TY  - JOUR
A1  - Masic, Anita
A1  - Valencia Hernandez, Ana Maria
A1  - Hazra, Sudipta
A1  - Glaser, Jan
A1  - Holzgrabe, Ulrike
A1  - Hazra, Banasri
A1  - Schurigt, Uta
T1  - Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice
JF  - PLoS One
N2  - Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches.
KW  - leishmania major
KW  - promastigotes
KW  - apoptosis
KW  - mitochondria
KW  - parasitic diseases
KW  - leishmania
KW  - leishmaniasis
KW  - mouse models
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125354
VL  - 10
IS  - 11
ER  - 
TY  - JOUR
A1  - Solbach, W.
A1  - Bogdan, C.
A1  - Moll, Heidrun
A1  - Lohoff, M.
A1  - Röllinghoff, M.
T1  - Parasitäre Evasionsmechanismen: Beispiel Leishmanien
T1  - Mechanisms of Parasite Evasion: Leishmania as an Example
N2  - Leishmanien besitzen eine Vielzahl von Mechanismen, die humorale und zelluläre Immunabwehr effektiv zu unterlaufen. Diese hängen eng mit der Expression von hauptsächlich zwei Glykokonjugaten auf der Parasitenoberfläche zusammen, dem gp63 und dem Lipophosphoglykan. Die Parasiten sind einerseits schlechte Aktivatoren des alternativen Komplementweges und umgehen damit ihre eigene extrazelluläre Lyse. Oberflächengebundene Komplementfaktoren fördern andererseits die Aufnahme der Leishmanien durch Makrophagen. Solange diese nicht durch T-Zellen aktiviert sind, dienen sie den Parasiten als "Refugium". Dies gilt insbesondere, als Leishmanien in der Lage sind, 1. den "oxidative burst" zu hemmen; 2. toxische Sauerstoffmetaboliten zu entgiften; 3. abbauende lysosomale Enzyme zu hemmen und 4. das saure Milieu in den Lysosomen für ihren eigenen Metabolismus auszunutzen. Schließlich unterlaufen Leishmanien die zelluläre Immunabwehr des Wirts, indem sie die Aktivierung von T-Lymphozyten hemmen und die Expansion von T-Zell-Sub-populationen bewirken, die für ihr eigenes Überleben nützlich sind.
N2  - Leishmania display a variety of mechanisms for effective evasion of the humoral and cellular immune responses of the host which are strongly associ-ated with the expression of two major surface glycoconjugates, gp63 and lipophosphoglycan. The parasites are poor activators of the alternative com-plement pathway thus avoiding their own extracellular lysis. Complement bound on the surface of promastigotes promotes the uptake of leishmania by macrophages which function as »safe targets« as long as they are not acti-vated by T lymphocytes. This is due to the fact that intracellular parasites are able to 1. decrease the oxidative burst; 2. scavenge toxic oxygen metabolites; 3. inhibit degradative lysosomal enzymes; 4. exploit the acidic milieu of lysosomes for their own metabolism. Finally, leishmania have been shown to evade the host's cellular immune response by down-regulating T cell-activat-ing processes and by initiating the expansion of T cell subpopulations which promote their own survival.
KW  - Leishmanien
KW  - Immunsystem
KW  - Evasionsmechanismen
KW  - Makrophagen
KW  - T-Zellen
KW  - leishmania
KW  - immune System
KW  - evasion mechanisms
KW  - macrophages
KW  - T cells
Y1  - 1989
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30920
ER  -