Intraperitoneal Administration of 17-DMAG as an Effective Treatment against Leishmania braziliensis Infection in BALB/c Mice: A Preclinical Study.

BACKGROUND: Leishmaniasis is a significant global public health issue that is caused by parasites from Leishmania genus. With limited treatment options and rising drug resistance, there is a pressing need for new therapeutic approaches. Molecular chaperones, particularly Hsp90, play a crucial role in parasite biology and are emerging as promising targets for drug development. OBJECTIVE: This study evaluates the efficacy of 17-DMAG in treating BALB/c mice from cutaneous leishmaniasis through in vitro and in vivo approaches. MATERIALS AND METHODS: We assessed 17-DMAG's cytotoxic effect on bone marrow-derived macrophages (BMMΦ) and its effects against L. braziliensis promastigotes and intracellular amastigotes. Additionally, we tested the compound's efficacy in BALB/c mice infected with L. braziliensis via intraperitoneal administration to evaluate the reduction in lesion size and the decrease in parasite load in the ears and lymph nodes of infected animals. RESULTS: 17-DMAG showed selective toxicity [selective index = 432) towards Leishmania amastigotes, causing minimal damage to host cells. The treatment significantly reduced lesion sizes in mice and resulted in parasite clearance from ears and lymph nodes. It also diminished inflammatory responses and reduced the release of pro-inflammatory cytokines (IL-6, IFN-γ, TNF) and the regulatory cytokine IL-10, underscoring its dual leishmanicidal and anti-inflammatory properties. CONCLUSIONS: Our findings confirm the potential of 17-DMAG as a viable treatment for cutaneous leishmaniasis and support further research into its mechanisms and potential applications against other infectious diseases.

The rs2601796 variant in ADCY9 gene is associated with severe asthma and less bronchodilator response.

Asthma is a respiratory disease caused by the interaction of genetic and environmental factors. The adenylyl cyclase type 9 (ADCY9) enzyme produces the cyclic-adenosinemonophosphate (cAMP), important mediator involved in bronchodilation and immunomodulatory response. The aim of this study was to investigate if rs2601796 and rs2532019 variants in the ADCY9 gene are associated with asthma and lung function. The study comprised 1,052 subjects. Logistic regressions were done using PLINK 1.9 adjusted by sex, age, BMI, smoke and principal components. Bronchodilator responsiveness was assessed using the percentage of difference in FEV1 before and after the bronchodilator use. The in silico analysis for gene expression was performed in the GTEx Portal. The variant rs2601796 (AA/AG genotype) was positively associated with asthma severity (OR: 1.60 IC95%: 1.08-2.39) and with obstruction in individuals with severe asthma (OR: 3.10, IC95%: 1.11-8.62). Individuals with severe asthma and the AA/AG genotype of rs2601796 had less responsiveness to bronchodilators and also a lower expression of ADCY9 in lung and whole blood. The variant rs2532019 (TT/GT genotype) also downregulated the ADCY9 gene expression, but no significant association with the studied phenotypes was found. Thus, the variant in ADCY9 was associated with worse asthma outcomes, including a lower response to bronchodilators, likely due to the impact on its gene expression rate. This variant may be useful in the future to assist in personalized management of patients with asthma.

Variants in interferon gamma inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) genes that modulate inflammatory response are associated with periodontitis.

OBJECTIVE: Evaluate the association of genetic variants of the interferon gamma inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) genes with periodontitis. METHODS: The study involved 117 individuals with periodontitis and 389 without periodontitis, all Brazilians, miscegenated. Individuals with periodontitis presented at least 4 teeth with ≥ 1 site with probing depth ≥ 4 mm; clinical attachment level ≥ 3 mm on the same site and bleeding upon stimulus. Genotyping was performed using the Infinium Multi-Ethnic AMR/AFR-8 Bead Chip focused on Hispanic and African American populations with approximately 2 million markers of the human genome. Multivariate logistic regression was performed to identify associations in additive, dominant and recessive models adjusted for covariates age, obesity, mouth breathing, flossing, asthma, and ancestry. RESULTS: In IFI16, the rs75985579-A is positively associated with periodontitis in the additive (Odds Ratio adjusted (ORadjusted) 2.65, 95% confidence interval (CI):1.25-5.60, p value: 0.007) and dominant models (ORadjusted 2.56, 95%CI:1.13-5.81, p value: 0.017). In AIM2, the rs76457189-G, is associated negatively with periodontitis in two genetic models evaluated, additive (ORadjusted 0.21, 95%CI:0.05-0.94, p value: 0.022) and dominant (ORadjusted 0.21, 95%CI:0.05-0.94, p value: 0.022). CONCLUSIONS: These results have shown that variants in the IFI16 and AIM2 genes are associated with periodontitis. Individuals with at least one A (adenine) allele of the rs75985579 (IFI16) are more than twice as likely to have periodontitis, while individuals with the G (guanine) allele of rs76457189 (AIM2) are less likely to be diagnosed with periodontitis, providing a negative association with periodontitis.

Adenylyl cyclase type 9 gene polymorphisms are associated with asthma and allergy in Brazilian children.

Asthma is a chronic inflammatory disease of the respiratory tract. This heterogeneous disease is caused by the interaction of interindividual genetic variability and environmental factors. The gene adenylyl cyclase type 9 (ADCY9) encodes a protein called adenylyl cyclase (AC), responsible for producing the second messenger cyclic AMP (cAMP). cAMP is produced by T regulatory cells and is involved in the down-regulation of T effector cells. Failures in cAMP production may be related to an imbalance in the regulatory immune response, leading to immune-mediated diseases, such as allergic disorders. The aim of this study was to investigate how polymorphisms in the ADCY9 are associated with asthma and allergic markers. The study comprised 1309 subjects from the SCAALA (Social Changes Asthma and Allergy in Latin America) program. Genotyping was accomplished using the Illumina 2.5 Human Omni bead chip. Logistic regression was used to assess the association between allergy markers and ADCY9 variation in PLINK 1.07 software with adjustments for sex, age, helminth infection and ancestry markers. The ADCY9 candidate gene was associated with different phenotypes, such as asthma, specific IgE, skin prick test, and cytokine production. Among 133 markers analyzed, 29 SNPs where associated with asthma and allergic markers in silico analysis revealed the functional impact of the 6 SNPs on ADCY9 expression. It can be concluded that polymorphisms in the ADCY9 gene are significantly associated with asthma and/or allergy markers. We believe that such polymorphisms may lead to increased expression of adenylyl cyclase with a consequent increase in immunoregulatory activity. Therefore, these SNPs may offer an impact on the occurrence of these conditions in admixture population from countries such as Brazil.