Mechanism of Epimedium intervention in heart failure based on network pharmacology and molecular docking technology.

To analyze the pharmacological mechanism of Epimedium in regulating heart failure (HF) based on the network pharmacology method, and to provide a reference for the clinical application of Epimedium in treating HF. Obtaining the main active ingredients and their targets of Epimedium through TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform) database. Access to major HF targets through Genecards, OMIM, PharmGKB, Therapeutic Target Database, Drug Bank database. Protein interaction analysis using String platform and construction of PPI network. Subsequently, Cytoscape software was used to construct the "Epimedium active ingredient-heart failure target" network. Finally, the molecular docking is verified through the Systems Dock Web Site. The core active ingredients of Epimedium to regulate HF are quercetin, luteolin, kaempferol, etc. The core targets are JUN, MYC, TP53, HIF1A, ESR1, RELA, MAPK1, etc. Molecular docking validation showed better binding activity of the major targets of HF to the core components of Epimedium. The biological pathways that Epimedium regulates HF mainly act on lipid and atherosclerotic pathways, PI3K-Akt signaling pathway, and chemoattractant-receptor activation. And its molecular functions are mainly DNA-binding transcription factor binding, RNA polymerase II-specific DNA-binding transcription factor binding, and neurotransmitter receptor activity. This study reveals the multi-component, multi-target and multi-pathway mechanism of action of Epimedium in regulating mental failure, and provides a basis for the clinical development and utilization of Epimedium to intervene in HF.

Macrophage Notch1 inhibits TAK1 function and RIPK3-mediated hepatocyte necroptosis through activation of ß-catenin signaling in liver ischemia and reperfusion injury.

BACKGROUND: Notch signaling is highly conserved and critically involved in cell differentiation, immunity, and survival. Activation of the Notch pathway modulates immune cell functions during the inflammatory response. However, it remains unknown whether and how the macrophage Notch1 may control the innate immune signaling TAK1, and RIPK3-mediated hepatocyte necroptosis in liver ischemia and reperfusion injury (IRI). This study investigated the molecular mechanisms of macrophage Notch1 in modulating TAK1-mediated innate immune responses and RIPK3 functions in liver IRI. METHODS: Myeloid-specific Notch1 knockout (Notch1M-KO) and floxed Notch1 (Notch1FL/FL) mice (n = 6/group) were subjected to 90 min partial liver warm ischemia followed by 6 h of reperfusion. In a parallel in vitro study, bone marrow-derived macrophages (BMMs) were isolated from these conditional knockout mice and transfected with CRISPR/Cas9-mediated ß-catenin knockout (KO) vector followed by LPS (100 ng/ml) stimulation. RESULTS: IR stress-induced Notch1 activation evidenced by increased nuclear Notch intracellular domain (NICD) expression in liver macrophages. Myeloid Notch1 deficiency exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil accumulation, and proinflammatory cytokines/chemokines production compared to the Notch1FL/FL controls. Unlike in the Notch1FL/FL controls, Notch1M-KO enhanced TRAF6, TAK1, NF-κB, RIPK3, and MLKL but reduced ß-catenin activation in ischemic livers. However, adoptive transfer of lentivirus ß-catenin-modified macrophages markedly improved liver function with reduced TRAF6, p-TAK1, RIPK3 and p-MLKL in IR-challenged livers. Moreover, disruption of RIPK3 in Notch1M-KO mice with an in vivo mannose-mediated RIPK3 siRNA delivery system diminished IR-triggered hepatocyte death. In vitro studies showed that macrophage NICD and ß-catenin co-localized in the nucleus, whereby ß-catenin interacted with NICD in response to LPS stimulation. Disruption of ß-catenin with a CRISPR/Cas9-mediated ß-catenin KO in Notch1FL/FL macrophage augmented TRAF6 activation leading to enhanced TAK1 function. While CRISPR/Cas9-mediated TRAF6 KO in Notch1M-KO macrophage inhibited RIPK3-mediated hepatocyte necroptosis after co-culture with primary hepatocytes. CONCLUSIONS: Macrophage Notch1 controls TAK1-mediated innate immune responses and RIPK3-mediated hepatocyte necroptosis through activation of ß-catenin. ß-catenin is required for the macrophage Notch1-mediated immune regulation in liver IRI. Our findings demonstrate that the macrophage Notch1-ß-catenin axis is a crucial regulatory mechanism in IR-triggered liver inflammation and provide novel therapeutic potential in organ IRI and transplant recipients. Video abstract.

Huangqi decoction attenuates renal interstitial fibrosis transforming growth factor-ß1/mitogen-activated protein kinase signaling pathways in 5/6 nephrectomy mice.

OBJECTIVE: To investigate the effect of Huangqi decoction on renal interstitial fibrosis and its association with the transforming growth factor-ß1 (TGF-ß1) / mitogen-activated protein kinase (MAPK) signaling pathway. METHODS: 120 C57/BL mice were randomly divided into six groups: sham group, Enalapril (20 mg/kg) group, 5/6 nephrectomy model group, and 5/6 nephrectomy model plus Huangqicoction (0.12, 0.36 and 1.08 g/kg respectively) groups. Detecting 24hours urinary protein, blood pressure, serum creatinine, urea nitrogen content changes. Periodic Acid-Schiff stain (PAS) and Masson's trichrome staining was used to observe the renal tissue pathological changes. Protein expression of TGF-ß1, Phosphorylated P38 mitogen activated protein kinases (P-P38), Phosphorylated c-jun N-terminal kinase (P-JNK), Phosphorylated extracellular regulated proteinhnase (P-ERK), Fibroblast-specific protein-1 (FSP-1), Alpha smooth muscle actin (α-SMA), Type III collagen (Collagen III), Connective tissue growth factor (CTGF), Bcl-2 Assaciated X protein (Bax) and B cell lymphoma 2 (Bcl-2) were measured with western blot and immunohistochemical. RESULTS: Both Huangqi decoction and Enalapril improved the kidney function, 24 h urinary protein and the fibrosis in 5/6 nephrectomy mice, Huangqi decoction downregulated the expressions of TGF-ß1, FSP-1, α-SMA, Collagen III and CTGF in a dose-dependent manner, and it has a significant difference ( 0.01) compared with model group.Huangqi decoction downregulated the expressions of P-P38, P-JNK, P-ERK and Bcl-2 in a dose-dependent manner, while upregulated the expression of Bax. CONCLUSIONS: The protective effect of Huangqi decoction for renal interstitial fibrosis in 5/6 nep-hrectomized mice the inhibition of Epithelial-Mesenchymal Transitions and downregulating the TGF-ß1/ MAPK signaling pathway.

A First-in-Human Study of the Bioheart Sirolimus-Eluting Bioresorbable Vascular Scaffold in Patients with Coronary Artery Disease: Two-Year Clinical and Imaging Outcomes.

INTRODUCTION: Newer generation bioresorbable scaffolds (BRSs) with thinner struts and improved deliverability are expected to enhance safety and efficacy profiles. Bioheart (Bio-Heart, Shanghai, China) BRS is constructed from a PLLA (poly-l-lactic acid) backbone coated with a PDLLA (poly D-l-lactic acid) layer eluting sirolimus. We report 2-year serial intracoronary imaging findings. METHODS: In this first-in-human study, 46 patients with single de novo lesions in native coronary vessels (vessel size 3.0-3.75 mm, lesion length ≤ 25 mm) were enrolled at a single institution. Baseline intravascular ultrasound (IVUS) and post-implantation IVUS and optical coherence tomography (OCT) examinations were mandatory. After successful implantations of BRS, the 46 patients were randomized to two different follow-up cohorts in a 2:1 ratio. Thirty patients in cohort 1 had to undergo angiography, IVUS, and OCT follow-ups at 6 and 24 months, respectively. The 16 patients in cohort 2 underwent the same types of imaging follow-ups at 12 and 36 months, respectively. Clinical follow-ups were scheduled uniformly in both cohorts at 1, 6, and 12 months and annually up to 5 years for all patients. RESULTS: Between August and November 2016, a total of 54 patients were assessed. However, 8 patients could not meet all the inclusion criteria; thus, the remaining 46 patients (age 57.5 ± 8.7 years, 34.8% female, 50.0% with unstable angina, 26.1% diabetics) with 46 target lesions were enrolled in this study. All patients in both cohorts were required to complete clinical follow-up uniformly and regularly. In cohort 1, one patient had definite scaffold thrombosis within 6 months of follow-up; thus, after 6 months, cohort 1 had 96.7% patients . Imaging follow-up was available in 24 patients, and in-scaffold late loss was 0.44 ± 0.47 mm; intracoronary imaging confirmed the late loss was mainly due to to neointimal hyperplasia, but not scaffold recoil. CONCLUSIONS: Serial 2-year clinical and imaging follow-up results confirmed the preliminary safety and efficacy of Bioheart BRS for treatment of simple coronary lesions.

Detection of hepatocellular carcinoma in a population at risk: iodine-enhanced multidetector CT and/or gadoxetic acid-enhanced 3.0 T MRI.

OBJECTIVE: To evaluate the diagnostic performance of iodine-enhanced multidetector CT and gadoxetic acid-enhanced 3.0 Tesla (T) MRI for detection of hepatocellular carcinoma of patients. DESIGN: Retrospective, multicentre cohort study. SETTING: The Gong'an County People's Hospital, Gong'an County, China and the First People's Hospital of Jingzhou City, China. PARTICIPANTS: Reports of CT, MRI and liver biopsies/histopathology data of a total of 815 patients who at risk were reviewed. PRIMARY AND SECONDARY OUTCOME MEASURES: The lesions that possessed detection in the plain scan phase, enhanced arterial phase and/or enhanced portal phase of CT images and the lesions that possessed enhancements in the plain scan phase, enhanced arterial phase, enhanced portal phase and/or hepatobiliary phases of MRI were considered hepatocellular carcinoma. The decision of hepatocellular carcinoma was made based on the current Liver Imaging and Data Reporting System for diagnosing hepatocellular carcinoma. RESULTS: True positive hepatocellular carcinoma (563 vs 521, p=0.0314), true negative hepatocellular carcinoma (122 vs 91, p=0.0275), false positive hepatocellular carcinoma (88 vs 123, p=0.0121), false negative hepatocellular carcinoma (42 vs 80, p=0.0005), specificity (58.10 vs 42.52, p=0.0478) and negative clinical utility (0.1 vs 0.073, p=0.0386) were superior for gadoxetic acid-enhanced 3.0 T MRI than those of iodine-enhanced multidetector CT. Sensitivity and accuracy for gadoxetic acid-enhanced 3.0 T MRI were 93.06% and 77.40 %, respectively, and those for iodine-enhanced multidetector CT were 86.69% and 75.09 %, respectively. Likelihood to detect hepatocellular carcinoma for gadoxetic acid-enhanced 3.0 T MRI was 0-0.894 diagnostic confidence/lesion, and that for iodine-enhanced multidetector CT was 0-0.887 diagnostic confidence/lesion. CONCLUSION: Gadoxetic acid-enhanced 3.0 T MRI facilitates the confidence of initiation of treatment of hepatocellular carcinoma. LEVEL OF EVIDENCE: III. TECHNICAL EFFICACY STAGE: 4.

Evaluating the Reproducibility of the Walking Test for Intermittent Claudication Associated with Lumbar Spinal Stenosis.

STUDY DESIGN: This is a multicenter, prospective study. PURPOSE: This study aimed to evaluate the reproducibility of the walking test for patients with lumbar spinal stenosis (LSS). OVERVIEW OF LITERATURE: Walking test is one of the useful procedures to investigate cauda equina syndrome with lumbar spinal stenosis. One the other hands, there were few studies to investigate the reproducibility of this test. METHODS: In this study, we prospectively examined 70 LSS patients with intermittent claudication symptoms at a multicenter outpatient clinic. A walking test was administered at baseline and week 4 to assess patients' walking distance and lower limb pain and numbness. Immediately after the walking test, patients were asked to use the Visual Analog Scale (VAS) to rate their pain and numbness in the front, back, outside, inside, and hip of the lower legs. The reproducibility of the walking test was evaluated using Cohen's κ analysis and intraclass correlation coefficients (ICCs). Meanwhile, the Swiss Spinal Stenosis (SSS) Questionnaire was used to evaluate the severity of the stenosis. RESULTS: The walking distance ICC at baseline and at week 4 remained unchanged at 0.7, with acceptable interobserver reliabilities for lower limb pain and numbness in both legs. The average VAS score for lower leg pain was 23.2±25.2 mm at baseline and 27.4±28.8 mm at week 4, while the corresponding average VAS score for numbness was 23.4±26.7 mm at baseline and 24.8±25.2 mm at week 4. The ICC score was 0.7 for leg pain and 0.7 for numbness. The mean SSS was 30.2±5.5 at baseline and 29.2±5.2 at week 4, and there was no significant difference in the severity. CONCLUSIONS: The walking test for LSS has acceptable reproducibility.

Effect of Curcumin on Diabetic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Clinical Trials.

BACKGROUND: Curcumin, a polyphenolic constituent from Curcuma longa, possesses antioxidant, hypolipidemic, and antidiabetic properties and has been reported to protect against diabetic kidney disease (DKD); however, the effect is inconsistent. OBJECTIVE: This systematic review and meta-analysis aimed to investigate the effect of curcumin supplementation on renal function, lipid profile, blood pressure, and glycemic control in DKD. METHODS: A systematic and comprehensive literature search of interrelated randomized controlled trials (RCTs) was conducted in PubMed, Embase, Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov from inception to July 30, 2021. Two investigators independently extracted data and assessed the risk of bias. Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated to describe the effect sizes using a fixed-effect model. Statistical analysis was performed using STATA 14.0 and RevMan 5.3. RESULTS: Five RCTs involving 290 participants with DKD were included. Curcumin supplementation significantly improved the serum creatinine (WMD: -0.16 mg/dL, 95% CI: -0.3 to -0.02, P = 0.029, I 2 = 0%, moderate certainty), total cholesterol (WMD: -10.13 mg/dL, 95% CI: -17.84 to -2.14, P = 0.01, I 2 = 0%, moderate certainty), systolic blood pressure (WMD: 3.94 mmHg, 95% CI: 1.86 to 6.01, P < 0.01, I 2 = 33.5%, moderate certainty), and fasting blood glucose (WMD: -8.29 mg/dL, 95% CI: -15.19 to -1.39, P = 0.019, I 2 = 43.7%, moderate certainty) levels; however, it had no significant effects on blood urea nitrogen, proteinuria, triglyceride, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and diastolic blood pressure levels. CONCLUSIONS: Curcumin may provide great potential effects against DKD. More large-scale and high-quality RCTs are required to confirm these findings.

Heterostructured TiO2@HKUST-1 for the enhanced removal of methylene blue by integrated adsorption and photocatalytic degradation.

Aiming at exploring an effective photocatalytic adsorbent for organic dye removal, a series of heterostructured TiO2@HKUST-1 photocatalysts, by incorporating HKUST-1 with different TiO2 nanoparticles loading, were prepared by single-step hydrothermal method. The morphology and surface characteristics of the as-prepared TiO2@HKUST-1were analyzed using SEM, HRTEM, XRD, FTIR, UV-vis DRS, and Photoluminescence techniques. The adsorption-photocatalytic degradation of the model dye methylene blue (MB) on the catalysts was investigated. It was indicated that the introduction of a certain amount of TiO2 on the surface of HKUST-1 could improve the transfer and separation of the photogenerated charge carriers, resulting in the enhanced photocatalytic activity. The optimal 0.02TiO2@HKUST-1 exhibited the highest MB removal rate with about 4.4 and 19.3 times as high MB removal efficiency as that of HKUST-1 and TiO2, respectively. Heterostructured TiO2@HKUST-1 materials for the removal of MB involved the integrated adsorption and visible light photocatalysis. Meanwhile, the composite exhibited good reusability in the process of cyclic experiments. Therefore, this work provides a potential MOF-based photocatalytic adsorbent for organic dye removal.

Identification of new probe substrates for human CYP20A1.

CYP20A1 is a well-conserved member of the human cytochrome P450 enzyme family for which no endogenous or xenobiotic substrate is known. We have recently shown that this enzyme has moderate activity towards two proluciferin probe substrates. In order to facilitate the search for physiological substrates we have tested nine additional proluciferins in this study and identified three such probe substrates that give much higher product yields. Using one of these probes, we demonstrate inhibition of CYP20A1 activity by 1-benzylimidazole, ketoconazole and letrozole. Finally, we show that the combination of two common single nucleotide polymorphisms (SNPs) of CYP20A1 leads to an enzyme (CYP20A1Leu97Phe346) with reduced activity.

Surgical masks as source of bacterial contamination during operative procedures.

BACKGROUND: Surgical masks (SMs) are used to reduce bacterial shedding from the mouth, nose and face. This study aimed to investigate whether SMs may be a potential source of bacterial shedding leading to an increased risk of surgical site infection. METHODS: Bacterial contamination of the SMs was tested by making an impression of the external surface of the mask on sterile culture media immediately. We investigated the difference in bacterial counts between the SMs worn by surgeons and those placed unused in the operating room (OR), and the bacterial count variation with indicated wearing time. Moreover, the difference in bacterial counts on the external surface between the first and second layers of double-layered SMs was also assessed. RESULTS: The bacterial count on the surface of SMs increased with extended operating times; significant difference was found between the 4- to 6-hour and 0-hour groups (p < 0.05). When we analysed the bacterial counts from the same surgeon, a significant increase was noted in the 2-hours group. Moreover, the bacterial counts were significantly higher among the surgeons than the OR. Additionally, the bacterial count of the external surface of the second mask was significantly higher than that of the first one. CONCLUSIONS: The source of bacterial contamination in SMs was the body surface of the surgeons rather than the OR environment. Moreover, we recommend that surgeons should change the mask after each operation, especially those beyond 2 hours. Double-layered SMs or those with excellent filtration function may also be a better alternative. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study provides strong evidence for the identification that SMs as source of bacterial contamination during operative procedures, which should be a cause for alarm and attention in the prevention of surgical site infection in clinical practice.

Mycotoxins, trace elements, and phthalates in marketed rice of different origin and exposure assessment.

The aim of this study was to determine levels of 11 mycotoxins, 10 trace elements, and 6 phthalates in rice samples from Serbian and Chinese market. Mycotoxins were not detected in any of the analysed rice samples. Results revealed similar median levels for following elements: Mn, 17.5 and 15.7 mg kg-1; Fe, 2.47 and 2.12 mg kg-1; Cu, 1.95 and 1.59 mg kg-1 in marketed samples from Serbia and China, respectively. Median concentration of Ni in Serbian marketed samples was 1.9 times higher than in Chinese ones. The median levels (µg kg-1) of phthalates ranged from 1.2 (benzylbutyl phthalate [BBP]) - 566 (di(2-ethyl-hexyl) phthalate [DEHP]) and 1.7 (BBP) - 348 (DEHP) in Serbian and Chinese marketed samples, respectively. The results were used to assess daily exposure of Serbian and Chinese adult consumers. The calculated target hazard quotients indicated that the potential risk attributable to the analysed contaminants in rice samples should not be of concern neither for the Serbian nor the Chinese consumers.

Medical Image Fusion Based on Rolling Guidance Filter and Spiking Cortical Model.

Medical image fusion plays an important role in diagnosis and treatment of diseases such as image-guided radiotherapy and surgery. Although numerous medical image fusion methods have been proposed, most of these approaches are sensitive to the noise and usually lead to fusion image distortion, and image information loss. Furthermore, they lack universality when dealing with different kinds of medical images. In this paper, we propose a new medical image fusion to overcome the aforementioned issues of the existing methods. It is achieved by combining with rolling guidance filter (RGF) and spiking cortical model (SCM). Firstly, saliency of medical images can be captured by RGF. Secondly, a self-adaptive threshold of SCM is gained by utilizing the mean and variance of the source images. Finally, fused image can be gotten by SCM motivated by RGF coefficients. Experimental results show that the proposed method is superior to other current popular ones in both subjectively visual performance and objective criteria.

Synthesis and electrochemical properties of modification LiNi1/3Co1/3Mn1/3O2 cathode materials for Li-ion battery.

The layered LiNi1/3CO1/3Mn1/3-xMg(x)O2 (x = 0, 0.01, 0.03, 0.05) cathode materials were prepared by solid state reaction, then copper oxide was coated on the product. The structures, morphologies and electrochemical properties of the LiNi1/3Co1/3Mn1/3-xMg(x)O2 and CuO-coated LiNi1/3Co1/3Mn1/3-xMg(x)O2 were characterized by X-ray diffractometry (XRD), scanning electron microscopy (SEM), and electrochemical tests. The results showed that the electrochemistry properties and cycle performance of magnesium doped LiNi1/3Co1/3Mn1/3O2 and CuO-coated LiNi1/3Co1/3Mn1/3-xMg(x)O2 materials were improved. The optimal doping content of Mg was x = 0.03 in the LiNi1/3Co1/3Mn1/3-xMg(x)O2 samples to achieve high discharge capacity and good cyclic stability, and the first discharge special capacity was 158.5 mAh/g at 0.2 C in the voltage of 2.5-4.3 V, then CuO-coated LiNi1/3Co1/3Mn1/3-0.03Mg0.03O2 was investigated. The electrode reaction reversibility and electronic conductivity were enhanced through Mg-doped and CuO-coated.

Ultrasound: a chemotherapy sensitizer.

Chemotherapy plays a very important role in cancer treatment. However, there are still some barriers in the successful use of such therapies, mainly because of the adverse side effects of the anticancer agents and due to the development of chemoresistance. This paper focuses on the use of ultrasound to enhance chemotherapy and to overcome drug resistance. The action of many anticancer agents can be improved with the use of ultrasonic exposure either in vitro or in vivo. Drug resistance can be circumvented using ultrasound alone. Furthermore, the reversal attributable to chemoresistance modifiers, such as verapamil and PSC 833, is augmented by ultrasound. Ultrasound-mediated chemosensitization is usually achieved via increasing intracellular drug accumulation, although other mechanisms are also involved. Ultrasound also can play a role in targeted chemotherapy, releasing anticancer chemicals directly and efficiently into the lesions. However, this promising modality has not been clinically adopted so far and the reasons are discussed.

Cellular compartmentation of zinc in leaves of the hyperaccumulator thlaspi caerulescens

Cellular compartmentation of Zn in the leaves of the hyperaccumulator Thlaspi caerulescens was investigated using energy-dispersive x-ray microanalysis and single-cell sap extraction. Energy-dispersive x-ray microanalysis of frozen, hydrated leaf tissues showed greatly enhanced Zn accumulation in the epidermis compared with the mesophyll cells. The relative Zn concentration in the epidermal cells correlated linearly with cell length in both young and mature leaves, suggesting that vacuolation of epidermal cells may promote the preferential Zn accumulation. The results from single-cell sap sampling showed that the Zn concentrations in the epidermal vacuolar sap were 5 to 6.5 times higher than those in the mesophyll sap and reached an average of 385 mM in plants with 20,000 &mgr;g Zn g-1 dry weight of shoots. Even when the growth medium contained no elevated Zn, preferential Zn accumulation in the epidermal vacuoles was still evident. The concentrations of K, Cl, P, and Ca in the epidermal sap generally decreased with increasing Zn. There was no evidence of association of Zn with either P or S. The present study demonstrates that Zn is sequestered in a soluble form predominantly in the epidermal vacuoles in T. caerulescens leaves and that mesophyll cells are able to tolerate up to at least 60 mM Zn in their sap.