Lerchepontoppidan3886

β-lactam antibiotics have long been the mainstay for the treatment of bacterial infections. New Delhi metallo-β-lactamase 1 (NDM-1) is able to hydrolyze nearly all β-lactam antibiotics and even clinically used serine-β-lactamase inhibitors. The wide and rapid spreading of NDM-1 gene among pathogenic bacteria has attracted extensive attention, therefore high potency NDM-1 inhibitors are urgently needed. Here we report a series of structure-guided design of D-captopril derivatives that can inhibit the activity of NDM-1 in vitro and at cellular levels. Structural comparison indicates the mechanisms of inhibition enhancement and provides insights for further inhibitor optimization.

In familial hypercholesterolemia (FH), statin treatment should be considered from 8 to 10 years of age, but the prevalence of statin use among children is not known.

Statin use (2008-2018) among children aged 10-14 and 15-19 years was obtained from the national prescription databases in Norway, Sweden and Denmark. We assumed that all statin users in these age groups had FH, and that the estimated prevalence of FH is 1 in 250 inhabitants. Changes in prevalence rates of statin use between 2008 and 2018 by country, age and sex were estimated using the Joinpoint Regression Program version 4.8.0.1. Differences in prevalence rate ratio each year between countries were analyzed using Poisson regression.

Among children aged 10-14 years, there was a significant increase in statin use in Norway and Denmark between 2008 and 2018, while in Sweden an increase was only seen after 2014. Among children aged 15-19 years, an increase in statin use was only observed in Norway and Sweden between 2008 and 2018. Statin use wes between the countries; statin use was 3-5 times more prevalent in Norway than in Sweden and Denmark, which may be due to a more widespread use of genetic testing for FH in Norway.

Peripheral artery disease (PAD) affects more than 200 million people worldwide. Increased low-density lipoprotein cholesterol (LDL-C)levels are a risk factor for PAD and the concentrations are influenced by proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 regulates the recycling of the LDL receptors to the cell membrane surface. Only a limited number of mostly small studies investigated the association between serum PCSK9 concentrations and PAD of different definition, which revealed contrasting results.

Serum PCSK9, lipoprotein(a) [Lp(a)] and other lipoprotein concentrations were measured in male participants of the CAVASIC study, a case-control study of 248 patients with intermittent claudication and 251 age and diabetes-matched controls.

PAD patients had significantly higher PCSK9 concentrations when compared to controls (250±77 vs. 222±68ng/mL, p<0.001). Logistic regression analysis with adjustment for age revealed that an increase in PCSK9 concentrations of 100ng/mL was associated with a 1.78-fold higher risk for PAD (95%CI 1.38-2.33, p=1.43×10

). The association attenuated, but was still significant when adjusting additionally for age, Lp(a)-corrected LDL cholesterol, HDL cholesterol, high-sensitivity-CRP, statin treatment, hypertension, diabetes mellitus and smoking (OR=1.49, 95%CI 1.03-2.18, p=0.035). The strongest association was observed when both PCSK9 concentrations were above the median and Lp(a) concentrations were above 30mg/dL (OR=3.35, 95%CI 1.49-7.71, p=0.0038).

Our findings suggest an association of higher PCSK9 concentrations with PAD, which was independent of other lipid parameters and classical cardiovascular risk factors.

Our findings suggest an association of higher PCSK9 concentrations with PAD, which was independent of other lipid parameters and classical cardiovascular risk factors.

Atopic dermatitis (AD) is an inflammatory chronic skin disease that is characterized by the dysfunction or lack of skin barrier proteins. Recent studies have proposed that the pharmacological upregulation of skin barrier proteins is an effective treatment for AD. Aryl hydrocarbon receptor (AhR) is a transcription factor that positively regulates the expression of skin barrier proteins upon its activation.

This study aimed to identify AhR agonists from phytochemicals and investigate its effect on skin barrier restoration as well as its mechanisms of action in AD.

A publicly available assay database and HaCaT cells stably transduced with a luciferase gene driven by an AhR-target gene promoter (CYP1A1) were used to screen for the activity of AhR agonists from phytochemicals. Normal human epidermal keratinocytes (NHEKs) and a human skin equivalent (HSE) model were used to investigate the effect of AhR agonists on skin restoration and its underlying mechanisms.

A Gaussia luciferase assaywas performed to scound to AhR. Furthermore, AhR knockdown abolished diosmin-induced filaggrin and loricrin expression.

These results suggest that diosmin is a potential treatment for AD that targets AhR.

These results suggest that diosmin is a potential treatment for AD that targets AhR.

This study aims to investigate the role of p38 Mitogen-activated protein kinase (MAPK) in imparting cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) cells.

Laboratory generated cisplatin resistant HNSCC cells were treated with p38 inhibitor and were subjected to increasing dosage of cisplatin. Western blot, immunohistochemistry and RT PCR analysis were performed to investigate expression level of p-p38 and Cancer stem cell (CSC) markers in cisplatin resistant HNSCC cells with or without p38 inhibitor. Chemoresistance, wound healing capacity and Spheroids formation capacity were assessed following p38 inhibition in cisplatin resistant HNSCC cell lines. In addition, alkaline comet assay and γ-H2AX immunostaining were performed to evaluate the DNA damage response and repair abilities in cisplatin resistant HNSCC cells after p38 inhibition.

It was observed that following p38 inhibition, cisplatin resistant HNSCC cells exhibited significant reduction in expression of CSC markers, β-catenin, reduced migration potential and sphere forming ability along with increased apoptotic index demonstrating there was increased sensitivity towards Cisplatin. Molecular docking study identified several interface amino acid residues between p-p38 with CSC markers (Klf4 and CD44). p38 inhibited cisplatin resistant HNSCC cells also exhibited increased DNA damage as measured by Comet assay and γ-H

AX foci formation index. There was significant decrease in DNA repair as confirmed by reduced ERRC1 expression.

Our study demonstrated that p38 MAPK inhibition can be a targeted approach to overcome resistance in HNSCC thereby escalating the effectiveness of chemotherapy in HNSCC.

Our study demonstrated that p38 MAPK inhibition can be a targeted approach to overcome resistance in HNSCC thereby escalating the effectiveness of chemotherapy in HNSCC.The fast growth of industrialization combined with the increasing population has led to an unparalleled demand for providing water in a safe, reliable, and cost-effective way, which has become one of the biggest challenges of the twenty-first century faced by global society. The application of nanotechnology in water treatment and pollution cleanup is a promising alternative in order to overcome the current limitations. In particular, the application of magnetic iron oxide nanoparticles (MIONs) for environmental remediation has currently received remarkable attention due to its unique combination of physicochemical and magnetic properties. Given the broadening use of these functional engineered nanomaterials, there is a growing concern about the adverse effects upon exposure of products and by-products to the environment. This makes vitally relevant the development of green chemistry in the synthesis processes combined with a trustworthy risk assessment of the nanotoxicity of MIONs as the scientific knowledge of the potential hazard of nanomaterials remains limited. This work provides comprehensive coverage of the recent progress on designing and developing iron oxide-based nanomaterials through a green synthesis strategy, including the use of benign solvents and ligands. Despite the limitations of nanotoxicity and environmental risks of iron oxide-based nanoparticles for the ecosystem, this critical review presents a contribution to the emerging knowledge concerning the theoretical and experimental studies on the toxicity of MIONs. Potential improvement of applications of advanced iron oxide-based hybrid nanostructures in water treatment and pollution control is also addressed in this review.Aquatic ecosystems are exposed to multiple stressors such as agricultural run-off (ARO) and climate-change related increase of temperature. We aimed to determine how ARO and the frequency of its input can affect shallow lake ecosystems through direct and indirect effects on primary producers and primary consumers, and whether warming can mitigate or reinforce the impact of ARO. We performed a set of microcosm experiments simulating ARO using a cocktail of three organic pesticides (terbuthylazine, tebuconazole, pirimicarb), copper and nitrate. Two experiments were performed to determine the direct effect of ARO on primary producers (submerged macrophytes, periphyton and phytoplankton) and on the grazing snail Lymnaea stagnalis, respectively. Three different ARO concentrations added as single doses or as multiple pulses at two different temperatures (22°C and 26°C) were applied. In a third experiment, primary producers and consumers were exposed together to allow trophic interactions. When functional groups were exposed alone, ARO had a direct positive effect on phytoplankton and a strong negative effect on L. stagnalis. When exposed together, primary producer responses were contrasting, as the negative effect of ARO on grazers led to an indirect positive effect on periphyton. https://www.selleckchem.com/products/c-75.html Periphyton in turn exerted a strong control on phytoplankton, leading to an indirect negative effect of ARO on phytoplankton. Macrophytes showed little response to the stressors. Multiple pulse exposure increased the effect of ARO on L. stagnalis and periphyton when compared with the same quantity of ARO added as a single dose. The increase in temperature had only limited effects. Our results highlight the importance of indirect effects of stressors, here mediated by grazers and periphyton, and the frequency of the ARO input in aquatic ecosystems.Beaches along the Great Lakes shorelines are important recreational and economic resources. However, contamination at the beaches can threaten their usage during the swimming season, potentially resulting in beach closures and/or advisories. Thus, understanding the dynamics that control nearshore water quality is integral to effective beach management. There have been significant improvements in this effort, including incorporating modeling (empirical, mechanistic) in recent years. Mechanistic modeling frameworks can contribute to this understanding of dynamics by determining sources and interactions that substantially impact fecal indicator bacteria concentrations, an index routinely used in water quality monitoring programs. To simulate E. coli concentrations at Jeorse Park beaches in southwest Lake Michigan, a coupled hydrodynamic and wave-current interaction model was developed that progressively added contaminant sources from river inputs, avian presence, bacteria-sediment interactions, and bacteria-sand-sediment interactions.