Anti-hypertensive effect and potential mechanism of gastrodia-uncaria granules based on network pharmacology and experimental validation.

Hypertension has become a major contributor to the morbidity and mortality of cardiovascular diseases worldwide. Despite the evidence of the anti-hypertensive effect of gastrodia-uncaria granules (GUG) in hypertensive patients, little is known about its potential therapeutic targets as well as the underlying mechanism. GUG components were sourced from TCMSP and HERB, with bioactive ingredients screened. Hypertension-related targets were gathered from DisGeNET, OMIM, GeneCards, CTD, and GEO. The STRING database constructed a protein-protein interaction network, visualized by Cytoscape 3.7.1. Core targets were analyzed via GO and KEGG using R package ClusterProfiler. Molecular docking with AutodockVina 1.2.2 revealed favorable binding affinities. In vivo studies on hypertensive mice and rats validated network pharmacology findings. GUG yielded 228 active ingredients and 1190 targets, intersecting with 373 hypertension-related genes. PPI network analysis identified five core genes: AKT1, TNF-α, GAPDH, IL-6, and ALB. Top enriched GO terms and KEGG pathways associated with the anti-hypertensive properties of GUG were documented. Molecular docking indicated stable binding of core components to targets. In vivo study showed that GUG could improve vascular relaxation, alleviate vascular remodeling, and lower blood pressure in hypertensive animal models possibly through inhibiting inflammatory factors such as AKT1, mTOR, and CCND1. Integrated network pharmacology and in vivo experiment showed that GUG may exert anti-hypertensive effects by inhibiting inflammation response, which provides some clues for understanding the effect and mechanisms of GUG in the treatment of hypertension.

Electronic-Structure Transformation of Platinum-Rich Nanowires as Efficient Electrocatalyst for Overall Water Splitting.

Platinum (Pt) has been widely used as cathodic electrocatalysts for the hydrogen evolution reaction (HER) but unfortunately neglected as an anodic electrocatalyst for the oxygen evolution reaction (OER) due to excessively strong bonding with oxygen species in water splitting electrolyzers. Herein we report that fine control over the electronic-structure and local-coordination environment of Pt-rich PtPbCu nanowires (NWs) by doping of iridium (Ir) lowers the overpotential of the OER and simultaneously suppresses the overoxidation of Pt in IrPtPbCu NWs during water electrolysis. In light of the one-dimensional morphology featured with atomically dispersed IrOx species and electronically modulated Pt-sites, the IrPtPbCu NWs exhibit an enhanced OER (175 mV at 10 mA cm-2) and HER (25 mV at 10 mA cm-2) electrocatalytic performance in acidic media and yield a high turnover frequency. For OER at the overpotential of 250 mV, the IrPtPbCu NWs show an enhanced mass activity of 1.51 A mg-1Pt+Ir (about 19 times higher) than Ir/C. For HER at the overpotential of 50 mV, NWs exhibit a remarkable mass activity of 1.35 A mg-1Pt+Ir, which is 2.6-fold relative to Pt/C. Experimental results and theoretical calculations corroborate that the doping of Ir in NWs has the capacity to suppress the formation of Ptx>4 derivates and ameliorate the adsorption free energy of reaction intermediates during the water electrolysis. This approach enabled the realization of a previously unobserved mechanism for anodic electrocatalysts.

Unveiling the Growth Mechanism of Ordered-Phase within Multimetallic Nanoplates.

Tuning the crystal phase of alloy nanocrystals (NCs) offers an alternative way to improve their electrocatalytic performance, but, how heterometals diffuse and form ordered-phase remains unclear. Herein, for the first time, the mechanism for forming tetrametallic ordered-phase nanoplates (NPLs) is unraveled. The observations reveal that the intermetallic ordered-phase nucleates through crystallinity alteration of the seeds and then propagates by reentrant grooves. Notably, the reentrant grooves act as intermediate NCs for ordered-phase, eventually forming intermetallic PdCuIrCo NPLs. These NPLs substantially outperform for oxygen evolution reaction (221 mV at 10 mA cm-2) and hydrogen evolution reaction (19 mV at 10 mA cm-2) compared to commercial Ir/C and Pd/C catalysts in acidic media. For OER at 1.53 V versus RHE, the PdCuIrCo/C exhibits an enhanced mass activity of 9.8 A mg-1 Pd+Ir (about ten times higher) than Ir/C. For HER at -0. 2 V versus RHE, PdCuIrCo/C shows a remarkable mass activity of 1.06 A mg-1 Pd+Ir, which is three-fold relative to Pd/C. These improvements can be ascribed to the intermetallic ordered-structure with high-valence Ir sites and tensile-strain. This approach enabled the realization of a previously unobserved mechanism for ordered-phase NCs. Therefore, this strategy of making ordered-phase NPLs can be used in diverse heterogeneous catalysis.

Effect of Selective Metallic Defects on Catalytic Performance of Alloy Nanosheets.

Defects in the crystal structure of nanomaterials are important for their diverse applications. As, defects in 2D framework allow surface confinement effects, efficient molecular accessibility, high surface-area to volume-ratio and lead to higher catalytic activity, but it is challenging to expose defects of specific metal on the surface of 2D alloy and find the correlation between defective structure and electrocatalytic properties with atomic precision. Herein, the work paves the way for the controlled synthesis of ultrathin porous Ir-Cu nanosheets (NSs) with selectively iridium (Ir) rich defects to boost their performance for acidic oxygen evolution reaction (OER). X-ray absorption spectroscopy reveals that the oxidized states of Ir in defects of porous NSs significantly impact the electronic structure and decline the energy barrier. As a result, porous Ir-Cu/C NSs deliver improved OER activity with an overpotential of 237 mV for reaching 10 mA cm-2 and exhibit significantly higher mass activity than benchmark Ir/C under acidic conditions. Therefore, the present work highlights the concept of constructing a selective noble metal defect-rich open structure for catalytic applications.

Atomically Dispersed CoN3 C1 -TeN1 C3 Diatomic Sites Anchored in N-Doped Carbon as Efficient Bifunctional Catalyst for Synergistic Electrocatalytic Hydrogen Evolution and Oxygen Reduction.

A encapsulation-adsorption-pyrolysis strategy for the construction of atomically dispersed Co-Te diatomic sites (DASs) that are anchored in N-doped carbon is reported as an efficient bifunctional catalyst for electrocatalytic hydrogen evolution reaction (HER) and oxygen reduction reaction (ORR). The as-constructed catalyst shows the stable CoN3 C1 -TeN1 C3 coordination structure before and after HER and ORR. The *OOH/*H intermediate species are captured by in situ Raman and in situ attenuated total reflectance-surface enhanced infrared absorption spectroscopy, indicating that the reactant O2 /H2 O molecule has a strong interaction with the Co site, revealing that Coδ+ is an effective active site. Theoretical calculations show that the Coδ+ has adsorption-activation function and the neighboring Teδ+ acts as an electron donor adjusting the electronic structure of Coδ+ , promoting the dissociation of H2 O molecules and the adsorption of H and oxygen-containing intermediates in HER and ORR. In the meanwhile, the nearest C atom around Co also profoundly affects the adsorption of H atoms. This results in the weakening of the OH adsorption and enhancement of H adsorption, as well as the more stable water molecule dissociation transition state, thus significantly boosting ORR and HER performance.

Geometric Calibration for Cameras with Inconsistent Imaging Capabilities.

Traditional calibration methods rely on the accurate localization of the chessboard points in images and their maximum likelihood estimation (MLE)-based optimization models implicitly require all detected points to have an identical uncertainty. The uncertainties of the detected control points are mainly determined by camera pose, the slant of the chessboard and the inconsistent imaging capabilities of the camera. The negative influence of the uncertainties that are induced by the two former factors can be eliminated by adequate data sampling. However, the last factor leads to the detected control points from some sensor areas having larger uncertainties than those from other sensor areas. This causes the final calibrated parameters to overfit the control points that are located at the poorer sensor areas. In this paper, we present a method for measuring the uncertainties of the detected control points and incorporating these measured uncertainties into the optimization model of the geometric calibration. The new model suppresses the influence from the control points with large uncertainties while amplifying the contributions from points with small uncertainties for the final convergence. We demonstrate the usability of the proposed method by first using eight cameras to collect a calibration dataset and then comparing our method to other recent works and the calibration module in OpenCV using that dataset.

Blood Pressure Goals in Acute Stroke.

Antihypertensive treatment is highly effective in both primary and secondary prevention of stroke. However, current guideline recommendations on the blood pressure goals in acute stroke are clinically empirical and generally conservative. Antihypertensive treatment is only recommended for severe hypertension. Several recent observational studies showed that the relationship between blood pressure and unfavorable clinical outcomes was probably positive in acute hemorrhagic stroke but J- or U-shaped in acute ischemic stroke with undetermined nadir blood pressure. The results of randomized controlled trials are promising for blood pressure management in hemorrhagic stroke but less so in ischemic stroke. A systolic blood pressure goal of 140 mm Hg is probably appropriate for acute hemorrhagic stroke. The blood pressure goal in acute ischemic stroke, however, is uncertain, and probably depends on the time window of treatment and the use of revascularization therapy. Further research is required to investigate the potential benefit of antihypertensive treatment in acute stroke, especially with regard to the possible reduction of blood pressure variability and more intensive blood pressure lowering in the acute and subacute phases of a stroke, respectively.

Cobalt Single Atom Incorporated in Ruthenium Oxide Sphere: A Robust Bifunctional Electrocatalyst for HER and OER.

The development of highly active and stable bifunctional noble-metal-based electrocatalysts for the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) is a crucial goal for clean and renewable energy, which still remains challenging. Herein, we report an efficient and stable catalyst comprising a Co single atom incorporated in an RuO2 sphere for HER and OER, in which the Co single atom in the RuO2 sphere was confirmed by XAS, AC-STEM, and DFT. This tailoring strategy uses a Co single atom to modify the electronic structures of the surrounding Ru atoms and thereby remarkably elevates the electrocatalytic activities. The catalyst requires ultralow overpotentials, 45 mV for HER and 200 mV for OER, to deliver a current density of 10 mA cm-2 . The theoretical calculations reveal that the energy barriers for HER and OER are lowered after incorporation of a cobalt single atom.

Enhancing fatigue life by ductile-transformable multicomponent B2 precipitates in a high-entropy alloy.

Catastrophic accidents caused by fatigue failures often occur in engineering structures. Thus, a fundamental understanding of cyclic-deformation and fatigue-failure mechanisms is critical for the development of fatigue-resistant structural materials. Here we report a high-entropy alloy with enhanced fatigue life by ductile-transformable multicomponent B2 precipitates. Its cyclic-deformation mechanisms are revealed by real-time in-situ neutron diffraction, transmission-electron microscopy, crystal-plasticity modeling, and Monte-Carlo simulations. Multiple cyclic-deformation mechanisms, including dislocation slips, precipitation strengthening, deformation twinning, and reversible martensitic phase transformation, are observed in the studied high-entropy alloy. Its improved fatigue performance at low strain amplitudes, i.e., the high fatigue-crack-initiation resistance, is attributed to the high elasticity, plastic deformability, and martensitic transformation of the B2-strengthening phase. This study shows that fatigue-resistant alloys can be developed by incorporating strengthening ductile-transformable multicomponent intermetallic phases.

Midkine Inhibits Cholesterol Efflux by Decreasing ATP-Binding Membrane Cassette Transport Protein A1 via Adenosine Monophosphate-Activated Protein Kinase/Mammalian Target of Rapamycin Signaling in Macrophages.

BACKGROUND: Midkine (MK), a heparin-binding protein, participates in multiple cellular processes, such as immunity, cellular growth and apoptosis. Overwhelming evidence indicates that MK plays an important role in various pathological processes, including chronic inflammation, autoimmunity, cancer, and infection. Recent studies demonstrated that MK may be involved in the development of atherosclerosis, yet the mechanism has not been fully explored. Therefore, this study aims to investigate the effect and mechanism of MK on macrophage cholesterol efflux.Methods and Results:Using Oil Red O staining, NBD-cholesterol fluorescence labeling and enzymatic methods, it observed that MK markedly promoted macrophage lipid accumulation. Liquid scintillation counting (LSC) showed that MK decreased cholesterol efflux. Moreover, cell immunofluorescence, western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) showed that MK downregulated ATP-binding membrane cassette transport protein A1 (ABCA1) expression. Functional promotion of ABCA1 expression attenuated the inhibitory effects of MK on cholesterol efflux, which reduced lipid accumulation. Additionally, intervention of adenosine monophosphate activated protein (AMPK)-mammalian target of rapamycin (mTOR) signaling molecule by the AMPK activator, AICAR, increased p-AMPK and ABCA1 expression, decreased p-mTOR expression and promoted cholesterol efflux, resulting in an obvious reduction in intracellular lipid content. CONCLUSIONS: These data suggest that MK reduces the expression of ABCA1, inhibits the efflux of cholesterol and promotes the accumulation of lipids in RAW264.7 macrophages, and AMPK-mTOR signaling is involved in MK-mediated regulation of cholesterol metabolism in RAW264.7 macrophages.

Triglyceride metabolism and angiopoietin-like proteins in lipoprotein lipase regulation.

Hypertriglyceridemia is a risk factor for a series of diseases, such as cardiovascular disease (CVD), diabetes and nonalcoholic fatty liver disease (NAFLD). Angiopoietin-like proteins (ANGPTLs) family, especially ANGPTL3, ANGPTL4 and ANGPTL8, which regulate lipoprotein lipase (LPL) activity, play pivotal roles in triglyceride (TG) metabolism and related diseases/complications. There are many transcriptional and post-transcriptional factors that participate in physiological and pathological regulation of ANGPTLs to affect triglyceride metabolism. This review is intended to focus on the similarity and difference in the expression, structural features, regulation profile of the three ANGPTLs and inhibitory models for LPL. Description of the regulatory factors of ANGPTLs and the properties in regulating the lipid metabolism involved in the underlying mechanisms in pathological effects on diseases will provide potential therapeutic approaches for the treatment of dyslipidemia related diseases.

Lipoprotein lipase transporter GPIHBP1 and triglyceride-rich lipoprotein metabolism.

Increased plasma triglyceride serves as an independent risk factor for cardiovascular disease (CVD). Lipoprotein lipase (LPL), which hydrolyzes circulating triglyceride, plays a crucial role in normal lipid metabolism and energy balance. Hypertriglyceridemia is possibly caused by gene mutations resulting in LPL dysfunction. There are many factors that both positively and negatively interact with LPL thereby impacting TG lipolysis. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), a newly identified factor, appears essential for transporting LPL to the luminal side of the blood vessel and offering a platform for TG hydrolysis. Numerous lines of evidence indicate that GPIHBP1 exerts distinct functions and plays diverse roles in human triglyceride-rich lipoprotein (TRL) metabolism. In this review, we discuss the GPIHBP1 gene, protein, its expression and function and subsequently focus on its regulation and provide critical evidence supporting its role in TRL metabolism. Underlying mechanisms of action are highlighted, additional studies discussed and potential therapeutic targets reviewed.

Role of AMPK in atherosclerosis via autophagy regulation.

Atherosclerosis is characterized by the accumulation of lipids and deposition of fibrous elements in the vascular wall, which is the primary cause of cardiovascular diseases. Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor of energy metabolism that regulates multiple physiological processes, including lipid and glucose metabolism and the normalization of energy imbalances. Overwhelming evidence indicates that AMPK activation markedly attenuates atherosclerosis development. Autophagy inhibits cell apoptosis and inflammation and promotes cholesterol efflux and efferocytosis. Physiological autophagy is essential for maintaining normal cardiovascular function. Increasing evidence demonstrates that autophagy occurs in developing atherosclerotic plaques. Emerging evidence indicates that AMPK regulates autophagy via a downstream signaling pathway. The complex relationship between AMPK and autophagy has attracted the attention of many researchers because of this close relationship to atherosclerosis development. This review demonstrates the role of AMPK and autophagy in atherosclerosis. An improved understanding of this interrelationship will create novel preventive and therapeutic strategies for atherosclerosis.

Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease.

Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I) and malignant transformation to hepatocellular carcinoma (HCC) is known to occur in some cases. However, the molecular pathogenesis of tumor development in GSD I is unclear. This study was conducted to systematically investigate chromosomal and genetic alterations in HCA associated with GSD I. Genome-wide SNP analysis and mutation detection of target genes was performed in ten GSD Ia-associated HCA and seven general population HCA cases for comparison. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Intriguingly, simultaneous gain of chromosome 6p and loss of 6q were only seen in GSD Ia HCA (three cases) with one additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (P = 0.012). Expression of IGF2R and LATS1 candidate tumor suppressor genes at 6q was reduced in more than 50% of GSD Ia HCA that were examined (n = 7). None of the GSD Ia HCA had biallelic mutations in the HNF1A gene. These findings give the first insight into the distinct genomic and genetic characteristics of HCA associated with GSD Ia. These results strongly suggest that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and may be in general population. These results also suggest an interesting relationship between GSD Ia HCA and steps to HCC transformation.

Seroprevalence of antibodies against Bartonella species and evaluation of risk factors and clinical signs associated with seropositivity in dogs.

OBJECTIVE: To determine the seroprevalence of antibodies against Bartonella spp in a population of sick dogs from northern California and identify potential risk factors and clinical signs associated with seropositivity. SAMPLE POPULATION: Sera from 3,417 dogs. PROCEDURE: Via an ELISA, sera were analyzed for antibodies against Bartonella vinsonii subsp berkhoffii, Bartonella clarridgeiae, and Bartonella henselae; test results were used to classify dogs as seropositive (mean optical density value > or = 0.350 for B henselae or > or = 0.300 for B clarridgeiae or B vinsonii subsp berkhoffi) or seronegative. Overall, 305 dogs (102 seropositive and 203 seronegative dogs) were included in a matched case-control study. RESULTS: 102 of 3,417 (2.99%) dogs were seropositive for > or = 1 species of Bartonella. Of these, 36 (35.3%) had antibodies against B henselae only, 34 (33.3%) had antibodies against B clarridgeiae only, 2 (2.0%) had antibodies against B vinsonii subsp berkhoffii only, and 30 (29.4%) had antibodies against a combination of those antigens. Compared with seronegative dogs, seropositive dogs were more likely to be herding dogs and to be female, whereas toy dogs were less likely to be seropositive. Seropositive dogs were also more likely to be lame or have arthritis-related lameness, nasal discharge or epistaxis, or splenomegaly. CONCLUSIONS AND CLINICAL RELEVANCE: Only a small percentage of dogs from which serum samples were obtained had antibodies against Bartonella spp. Breed appeared to be an important risk factor for seropositivity. Bartonella infection should be considered in dogs with clinical signs of lameness, arthritis-related lameness, nasal discharge or epistaxis, or splenomegaly.