Cardiac computed tomography angiography for assessment of endothelial insufficiency of left atrial appendage disc-like occluder.

INTRODUCTION: This study was performed to explore the diagnostic value of cardiac computed tomography angiography (CCTA) for endothelial insufficiency (EIS) of a left atrial appendage (LAA) disc-like occluder. METHODS: Fifty-nine patients with nonvalvular atrial fibrillation who underwent placement of an LAA disc-like occluder (LAmbre; Lifetech Scientific) in our hospital were retrospectively analyzed. Patients who were found to have contrast agent entering the LAA at the 3-month postoperative CCTA examination underwent Hounsfield unit (HU) measurement of the LAA and construction of a three-dimensional (3D) model of the device for preliminary discernment between peri-device leakage (PDL) and EIS. These patients were then further examined by transesophageal echocardiography (TEE) to check for concordance with the computed tomography (CT) findings. According to the CT and TEE results, all patients were divided into the PDL group, total endothelialization group, and EIS group. The endothelial conditions and other implantation-related results were also tracked at the 6-month follow-up. RESULTS: All 59 patients underwent successful implantation of the LAmbre LAA closure device with no severe adverse events during the procedure. Thirty-five patients were found to have contrast agent entering the LAA at the 3-month postoperative CCTA follow-up. Based on the CT HU measurement and the 3D construction analysis results, these 35 patients were divided into the PDL group (19 patients) and the EIS group (16 patients). In the PDL group, the contrast agent infiltrated from the shoulder along the periphery of the occluder on two-dimensional (2D) CT images, and the 3D model showed a gap between the LAA and the device cover. However, the CCTA images of the other 16 patients in the EIS group showed that the contrast agent in the occluder on the 2D CTA images and 3D construction model confirmed the absence of a gap between the LAA and the device cover. TEE confirmed all of the CT results. The 6-month follow-up results showed that 14 of 19 patients in the EIS group achieved total endothelialization, whereas this number in the PDL group was only five of 19 patients. CONCLUSION: CCTA can replace TEE for examination of the endothelialization status, and patients with EIS have a higher chance of endothelialization than patients with PDL.

Ferrostatin-1 Blunts Right Ventricular Hypertrophy and Dysfunction in Pulmonary Arterial Hypertension by Suppressing the HMOX1/GSH Signaling.

Ferroptosis plays a critical role in pulmonary arterial hypertension (PAH)-induced right ventricular (RV) dysfunction, but key genes remain largely unclear. We here identified HMOX1 as an essential ferroptosis-related differentially expressed gene in PAH by bioinformatic analysis using FerrDb, GSE119754, and GSE3675 datasets, respectively. Notably, there were marked increases in HMOX1 and iron levels in RV of monocrotaline-induced PAH rats with reduced TAPSE levels. More importantly, treatment with ferrostatin-1 effectively attenuated RV hypertrophy, remodeling, myocardial fibrosis, and dysfunction in PAH rats. In cultured H9C2 cells and primary neonatal rat cardiomyocytes, pretreatment with ferrostatin-1 and knockdown HMOX1 by siRNA strikingly blunted hypoxia-induced promotion of lipid peroxidation, ferroptosis, and cardiomyocyte injury by potentiating glutathione (GSH) and nitric oxide signaling, respectively. In summary, ferrostatin-1 attenuates RV hypertrophy, fibrosis, and dysfunction in PAH by suppressing the HMOX1/GSH signaling. Targeting HMOX1 ferroptosis signaling functions as a potential therapeutic strategy for patients with PAH.

The prognostic value and economic benefits of coronary angiography-derived fractional flow reserve-guided strategy in patients with coronary artery disease.

Objective: This study aims to investigate the prognostic value and economic benefit of coronary angiography-derived fractional flow reserve (caFFR) guided percutaneous coronary intervention (PCI) in patients with coronary artery disease. Methods: All patients with coronary artery disease (CAD) who underwent coronary angiography in our center between April 2021 and November 2021 were retrospectively enrolled and divided into the caFFR guidance group (n = 160) and angiography guidance group (n = 211). A threshold of caFFR≤0.8 was used for revascularization. Otherwise, delayed PCI was preferred. The patients were prospectively followed up by telephone or outpatient service at six months for major adverse cardiovascular events (MACE) of all-cause death, myocardial infarction or target vessel revascularization, stent thrombosis, and stroke. All in-hospital expenses were recorded, including initial hospitalization and re-hospitalization related to MACE. Results: There was no significant difference in the baseline characteristics between the two groups. There were 2 (1.2%) patients in the caFFR guidance group and 5 (2.4%) patients in the angiography guidance group with MACE events during the following six months. Compared with angiography guidance, caFFR guidance reduced the revascularization rate (63.7% vs. 84.4%, p = 0.000), the average length of stents implanted (0.52 ± 0.88 vs. 1.1 ± 1.4, P < 0.001). The cost of consumables in the caFFR guidance group was significantly lower than that in the angiography guidance group (33257 ± 19595 CNY vs. 38341 ± 16485 CNY, P < 0.05). Conclusion: Compared with coronary angiography guidance, caFFR guidance is of great significance in reducing revascularization and cost, which has significant health and economic benefits.

Plasma levels of bone morphogenic protein-4 are downregulated in elderly hypertensive patients with heart failure with preserved ejection fraction.

OBJECTIVE: This study aimed to evaluate the association between plasma bone morphogenic protein-4 (BMP-4) levels and heart failure (HF) with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF) in elderly hypertensive patients. METHODS: A total of 222 hypertensive individuals meeting the inclusion criteria were enrolled from October 2021 to July 2022. Data were collected including clinical characteristics, laboratory tests and echocardiogram measurements. Plasma BMP-4 levels were tested using enzyme-linked immunosorbent assay analysis. RESULTS: Among 222 elderly hypertensive patients, 149 were without HF, 59 had HFpEF, and 14 had HFmrEF. Plasma BMP-4 levels were strikingly downregulated in hypertensive patients with HFpEF/HFmrEF [median (25th, 75th percentile): 15.89 (7.69, 23.12) pg/mL vs. 19.67 (10.60, 33.04) pg/mL; P = 0.002]. After univariate and multivariate logistic regression analysis, the risk of HFpEF/HFmrEF was declined in the 4th quartile BMP-4 group when compared with the 1st quartile BMP-4 group (odds ratio, 0.20, 95% confidence interval (CI), 0.04 to 1.00; P = 0.050, P for trend = 0.025). Receiver operating characteristic curve analysis revealed that BMP-4 ≤ 28.5 pg/mL exhibited a sensitivity of 95.9% and a specificity of 28.2% in HFpEF/HFmrEF diagnosis. Furthermore, the area under the curve (AUC) was 0.619 (95% CI:0.540-0.698, P < 0.001). The corresponding AUC for brain natriuretic peptide (BNP) was 0.781 (95% CI: 0.710-0.852), P < 0.001. Adding BMP-4 to BNP increased the AUC to 0.790 (95% CI: 0.724-0.856), vs. BMP-4, P < 0.001; vs. BNP, P = 0.730, respectively. CONCLUSIONS: Plasma BMP-4 levels are downregulated in elderly hypertensive patients with HFpEF. BMP-4 is a promising biomarker for diagnosing HFpEF/HFmrEF during hypertension.

Gas-Dependent Active Sites on Cu/ZnO Clusters for CH3OH Synthesis.

This study describes an instantaneously gas-induced dynamic transition of an industrial Cu/ZnO/Al2O3 catalyst. Cu/ZnO clusters become "alive" and lead to a promotion in reaction rate by almost one magnitude, in response to the variation of the reactant components. The promotional changes are functions of either CO2-to-CO or H2O-to-H2 ratio which determines the oxygen chemical potential thus drives Cu/ZnO clusters to undergo reconstruction and allows the maximum formation of Cu-Zn2+ sites for CH3OH synthesis.

Elabela blunts doxorubicin-induced oxidative stress and ferroptosis in rat aortic adventitial fibroblasts by activating the KLF15/GPX4 signaling.

Doxorubicin (DOX) is a chemotherapeutic drug for a variety of malignancies, while its application is restricted by the cardiovascular toxic effects characterized by oxidative stress. Ferroptosis is a novel iron-dependent regulated cell death driven by lipid peroxidation. Our study aimed to investigate the role of Elabela (ELA) in DOX-induced oxidative stress and ferroptosis. In cultured rat aortic adventitial fibroblasts (AFs), stimulation with DOX dramatically induced cytotoxicity with reduced cell viability and migration ability, and enhanced lactate dehydrogenase (LDH) activity. Importantly, ELA and ferrostatin-1 (Fer-1) mitigated DOX-mediated augmentation of reactive oxygen species (ROS) in rat aortic AFs, accompanied by upregulated levels of Nrf2, SLC7A11, GPX4, and GSH. In addition, ELA reversed DOX-induced dysregulation of apoptosis- and inflammation-related factors including Bax, Bcl2, interleukin (IL)-1ß, IL6, IL-10, and CXCL1. Intriguingly, knockdown of Krüppel-like factor 15 (KLF15) by siRNA abolished ELA-mediated alleviation of ROS production and inflammatory responses. More importanly, KLF15 siRNA impeded the beneficial roles of ELA in DOX-pretreated rat aortic AFs by suppressing the Nrf2/SLC7A11/GPX4 signaling. In conclusion, ELA prevents DOX-triggered promotion of cytotoxicity, and exerts anti-oxidative and anti-ferroptotic effects in rat aortic AFs via activation of the KLF15/GPX4 signaling, indicating a promising therapeutic value of ELA in antagonizing DOX-mediated cardiovascular abnormality and disorders.

Sirtuin 7 mitigates renal ferroptosis, fibrosis and injury in hypertensive mice by facilitating the KLF15/Nrf2 signaling.

Hypertension is one of the leading causes of chronic kidney disease characterized with renal fibrosis. This study aimed to investigate roles and mechanisms of sirtuin 7 (SIRT7) in hypertensive renal injury. Mini-pumps were implanted to male C57BL/6 mice to deliver angiotensin (Ang) Ⅱ (1.5 mg/kg/d) or saline for 2 weeks. Ang Ⅱ infusion resulted in marked increases in systolic blood pressure levels, renal ferroptosis and interstitial fibrosis in hypertensive mice, concomitantly with downregulated SIRT7 and Krüppel-like factor 15 (KLF15) levels. Notably, administration of recombinant adeno-associated virus-SIRT7 or ferroptosis inhibitor ferrostatin-1 effectively mitigated Ang Ⅱ-triggered renal ferroptosis, epithelial-mesenchymal transition (EMT), interstitial fibrosis, renal functional and structural injury in hypertensive mice by blunting the KIM-1/NOX4 signaling and enforcing the KLF15/Nrf2 and xCT/GPX4 signaling, respectively. In primary cultured mouse renal tubular epithelial cells (TECs), Ang Ⅱ pretreatment led to repressed SIRT7 expression and augmented ferroptosis as well as partial EMT, which were substantially antagonized by rhSIRT7 or ferrostatin-1 administration. Additionally, both Nrf2 inhibitor ML385 and KLF15 siRNA strikingly abolished the rhSIRT7-mediated beneficial roles in mouse renal TECs in response to Ang Ⅱ with reduced expression of Nrf2, xCT and GPX4. More importantly, ML385 administration remarkably amplified Ang Ⅱ-mediated ROS generation, lipid peroxidation and ferroptosis in renal TECs, which were significantly reversed by ferrostatin-1. In conclusion, SIRT7 alleviates renal ferroptosis, lipid peroxidation, and partial EMT under hypertensive status by facilitating the KLF15/Nrf2 signaling, thereby mitigating renal fibrosis, injury and dysfunction. Targeting SIRT7 signaling serves as a promising strategy for hypertension and hypertensive renal injury.

Association of plasma bone morphogenetic protein-4 levels with arterial stiffness in hypertensive patients.

BACKGROUND: Arterial stiffness interacts with hypertension, becoming an early marker of hypertension-mediated target organ damage. This study aimed to assess the association between plasma concentrations of bone morphogenetic protein-4 (BMP-4) and arterial stiffness during hypertension. METHODS: Using cardio-ankle vascular index (CAVI) to determine arterial stiffness status, 204 individuals with essential hypertension were classified into two groups, high CAVI (abnormal) group (n = 94) and low (normal) CAVI group (n = 110). Data were collected including clinical characteristics and laboratory measurements. Plasma levels of BMP-4 were tested by using ELISA analysis. RESULTS: Plasma levels of BMP-4 were substantially greater in high CAVI group than that in low CAVI group [38.51 (31.79-50.83) pg/mL vs. 31.15 (29.38-32.37) pg/mL; p < 0.001]. As shown by spearman correlation analysis, BMP-4 concentrations were correlated with CAVI values in hypertensive individuals (r = 0.406, p < 0.001). After adjustment for potential confounders, elevated BMP-4 levels were related with high CAVI (OR, 1.070; 95% CI, 1.003-1.108; p < 0.001). The best BMP-4 cutoff value for identifying high CAVI, as determined by ROC curve analysis, was 33.34 pg/mL (AUC, 0.751; 95% CI, 0.683-0.818; p < 0.001). CONCLUSION: Plasma levels of BMP-4 are increased in hypertensive individuals with high CAVI. Elevated BMP-4 levels are strongly correlated with higher CAVI values, implying a predictive value of BMP-4 in arterial stiffness during hypertension.

Sirtuin 7 serves as a promising therapeutic target for cardiorenal diseases.

Cardiovascular disorders and associated renal diseases account for the main cause of morbidity and mortality worldwide, necessitating the development of novel effective approaches for the prevention and treatment of cardiorenal diseases. Mammalian sirtuins (SIRTs) function as nicotinamide adenine dinucleotide (NAD+)-dependent protein/histone deacetylases. Seven members of SIRTs share a highly invariant catalytic core domain responsible for the specific enzymatic activity. Intriguingly, the broad distribution of SIRTs and alternative isoforms implicate its distinct functions in diverse cardiac and renal cells and tissue types. Notably, SIRT7 has been shown to exert beneficial effects in cardiorenal physiology and pathophysiology via modulation of senescence, DNA damage repair, ribosomal RNA synthesis, protein biosynthesis, angiogenesis, apoptosis, superoxide generation, cardiorenal metabolism, and dysfunction. Furthermore, SIRT7 has emerged as a critical modulator of a broad range of cellular activities including oxidative stress, inflammation response, endoplasmic reticulum stress, and mitochondrial homeostasis, which are all of great significance in postponing the progression of cardiorenal diseases. More importantly, SIRT7 has been implicated in cardiorenal hypertrophy, fibrosis, remodeling, heart failure, atherosclerosis as well as renal acid-base and electrolyte homeostasis as an essential regulator. In this article, we focus on the involvement in cardiorenal physiology and pathophysiology, diverse actions and underlying mechanisms of the SIRT7 signaling, highlighting its updated research progress in heart failure, atherosclerosis, diabetic nephropathy and other cardiorenal diseases. Targeting SIRT7 signaling could be potentially exploited as a therapeutic strategy aiming to prevent and treat cardiorenal diseases.

MicroRNA-122-5p Aggravates Angiotensin II-Mediated Myocardial Fibrosis and Dysfunction in Hypertensive Rats by Regulating the Elabela/Apelin-APJ and ACE2-GDF15-Porimin Signaling.

Hypertension is the leading risk factor for cardiovascular disorders. This study aimed to explore roles of microRNA (miR)-122-5p in hypertension. Angiotensin II (Ang II; 1.5 mg/kg/day) with an osmotic minipump was used to induce hypertensive rats pretreated by rAAV-miR-122-5p or rAAV-GFP, respectively. Notably, Ang II infusion caused marked increases in myocardial fibrosis, inflammation, oncosis, and oxidant injury in rats, which were aggravated by rAAV-miR-122-5p. RAAV-miR-122-5p exacerbated Ang II-mediated cardiac dysfunction and structural injury in hypertensive rats, with downregulated levels of apelin, elabela, ACE2, and GDF15, as well as upregulated expression of porimin and CTGF. In cultured rat cardiac fibroblasts, Ang II contributed to augmentation of cellular oncosis, migration, inflammation, and oxidative stress, with reduction of apelin, elabela, ACE2, and GDF15 levels, which were rescued by miR-122 inhibitor. In summary, miR-122-5p exacerbates myocardial fibrosis and dysfunction in hypertensive rats by modulating the elabela/apelin-ACE2-GDF15 signaling. MiR-122-5p has potential therapeutic significance for hypertension and hypertensive cardiac injury.

Elabela alleviates ferroptosis, myocardial remodeling, fibrosis and heart dysfunction in hypertensive mice by modulating the IL-6/STAT3/GPX4 signaling.

Hypertension-mediated pathological cardiac remodeling often progresses to heart failure. Elabela, mainly expressed in the cardiac microvascular endothelial cells (CMVECs), functions as a new endogenous ligand for apelin receptor. However, the exact roles of elabela in hypertension remain largely unclear. In this study, 10-week-old male C57BL/6 mice were randomly subjected to infusion of angiotensin (Ang) II (1.5 mg/kg/d) or saline for 2 weeks. Ang II infusion led to marked increases in systolic blood pressure levels and reduction of elabela levels in hypertensive mice with augmented myocardial hypertrophy and fibrosis. Furthermore, administration of elabela or ferroptosis inhibitor ferrostatin-1 significantly prevented Ang II-mediated pathological myocardial remodeling, dysfunction, and ultrastructural injury in hypertensive mice with downregulated expression of inflammation-, hypertrophy-, and fibrosis-related genes. Notably, elabela strikingly alleviated Ang II-induced upregulation of iron levels and lipid peroxidation in hypertensive mice by suppressing cardiac interleukin-6 (IL-6)/STAT3 signaling and activating the xCT/glutathione peroxidase (GPX4) signaling. In cultured CMVECs, exposure to Ang II resulted in a marked decrease in elabela levels and obvious increases in cellular ferroptosis, proliferation, inflammation, and superoxide production, which were rescued by elabela or ferrostatin-1 while were blocked by co-treatment with rhIL-6. Furthermore, knockdown of elabela by siRNA in CMVECs contributed to Ang II-mediated augmentations in cellular proliferation, migration, and oxidative stress in cultured cardiac fibroblasts and cardiomyocytes, respectively. In conclusion, elabela antagonizes Ang II-mediated promotion of CMVECs ferroptosis, adverse myocardial remodeling, fibrosis and heart dysfunction through modulating the IL-6/STAT3/GPX4 signaling pathway. Targeting elabela-APJ axis serves as a novel strategy for hypertensive heart diseases.

MicroRNA-122-5p promotes renal fibrosis and injury in spontaneously hypertensive rats by targeting FOXO3.

Hypertensive renal injury is accompanied by tubular interstitial fibrosis leading to increased risk for renal failure. This study aimed to explore the influences of miR-122-5p in hypertension-mediated renal fibrosis and damage. 14-week-old male SHR and WKY rats were randomly assigned to treat with rAAV-miR-122-5p or rAAV-GFP for 8 weeks. There were marked increases in miR-122-5p and Kim-1 levels and decreases in FOXO3 and SIRT6 levels in hypertensive rats. Transfection with rAAV-miR-122-5p triggered exacerbation of renal fibrosis, apoptosis and inflammatory injury in SHR, associated with downregulated levels of FOXO3, SIRT6, ATG5 and BNIP3 as well as upregulated expression of Kim-1, NOX4, CTGF, and TGF-ß1. In cultured primary mouse renal tubular interstitial fibroblasts, exposure to angiotensin II resulted in obvious downregulation of FOXO3, SIRT6, ATG5, BNIP3 and nitric oxide levels as well as augmented cellular migration, oxidative stress, and inflammation, which were exacerbated by miR-122-5p mimic while rescued by miR-122-5p inhibitor and rhFOXO3, respectively. Notably, knockdown of FOXO3 strikingly blunted cellular protective effects of miR-122-5p inhibitor. In summary, miR-122-5p augments renal fibrosis, inflammatory and oxidant injury in hypertensive rats by suppressing the expression of FOXO3. Pharmacological inhibition of miR-122-5p has potential therapeutic significance for hypertensive renal injury and fibrosis-related kidney diseases.

Targeting the elabela/apelin-apelin receptor axis as a novel therapeutic approach for hypertension.

ABSTRACT: Hypertension is the leading risk factor for global mortality and morbidity and those with hypertension are more likely to develop severe symptoms in cardiovascular and cerebrovascular system, which is closely related to abnormal renin-angiotensin system and elabela/apelin-apelin receptor (APJ) axis. The elabela/apelin-APJ axis exerts essential roles in regulating blood pressure levels, vascular tone, and cardiovascular dysfunction in hypertension by counterbalancing the action of the angiotensin II/angiotensin II type 1 receptor axis and enhancing the endothelial nitric oxide (NO) synthase/NO signaling. Furthermore, the elabela/apelin-APJ axis demonstrates beneficial effects in cardiovascular physiology and pathophysiology, including angiogenesis, cellular proliferation, fibrosis, apoptosis, oxidative stress, and cardiovascular remodeling and dysfunction during hypertension. More importantly, effects of the elabela/apelin-APJ axis on vascular tone may depend upon blood vessel type or various pathological conditions. Intriguingly, the broad distribution of elabela/apelin and alternative isoforms implicates its distinct functions in diverse cardiac and vascular cells and tissue types. Finally, both loss-of-function and gain-of-function approaches have defined critical roles of the elabela/apelin-APJ axis in reducing the development and severity of hypertensive diseases. Thus, targeting the elabela/apelin-APJ axis has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of hypertension, and an increased understanding of cardiovascular actions of the elabela/apelin-APJ axis will help to develop effective interventions for hypertension. In this review, we focus on the physiology and biochemistry, diverse actions, and underlying mechanisms of the elabela/apelin-APJ axis, highlighting its role in hypertension and hypertensive cardiovascular injury and dysfunction, with a view to provide a prospective strategy for hypertensive disease therapy.

Long non-coding RNA MALAT1 modulates myocardial ischemia-reperfusion injury through the PI3K/Akt/eNOS pathway by sponging miRNA-133a-3p to target IGF1R expression.

The mechanism of myocardial ischemia-reperfusion injury (MIRI) is a complex pathophysiological process that can lead to poor patient outcomes. Although LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is reported to be highly expressed in myocardial ischemia reperfusion (IR) injury, the specific mechanism remains largely unknown. This study aimed to elucidate the roles and possible mechanism of MALAT1 in myocardial IR injury. IR model was established in rats by ligation of the anterior descending artery in vivo, and H9c2 and HL-1 cells were treated by hypoxia/reoxygenation (HR) to construct the model in vitro. The small interfering RNA (siRNA) for MALAT1 and miR-133a-3p mimics, inhibitor was used to transfect the cells. The expression of MALAT1, miR-133a-3p in MIRI were evaluated using real-time quantitative polymerase chain reaction (qRT-PCR)，immunohistochemistry (IHC) and western blot (WB). Relationships between MALAT1, insulin-like growth factor 1 receptor (IGF1R) with miR-133a-3p were confirmed by luciferase reporter assay. Annexin V-FITC/PI double-labeled flow cytometry, terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), Cell Counting Kit-8 (CCK-8), serum creatine kinase MB (CK-MB), and lactate dehydrogenase (LDH) were evaluated to examine the impact of MALAT1 on MIRI. Our results revealed that MALAT1 was highly expressed, while miR-133a-3p and IGF1R were repressed in IR and HR groups. Knockdown of MALAT1 alleviate the pro-apoptotic effect and myocardial injury in vitro and in vivo. Systematically, MALAT1 may serve as a sponge for miR-133a-3p to suppress IGF1R, which a direct target of miR-133a-3p, then inhibit the PI3K/Akt/eNOS survival pathway. Mechanistically, our study demonstrated that MALAT1 regulates PI3K/Akt/eNOS signaling via miR-133a-3p. In summary, these results suggest that MALAT1 and miR-133a-3p play important roles in MIRI. MALAT1 regulates miR-133a-3p /IGF1R axis. These results show light on the underlying mechanisms of MIRI and provide potential therapeutic targets for MIRI.

Interactions between PAMAM-NH2 and 6-Mercaptopurine: Qualitative and Quantitative NMR studies.

Despite being used as an anti-leukemic drug, the poor solubility of 6-mercaptopurine (6-MP) limits its use in topical and parenteral applications. Dendrimers are commonly used as drug carriers to improve their solubility in aqueous solution. In this work, the interactions between 6-MP and the amine-terminated poly(amidoamine) dendrimers (PAMAM-NH2 ) were investigated by various NMR technology. The chemical shift titrations disclosed that the 6-MP interacted with the surface of PAMAM-NH2 mainly through electrostatics. The determination of diffusion coefficient and relaxation measurements further confirmed the presence of interactions in 6-MP/PAMAM-NH2 complexes. In addition, the encapsulation of 6-MP within the cavity of PAMAM-NH2 was revealed through nuclear Overhauser effect spectroscopy and Saturation Transfer Double Difference analysis. Finally, the binding strength (H-8 is 100% and H-2 is 70%) of 6-MP to PAMAM-NH2 was quantitatively expressed using epitope maps. This study provides a systematic methodology for qualitative and quantitative studies of the interactions between dendrimers and drug molecules in general.

Elabela prevents angiotensin II-induced apoptosis and inflammation in rat aortic adventitial fibroblasts via the activation of FGF21-ACE2 signaling.

Apoptosis, inflammation, and fibrosis contribute to vascular remodeling and injury. Elabela (ELA) serves as a crucial regulator to maintain vascular function and has been implicated in the pathogenesis of hypertensive vascular remodeling. This study aims to explore regulatory roles and underlying mechanisms of ELA in rat aortic adventitial fibroblasts (AFs) in response to angiotensin II (ATII). In cultured AFs, exposure to ATII resulted in marked decreases in mRNA and protein levels of ELA, fibroblast growth factor 21 (FGF21), and angiotensin-converting enzyme 2 (ACE2) as well as increases in apoptosis, inflammation, oxidative stress, and cellular migration, which were partially blocked by the exogenous replenishment of ELA and recombinant FGF21, respectively. Moreover, treatment with ELA strikingly reversed ATII-mediated the loss of FGF21 and ACE2 levels in rat aortic AFs. FGF21 knockdown with small interfering RNA (siRNA) significantly counterbalanced protective effects of ELA on ATII-mediated the promotion of cell migration, apoptosis, inflammatory, and oxidative injury in rat aortic AFs. More importantly, pretreatment with recombinant FGF21 strikingly inhibited ATII-mediated the loss of ACE2 and the augmentation of cell apoptosis, oxidative stress, and inflammatory injury in rat aortic AFs, which were partially prevented by the knockdown of ACE2 with siRNA. In summary, ELA exerts its anti-apoptotic, anti-inflammatory, and anti-oxidant effects in rat aortic AFs via activation of the FGF21-ACE2 signaling. ELA may represent a potential candidate to predict vascular damage and targeting the FGF21-ACE2 signaling may be a promising therapeutic intervention for vascular adventitial remodeling and related disorders.

Probing the interactions of GlcNH2 with boric acid via NMR spectroscopy.

The essential role of boronic esters in controlling both the direction and selectivity of chemical reactions as well as their significant function in catalytic activity have been demonstrated for industrially important processes. The specific interaction analyses of the monosaccharide GlcNH2 with boric acid are of interest since monosaccharides serve as model systems for the more sophisticated carbohydrate molecules. The interaction of GlcNH2 with boric acid was systematically investigated by numerous NMR techniques. A 1 : 1 chelate boron complex coordinated at the cis-1,2 position of GlcNH2 was identified as the major species in DMSO-d6 solution via1H and 13C INEPT DOSY NMR spectroscopy. This specific boron nitrogen coordination mechanism was further supported by the 1H-15N HSQC spectra. Variations in the spin-lattice relaxation times (T1) of the 13C1 nucleus also provided quantitative data regarding this non-covalent interactions. This is an application of 1H, 13C INEPT DOSY, 1H-15N HSQC, and relaxation methods to study such aggregations in solutions. These methods have potential applications in the characterization of reactive intermediates in biomass conversions.

Abnormal apelin-ACE2 and SGLT2 signaling contribute to adverse cardiorenal injury in patients with COVID-19.

BACKGROUND: Angiotensin converting enzyme 2 (ACE2) has recently been identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent response for novel coronavirus disease 2019 (COVID-19). This study aimed to explore the roles of ACE2, apelin and sodium-glucose cotransporter 2 (SGLT2) in SARS-CoV-2-mediated cardiorenal damage. METHODS AND RESULTS: The published RNA-sequencing datasets of cardiomyocytes infected with SARS-CoV-2 and COVID-19 patients were used. String, UMAP plots and single cell RNA sequencing data were analyzed to show the close relationship and distinct cardiorenal distribution patterns of ACE2, apelin and SGLT2. Intriguingly, there were decreases in ACE2 and apelin expression as well as marked increases in SGLT2 and endothelin-1 levels in SARS-CoV-2-infected cardiomyocytes, animal models with diabetes, acute kidney injury, heart failure and COVID-19 patients. These changes were linked with downregulated levels of interleukin (IL)-10, superoxide dismutase 2 and catalase as well as upregulated expression of profibrotic genes and pro-inflammatory cytokines/chemokines. Genetic ACE2 deletion resulted in upregulation of pro-inflammatory cytokines containing IL-1ß, IL-6, IL-17 and tumor necrosis factor α. More importantly, dapagliflozin strikingly alleviated cardiorenal fibrosis in diabetic db/db mice by suppressing SGLT2 levels and potentiating the apelin-ACE2 signaling. CONCLUSION: Downregulation of apelin and ACE2 and upregulation of SGLT2, endothelin-1 and pro-inflammatory cytokines contribute to SARS-CoV-2-mediated cardiorenal injury, indicating that the apelin-ACE2 signaling and SGLT2 inhibitors are potential therapeutic targets for COVID-19 patients.

Expression Profiles of Circular RNA in Aortic Vascular Tissues of Spontaneously Hypertensive Rats.

Background: Circular RNAs (circRNAs), as a kind of endogenous non-coding RNA, have been implicated in ischemic heart diseases and vascular diseases. Based on theirs high stability with a closed loop structure, circRNAs function as a sponge and bind specific miRNAs to exert inhibitory effects in heart and vasculature, thereby regulating their target gene and protein expression, via competitive endogenous RNA (ceRNA) mechanism. However, the exact roles and underlying mechanisms of circRNAs in hypertension and related cardiovascular diseases remain largely unknown. Methods and Results: High-throughput RNA sequencing (RNA-seq) was used to analyze the differentially expressed (DE) circRNAs in aortic vascular tissues of spontaneously hypertensive rats (SHR). Compared with the Wistar-Kyoto (WKY) rats, there were marked increases in the levels of systolic blood pressure, diastolic blood pressure and mean blood pressure in SHR under awake conditions via the tail-cuff methodology. Totally, compared with WKY rats, 485 DE circRNAs were found in aortic vascular tissues of SHR with 279 up-regulated circRNAs and 206 down-regulated circRNAs. Furthermore, circRNA-target microRNAs (miRNAs) and the target messenger RNAs (mRNAs) of miRNAs were predicted by the miRanda and Targetscan softwares, respectively. Additionally, real-time RT-PCR analysis verified that downregulation of rno_circRNA_0009197, and upregulation of rno_circRNA_0005818, rno_circRNA_0005304, rno_circRNA_0005506, and rno_circRNA_0009301 were observed in aorta of SHR when compared with that of WKY rats. Then, the potential ceRNA regulatory mechanism was constructed via integrating 5 validated circRNAs, 31 predicted miRNAs, and 266 target mRNAs. More importantly, three hub genes (NOTCH1, FOXO3, and STAT3) were recognized according to PPI network and three promising circRNA-miRNA-mRNA regulatory axes were found in hypertensive rat aorta, including rno_circRNA_0005818/miR-615/NOTCH1, rno_circRNA_0009197/ miR-509-5p/FOXO3, and rno_circRNA_0005818/miR-10b-5p/STAT3, respectively. Conclusions: Our results demonstrated for the first time that circRNAs are expressed aberrantly in aortic vascular tissues of hypertensive rats and may serve as a sponge linking with relevant miRNAs participating in pathogenesis of hypertension and related ischemic heart diseases via the circRNA-miRNA-mRNA ceRNAnetwork mechanism.

Dictionary Learning-Based Ultrasound Image Combined with Gastroscope for Diagnosis of Helicobacter pylori-Caused Gastrointestinal Bleeding.

The study is aimed at evaluating the application value of ultrasound combined with gastroscopy in diagnosing gastrointestinal bleeding (GIB) caused by Helicobacter pylori (HP). An ultrasound combined with a gastroscopy diagnostic model based on improved K-means Singular Value Decomposition (N-KSVD) was proposed first. 86 patients with Peptic ulcer (PU) and GIB admitted to our Hospital were selected and defined as the test group, and 86 PU patients free of GIB during the same period were selected as the control group. The two groups were observed for clinical manifestations and HP detection results. The results showed that when the noise ρ was 10, 30, 50, and 70, the Peak Signal to Noise Ratio (PSNR) values of N-KSVD dictionary after denoising were 35.55, 30.47, 27.91, and 26.08, respectively, and the structure similarity index measure (SSIM) values were 0.91, 0.827, 0.763, and 0.709, respectively. Those were greater than those of DCT dictionary and Global dictionary and showed statistically significant differences versus the DCT dictionary (P < 0.05). In the test group, there were 60 HP-positives and 26 HP-negatives, and there was significant difference in the numbers of HP-positives and HP-negatives (P < 0.05), but no significant difference in gender and age (P > 0.05). Of the subjects with abdominal pain, HP-positives accounted for 59.02% and HP-negatives accounted for 37.67%, showing significant differences (P < 0.05). Finally, the size of the ulcer lesion in HP-positives and HP-negatives was compared. It was found that 71.57% of HP-positives had ulcers with a diameter of 0-1 cm, and 28.43% had ulcers with a diameter of ≥1 cm. Compared with HP-negatives, the difference was statistically significant (P < 0.05). In conclusion, N-KSVD-based ultrasound combined with gastroscopy demonstrated good denoising effects and was effective in the diagnosis of GIB caused by HP.