Lysophosphatidylcholine (LPC) is the main phospholipid component of oxidized low-density lipoprotein (oxLDL) and is usually noted as a marker of several human diseases, such as atherosclerosis, cancer and diabetes. Some studies suggest that oxLDL modulates Toll-like receptor (TLR) signaling. However, effector molecules that are present in oxLDL particles and can trigger TLR signaling are not yet clear. LPC was previously described as an attenuator of sepsis and as an immune suppressor. In the present study, we have evaluated the role of LPC as a dual modulator of the TLR-mediated signaling pathway. HEK 293A cells were transfected with TLR expression constructs and stimulated with LPC molecules with different fatty acid chain lengths and saturation levels. All LPC molecules activated both TLR4 and TLR2-1 signaling, as evaluated by NF-қB activation and IL-8 production. These data were confirmed by Western blot analysis of NF-қB translocation in isolated nuclei of peritoneal murine macrophages. However, LPC counteracted the TLR4 signaling induced by LPS. In this case, NF-қB translocation, nitric oxide (NO) synthesis and the expression of inducible nitric oxide synthase (iNOS) were blocked. Moreover, LPC activated the MAP Kinases p38 and JNK, but not ERK, in murine macrophages. Interestingly, LPC blocked LPS-induced ERK activation in peritoneal macrophages but not in TLR-transfected cells. The above results indicate that LPC is a dual-activity ligand molecule. It is able to trigger a classical proinflammatory phenotype by activating TLR4- and TLR2-1-mediated signaling. However, in the presence of classical TLR ligands, LPC counteracts some of the TLR-mediated intracellular responses, ultimately inducing an anti-inflammatory phenotype; LPC may thus play a role in the regulation of cell immune responses and disease progression.

Toxoplasmosis, a zoonotic disease caused by Toxoplasma gondii, is an important public health problem and veterinary concern. Although there is no vaccine for human toxoplasmosis, many attempts have been made to develop one. Promising vaccine candidates utilize proteins, or their genes, from microneme organelle of T. gondii that are involved in the initial stages of host cell invasion by the parasite. In the present study, we used different recombinant microneme proteins (TgMIC1, TgMIC4, or TgMIC6) or combinations of these proteins (TgMIC1-4 and TgMIC1-4-6) to evaluate the immune response and protection against experimental toxoplasmosis in C57BL/6 mice. Vaccination with recombinant TgMIC1, TgMIC4, or TgMIC6 alone conferred partial protection, as demonstrated by reduced brain cyst burden and mortality rates after challenge. Immunization with TgMIC1-4 or TgMIC1-4-6 vaccines provided the most effective protection, since 70% and 80% of mice, respectively, survived to the acute phase of infection. In addition, these vaccinated mice, in comparison to non-vaccinated ones, showed reduced parasite burden by 59% and 68%, respectively. The protective effect was related to the cellular and humoral immune responses induced by vaccination and included the release of Th1 cytokines IFN-γ and IL-12, antigen-stimulated spleen cell proliferation, and production of antigen-specific serum antibodies. Our results demonstrate that microneme proteins are potential vaccines against T. gondii, since their inoculation prevents or decreases the deleterious effects of the infection.

Galectin‐3, an endogenous glycan‐binding protein, plays essential roles during microbial infection by modulating innate and adaptive immunity. However, the role of galectin‐3 within the CD4⁺CD25⁺Foxp3⁺ T regulatory (T_REG) cell compartment has not yet been explored. Here, we found, in a model of Leishmania major infection, that galectin‐3 deficiency increases the frequency of peripheral T_REG cells both in draining lymph nodes (LNs) and sites of infection. These observations correlated with an increased severity of the disease, as shown by increased footpad swelling and parasite burden. Galectin‐3‐deficient (Lgals3^−/−) T_REG cells displayed higher CD103 expression, showed greater suppressive capacity, and synthesized higher amounts of IL‐10 compared with their wild‐type (WT) counterpart. Furthermore, both T_REG cells and T effector (T_EFF) cells from Lgals3^−/− mice showed higher expression of Notch1 and the Notch target gene Hes‐1. Interestingly, Notch signaling components were also altered in both T_REG and T_EFF cells from uninfected Lgals3^−/− mice. Thus, endogenous galectin‐3 regulates the frequency and function of CD4⁺CD25⁺Foxp3⁺ T_REG cells and alters the course of L. major infection.

The parasite Trypanosoma cruzi causes Chagas disease, which remains a serious public health concern and continues to victimize thousands of people, primarily in the poorest regions of Latin America. In the search for new therapeutic drugs against T. cruzi, here we have evaluated both the in vitro and the in vivo activity of 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-benzyl dithiocarbazate) (H₂bdtc) as a free compound or encapsulated into solid lipid nanoparticles (SLN); we compared the results with those achieved by using the currently employed drug, benznidazole. H₂bdtc encapsulated into solid lipid nanoparticles (a) effectively reduced parasitemia in mice at concentrations 100 times lower than that normally employed for benznidazole (clinically applied at a concentration of 400 µmol kg⁻¹ day⁻¹); (b) diminished inflammation and lesions of the liver and heart; and (c) resulted in 100% survival of mice infected with T. cruzi. Therefore, H₂bdtc is a potent trypanocidal agent. The protozoan parasite Trypanosoma cruzi causes Chagas disease, a condition that affects the poorest regions of Latin America mainly. The chronic phase of this disease disables thousands of patients, constituting an important public health issue. The pharmacotherapy that is currently applied to treat the disease emerged many decades ago, is ineffective in most patients, mainly during the chronic phase, and has serious side effects. In a recent study, we showed that the compound 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-benzyldithiocarbazate) (H₂bdtc) is a potential drug candidate against the in vitro trypomastigote form of Tulahuen strains of T. cruzi. Here we report that H₂bdtc loaded into solid lipid nanoparticles (H₂bdtc-SLNs) displays good trypanocidal activity against the trypomastigote form of the Y strain of T. cruzi both in vitro and in vivo. Our in vivo experiments revealed that H₂bdtc-SLN is 100 times more active than benznidazole (BZN), the drug that is commercially available to treat Chagas disease. Surprisingly, this compound has no side effects on the T. cruzi acute phase. Hence, we propose that H₂bdtc-SLNs possesses interesting anti-Trypanosoma properties.

Stable organogold(III) compounds of the composition [Au^III(Hdamp)(L1)]Cl are formed from reactions of [AuCl₂(damp)] with H₂L1 (damp⁻ = dimethylaminomethylphenyl; H₂L1 = N′-(diethylcarbamothioyl)benzimidothiosemicarbazides). The cationic complexes can be neutralized by reactions with weak bases under the formation of [Au^III(damp)(L1)] compounds. The structures of the products show interesting features like relatively short Au⋯H contacts between the methylene protons of the Hdamp ligand and the gold(III) ions. Preliminary biological studies on the uncoordinated compounds H₂L1 and their gold complexes indicate considerable cytotoxicity for the [Au^III(Hdamp)(L1)]Cl complexes against MCF-7 cells. The in vitro trypanocidal activity was evaluated against the intracellular form of Trypanosoma cruzi. The organometallic complexes display a remarkable activity, which is dependent on the alkyl substituents of the thiosemicarbazone building blocks of the ligands. One representative of the cationic [Au^III(Hdamp)(L1)]Cl complexes, where H₂L1 contains a dimethylthiosemicarbazide building block, shows a trypanocidal activity against the intracellular amastigote form in the same order of magnitude as that of the standard drug benznidazole. Furthermore, no appreciable toxicity to mice spleen cells is observed for this compound resulting in a therapeutic index of about 30, which strongly recommends it as a promising candidate for the development of a future antiparasitic drug.