piperidines and Schistosomiasis-mansoni

Hepatic Stellate Cells (HSCs) play a crucial role in pathogenesis of liver inflammation and fibrosis. During chronic liver injury, HSCs lose vitamin A and transform into myofibroblastic cells. In schistosomal granulomas, these activated HSCs are called GR-HSCs. Schistosomal-triggered hepatic fibrogenesis has TGF-β as the most potent fibrogenic stimulus, that also controls gene expression of the angiogenic molecule VEGF in HSCs. COX-dependent production of prostaglandins (PGs) also play role in angiogenic processes. Besides angiogenic roles, prostanoids control immunomodulation of Schistosoma mansoni infection. Specifically, schistosoma-derived PGD2 has emerged as a key parasite regulator of immune defense evasion, while no role is still established to host PGD2. Therefore, the aim of this work is to investigate the ability of GR-HSCs to synthesize COX-derived PGD2 and a potential role of this prostanoid in VEGF production by GR-HSCs in vitro. Here, we confirmed that GR-HSCs express COX-2, which displayed perinuclear localization. While unstimulated GR-HSCs produce basal levels of PGD2, TGF-β stimulation besides increasing COX2- mRNA levels, enhanced synthesis/secretion of PGD2 in GR-HSCs supernatant. Moreover, GR-HSCs-derived PGD2 mediate VEGF production by TGF-β-stimulated GR-HSCs, since the pre-treatment with HQL-79, an inhibitor of hematopoietic PGD synthase inhibited both PGD2 synthesis and VEGF secretion by TGF-β-stimulated GR-HSCs. All together, our findings show an autocrine/paracrine activity of GR-HSCs-derived PGD2 on TGF-β-induced VEGF production by GR-HSCs, unveiling a role for PGD2 as important regulator of HSCs activation in hepatic granulomas from schistosome infected mice.

Topics: Animals; Cell Communication; Cells, Cultured; Cyclooxygenase 2; Granuloma; Hepatic Stellate Cells; In Vitro Techniques; Liver; Male; Mice; Piperidines; Prostaglandin D2; Schistosomiasis mansoni; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Drug discovery for the neglected tropical disease schistosomiasis has a high priority. Anticancer drugs, especially protein kinase inhibitors, might serve as a starting point for drug discovery owing to the importance of protein kinases in helminth growth and development. Furthermore, the Schistosoma mansoni genome encodes several genes for targets of drugs marketed for human use, including several anticancer drugs.. In this study, we screened the approved oncology drug set of the National Cancer Institute's Developmental Therapeutic Program for antischistosomal activity. Drugs were tested in vitro against the larval and adult stage of S. mansoni. IC50 values and albumin binding were determined for active compounds. Lead compounds were tested in the chronic S. mansoni mouse model.. Eleven of the 114 compounds tested revealed IC50 values ≤ 10 μM against both S. mansoni stages. Five of these lost activity against adult S. mansoni in the presence of serum albumin. Of 6 compounds studied in vivo, the highest activity was observed from two kinase inhibitors trametinib, and vandetanib, which reduced worm burden by 63.6 and 48.1% respectively, after a single oral dose of 400 mg/kg body weight.. Our study has confirmed that oncology drugs possess antischistosomal activity. There is space for further investigation, including elucidation of the mechanisms of action of schistosome-active cancer drugs, application of different treatment courses, and structure-activity relationship studies for improving drug potency.

Topics: Animals; Antineoplastic Agents; Drug Repositioning; Inhibitory Concentration 50; Mice; Piperidines; Pyridones; Pyrimidinones; Quinazolines; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides

N,N-diethyl-3-methylbenzamide (DEET) has recently been reported to kill cercariae of Schistosoma mansoni in vitro. In addition, it blocked cercarial entry into mouse tail skin. We confirmed these results and compared the efficacy of DEET to a second insect repellent, 1-(3-Cyclohexen-1-yl-carbonyl)-2-methylpiperidine (AI3-37220), in preventing S. mansoni infections in mice. Both AI3-37220 and DEET conferred 100% protection against S. mansoni infection via percutaneous exposure to cercariae.

Topics: Animals; DEET; Insect Repellents; Intestines; Liver; Male; Mice; Mice, Inbred CBA; Piperidines; Schistosoma mansoni; Schistosomiasis mansoni; Skin

The activity of the synthetic immunomodulator LF 1695 on the efficiency of two effector cell populations--macrophages and blood platelets--involved in IgE-dependent cytotoxic processes against parasites, was evaluated. Oxygen metabolite production and anti-parasite cytotoxic properties of both macrophages and platelets were increased following LF 1695 treatment in vivo (in rat) or in vitro (in rat and in man). The phagocytic properties of rat peritoneal macrophages were also potentiated by their in vitro incubation with the drug. In addition to these effector functions, the lysosomal enzyme content and the migration ability of rat peritoneal macrophages were stimulated after incubation with LF 1695. In the presence of the drug, rat macrophages were also shown to produce increased level of IL-1--measured by the mitogen-induced proliferation of murine thymocytes--when compared to unstimulated phagocytes. Finally, the oral treatment of rats with LF 1695, in the course of an experimental infection with schistosome parasites, induced a higher degree of immune protection (80%) against a challenge infection than untreated, infected control rats (40%). These results bring evidence of a stimulatory role for LF 1695 on immune effector functions of cells participating to defense mechanisms against multicellular pathogens.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Helminth; Blood Platelets; Cytotoxicity, Immunologic; Female; Humans; In Vitro Techniques; Interleukin-1; Macrophages; Male; Piperidines; Rats; Schistosoma mansoni; Schistosomiasis mansoni