Targeted Delivery of Amoxicillin to C. trachomatis by the Transferrin Iron Acquisition Pathway

Weak intracellular penetration of antibiotics makes some infections difficult to treat. The Trojan horse strategy for targeted drug delivery is among the interesting routes being explored to overcome this therapeutic difficulty. Chlamydia trachomatis, as an obligate intracellular human pathogen, is responsible for both trachoma and sexually transmitted diseases. Chlamydia develops in a vacuole and is therefore protected by four membranes (plasma membrane, bacterial inclusion membrane, and bacterial membranes). In this work, the iron-transport protein, human serum-transferrin, was used as a Trojan horse for antibiotic delivery into the bacterial vacuole. Amoxicillin was grafted onto transferrin. The transferrin-amoxicillin construct was characterized by mass spectrometry and absorption spectroscopy. Its affinity for transferrin receptor 1, determined by fluorescence emission titration [K_affTf-amox = (1.3 ± 1.0) x 10⁸], is very close to that of transferrin [4.3 x 10⁸]. Transmission electron and confocal microscopies showed a co-localization of transferrin with the bacteria in the vacuole and were also used to evaluate the antibiotic capability of the construct. It is significantly more effective than amoxicillin alone. These promising results demonstrate targeted delivery of amoxicillin to suppress Chlamydia and are of interest for Chlamydiaceae and maybe other intracellular bacteria therapies.     

Host-parasite relationship 2- cholinesterase activity of the larvae of the rice mothCorcyra cephalonica [Lep.: Pyralidae] parasitized byBracon hebetor [Hym.: Braconidae]

The parasitic waspBracon hebetor Say paralyses its host, the larvae of the rice mothCorcyra cephalonica Staint, before oviposition. The effect of injected venom on the activity of cholinesterase was studied. The ChE activity of the paralysed larvae showed a partial inhibition of about 40% than that of the normal larvae. Such inhibition in ChE activity interferes with the synaptic transmission and/or may result in neuromuscular block causing the observed paralysis.     

Hormonal control of diapause in the tick Argas arboreus

During the mid-diapause period of the female tick Argas arboreus, nerve ganglion (G) extract (GE) from nondiapause (ND) females injected into diapause (D) female haemocoel after feeding, but not before feeding, terminated diapause in 50% of the ticks. ND haemolymph (H) failed to terminate diapause. Reciprocal injections of D GE, and H induced diapause in most ND females. During the late diapause season, ND GE, and H terminated diapause in D females and reciprocal injections of D GE, and H failed to induce diapause in ND females. The results suggest that in A. arboreus the facultative diapause results from gonadotropic hormone (GTH) deficiency in the presence of a diapause inducing factor (DIF). We suggest that the DIF is formed under the influence of short photoperiod in unfed females. The DIF interferes with normal release of the GTH formed in ganglion after feeding and also with the effect of GTH in the H by direct inhibition and/or by preventing the target organs (ovary and/or gut cells) from responding to GTH. The DIF is degraded slowly during short photoperiod and rapidly during long photoperiod.     

Structure-activity relationships in platelet-activating factor. Part 14: synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 activity

As HIV-associated dementia prevalence has risen with the lifespan of HIV-infected individuals, there is an important need for antiretroviral and anti-inflammatory drugs targeting the central nervous system. Platelet-activating factor, a mediator of inflammation, is an HIV-induced neurotoxin secreted in the infected brain. In this work, we developed piperazine derivatives bearing a heterocyclic moiety as PAF-antagonists and HIV-1 replication inhibitors with micromolar potency.     

Acute negative inotropic effects of homocysteine are mediated via the endothelium

Previous studies have shown that chronic hyperhomocysteinemia is associated with an adverse cardiac remodeling and heart failure. This study, which utilized coronary-perfused hearts and superfused papillary muscle, was designed to determine whether homocysteine acts acutely to alter cardiac contractile function. Left ventricular developed pressure was used as a measure of systolic function in the Langendorff-perfused heart, whereas isometric developed tension was used in papillary muscle. All preparations were bathed in physiological buffer and paced electrically. Initial results showed that homocysteine elicits a relatively rapid onset (maximum effect observed within 5 min), concentration-dependent (10-300 microM), and moderate negative inotropic action (maximum decrease in tension was approximately 15% of control values) in Langendorff-perfused hearts but not in papillary muscle. In contrast, effluent from homocysteine-treated hearts decreased contractility in papillary muscle, and all inotropic actions were largely eliminated when brief Triton X-100 treatment was utilized to inactivate the coronary endothelium in the intact heart. The homocysteine-induced decrease in contractile function was not antagonized by N(omega)-nitro-l-arginine, a nitric oxide synthase inhibitor, or the cyclooxygenase inhibitor indomethacin. Thus data suggest that pathophysiological concentrations of homocysteine elicit an acute negative inotropic effect on ventricular myocardium that is mediated by a coronary endothelium-derived agent other than nitric oxide or products of cyclooxygenase. Future studies are required to elucidate the mechanism by which homocysteine acts to elicit the release of the proposed endothelial mediator, the identity of the proposed paracrine agent, and the mechanism of its negative inotropic action.     

Stereodefined and polyunsaturated inhibitors of histone deacetylase based on (2E,4E)-5-arylpenta-2,4-dienoic acid hydroxyamides

Syntheses of (2E,4E)-5-arylpenta-2,4-dienoic acid hydroxyamides are described, some of which are potent inhibitors of histone deacetylase, a double bond conferring more than a 10-fold increase in potency compared with the triple bond analogue oxamflatin. Variation of substituents on the aromatic ring has a marked effect on potency, in vitro IC(50) values down to 50 nM being obtained.     

Role of Challenger pesticide and plant extracts on some physiological parameters of the cotton leafworm,Spodoptera littoralis (Boisd.)

Fourth instar larvae of cotton leafworm, Spodoptera littoralis (Boisd.), fed on castor bean leaves treated with sub-lethal concentrations of both alcohol and hexane extracts of Egyptian conyza and Challenger 36% SC insecticide as well to study their effects on mortality, food consumption and utilisation of food. The tested insecticides exhibited relatively high mortality in alcoholic extract of Egyptian conyza (5.0% concentration) followed by Challenger (1.0% concentration). Results showed a slight reduction in the consumption index for larvae treated with both alcoholic extract and Challenger at low concentrations, while hexane extract (5%) recorded significant increase. The approximate digestibility (AD) was reduced in all treatments of alcoholic extract and the relative growth rate insignificantly decreased at 5% concentration, whereas AD increased for larvae fed on Challenger 0.25% concentration. The lower concentration of alcoholic extract of conyza and all treatments of Challenger pesticides induced insignificant decrease in the efficiency of conversion of the ingested food, while hexane extract exhibited insignificant increase. Challenger at all tested concentrations achieved insignificant decrease in the efficiency of the conversion of digested food with respect to the control.     

Macrophage inflammatory protein (MIP)1α and MIP1β differentially regulate release of inflammatory cytokines and generation of tumoricidal monocytes in malignancy

The C–C chemokines, macrophage inflammatory protein (MIP)1α and MIP1β are potent chemoattractants for the monocytes, which form an important component of the stroma of tumor tissue and may regulate tumor growth and associated inflammation. We examined the role of MIP1α and MIP1β in inducing the release of inflammatory cytokines and the generation of tumoricidal monocytes from the peripheral blood monocytes (PBM) of healthy women and patients with carcinoma of breast (CaBr). Interleukin-1 (IL-1) and tumor necrosis factor (TNF) α release by the PBM was markedly stimulated by MIP1α in CaBr patients, but only marginally so in healthy women. In contrast, MIP1β stimulated the release of these cytokines by the PBM of healthy women, but failed to do so in CaBr patients. MIP1α, but not MIP1β, synergized with LPS in inducing the release of IL-1 from the PBM of both healthy women and CaBr patients. Both MIP1α and MIP1β augmented respiratory bursts in PBM and generated tumoricidal PBM that killed T24 cells, MIP1α being more effective in CaBr patients and MIP1β in healthy women. IFN-γ co-stimulated and IL-4 suppressed MIP1α and β-induced cytotoxicity in PBM. The synergy of IFN-γ was more marked with MIP1α than with MIP1β. The differential effects of MIP1α and MIP1β on the PBM of healthy women and CaBr patients co-related with the levels of expression of CCR1 and CCR5 in these monocytes. The expression of CCR5 was higher than that of CCR1 in the PBM of healthy women and the PBM of the CaBr patients showed overexpression of CCR1 and downregulation of CCR5.     

Fasciola hepatica and Schistosoma mansoni: identification of common proteins by comparative proteomic analysis

It is not unusual to find common molecules among parasites of different species, genera, or phyla. When those molecules are antigenic, they may be used for developing drugs or vaccines that simultaneously target different species or genera of parasite. In the present study, we used a proteomic-based approach to identify proteins that are common to adult Fasciola hepatica and Schistosoma mansoni. Whole-worm extracts from each parasite were separated by 2-dimensional electrophoresis (2-DE), and digital images of both proteomes were superimposed using imaging software to identify proteins with identical isoelectric points and molecular weights. Protein identities were determined by mass spectrometry. Imaging and immunoblot analyses identified 28 immunoreactive proteins that are common to both parasites. Among these molecules are antioxidant proteins (thioredoxin and glutathione-S-transferase), glycolytic enzymes (glyceraldehyde 6-phosphate dehydrogenase and enolase), proteolytic enzymes (cathepsin-L and -D), inhibitors (Kunitz-type, Stefin-1), proteins with chaperone activity (heat shock protein 70 and fatty acid-binding protein), and structural proteins (calcium-binding protein, actin, and myosin). Some of the identified proteins could be used to develop drugs and vaccines against fascioliasis and schistosomiasis.