothelial injury and senescence in HUVECs via activation of the SIRT1 pathway.

Machine learning algorithms identify target genes and the molecular mechanism of matrine against diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma worldwide. Novel treatment strategies are still needed for refractory or relapsed DLBCL. OBJECTIVE: The present study aimed to systematically explore the potential targets and molecular mechanisms of matrine in the treatment of DLBCL. METHODS: Potential matrine targets were collected from multiple platforms. Microarray data and clinical characteristics of DLBCL were downloaded from publicly available databases. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were applied to identify the hub genes of DLBCL using R software. Then, the shared target genes between matrine and DLBCL were identified as the potential targets of matrine against DLBCL. The least absolute shrinkage and selection operator (LASSO) algorithm was used to determine the final core target genes, which were further verified by molecular docking simulation and receiver operating characteristic (ROC) curve analysis. Functional analysis was also performed to elucidate the potential mechanisms. RESULTS: A total of 222 matrine target genes and 1269 DLBCL hub genes were obtained through multiple databases and machine learning algorithms, respectively. From the nine shared target genes of matrine and DLBCL, five final core target genes, including CTSL, NR1H2, PDPK1, MDM2, and JAK3, were identified. Molecular docking showed that the binding of matrine to the core genes was stable. ROC curves also suggested close associations between the core genes and DLBCL. Additionally, functional analysis showed that the therapeutic effect of matrine against DLBCL may be related to the PI3K-Akt signaling pathway. CONCLUSION: Matrine may target five genes and the PI3K-Akt signaling pathway in DLBCL treatment.