Mitochondrial dysfunction from malathion and chlorpyrifos exposure is associated with degeneration of GABAergic neurons in Caenorhabditis elegans

Toxicity resulting from off-target effects, beyond acetylcholine esterase inhibition, for the commonly used organophosphate (OP) insecticides chlorpyrifos (CPS) and malathion (MA) was investigated using Saccharomyces cerevisiae and Caenorhabditis elegans model systems. Mitochondrial damage and dysfunction were observed in yeast following exposure to CPS and MA, suggesting this organelle is a major target. In the C. elegans model, the mitochondrial unfolded protein response pathway showed the most robust induction from CPS and MA treatment among stress responses examined. GABAergic neurodegeneration was observed with CPS and MA exposure. Impaired movement observed in C. elegans exposed to CPS and MA may be the result of motor neuron damage. Our analysis suggests that stress from CPS and MA results in mitochondrial dysfunction, with GABAergic neurons sensitized to these effects. These findings may aid in the understanding of toxicity from CPS and MA from high concentration exposure leading to insecticide poisoning.     

Identification of B cell epitopes of Per a 5 allergen using bioinformatic approach

BackgroundImmune epitopes of allergens are pivotal for development of novel diagnostic and therapeutic modalities. Present study aims to identify antigenic determinants of Per a 5, a clinically relevant cross reactive cockroach allergen.MethodsThe three dimensional structure of Per a 5 was modelled using Modeller 9v11 software. A combination of sequence and structure based computational tools were employed for predicting B cell epitopes. Epitopes were synthesized and immunoreactivity was assessed by ELISA using cockroach hypersensitive patient’s sera. Cross-reactivity potential of predicted epitopes was assessed with SDAP and ConSurf and validated by IgE ELISA with fungal and mite hypersensitive patient’s sera.ResultsPer a 5 structure exhibited good quality factor in ERRAT and high stereochemical stability. In silico analysis revealed six B cell epitopes (BC-P1 to P6). BC-P3 demonstrated significant IgE binding followed by BC-P2 and BC-P1 with cockroach hypersensitive patient’s sera. Per a 5 epitopes demonstrate considerable similarity with broad spectrum of allergens from fungal, mites, helminths, fruits and nuts. Analysis of PD values indicate BC-P4 to be well conserved among dust mite and helminth GSTs (8.89, 10.63 and 10.69 with D. pteronyssinus, W. bancrofti and F. hepatica respectively). ConSurf analysis of Per a 5 revealed specific enrichment of evolutionarily similar amino acid residues in BC-P2 (with fungal and mite GSTs) and BC-P4 (with mite and helminth GSTs). Further, IgE binding analysis of epitopes demonstrate BC-P2, BC-P3 and BC-P5 as high IgE binders in fungal hypersensitive sera while BC-P1, BC-P2, BC-P4 and BC-P5 demonstrated significant IgE binding with mite hypersensitive sera.ConclusionsAmong the predicted epitopes, BC-P3 demonstrates maximal IgE binding ability. Computational analysis suggests strong evolutionary conservation and cross reactive potential of BC-P4 with allergens in dust mite and helminths. ELISA highlights predictive potential of analysing evolutionarily conserved residues for uncovering potentially cross reactive antigenic determinants.General significanceImmune epitopes of Per a 5 were identified for aiding molecular diagnosis and potential cross reactivity.     

Contradictory to its effects on thrombin,C1-inhibitor reduces plasmin generation in the presence of thrombomodulin

Journal of Thrombosis and Thrombolysis - C1-inhibitor (C1INH) was shown to enhance thrombin generation (TG) in the presence of thrombomodulin (TM) by reducing production of activated protein C....     

Association between serum 25-hydroxyvitamin D concentration and severity of first-diagnosed bullous pemphigoid in older adults

BackgroundHigher vitamin D status has been associated with symptom improvement and decreased risk of various autoimmune disorders. Our objective was to determine whether higher serum 25-hydroxyvitamin D (25OHD) concentration correlated with less severe first-diagnosed bullous pemphigoid (BP) in older inpatients.MethodsThis cross-sectional study was performed from November 2012 to February 2014 among 30 consecutive older inpatients (21 women; mean ± SD, 83 ± 7 years; all Caucasian) with a de novo diagnosis of active BP recruited in the Department of Dermatology of Angers University Hospital, France. The severity of BP was graded clinically on the basis of i) the number of bullae during the first three days of hospitalization (grade 0–4, worse), and ii) the extent of the lesions (grade 0–5, worse).ResultsSixteen participants had ≤ 5 bullae at the time of diagnosis, 8 had 6–20 bullae, 3 had 20–50 bullae, and 3 had >50 bullae. The lesions were spread over 5 cutaneous areas in 5 participants (17%). The median 25OHD concentration was 23 [IQR, 16–42] nmol/L. Serum 25OHD concentration was inversely correlated with the bullae grade (ρ = − 0.38, p = 0.04) and the lesion extension grade (ρ = − 0.50, p = 0.005).ConclusionsHigher serum 25OHD concentration correlated with less severe BP prior to initiation of treatment among our sample of older inpatients. This result suggests that vitamin D may be involved in the pathophysiology of BP and could serve as prognostic biomarker of BP.     

Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.