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•EBSD misorentation analysis is developed to depict localized creep-fatigue damage.•GND density map is explored to understand creep-fatigue failure physical ...mechanism.•Semi-quantitative study of EBSD parameters supports microscopic damage degree.
A large number of strain-controlled creep-fatigue tests under wide loading waveforms are conducted at 650 ℃ in nickel-based forged GH4169 superalloy. Comprehensive characterizations, including scanning electron microscope (SEM), electron backscatter diffraction (EBSD) and transmission electron microscope (TEM), are observed from the post-test examinations. Particular focus is brought to the physical understanding of damage mechanisms under wide creep-fatigue loading conditions using EBSD analysis. The representative misorientation parameters are calculated for constructing diffraction-based misorientation mapping. Semi-quantitative analysis of longitudinal EBSD observations is conducted to prove that strain ratio has little influence on creep-fatigue damage degrees, while dwell time causes noticeable changes to damage progressions. In particular for geometrically necessary dislocation (GND) map explored in this work, more fundamental information based on failure physics is obtained to analyze the creep-fatigue crack initiation mechanism.
Atherosclerotic lesions are lipometabolic disorder characterized by chronic progressive inflammation in arterial walls. Previous studies have shown that macrophage-derived lipoprotein lipase (LPL) ...might be a key factor that promotes atherosclerosis by accelerating lipid accumulation and proinflammatory cytokine secretion. Increasing evidence indicates that microRNA-27 (miR-27) has beneficial effects on lipid metabolism and inflammatory response. However, it has not been fully understood whether miR-27 affects the expression of LPL and subsequent development of atherosclerosis in apolipoprotein E knockout (apoE KO) mice. To address these questions and its potential mechanisms, oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages were transfected with the miR-27 mimics/inhibitors and apoE KO mice fed high-fat diet were given a tail vein injection with miR-27 agomir/antagomir, followed by exploring the potential roles of miR-27. MiR-27 agomir significantly down-regulated LPL expression in aorta and peritoneal macrophages by western blot and real-time PCR analyses. We performed LPL activity assay in the culture media and found that miR-27 reduced LPL activity. ELISA showed that miR-27 reduced inflammatory response as analyzed in vitro and in vivo experiments. Our results showed that miR-27 had an inhibitory effect on the levels of lipid both in plasma and in peritoneal macrophages of apoE KO mice as examined by HPLC. Consistently, miR-27 suppressed the expression of scavenger receptors associated with lipid uptake in ox-LDL-treated THP-1 macrophages. In addition, transfection with LPL siRNA inhibited the miR-27 inhibitor-induced lipid accumulation and proinflammatory cytokines secretion in ox-LDL-treated THP-1 macrophages. Finally, systemic treatment revealed that miR-27 decreased aortic plaque size and lipid content in apoE KO mice. The present results provide evidence that a novel antiatherogenic role of miR-27 was closely related to reducing lipid accumulation and inflammatory response via downregulation of LPL gene expression, suggesting a potential strategy to the diagnosis and treatment of atherosclerosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Osteoporosis (OP), a common metabolic bone disease, is accompanied by reduced bone mass, bone mineral density (BMD), as well as microstructure destruction of bone. Previously, microRNA‐196a‐2 ...(miR‐196a‐2) and miR‐196a‐3p were reported for its involvement in BMD. Herein, this study set out to identify the functional relevance of miR‐196a in osteogenic differentiation in osteoporotic mice and explore the associated mechanism by establishing an OP mouse model. Guanine nucleotide binding protein, alpha stimulating (GNAS) was verified as a target gene of miR‐196a, which was decreased in OP mice. Furthermore, the bone marrow stromal cells (BMSCs) were then extracted from OP mice and treated with miR‐196 mimic/inhibitor or small interfering RNA against GNAS to investigate miR‐196a interaction with GNAS and the Hedgehog signaling pathway. BMSCs in OP mice transfected with miR‐196a mimic or si‐GNAS displayed the elevated expression of Smo, ALP, Runx2, and OPN, as well as bone gla protein and tartrate‐resistant acid phosphatase, elevated ALP vitality and bone formation ability as well as reduced expression of GNAS and PTCH. Taken conjointly, overexpression of miR‐196a repressed GNAS expression by activating the Hedgehog signaling pathway, thus promoting osteogenic differentiation in mice with OP.
Despite optimization of renin-angiotensin-aldosterone system (RAAS) inhibition, patients with immunoglobulin A nephropathy (IgAN) and persistent proteinuria remain at risk for kidney failure. We ...evaluated the efficacy and safety of hydroxychloroquine (HCQ), an immunomodulator, when added to the treatment regimen of patients with IgAN.
Double-blind, randomized, placebo-controlled, phase 2 clinical trial.
Participants had IgAN (proteinuria with protein excretion of 0.75-3.5g/d and estimated glomerular filtration rate>30mL/min/1.73m2) and were receiving optimized RAAS inhibitor therapy.
Patients were randomly assigned 1:1 to receive daily oral HCQ or a placebo for 6 months.
The primary outcome was percentage change in proteinuria between baseline and 6 months.
60 participants (mean estimated glomerular filtration rate, 53.8mL/min/1.73m2; median urine protein excretion, 1.7g/d) were recruited and randomly assigned to receive HCQ (n=30) or placebo (n=30). Percentage change in proteinuria at 6 months was significantly different between the HCQ group and the placebo group (−48.4% IQR, −64.2%, −30.5% vs 10.0% IQR, −38.7%, 30.6%; P<0.001, respectively). At 6 months, median proteinuria level was significantly lower in the HCQ group than in the placebo group (0.9 IQR, 0.6, 1.0 g/d vs 1.9 IQR, 0.9, 2.6 g/d; P=0.002, respectively). No serious adverse events were recorded during the study in either study group.
The short treatment period and lack of postwithdrawal observations limit conclusions about long-term renoprotective efficacy and safety.
HCQ in addition to optimized RAAS inhibition significantly reduced proteinuria in patients with IgAN over 6 months without evidence of adverse events. These findings require confirmation in larger treatment trials.
This study was supported by grants from a government entity, the Capital of Clinical Characteristics, and the Applied Research Fund.
Registered at ClinicalTrials.gov with study number NCT02942381.
The goal this review is to clarify the effects of the fat mass and obesity-associated protein (FTO) in lipid metabolism regulation and related underlying mechanisms through the FTO-mediated ...demethylation of m6A modification. FTO catalyzes the demethylation of m6A to alter the processing, maturation and translation of the mRNAs of lipid-related genes. FTO overexpression in the liver promotes lipogenesis and lipid droplet (LD) enlargement and suppresses CPT-1–mediated fatty acid oxidation via the SREBP1c pathway, promoting excessive lipid storage and nonalcoholic fatty liver diseases (NAFLD). FTO enhances preadipocyte differentiation through the C/EBPβ pathway, and facilitates adipogenesis and fat deposition by altering the alternative splicing of RUNX1T1, the expression of PPARγ and ANGPTL4, and the phosphorylation of PLIN1, whereas it inhibits lipolysis by inhibiting IRX3 expression and the leptin pathway, causing the occurrence and development of obesity. Suppression of the PPARβ/δ and AMPK pathways by FTO-mediated m6A demethylation damages lipid utilization in skeletal muscles, leading to the occurrence of diabetic hyperlipidemia. m6A demethylation by FTO inhibits macrophage lipid influx by downregulating PPARγ protein expression and accelerates cholesterol efflux by phosphorylating AMPK, thereby impeding foam cell formation and atherosclerosis development. In summary, FTO-mediated m6A demethylation modulates the expression of lipid-related genes to regulate lipid metabolism and lipid disorder diseases.
Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and ...mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 enzymes in rat liver. Rats were orally exposed to micro-copper (400 mg/kg), Cu ion (100 mg/kg), or nano-copper (100, 200 and 400 mg/kg) daily for seven consecutive days. Histopathological, inflammatory and oxidative stress were measured in the livers of all rats. The mRNA levels and activity of CYP450 enzymes, as well as the mRNA levels of select nuclear receptors, were determined. Exposure to nano-copper (400 mg/kg) induced significant oxidative stress and inflammation relative to the controls, indicated by increased levels of interleukin (IL)-2, IL-6, interferon (IFN)-γ, macrophage inflammatory protein (MIP-1), total antioxidant capacity (T-AOC), malondialdehyde (MDA), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after exposure. The levels of mRNA expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AHR) were significantly decreased in 400 mg/kg nano-copper treated rats. Nano-copper activated the expression of the NF-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)3 signaling pathways. Nano-copper decreased the mRNA expression and activity of CYP 1A2, 2C11, 2D6, 2E1 and 3A4 in a dose-dependent manner. The adverse effects of micro-copper are less severe than those of nano-copper on the CYP450 enzymes of rats after oral exposure. Ingestion of large amounts of nano-copper in animals severely affects the drug metabolism of the liver by inhibiting the expression of various CYP450 enzymes, which increases the risk of drug-drug interactions in animals.
In this study, a miniaturized multilayer flexible electromagnetic acoustic transducer (EMAT) probe was designed for the detection of small-scale delamination defects, successfully identifying a 2 mm ...delamination defect. Additionally, an innovative characterization method was introduced, which involves analyzing the ratio of the defect echo to the bottom echo at the peak of the defect echo, thereby characterizing the defect features. This approach effectively analyzes delamination that are smaller in width than the diameter of the coil. Finite element simulations were carried out to model the ultrasonic reflections within a specimen containing a 2 mm delamination defect under EMAT excitation. Based on the simulation results, an EMAT with a diameter of 5.5 mm was designed to characterize the sample, and the center point of the EMAT at the peak of the defect echo during scanning was defined as the positioning point. The displacement size of the positioning point relative to the defect center was analyzed for a 5.5 mm coil sample across different widths of delamination defects, aiding in determining the center position of defects in experiments. Subsequently, the ratio of the defect echo to the bottom echo at the positioning point was examined, and segmented fitting was performed based on the variations in defect positioning points, to assist in judging the size of delamination defects in actual experiments. Finally, the feasibility of the theory was validated through practical experiments. This demonstrates the effectiveness of the EMAT design and the method for characterizing small-scale delamination defects proposed in this article.
The topoisomerase enzymes play an important role in DNA metabolism, and searching for enzyme inhibitors is an important target in the search for new anticancer drugs. Discovery of new anticancer ...chemotherapeutical capable of inhibiting topoisomerase enzymes is highlighted in anticancer research. Therefore, biologists, organic chemists and medicinal chemists all around the world have been identifying, designing, synthesizing and evaluating a variety of novel bioactive molecules targeting topoisomerase. This review summarizes types of topoisomerase inhibitors in the past decade, and divides them into nine classes by structural characteristics, including N-heterocycles compounds, quinone derivatives, flavonoids derivatives, coumarin derivatives, lignan derivatives, polyphenol derivatives, diterpenes derivatives, fatty acids derivatives, and metal complexes. Then we discussed the application prospect and development of these anticancer compounds, as well as concluded parts of their structural-activity relationships. We believe this review would be invaluable in helping to further search potential topoisomerase inhibition as antitumor agent in clinical usage.
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•Topoisomerase inhibitors were primarily classified into nine structural classes.•Some exhibited exciting biological results better than the first line treatments.•Topo IIα inhibitors are more favorable than topo IIβ, but still with toxic to normal cells.•The mechanism of action needs further research.•The selectivity on the target and the in vivo tests should be focused on.
Compound
C5 exhibited the most potent EGFR inhibitory activity with IC
50 of 0.07
μM, which was comparable to the positive control erlotinib. Docking simulation was performed to position compound
C5 ...into the EGFR active site to determine the probable binding model. Besides, compound
C5 showed significant antiproliferative activity against MCF-7 with IC
50 of 0.08
μM, which would be a potential anticancer agent.
Two series of pyrazole derivatives designing for potential EGFR kinase inhibitors have been discovered. Some of them exhibited significant EGFR inhibitory activity. Compound
3-(3,4-dimethylphenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (
C5) displayed the most potent EGFR inhibitory activity with IC
50 of 0.07
μM, which was comparable to the positive control erlotinib. Docking simulation was performed to position compound
C5 into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicating that some of the pyrazole derivatives own high antiproliferative activity against MCF-7. Compound
C5 showed significant antiproliferative activity against MCF-7 with IC
50 of 0.08
μM. Therefore, compound
C5 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent.
Currently, no consensus exists regarding Sotos syndrome in the Chinese population. Here, we present a case of neonatal Sotos syndrome, followed by a retrospective analysis of five cases of neonatal ...Sotos syndrome, reported in China. The study subject was a twin premature infant, heavier than gestational age, with characteristic facial features, limb shaking, and hypertonia. Transient hypoglycemia, abnormal cranial magnetic resonance imaging, multiple nodules in polycystic kidneys and liver, abnormal hearing, patent ductus arteriosus, and an atrial septal defect were also noted. The subject showed overgrowth and developmental retardation at 3 months of age. Sequencing revealed a novel missense mutation, c.5000C>A, in the nuclear receptor binding the SET domain protein 1 gene, resulting in an alanine-to-glutamate substitution. The bioinformatics analysis suggested high pathogenicity at this site. This study provides insights into diagnosis of neonatal Sotos syndrome based on specific phenotypes. Subsequent treatment and follow-up should focus on developmental retardation, epilepsy, and scoliosis.
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