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

Production and evaluation of doubled haploid lines of barley via detached-tiller culture method

This research was conducted to compare the classic (C) and detached-tiller methods (a: sterile by clip and scissors D1; b: sterile by hot water D2) for producing haploids in barley. The parental materials used in this research were F1 four genotypes of Hordeum vulgare: B1: Reihane × Legia; B2: Reihan × Igri; B3: Kavir × Igri; B4: Kavir × Legia, and the Hordeum bulbosum was PB1 genotype (Plant Breeding Institute). The traits such as seed set percentage, embryo development, haploid seedling development and produced doubled haploid lines were analyzed statically using χ2 test. The comparison was made among arable barley B1, B2, B3, B4 crossing wild barley of H. bulbosum. In C approach, there was no significant difference concerning the percent of forming seed, embryo and haploid production. While in D1 approach, there was a significant difference in embryo forming percent but no significant difference was observed for haploid plant and seed set percent. Moreover, in D2 approach, there was a significant difference for seed set percent. However, for haploid production and embryo development percent, the approach D1 in regards with the percent of forming embryo and production of haploids was superior to the other two approaches, C and D2.Key words: Detached-tiller culture, haploid, doubled haploid, Hordeum bulbosum, Hordeum vulgare

Evaluacija svojstava vezanja sluzi sjemenki biljke Plantago psyllium

Mucilage extracted from Plantago psyllium seeds was evaluated for inertness and safety parameters. The suitability of psyllium mucilage for a pharmaceutical binder was assessed in paracetamol tablets. Properties of the granules prepared using different concentrations of psyllium mucilage was compared with PVP and tragacanth. Psyllium mucilage at 5 % (m⁄m) level was found to be comparable with 3 % (m⁄m) of PVP. Investigated paracetamol tablets indicated that psyllium mucilage can retard the drug release.U radu je ispitivana neškodljivost i sigurnost uporabe sluzi ekstrahirane iz sjemenki biljke Plantago psyllium. Primjenjivost te sluzi kao veziva u farmaceutskim pripravcima ispitana je na tabletama paracetamola. Granule pripravljene s različitim koncentracijama sluzi uspoređene su s granulama s PVP-om i tragakantom. Sluz s udjelom 5 % (m/m) usporediva je s otopinom PVP-a masenog udjela 3 %. Pripravljene tablete paracetamola ukazuju na to da ispitivana sluz može usporiti oslobađanje lijeka

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)

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

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

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

The main risk factors of pulmonary tuberculosis acquisition in hospitalized patients in Razi hospital, Ahvaz-Iran (2001-07)

Background and Objective: Risk factors of tuberculosis vary in communities according to different socioeconomic conditions. Knowing these risk factors help to control the disease. This study was done to determine the main risk factors of pulmonary tuberculosis acquisition in hospitalized patients. Materials and Methods: In this data based, case-control study 173 tuberculosis patients (as cases) and 305 non tuberculosis patients (as controls) hospitalized in Razi hospital in Ahvaz, Iran during 2001-07 were gone under investigation. Risk factors included injecting drug addiction, smoking, HIV infection, diabetes mellitus, imprisonment and corticosteroid usage. Data were analyzed using SPSS-13, Chi-Square and Fisher exact tests. Odds ratio was determined for risk factors. Results: Frequencies of the main risk factors in case and control groups were as: smoking 54.3%, 14.8% (p=0.0001, OR: 6.5), HIV infection 11.5%, 3% (p=0.0002, OR: 4.3), injecting drug addiction 18%, 3.3% (p=0.0001, OR: 6.7), diabetes mellitus 22.5%, 5.9% (p=0.0001, OR: 4.6) and imprisonment 20.2%, 3.9% (p=0.0001, OR: 6.2), respectively. Corticosteroid use and renal failure were similar in cases and controls. Conclusion: This study showed that smoking, HIV infection, injecting drug addiction, diabetes mellitus and imprisonment were the main risk factors for tuberculosis acquisition in this region