Interaction of Opiates with Opioid Binding Sites in the Bovine Adrenal Medulla: I. Interaction with δ and μ Sites

In the present study we examined the interaction of opiates with the delta and mu opioid binding sites in the bovine adrenal medulla. [3H][D-Ala2, D-Leu5]-enkephalin ( [3H]DADLE) in the presence of saturating concentrations of morphiceptin was used to analyze delta site interactions, whereas either [3H]DADLE in the presence of saturation concentrations of [D-Ser2, Leu5]-enkephalin-Thr6 (DSLET) or [3H][D-Ala2, Me-Phe4, Gly5-ol]-enkephalin ( [3H]DAGO) was used for the determination of mu sites. Both binding sites were found to interact stereoselectively with opiates. The binding was affected differentially by proteolytic enzymes (trypsin, alpha-chymotrypsin, pepsin), N-ethylmaleimide, and A2-phospholipase. Kinetic and equilibrium binding studies revealed that in each case radiolabeled opiates interact with one class of binding sites, following simple second-order bimolecular kinetics. Competition for binding by opiates and opioid peptides confirmed the delta and mu selectivity of these sites. Monovalent (Na+, Li+, K+) and divalent (Mg2+, Mn2+, Ca2+) ions interacted differentially with these two binding sites: In general, monovalent cations affected preferentially the apparent number of binding sites, whereas divalent ions modified the equilibrium dissociation constant. Furthermore, positive or negative cooperativity and an apparent heterogeneity of binding sites were detected under some ionic conditions.     

Direct interaction of tricyclic antidepressants with opiate binding sites in the bovine adrenal medulla

This note reports the interaction of three currently used tricyclic antidepressant drugs (clomipramine, imipramine and amitriptyline) with delta, mu and kappa opioid binding sites in the bovine adrenal medulla. Clomipramine was the only drug interacting with delta and mu sites. On the contrary, all three drugs showed a significant interactions with subtypes of the kappa binding site. Clomipramine was the most active on the kappa 2 and kappa 3 subtypes while amitriptyline showed the highest interaction with the kappa 1 subtype. On the contrary the tricyclic cyproheptadine did not present any interaction with opioid binding sites in our system. This interaction between tricyclic antidepressants and opioid binding sites might be the origin of their analgesic action.     

Therapeutic Potential of Clove Essential Oil in Diabetes: Modulation of Pro-Inflammatory Mediators,Oxidative Stress and Metabolic Enzyme Activities

Type 1 diabetes is characterized by insulin deficiency due to the destruction of pancreatic β cells, leading to hyperglycemia, which in turn induces vascular complications. In the current study, we investigated the effect of intraperitoneal administration of clove essential oil (CEO: 20 mg/kg body weight) on certain oxidative stress and glucose metabolism enzymes, as well as the expression of proinflammatory mediators. Administration of CEO to diabetic rats showed a significant decline in blood glucose levels, total cholesterol, and xanthine oxidase, compared to the streptozotocin group. Furthermore, these treated rats elicited a notable attenuation in the levels of lipid peroxides, and thiols groups in both liver and brain tissues. The activities of antioxidant and metabolic enzymes were reverted to normality in diabetic upon CEO administration. In addition to its protective effects on red blood cell hemolysis, CEO is a potent α-amylase inhibitor with an IC₅₀=298.0±2.75 μg/mL. Also, treatment of diabetic rats with CEO significantly reduced the iNOS expression in the spleen. Our data showed that CEO has potential beneficial effects on diabetes, which can possibly prevent the pathogenesis of diabetic micro- and macrovascular complications.     

Chemical Composition and Insecticidal Activity against Tribolium Castaneum of Thapsia garganica L. Seed Essential Oil

Due to the several side effects of synthetic pesticides, including environmental pollution, threats to human health, and the development of pest resistance to insecticides, the use of alternative healthy, available and efficient agents in pest management strategies is necessary. Recently, the use of essential oil obtained from aromatic plants has shown significant potential for insect pest management. For this reason, the essential oil isolated from seeds of Thapsia garganica L. was investigated for the first time for its chemical profile, and its toxicity and repellency effects against Tribolium castaneum adults. Qualitative and quantitative analyses of the chemical composition by gas chromatography coupled to mass spectrometry (GC/MS) revealed the presence of 18 organic volatiles representing 96.8 % of the total constituents. The main compounds were 1,4-dimethylazulene (51.3 %) followed by methyl palmitate (8.2 %), methyl linoleate (6.2 %) and costol (5.1 %). Concerning the repellent effect, results revealed that SEO (Seed Essential Oil) was very repellent towards T. castaneum adults, with 100 % repellency after 2 h of exposure. Furthermore, the essential oil exhibited remarkable contact toxicity against T. castaneum (93.3 % of mortality) at the concentration of 10 % (v/v). The median lethal dose (LD₅₀) of the topical application of the seed essential oil was 4.4 %. These encouraging outcomes suggested that the essential oil from T. garganica seeds could be considered a potent natural alternative to residual persistent and toxic insecticides.     

The complex translocation (9;14;14) involving IGH and CEBPE genes suggests a new subgroup in B-lineage acute lymphoblastic leukemia

Many subtypes of acute lymphoblastic leukemia (ALL) are associated with specific chromosomal rearrangements. The complex translocation t(9;14;14), a variant of the translocation (14;14)(q11;q32), is a rare but recurrent chromosomal abnormality involving the immunoglobulin heavy-chain (IGH) and CCAAT enhancer-binding protein (CEBPE) genes in B-lineage ALL (B-ALL) and may represent a new B-ALL subgroup. We report here the case of a 5-year-old girl with B-ALL, positive for CD19, CD38 and HLA-DR. A direct technique and G-banding were used for chromosomal analysis and fluorescentin situ hybridization (FISH) with BAC probes was used to investigate a possible rearrangement of the IGH andCEBPE genes. The karyotype exhibit the chromosomal aberration 46,XX,del(9)(p21),t(14;14)(q11;q32). FISH with dual-color break-apartIGH-specific and CEPBE-specific bacterial artificial chromosome (BAC) probes showed a complex t(9;14;14) associated with a deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A) and paired box gene 5 (PAX5) at 9p21-13 and duplication of the fusion gene IGH-CEBPE.     

Achievements and challenges of lymphatic filariasis elimination in Sierra Leone

BackgroundLymphatic filariasis (LF) is targeted for elimination in Sierra Leone. Epidemiological coverage of mass drug administration (MDA) with ivermectin and albendazole had been reported >65% in all 12 districts annually. Eight districts qualified to implement transmission assessment survey (TAS) in 2013 but were deferred until 2017 due to the Ebola outbreak (2014–2016). In 2017, four districts qualified for conducting a repeat pre-TAS after completing three more rounds of MDA and the final two districts were also eligible to implement a pre-TAS.Methodology/Principal findingsFor TAS, eight districts were surveyed as four evaluation units (EU). A school-based survey was conducted in children aged 6–7 years from 30 clusters per EU. For pre-TAS, one sentinel and one spot check site per district (with 2 spot check sites in Bombali) were selected and 300–350 persons aged 5 years and above were selected. For both surveys, finger prick blood samples were tested using the Filariasis Test Strips (FTS).For TAS, 7,143 children aged 6–7 years were surveyed across four EUs, and positives were found in three EUs, all below the critical cut-off value for each EU. For the repeat pre-TAS/pre-TAS, 3,994 persons over five years of age were surveyed. The Western Area Urban had FTS prevalence of 0.7% in two sites and qualified for TAS, while other five districts had sites with antigenemia prevalence >2%: 9.1–25.9% in Bombali, 7.5–19.4% in Koinadugu, 6.1–2.9% in Kailahun, 1.3–2.3% in Kenema and 1.7% - 3.7% in Western Area Rural.Conclusions/SignificanceEight districts in Sierra Leone have successfully passed TAS1 and stopped MDA, with one more district qualified for conducting TAS1, a significant progress towards LF elimination. However, great challenges exist in eliminating LF from the whole country with repeated failure of pre-TAS in border districts. Effort needs to be intensified to achieve LF elimination.     

Impact of Three Rounds of Mass Drug Administration on Lymphatic Filariasis in Areas Previously Treated for Onchocerciasis in Sierra Leone

Background

1974–2005 studies across Sierra Leone showed onchocerciasis endemicity in 12 of 14 health districts (HDs) and baseline studies 2005–2008 showed lymphatic filariasis (LF) endemicity in all 14 HDs. Three integrated annual mass drug administration (MDA) were conducted in the 12 co-endemic districts 2008–2010 with good geographic, programme and drug coverage. Midterm assessment was conducted 2011 to determine impact of these MDAs on LF in these districts.

Methodology/Principal Findings

The mf prevalence and intensity in the 12 districts were determined using the thick blood film method and results compared with baseline data from 2007–2008. Overall mf prevalence fell from 2.6% (95% CI: 2.3%–3.0%) to 0.3% (95% CI: 0.19%–0.47%), a decrease of 88.5% (p = 0.000); prevalence was 0.0% (100.0% decrease) in four districts: Bo, Moyamba, Kenema and Kono (p = 0.001, 0.025, 0.085 and 0.000 respectively); and seven districts had reductions in mf prevalence of between 70.0% and 95.0% (p = 0.000, 0.060, 0.001, 0.014, 0.000, 0.000 and 0.002 for Bombali, Bonthe, Kailahun, Kambia, Koinadugu, Port Loko and Tonkolili districts respectively). Pujehun had baseline mf prevalence of 0.0%, which was maintained. Only Bombali still had an mf prevalence ≥1.0% (1.58%, 95% CI: 0.80%–3.09%)), and this is the district that had the highest baseline mf prevalence: 6.9% (95% CI: 5.3%–8.8%). Overall arithmetic mean mf density after three MDAs was 17.59 mf/ml (95% CI: 15.64 mf/ml–19.55 mf/ml) among mf positive individuals (65.4% decrease from baseline of 50.9 mf/ml (95% CI: 40.25 mf/ml–61.62 mf/ml; p = 0.001) and 0.05 mf/ml (95% CI: 0.03 mf/ml–0.08 mf/ml) for the entire population examined (96.2% decrease from baseline of 1.32 mf/ml (95% CI: 1.00 mf/ml–1.65 mf/ml; p = 0.000)).

Conclusions/Significance

The results show that mf prevalence decreased to <1.0% in all but one of the 12 districts after three MDAs. Overall mf density reduced by 65.0% among mf-positive individuals, and 95.8% for the entire population.