Syntheses and antiproliferative evaluation of oxyphenisatin derivatives

Syntheses and structure-antiproliferative relationship for oxyphenisatin analogues are described. The cell proliferation data showed that the presence of substituents (especially F, Cl, Me, CF(3), and OMe) in the 6- and 7-position of oxyphenisatin markedly enhanced the potency in the MDA-468 cell line without affecting the MDA-231 cell line. The best compounds from this series showed low nanomolar antiproliferative activity towards the MDA-468 cell line and a 1000-fold selectivity over the MDA-231 cell line.     

Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis

Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy.     

Influenza virus A (H5N1): a pandemic risk?

Influenza A subtype H5N1 has represented a growing alarm since its recent identification in Asia. Previously thought to infect only wild birds and poultry, H5N1 has now infected humans, cats, pigs and other mammals in an ongoing outbreak, often with a fatal outcome. In order to evaluate the risk factors for human infection with influenza virus H5N1, here we summarize 53 case patients confirmed with H5N1 infection during 2006. The review also compares the mortality rate among human cases from late 2003 until 15 June 2006 in different countries. Neither how these viruses are transmitted to humans nor the most effective way to reduce the risk for infection is fully understood. The association between household contact with diseased poultry in human infection has been demonstrated. This association could possibly operate by 2 mechanisms. First, transmission may be by inhalation or conjunctival deposition of large infectious droplets which may travel only in short distances. Second, having infected poultry in the home and preparation of infected poultry for consumption may result in exposure to higher virus concentrations than other types of exposure. There is so far no significant evidence for repeated human to human transmission, yet some cases of human to human transmission among the family relatives in Indonesia, Azerbaijan, Iraq and Turkey have been described. Recent outbreaks of highly pathogenic avian influenza A virus (H5N1 subtype) infections in poultry and humans (through direct contact with infected birds) have raised concerns that a new influenza pandemic might occur in the near future.     

Considerations for community engagement when conducting clinical trials during infectious disease emergencies in West Africa

Community engagement in research, including public health related research, is acknowledged as an ethical imperative. While medical care and public health action take priority over research during infectious disease outbreaks, research is still required in order to learn from epidemic responses. The World Health Organisation developed a guide for community engagement during infectious disease epidemics called the Good Participatory Practice for Trials of Emerging (and Re‐emerging) Pathogens that are Likely to Cause Severe Outbreaks in the Near Future and for which Few or No Medical Counter‐Measures Exist (GPP‐EP). This paper identified priorities for community engagement for research conducted during infectious disease outbreaks drawing on discussions held with a purposive sample of bioethicists, social scientists, researchers, policy makers and laypersons who work with ethics committees in West Africa. These perspectives were considered in the light of the GPP‐EP, which adds further depth and dimension to discussions on community engagement frameworks. It concludes that there is no presumptive justification for the exclusion of communities in the design, implementation and monitoring of clinical trials conducted during an infectious disease outbreak. Engagement that facilitates collaboration rather than partnership between researchers and the community during epidemics is acceptable.     

Responses of rice (Oryza sativa L.) genotypes to different levels of submergence

The study aims at identifying some submergence-tolerant rice genotypes through morphological and molecular characterization and their genetic variability analysis. Ten rice genotypes including two submergence-tolerant checks, two susceptible varieties and six advanced lines were evaluated for submergence tolerance in the laboratory and in the field during January–December 2015. The experiment was conducted in the field following randomized complete block design in a two-factor arrangement using five replications. Ten characters, viz. days to flowering, plant height, tiller number plant^?1, effective tiller plant^?1, and yield plant^?1 etc. were studied for four treatments. A significant genotype × environment interaction was observed for all traits studied in this experiment. The yield was reduced for all genotypes at a different level of submergence stress compared to control. Binadhan-11, Binadhan-12, RC 249 and RC 251 showed tolerance, whereas RC 192, RC 193 and RC 225 showed moderate tolerance in submerged condition. The phenotypic coefficient of variance (PCV) was higher than the genotypic coefficient of variance (GCV) in all the studies traits. High heritability (75–97%) was found for all traits. High heritability along with high genetic advance was found for days to flowering (45.55) and plant height (40.05). Molecular characterization of the used genotypes was done with three SSR markers viz. RM 24, and submergence specific SC3 and SUB1. SC3 was found reliable for detection of submergence tolerant genotypes due to the highest gene diversity (0.840) compared to others. The banding pattern of the submergence specific markers SC3 and SUB1 identified in Binadhan-11, Binadhan-12, RC 192, RC 193, RC 225, RC 227, RC 249, and RC 251, which possess the SUB1 gene. Finally, clustering also separates the tolerant genotypes from the susceptible by dividing them into different clusters. The identified genotypes might be useful for the breeding programme for the development of submergence tolerant as well as resistant rice variety in Bangladesh.     

Role of IRAK-M in Alcohol Induced Liver Injury

Increasing evidence suggests that innate immunity plays an important role in alcohol-induced liver injury and most studies have focused on positive regulation of innate immunity. The main objective of this study was to investigate the negative regulator of innate immunity, IL-1/Toll-like receptor (TLR) signaling pathways and interleukin receptor-associated kinase-M (IRAK-M) in alcoholic liver injury. We established an alcohol-induced liver injury model using wild type and IRAK-M deficient B6 mice and investigated the possible mechanisms. We found that in the absence of IRAK-M, liver damage by alcohol was worse with higher alanine transaminase (ALT), more immune cell infiltration and increased numbers of IFNγ producing cells. We also found enhanced phagocytic activity in CD68⁺ cells. Moreover, our results revealed altered gut bacteria after alcohol consumption and this was more striking in the absence of IRAK-M. Our study provides evidence that IRAK-M plays an important role in alcohol-induced liver injury and IRAK-M negatively regulates the innate and possibly the adaptive immune response in the liver reacting to acute insult by alcohol. In the absence of IRAK-M, the hosts developed worse liver injury, enhanced gut permeability and altered gut microbiota.