Onealstokholm8212

This review will critically outline the roles of CO in hypertension-associated vascular remodeling and discuss the underlying mechanisms for the protective effects of CO against hypertension and vascular remodeling. In addition, we will propose the challenges and perspectives of CO in hypertensive vascular remodeling. It is expected that a comprehensive understanding of CO in the vasculature might be essential to translate CO to be a novel pharmacological agent for hypertension-induced vascular remodeling.Pigment epithelial-derived factor (PEDF) exerts a broad spectrum of activities and has been implicated in diverse biological processes and a variety of diseases. However, the role of PEDF in myeloproliferative neoplasms (MPN) remains unknown. In this study, we found that PEDF expression was down-regulated in MPN patients and MPLW515L-transuduced mice. Exogenous PEDF inhibited the peripheral blood cell proliferation in MPLW515L-transuduced mice, reduced tumor cells in bone marrow and spleen, ameliorated hepatosplenomegaly, reduced extramedullary hemopoiesis in the spleen, and prolonged the overall survival of MPN mice. More importantly, PEDF inhibited the progression of myelofibrosis. Moreover, PEDF significantly reduced the proliferation of MPN cells in vitro, especially megakaryocyte-biased HSCs. Furthermore, PEDF induced the apoptosis of MPN cells and reduced the secretion of TGF-β1 in cell culture supernatant. Exogenous PEDF inhibits the proliferation of MPN cells and the progression of myelofibrosis, indicating that it might play an anti-tumor and anti-fibrotic role in MPN. This study implies that PEDF might be a novel agent for the treatment of MPN.Aflatoxins B1 (AFB1) is a hepatoxic compound produced by Aspergillus flavus and Aspergillus parasiticus, seriously threatening food safety and the health of humans and animals. Understanding the metabolism of AFB1 is important for developing detoxification and intervention strategies. In this review, we summarize the AFB1 metabolic fates in humans and animals and the key enzymes that metabolize AFB1, including cytochrome P450s (CYP450s) for AFB1 bioactivation, glutathione-S-transferases (GSTs) and aflatoxin-aldehyde reductases (AFARs) in detoxification. Furthermore, AFB1 metabolism in microbes is also summarized. Microorganisms specifically and efficiently transform AFB1 into less or non-toxic products in an environmental-friendly approach which could be the most desirable detoxification strategy in the future. This review provides a wholistic insight into the metabolism and biotransformation of AFB1 in various organisms, which also benefits the development of protective strategies in humans and animals.Eugenol (EUG) is a phenylpropanoid widely used in the food and cosmetic industries. It is commonly referred to in the literature by its biological activities such as antioxidant, anti-inflammatory, antimicrobial, and relaxing in organs of laboratory animals, especially in rodent vessels. However, its vasorelaxant potential in human tissue, has not been investigated. Thus, this study characterizes the vasodilatory effect of EUG in the human umbilical artery (HUA). HUAs were isolated, cleaned, sectioned (3-4 mm) and placed in an organ bath (10 mL Krebs Henseleit, 37 °C; and carbogenic mixture). EUG (100-1400 μM), obtained total relaxation of electromechanical contractions induced by KCl (60 mM), and pharmacomechanical contractions (30-1200 μM), induced by serotonin (10 μM) and by histamine (10 μM), showing statistically significant concentrations 600 μM, 400 μM and 200 μM, and EC50 values 759.8 ± 6.5 μM, 229.9 ± 7.9 and 279.0 ± 3.4 μM, respectively. EUG (1200 and 1400 μM) prevented the contraction promoted by BaCl2 (0.1-30 mM), similar to the effects of nifedipine (10 μM), sugesting the involvement of EUG in blocking VOCCs. In the presence of tetraethylammonium (10 μM), EUG (30-1200 μM) did not produce a total relaxation (88.6%), suggesting that an alternative pathway where potassium channels, may partially mediate EUG effect. In the presence of 4-aminopyridine (1 mM), glibenclamide (10 μM), and tetraethylammonium (1 mM), EUG relaxed HUAs 100%, although the pharmacological potency was statistically altered, demonstrating the participation of K+ channels (Kv, KATP, BKCa). Our data indicates that EUG has a vasorelaxant effect on HUAs, had a greater pharmacological potency in the serotoninergic pathway, showing effective participation of VOCCs and a partial modulation of K+ channels. These data suggest new possibilities for the use of EUG in human vascular dysfunctions, such as preeclampsia. More studies are necessary to confirm the safety and effectivity in future treatments.This commentary describes a highly cited paper by Eli Finkelstein, Gerald M. Rosen, and Elmer J. Raukman that appeared in Archives of Biochemistry and Biophysics published in 1980. They reviewed many reports being regularly appearing in the literature describing spin trapping and hydroxyl radicals from various sources and contributed to the development and progress that has been made in oxidative stress research.N6-methyladenosine (m6A) is the reversible epigenetic modification of mRNA biogenesis. However, its potential role in HSCs activation and liver fibrosis remains poorly understood. Here we report m6A RNA modification serves as a key layer of HSCs activation and liver fibrosis. The effects of m6A demethylase ALKBH5 on the HSCs activation and liver fibrosis were detected by loss-of-function and gain-of-function analyses. A combination of in vitro and in vivo models, including HSCs and clinical cases or CCl4-induced mice liver fibrosis, was performed to identify the regulation and function of ALKBH5 in liver fibrosis and HSCs activation. Here, we show that the level of ALKBH5 and PTCH1 was decreased in fibrosis livers; however, genetic over expression of LV5-ALKBH5 substantially reduced α-SMA and type I of collagen levels, collagen accumulation, and interstitial fibrosis, while significantly increased PTCH1 levels. Interestingly, the expression of ALKBH5 and PTCH1 was decreased in HSCs treated by TGF-β1. Moreover, over expression of ALKBH5 reduced HSCs proliferation and migration, whereas ALKBH5 knockdown facilitated HSCs proliferation and migration. Mechanistically, ALKBH5 mediated PTCH1 activation via a m6A-dependent manner. PTCH1 upregulation resulted in the hedgehog signaling inactivation, which inhibited HSCs activation. These findings indicated that ALKBH5 ameliorated liver fibrosis and suppressed HSCs activation via triggering PTCH1 activation in a m6A dependent manner, and provides insight into critical roles of m6A methylation in liver fibrosis.Parkinson's disease (PD) always causes dyskinesia and cognitive impairments. The alpha-synuclein (α-syn) accumulation, one of the main pathological characteristics of PD, may impair synaptic structural and synaptic functions. Nano-MgO composites has been reported to interfere α-syn expression. The present study is aim to investigate the roles of nano-MgO composites on cognitive impairments in PD rats. PD rats were formed by 6-hydroxydopamine (6-OH DA) and α-syn expression were evaluated by Western blot. Hippocampal dendritic morphology was examined by Golgi staining. Morris water maze (MWM) test was applied to evaluate learning and memory abilities and population spike was recorded by electrophysiological records in vivo. The results showed that 6-OH DA-treated up-regulated α-syn levels in striatum and hippocampus and increased the rotational times by APO, but nano-MgO composites could down-regulated α-syn levels. The overall length of dendritic and the total number of intersections were reduced by 6-OH DA, accompanied by the decrease of the dendritic spine density in hippocampal CA1, CA3 and DG regions. Interestingly, nano-MgO composites could alleviate the morphological damages of dendrites. In the MWM test, the escape latencies and the swimming distances in PD rats were increased as compared to the sham group, and nano-MgO composites could reduce the escapes latencies and the swimming distances. Furthermore, 6-OH DA reduced the amplitudes of long-term potentiation (LTP) in hippocampal CA1 region, and 6 mg/kg nano-MgO composites could improve LTP amplitudes. In conclusion, the current findings would be helpful to explore the roles of nano-MgO composites on neuroprotection in PD.Quantifying the heterogeneous nature of protein aggregates is important to understanding the impact aggregates may have on the performance of antibody therapeutics. The spatially averaged density ρp of aggregates, defined as the total mass, including water, divided by the volume, is a parameter that can be used to relate size distributions measured by orthogonal methods, to characterize protein particles, and perhaps to estimate the amount of aggregated protein in a sample. We report measurements by two methods on the distribution of density values for different aggregate sizes, where the aggregates were produced by stir-stressing fluorescently labeled monoclonal antibody (NISTmAb). A fluorescence microscope was used to image particles. Each particle was analyzed for brightfield equivalent circular diameter (ECD) and fluorescence intensity and the results converted to average density. Measurements were also obtained using video holography. The aggregates were highly porous with median density decreasing from 1.07 g/cm3 to 1.02 g/cm3 as the size increased from 0.9 μm to 6 μm by fluorescence, and similar results by video holography. The distribution in density for a given particle size was asymmetrical and broad. For example, particles with an ECD of 2.5 μm ranged in density from 1.005 g/cm3 to 1.1 g/cm3.High-throughput analysis of low-volume samples for detection of subvisible particles (SVPs) in biologic formulations remains an unmet need in the pharmaceutical industry. Some commonly used methods, such as light obscuration and microflow imaging, for SVP analysis are not high throughput and require significant amounts of sample volume, which may impede the collection of SVP data when therapeutic protein amounts are limited, typically during early stages of formulation development. We evaluated backgrounded membrane imaging (BMI) as an orthogonal method for SVP analysis and identified critical experimental parameters. Protein concentration, sample viscosity, and membrane coverage area had to be adjusted for each sample, especially those with high protein concentrations. A comparative analysis of particle counts obtained from BMI, light obscuration, and microflow imaging for five protein samples revealed that particle counts obtained with BMI were significantly higher than those acquired with the other two techniques for all particle size categories. BMI could not accurately count particles in protein-containing samples, as the image analysis software could not accurately trace the boundaries of translucent particles. Based on our results, BMI could be used as an orthogonal method for particle characterization when sample material is limited, such as during the early stages of formulation development or screening.The COVID-19 pandemic has decreased uptake of pediatric preventive care, including immunizations. We estimate the prevalence of missed pediatric routine medical visits and vaccinations over the first year of the COVID-19 pandemic. We conducted a cross-sectional online survey of 2074 US parents of children ≤12 years in March 2021 to measure the proportion of children who missed pediatric care and vaccinations over the first 12 months of the COVID-19 pandemic. Poisson regression models were fitted to estimate adjusted prevalence ratios (aPR). All analyses were weighted to represent the target population. Overall, 41.3% (95%CI 38.3-43.8) of parents reported their youngest child missed a routine medical visit due to the COVID-19 pandemic. Missed care was more common among children ≥2 years compared to less then 2 years (aPR 1.82; 95%CI 1.47-2.26) and Hispanics compared to non-Hispanic Whites (aPR 1.31; 95%CI 1.14-1.51). A third of parents (33.1%; 95%CI 30.7-35.5) reported their child had missed a vaccination. Compared to the 2019-20 flu season, pediatric influenza vaccination decreased in 2020-21 (51.