Caspase Dependent Programmed Cell Death in Developing Embryos: A Potential Target for Therapeutic Intervention against Pathogenic Nematodes

Pathogenic nematodes currently infect billions of people around the world and pose serious challenges to the economic welfare and public health in most developing countries. At present, limitations of existing therapies warrant identification of new anti-parasitic drugs/drug targets to effectively treat and control neglected tropical diseases [NTD] caused by nematode pathogens. The current gold standard for measuring/screening drug effectiveness against most helminth parasites is in-vitro assessment of motility of parasites/larvae and larval development assays which fails to provide any conclusive idea about the precise mechanism of death of parasitic worms or their larval stages. Given the huge load of parasites or their larval stages in an infected host, a compound which shows promise in in-vitro/motility screening assays but induces necrotic death in parasites/larvae will be of limited use, as it may elicit severe inflammatory response in infected hosts. In this context, the present study, which demonstrates induction of apoptotic death in developing embryos of a pathogenic nematode as a potential drug target for the first time, and provides scope for high throughput screening of pharmacological agents for their apoptogenicity against nematode embryos, is a step forward to develop novel anti-parasitic measures to challenge NTD caused by nematode pathogens

The Chemotherapeutic Drug 5-Fluorouracil Promotes PKR-Mediated Apoptosis in a p53- Independent Manner in Colon and Breast Cancer Cells

The chemotherapeutic drug 5-FU is widely used in the treatment of a range of cancers, but resistance to the drug remains a major clinical problem. Since defects in the mediators of apoptosis may account for chemo-resistance, the identification of new targets involved in 5-FU-induced apoptosis is of main clinical interest. We have identified the ds-RNA-dependent protein kinase (PKR) as a key molecular target of 5-FU involved in apoptosis induction in human colon and breast cancer cell lines. PKR distribution and activation, apoptosis induction and cytotoxic effects were analyzed during 5-FU and 5-FU/IFNα treatment in several colon and breast cancer cell lines with different p53 status. PKR protein was activated by 5-FU treatment in a p53-independent manner, inducing phosphorylation of the protein synthesis translation initiation factor eIF-2α and cell death by apoptosis. Furthermore, PKR interference promoted a decreased response to 5-FU treatment and those cells were not affected by the synergistic antitumor activity of 5-FU/IFNα combination. These results, taken together, provide evidence that PKR is a key molecular target of 5-FU with potential relevance in the clinical use of this drug

Induction of GADD34 Is Necessary for dsRNA-Dependent Interferon-β Production and Participates in the Control of Chikungunya Virus Infection

Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR) phosphorylates translation initiation factor 2-alpha (eIF2α) and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a), an important component of the unfolded protein response (UPR), is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs) in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection

Analysis of Effects of Meteorological Factors on Dengue Incidence in Sri Lanka Using Time Series Data

In tropical and subtropical regions of eastern and South-eastern Asia, dengue fever (DF) and dengue hemorrhagic fever (DHF) outbreaks occur frequently. Previous studies indicate an association between meteorological variables and dengue incidence using time series analyses. The impacts of meteorological changes can affect dengue outbreak. However, difficulties in collecting detailed time series data in developing countries have led to common use of monthly data in most previous studies. In addition, time series analyses are often limited to one area because of the difficulty in collecting meteorological and dengue incidence data in multiple areas. To gain better understanding, we examined the effects of meteorological factors on dengue incidence in three geographically distinct areas (Ratnapura, Colombo, and Anuradhapura) of Sri Lanka by time series analysis of weekly data. The weekly average maximum temperature and total rainfall and the total number of dengue cases from 2005 to 2011 (7 years) were used as time series data in this study. Subsequently, time series analyses were performed on the basis of ordinary least squares regression analysis followed by the vector autoregressive model (VAR). In conclusion, weekly average maximum temperatures and the weekly total rainfall did not significantly affect dengue incidence in three geographically different areas of Sri Lanka. However, the weekly total rainfall slightly influenced dengue incidence in the cities of Colombo and Anuradhapura