Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C-4 and various carboxamide substituents at C-3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C-4 position and compounds with 4-chlorophenyl carboxamide at C-3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 mu M, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 mu M, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal

Visualizing the vibration effect on the tandem-pulsed gas metal arc welding in the presence of surface tension active elements

In this study, a three-dimensional model of the tandem-pulsed gas metal arc welding process is simulated to investigate the heat transfer and material flow in the presence of vibration and the surface tension active elements. The simulation results are in agreement with optical microscopy images of weld cross-section obtained with different conditions, including with and without vibration-assisted welding. The material flow is visualized using 2D and 3D streamlines on the temperature contour maps. It is found that during the operation of pulsed welding, the heat follows a very stable pattern, although the fluid streams continuously change in the rear region of the weld pool, which is responsible for the final geometry of penetration. Consideration of the effect of surface tension active elements on the Marangoni force improves the simulation results noticeably. A novel approach addresses the effect of sulfur content that comes from both workpiece and filler material. Applying the vibration leads to lower heat input by affecting the free surface behavior and plays an important role in the penetration shape change. © 202

A statistical downscaling framework for environmental mapping

In recent years, knowledge extraction from data has become increasingly popular, with many numerical forecasting models, mainly falling into two major categories—chemical transport models (CTMs) and conventional statistical methods. However, due to data and model variability, data-driven knowledge extraction from high-dimensional, multifaceted data in such applications require generalisations of global to regional or local conditions. Typically, generalisation is achieved via mapping global conditions to local ecosystems and human habitats which amounts to tracking and monitoring environmental dynamics in various geographical areas and their regional and global implications on human livelihood. Statistical downscaling techniques have been widely used to extract high-resolution information from regional-scale variables produced by CTMs in climate model. Conventional applications of these methods are predominantly dimensional reduction in nature, designed to reduce spatial dimension of gridded model outputs without loss of essential spatial information. Their downside is twofold—complete dependence on unlabelled design matrix and reliance on underlying distributional assumptions. We propose a novel statistical downscaling framework for dealing with data and model variability. Its power derives from training and testing multiple models on multiple samples, narrowing down global environmental phenomena to regional discordance through dimensional reduction and visualisation. Hourly ground-level ozone observations were obtained from various environmental stations maintained by the US Environmental Protection Agency, covering the summer period (June–August 2005). Regional patterns of ozone are related to local observations via repeated runs and performance assessment of multiple versions of empirical orthogonal functions or principal components and principal fitted components via an algorithm with fully adaptable parameters. We demonstrate how the algorithm can be extended to weather-dependent and other applications with inherent data randomness and model variability via its built-in interdisciplinary computational power that connects data sources with end-users

The Expression of BAFF, APRIL and TWEAK Is Altered in Eczema Skin but Not in the Circulation of Atopic and Seborrheic Eczema Patients

The TNF family cytokines BAFF (B-cell activating factor of the TNF family) and APRIL (a proliferation-inducing ligand) are crucial survival factors for B-cell development and activation. B-cell directed treatments have been shown to improve atopic eczema (AE), suggesting the involvement of these cytokines in the pathogenesis of AE. We therefore analyzed the expression of these TNF cytokines in AE, seborrheic eczema (SE) and healthy controls (HC). The serum/plasma concentration of BAFF, APRIL and a close TNF member TWEAK (TNF-like weak inducer of apoptosis) was measured by ELISA. The expression of these cytokines and their receptors in skin was analyzed by quantitative RT-PCR and immunofluorescence. Unlike other inflammatory diseases including autoimmune diseases and asthma, the circulating levels of BAFF, APRIL and TWEAK were not elevated in AE or SE patients compared with HCs and did not correlate with the disease severity or systemic IgE levels in AE patients. Interestingly, we found that the expression of these cytokines and their receptors was altered in positive atopy patch test reactions in AE patients (APT-AE) and in lesional skin of AE and SE patients. The expression of APRIL was decreased and the expression of BAFF was increased in eczema skin of AE and SE, which could contribute to a reduced negative regulatory input on B-cells. This was found to be more pronounced in APT-AE, the initiating acute stage of AE, which may result in dysregulation of over-activated B-cells. Furthermore, the expression levels of TWEAK and its receptor positively correlated to each other in SE lesions, but inversely correlated in AE lesions. These results shed light on potential pathogenic roles of these TNF factors in AE and SE, and pinpoint a potential of tailored treatments towards these factors in AE and SE

Effects of COVID-19 prevention procedures on other common infections: a systematic review

Introduction: Since the outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) began, necessary measures to prevent virus transmission and reduce mortality have been implemented, including mandatory public use of masks, regular hand-sanitizing and hand-washing, social distancing, avoidance of crowds, remote work, and cancellation of public events. During and after the introduction of COVID-19 lockout, we performed a systematic review of available published literature to investigate the incidence of seasonal influenza and other respiratory viral infections. Methods: PubMed, Embase, Web of Science, Scopus, Science Direct, Google Scholar, Research Gate, and the World Health Organization databases and websites were systematically searched for original studies concerning the impact of COVID-19 prevention means and measures on other common respiratory infectious diseases during the pandemic published by March 2021. Results: The findings showed that the adherence to health protocols to prevent COVID-19 could help to reduce the incidence of other infectious diseases such as influenza, pneumonia, and Mycobacterium tuberculosis. Conclusion: The implemented prevention measures and protocols might have reduced the incidence of influenza and some other common respiratory infections. However, controversies exist on this matter and future large population-based studies might provide further information to address these controversies. © 2021, The Author(s)

Global Expression Profiling in Atopic Eczema Reveals Reciprocal Expression of Inflammatory and Lipid Genes

Atopic eczema (AE) is a common chronic inflammatory skin disorder. In order to dissect the genetic background several linkage and genetic association studies have been performed. Yet very little is known about specific genes involved in this complex skin disease, and the underlying molecular mechanisms are not fully understood.We used human DNA microarrays to identify a molecular picture of the programmed responses of the human genome to AE. The transcriptional program was analyzed in skin biopsy samples from lesional and patch-tested skin from AE patients sensitized to Malassezia sympodialis (M. sympodialis), and corresponding biopsies from healthy individuals. The most notable feature of the global gene-expression pattern observed in AE skin was a reciprocal expression of induced inflammatory genes and repressed lipid metabolism genes. The overall transcriptional response in M. sympodialis patch-tested AE skin was similar to the gene-expression signature identified in lesional AE skin. In the constellation of genes differentially expressed in AE skin compared to healthy control skin, we have identified several potential susceptibility genes that may play a critical role in the pathological condition of AE. Many of these genes, including genes with a role in immune responses, lipid homeostasis, and epidermal differentiation, are localized on chromosomal regions previously linked to AE.Through genome-wide expression profiling, we were able to discover a distinct reciprocal expression pattern of induced inflammatory genes and repressed lipid metabolism genes in skin from AE patients. We found a significant enrichment of differentially expressed genes in AE with cytobands associated to the disease, and furthermore new chromosomal regions were found that could potentially guide future region-specific linkage mapping in AE. The full data set is available at http://microarray-pubs.stanford.edu/eczema

Anticonvulsant effects of aerial parts of Passiflora incarnata extract in mice: involvement of benzodiazepine and opioid receptors

<p>Abstract</p> <p>Background</p> <p>Passion flower (<it>Passiflora incarnata</it>) is used in traditional medicine of Europe and South America to treat anxiety, insomnia and seizure. Recently, it has shown antianxiety and sedative effects in human.</p> <p>Methods</p> <p>In this study, anticonvulsant effects of hydro- alcoholic extract of Passiflora, Pasipay, were examined by using pentylentetrazole model (PTZ) on mice. Pasipay, diazepam, and normal saline were injected intraperitoneally at the doses 0.4–0.05 mg/kg, 0.5–1 mg/kg and 10 ml/kg respectively 30 minutes before PTZ (90 mg/kg, i.p). The time taken before the onset of clonic convulsions, the duration of colonic convulsions, and the percentage of seizure and mortality protection were recorded. For investigating the mechanism of Pasipay, flumazenil (2 mg/kg, i.p) and naloxone (5 mg/kg, i.p) were also injected 5 minutes before Pasipay.</p> <p>Results</p> <p>An ED₅₀value of Pasipay in the PTZ model was 0.23 mg/kg (%95 CL: 0.156, 0.342). Pasipay at the dose of 0.4 mg/kg prolonged the onset time of seizure and decreased the duration of seizures compared to saline group (p < 0.001). At the dose of 0.4 mg/kg, seizure and mortality protection percent were 100%. Flumazenil and naloxone could suppress anticonvulsant effects of Pasipay.</p> <p>Conclusion</p> <p>It seems that Pasipay could be useful for treatment absence seizure and these effects may be related to effect of it on GABAergic and opioid systems. More studies are needed in order to investigate its exact mechanism.</p

Sastav eteričnog ulja biljke Teucrium scordium L.

Composition of the essential oil obtained from dried flowering aerial parts of Teucrium scordium L. (Labiatae) was analyzed by GC and GC/MS. Fifty-six components were identified in the essential oil of T. scordium. The major constituents of the oil were betha-caryophyllene (22.8%), (E)-betha-farnesene (10.4%), caryophyllene oxide (8.6%), 1,8-cineole (6.1%) and betha-eudesmol (5.1%).Sastav eteričnog ulja iz osušenih nadzemnih dijelova biljke Teucrium scordium L. (Labiatae) u cvatu analiziran je pomoću GC i GC/MS. Identificirano je pedeset šest komponenata, a najvažniji sastojci ulja su beta-kariofilen (22,8%), (E)-beta-farnesen (10,4%), oksid kariofilen (8,6%), 1,8-cineol (6,1%) i beta-eudezmol (5,1%)

Analysis of Hypoxia and Hypoxia-Like States through Metabolite Profiling

In diverse organisms, adaptation to low oxygen (hypoxia) is mediated through complex gene expression changes that can, in part, be mimicked by exposure to metals such as cobalt. Although much is known about the transcriptional response to hypoxia and cobalt, little is known about the all-important cell metabolism effects that trigger these responses.Herein we use a low molecular weight metabolome profiling approach to identify classes of metabolites in yeast cells that are altered as a consequence of hypoxia or cobalt exposures. Key findings on metabolites were followed-up by measuring expression of relevant proteins and enzyme activities. We find that both hypoxia and cobalt result in a loss of essential sterols and unsaturated fatty acids, but the basis for these changes are disparate. While hypoxia can affect a variety of enzymatic steps requiring oxygen and heme, cobalt specifically interferes with diiron-oxo enzymatic steps for sterol synthesis and fatty acid desaturation. In addition to diiron-oxo enzymes, cobalt but not hypoxia results in loss of labile 4Fe-4S dehydratases in the mitochondria, but has no effect on homologous 4Fe-4S dehydratases in the cytosol. Most striking, hypoxia but not cobalt affected cellular pools of amino acids. Amino acids such as aromatics were elevated whereas leucine and methionine, essential to the strain used here, dramatically decreased due to hypoxia induced down-regulation of amino acid permeases.These studies underscore the notion that cobalt targets a specific class of iron proteins and provide the first evidence for hypoxia effects on amino acid regulation. This research illustrates the power of metabolite profiling for uncovering new adaptations to environmental stress