LdCyPA attenuates MAPK pathway to assist Leishmania donovani immune escape in host cells.

BACKGROUND: Visceral leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Macrophages serve as the primary host cells for L. donovani, the immune response capability of these host cells is crucial for parasites' intracellular survival. L. donovani peptidyl-prolyl cis/trans isomerase Cyclophilin A (LdCypA) is a key protein for L. donovani intracellular proliferation, while the molecular mechanism conducive to intracellular survival of parasites remains elusive. METHODS: In this study, we generated a macrophage cell line overexpressing LdCyPA to investigate its role in controlling host immunity and promoting intracellular immune escape of L. donovani. RESULTS: It was discovered that the overexpression of the LdCyPA cell line regulated the host immune response following infection by downregulating the proportion of M1-type macrophages, promoting the secretion of the anti-inflammatory factor IL-4, and inhibiting the secretion of pro-inflammatory factors like IL-12, IFN-γ, TNF-α, and INOS. Transcriptome sequencing and mechanistic validation, meanwhile, demonstrated that cells overexpressing LdCyPA controlled the immune responses that followed infection by blocking the phosphorylation of P38 and JNK1/2 proteins in the MAPK signaling pathway and simultaneously increasing the phosphorylation of ERK proteins, which helped the L. donovani escape immune recognition. CONCLUSION: Our findings thus pave the way for the development of host-directed antiparasitic drugs by illuminating the pro-Leishmania survival mechanism of L. donovani cyclophilin A and exposing a novel immune escape strategy for L. donovani that targets host cellular immune regulation.

Ring Opening of Donor-Acceptor Cyclopropanes with Acyclic 1,3-Diketones for the Synthesis of 1,6-Dicarbonyl Compounds.

1,6-Dicarbonyl compounds, representing the formal addition products of the α-position of acetophenone derivatives to donor-acceptor cyclopropanes, were synthesized in two steps via first ring opening of donor-acceptor cyclopropanes with acyclic 1,3-diketones followed by DBU catalyzed retro-Claisen-type C-C bond cleavage reactions. In the first step, acyclic 1,3-diketones selectively worked as C-nucleophiles to add to donor-acceptor cyclopropanes. In the second step, the alkyl ketone part of the ring-opening products resulting from unsymmetrical 1,3-diketones was selectively cleaved in the presence of DBU in methanol.

Ring-opening reactions of donor-acceptor cyclopropanes with cyclic ketals and thiol ketals.

1,3-Cyclohexandione derived cyclic ketals and thiol ketals were used as O- and S-nucleophiles, respectively, for the ring opening of donor-acceptor cyclopropanes catalyzed by Cu(OTf)2 and a series of functionalized alkylene glycol diethers and dithiol diethers were obtained in good to high yields under mild conditions.

Desymmetrization of 1-Symmetrical Donor-Acceptor (D-A) Cyclopropanes via Reactions with 1,3-Cyclodiones.

A new type of 1-unsymmetrical D-A cyclopropanes containing a cyclic enone motif was obtained by the desymmetrization of 1-symmetrical D-A cyclopropanes via first the Lewis acid-catalyzed O-nucleophilic ring-opening reaction with 1,3-cyclodiones followed by an organobase-promoted unexpected multistep intramolecular transformation.

Direct Catalytic Asymmetric Synthesis of Oxindole-Derived δ-Hydroxy-ß-ketoesters by Aldol Reactions.

Direct asymmetric synthesis of δ-hydroxy-ß-ketoesters was accomplished via regio- and enantioselective aldol reactions of ß-ketoesters with isatins catalyzed by cinchona alkaloid thiourea derivatives. The C-C bond formation of the reactions occurred only at the γ-position of the ß-ketoesters. Reaction progress monitoring and product stability analyses under the conditions that included the catalyst indicated that the γ-position reaction products were formed kinetically. Various δ-hydroxy-ß-ketoesters bearing 3-alkyl-3-hydroxyoxindole cores relevant to the development of bioactive molecules were synthesized.

Synthesis of poly-functionalized benzofurans via one-pot domino oxidation/[3+2] cyclization reactions of a hydroquinone ester and ynamides.

Densely substituted amino-functionalized benzofurans were concisely accessed via the first one-pot domino oxidation/[3+2] cyclization of a hydroquinone ester and easily accessible ynamides under mild conditions in a short time. The complex benzofurans were able to be efficiently synthesized all from simple and inexpensive starting materials in two steps.