Synthesis and Evaluation of Antimicrobial Activity of Some Pyrimidine Glycosides

Reaction of ethyl 4-thioxo-3,4-dihydropyrimidine-5-carboxylate derivatives 1a,b and ethyl 4-oxo-3,4-dihydropyrimidine-5-carboxylate 1c with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in KOH or TEA afforded ethyl 2-aryl-4-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosylthio or/ oxy)-6-methylpyrimidine-5-carboxylate 6a-c. The glucosides 6a and 6b were obtained by the reaction of 1a and 1b with peracetylated glucose3 under MW irradiation. Mercuration of 1a followed by reaction with acetobromoglucose gave the same product 6a. The reaction of 1a-c with peracetylated ribose 4 under MW irradiation gave ethyl 2-aryl-4-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosylthio)-6-methylpyrimidine-5-carboxylate 8a–c. The deprotection of 6a–c and 8a–c in the presence of methanol and TEA/H₂O afforded the deprotected products 7a–c and 9a–c. The structure were confirmed by using ¹H and ¹³CNMR spectra. Selected members of these compounds were screened for antimicrobial activity.     

Association between TNF promoter −308 G>A and LTA 252 A>G polymorphisms and systemic lupus erythematosus

Tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) are pivotal cytokines in the pathogenesis of systemic lupus erythematosus (SLE). To investigate the possible association of the polymorphism of the TNF promoter gene ?308 and that of the LTA gene 252 with susceptibility to SLE and with phenotypic disease features in Egyptian patients. A case control study involving 100 SLE patients and 100 unrelated healthy controls. Polymerase chain reaction and restriction fragment length polymorphism methods were applied to detect genetic polymorphism. We found that TNF?308 genotype AA was significantly increase by 26 % in SLE patients compared to 10 % in the control group (p = 0.003; OR 3.16; CI 1.43–6.98) and the frequency of the A allele of the TNF promoter ?308 was significantly higher in the SLE patients (42 %) than in the control subjects (24 %) (p < 0.001; OR 2.29; 95 % CI 1.49–3.52). Genotype LTA 252 GG showed a significant increase by 22 % in SLE patients compared to 6 % in the control group (p = 0.001; OR 4.42; 95 % CI 1.71–11.44), and the frequency of the G allele of the LTA was significantly higher in the SLE patients (38 %) than in the control subjects (21 %) (p < 0.001; OR 2.31; 95 % CI 1.48–3.6). Genotype (AA+GA) of TNF was significantly associated with clinical manifestations as malar rash, arthritis, oral ulcers, serositis and systemic lupus erythematosus disease activity index. Genotype (GG+GA) of LTA was significantly associated with arthritis. These results suggest that TNF and LTA genetic polymorphisms contribute to SLE susceptibility in the Egyptian population and are associated with disease characteristics. TNF?308 and LTA+252 polymorphic markers may be used for early diagnosis of SLE and early prediction of clinical manifestations, like arthritis.     

Loss of P2Y2 Nucleotide Receptors Enhances Early Pathology in the TgCRND8 Mouse Model of Alzheimer's Disease

Neuroinflammation is a prominent feature in Alzheimer's disease (AD) and activation of the brain's innate immune system, particularly microglia, has been postulated to both retard and accelerate AD progression. Recent studies indicate that the G protein-coupled P2Y₂ nucleotide receptor (P2Y₂R) is an important regulator of innate immunity by assisting in the recruitment of monocytes to injured tissue, neutrophils to bacterial infections and eosinophils to allergen-infected lungs. In this study, we investigated the role of the P2Y₂R in progression of an AD-like phenotype in the TgCRND8 mouse model that expresses Swedish and Indiana mutations in amyloid precursor protein (APP). Our results indicate that P2Y ₂ R expression is upregulated in TgCRND8 mouse brain within 10 weeks of age and then decreases after 25 weeks of age, as compared to littermate controls expressing low levels of the P2Y ₂ R. TgCRND8 mice with homozygous P2Y ₂ R deletion survive less than 5 weeks, whereas mice with heterozygous P2Y ₂ R deletion survive for 12 weeks, a time point when TgCRND8 mice are fully viable. Heterozygous P2Y ₂ R deletion in TgCRND8 mice increased β-amyloid (Aβ) plaque load and soluble Aβ_1–42 levels in the cerebral cortex and hippocampus, decreased the expression of the microglial marker CD11b in these brain regions and caused neurological deficits within 10 weeks of age, as compared to age-matched TgCRND8 mice. These findings suggest that the P2Y₂R is important for the recruitment and activation of microglial cells in the TgCRND8 mouse brain and that the P2Y₂R may regulate neuroprotective mechanisms through microglia-mediated clearance of Aβ that when lost can accelerate the onset of an AD-like phenotype in the TgCRND8 mouse.     

Swimming exercise versus L-carnosine supplementation for Alzheimer’s dementia in rats: implication of circulating and hippocampal FNDC5/irisin

Journal of Physiology and Biochemistry - Recent studies have suggested that irisin may act as a potential neurokine. Exercise and L-carnosine supplementation showed neuroprotective effects in...     

Catharanthus terpenoid indole alkaloids: biosynthesis and regulation

Catharanthus roseus is still the only source for the powerful antitumour drugs vinblastine and vincristine. Some other pharmaceutical compounds from this plant, ajmalicine and serpentine are also of economical importance. Although C. roseus has been studied extensively and was subject of numerous publications, a full characterization of its alkaloid pathway is not yet achieved. Here we review some of the recent work done on this plant. Most of the work focussed on early steps of the pathway, particularly the discovery of the 2-C-methyl-d-erythritol 4-phosphate (MEP)-pathway leading to terpenoids. Both mevalonate and MEP pathways are utilized by plants with apparent cross-talk between them across different compartments. Many genes of the early steps in Catharanthus alkaloid pathway have been cloned and overexpressed to improve the biosynthesis. Research on the late steps in the pathway resulted in cloning of several genes. Enzymes and genes involved in indole alkaloid biosynthesis and various aspects of their localization and regulation are discussed. Much progress has been made at alkaloid regulatory level. Feeding precursors, growth regulators treatments and metabolic engineering are good tools to increase productivity of terpenoid indole alkaloids. But still our knowledge of the late steps in the Catharanthus alkaloid pathway and the genes involved is limited.     

Plasma Current Sheath Shape and Trapping Efficiency in the 2.2-kJ EAEA-PF1 Plasma Focus Device

Plasma Physics Reports - The plasma current sheath (PCS) shape and trapping efficiency η are investigated experimentally. The experiments are carried out at the 2.2-kJ Egyptian Atomic Energy...     

Health Reporting in Print Media in Lebanon: Evidence,Quality and Role in Informing Policymaking

Background

Media plays a vital role in shaping public policies and opinions through disseminating health-related information. This study aims at exploring the role of media in informing health policies in Lebanon, identifying the factors influencing health reporting and investigating the role of evidence in health journalism and the quality of health reporting. It also identifies strategies to enhance the use of evidence in health journalism and improve the quality of health reporting.

Methods

Media analysis was conducted to assess the way media reports on health-related issues and the quality of reporting using a quality assessment tool. Semi-structured interviews were also conducted with 27 journalists, researchers and policymakers to explore their perception on the role of media in health policymaking and the factors influencing health reporting. In addition, a validation workshop was conducted.

Results

Out of 1,279 health-related news articles identified, 318 articles used certain type of evidence to report health issues 39.8% of which relied on experts’ opinions as their source of evidence while only 5.9% referenced peer-reviewed research studies. The quality of health reporting was judged to be low based on a quality assessment tool consisting of a set of ten criteria. Journalists raised concerns about issues impeding them from referring to evidence. Journalists also reported difficulties with the investigative health journalism. Policymakers and researchers viewed media as an important tool for evidence-informed health policies, however, serious concerns were voiced in terms of the current practice and capacities.

Conclusion

Our study provides a structured reflection on the role of media and the factors that influence health reporting including context-specific strategies that would enhance the quality and promote the use of evidence in health reporting. In the light of the political changes in many Middle Eastern countries, findings from this study can contribute to redefining the role of media in strengthening health systems.     

Pluripotency Gene Expression and Growth Control in Cultures of Peripheral Blood Monocytes during Their Conversion into Programmable Cells of Monocytic Origin (PCMO): Evidence for a Regulatory Role of Autocrine Activin and TGF-β

Previous studies have shown that peripheral blood monocytes can be converted in vitro to a stem cell-like cell termed PCMO as evidenced by the re-expression of pluripotency-associated genes, transient proliferation, and the ability to adopt the phenotype of hepatocytes and insulin-producing cells upon tissue-specific differentiation. However, the regulatory interactions between cultured cells governing pluripotency and mitotic activity have remained elusive. Here we asked whether activin(s) and TGF-β(s), are involved in PCMO generation. De novo proliferation of PCMO was higher under adherent vs. suspended culture conditions as revealed by the appearance of a subset of Ki67-positive monocytes and correlated with down-regulation of p21^WAF1 beyond day 2 of culture. Realtime-PCR analysis showed that PCMO express ActRIIA, ALK4, TβRII, ALK5 as well as TGF-β1 and the β_A subunit of activin. Interestingly, expression of ActRIIA and ALK4, and activin A levels in the culture supernatants increased until day 4 of culture, while levels of total and active TGF-β1 strongly declined. PCMO responded to both growth factors in an autocrine fashion with intracellular signaling as evidenced by a rise in the levels of phospho-Smad2 and a drop in those of phospho-Smad3. Stimulation of PCMO with recombinant activins (A, B, AB) and TGF-β1 induced phosphorylation of Smad2 but not Smad3. Inhibition of autocrine activin signaling by either SB431542 or follistatin reduced both Smad2 activation and Oct4A/Nanog upregulation. Inhibition of autocrine TGF-β signaling by either SB431542 or anti-TGF-β antibody reduced Smad3 activation and strongly increased the number of Ki67-positive cells. Furthermore, anti-TGF-β antibody moderately enhanced Oct4A/Nanog expression. Our data show that during PCMO generation pluripotency marker expression is controlled positively by activin/Smad2 and negatively by TGF-β/Smad3 signaling, while relief from growth inhibition is primarily the result of reduced TGF-β/Smad3, and to a lesser extent, activin/Smad2 signaling.