Combination of paromomycin plus human anti-TNF-α antibodies to control the local inflammatory response in BALB/ mice with cutaneous leishmaniasis lesions

Schwartz, Juana; Moreno, Esther; Calvo, Alba; Blanco, Laura; Fernández-Rubio, Celia; Sanmartín, Carmen; Nguewa, Paul A.; Irache, Juan M.; Larrea, Esther; Espuelas, Socorro

doi:10.1016/j.jdermsci.2018.07.005

Cited by 15 publications

(15 citation statements)

References 45 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The PLE was compared with an O/W cream (composition summarized in Table 2), in which DAP was incorporated as a micronized powder at the same final concentration (10% w / v ). This vehicle was the same as that used for the topical administration of PM (used as control for effective treatment) [15]. A priori, a similar and maximal thermodynamic activity of 1 can be assumed for both types of formulations of DAP, either PLE or O/W cream, because of the drug solubilization at its saturation level in each one, although the amount of solubilized drug could be greatly different.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of Skin Permeation and Retention of Topical Dapsone in Murine Cutaneous Leishmaniasis Lesions

et al. 2019

Self Cite

View full text Add to dashboard Cite

The oral administration of dapsone (DAP) for the treatment of cutaneous leishmaniasis (CL) is effective, although serious hematological side effects limit its use. In this study, we evaluated this drug for the topical treatment of CL. As efficacy depends on potency and skin penetration, we first determined its antileishmanial activity (IC50 = 100 μM) and selectivity index in vitro against Leishmania major-infected macrophages. In order to evaluate the skin penetration ex vivo, we compared an O/W cream containing DAP that had been micronized with a pluronic lecithin emulgel, in which the drug was solubilized with diethylene glycol monoethyl ether. For both formulations we obtained similar low flux values that increased when the stratum corneum and the epidermis were removed. In vivo efficacy studies performed on L. major-infected BALB/c mice revealed that treatment not only failed to cure the lesions but made their evolution and appearance worse. High plasma drug levels were detected and were concomitant with anemia and iron accumulation in the spleen. This side effect was correlated with a reduction of parasite burden in this organ. Our results evidenced that DAP in these formulations does not have an adequate safety index for use in the topical therapy of CL.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The formulation was stored and protected from light in a plastic container at room temperature. This cream composition was chosen because PM (15% w / v ) solubilized in this vehicle was used as an effective treatment in a CL mice model [15].…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Skin Permeation and Retention of Topical Dapsone in Murine Cutaneous Leishmaniasis Lesions

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Seventy-two hours after the last LL-37 injection, skin tissues were harvested and either snap-frozen in liquid N 2 for RNA analysis or fixed in 10% formalin solution for H&E staining. Skin inflammation was scored as described previously by Schwartz et al (41). Briefly, an objective scoring system was employed in a blinded fashion.…”

Section: Cathelicidin Ll-37-induced Rosacea Modelmentioning

confidence: 99%

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

et al. 2020

View full text Add to dashboard Cite

Mast cells are tissue-resident innate immune cells known for their prominent role in mediating allergic reactions. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a promiscuous G-protein coupled receptor (GPCR) expressed on mast cells that is activated by several ligands that share cationic and amphipathic properties. Interestingly, MRGPRX2 ligands include certain FDA-approved drugs, antimicrobial peptides, and neuropeptides. Consequently, this receptor has been implicated in causing mast cell-dependent pseudo-allergic reactions to these drugs and chronic inflammation associated with asthma, urticaria and rosacea in humans. In the current study we examined the role of osthole, a natural plant coumarin, in regulating mast cell responses when activated by the MRGPRX2 ligands, including compound 48/80, the neuropeptide substance P, and the cathelicidin LL-37. We demonstrate that osthole attenuates both the early (Ca 2+ mobilization and degranulation) and delayed events (chemokine/cytokine production) of mast cell activation via MRGPRX2 in vitro. Osthole also inhibits MrgprB2-(mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Molecular docking analysis suggests that osthole does not compete with the MRGPRX2 ligands for interaction with the receptor, but rather regulates MRGPRX2 activation via allosteric modifications. Furthermore, flow cytometry and confocal microscopy experiments reveal that osthole reduces both surface and intracellular expression levels of MRGPRX2 in mast cells. Collectively, our data demonstrate that osthole inhibits MRGPRX2/MrgprB2-induced mast cell responses and provides a rationale for the use of this natural compound as a safer alternative treatment for pseudo-allergic reactions in humans.

show abstract

“…For some experiments, mice were injected with a single dose of LL-37 (50 µL of 320 µM) after the SKF treatments and the skin tissues were harvested and fixed in 10% formalin solution 30 min after the LL-37 injection. Skin inflammation was scored as described previously by Schwartz et al (42). Briefly, an objective scoring system was employed in a blinded fashion.…”

Section: Experimental Rosacea Modelmentioning

confidence: 99%

Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

et al. 2020

View full text Add to dashboard Cite

Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca 2+) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca 2+ levels; however, the Ca 2+ mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca 2+ entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response in vitro. Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans.

show abstract

Combination of paromomycin plus human anti-TNF-α antibodies to control the local inflammatory response in BALB/ mice with cutaneous leishmaniasis lesions

Abstract: In terms of parasite elimination and inflammation reduction, topical application of Ab in combination with PM was more effective than the drug alone.

Cited by 15 publications

References 45 publications

Evaluation of Skin Permeation and Retention of Topical Dapsone in Murine Cutaneous Leishmaniasis Lesions

Evaluation of Skin Permeation and Retention of Topical Dapsone in Murine Cutaneous Leishmaniasis Lesions

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

Contact Info

Product

Resources

About