Phytochemical Extract from Carica papaya Leaves and Punica granatum Seeds as Therapy Against Cognitive Impairment in a Murine Model.

Mild cognitive impairment (MCI) is defined as inter-stage between normal cognitive aging and major neurocognitive disorder (MND). This state of decay is a crucial factor in treatment to prevent the progression to MND. In this study, our group developed a virtual screening process to evaluate 2568 phytochemical compounds against 5 key proteins associated with MCI and MND. As a result, two potential candidates were identified: carpaine, found in Carica papaya leaves, and punicalagin, present in Punica granatum. A model of cognitive impairment (CI) was developed in 10-month-old male Sprague Dawley rats by administering aluminum chloride (AlCl3) at a dose of 100 mg/kg/day for 30 days. After AlCl3 administration period, one of the groups received carpaine and punicalagin in a phytochemical extract (PE) by oral gavage for 30 days. Novel object recognition test (NOR) was assessed at three different time points (T1 - before CI, T2 - after CI, and T3 - after PE treatment). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were identified in the hippocampus of rats at the end of the study period. After administration of AlCl3, a reduction in discrimination index vs control rats (CI = 0.012 ± 0.08 vs Control = 0.076 ± 0.03), was observed. After phytochemical extract treatment, a significant increase in discrimination index values was observed in the PE group 0.4643 ± 0.13 vs CI group 0.012 ± 0.08. Additionally, the evaluation of immunohistochemistry showed an increase in GFAP positivity in the hippocampus of the CI groups, while a slight decrease was observed in the PE group. This work addressed a comprehensive methodology that utilized in silico tools to identify phytochemical compounds (carpaine and punicalagin) as potential candidates for affecting key proteins in CI. The phytochemical extract containing carpaine and punicalagin resulted in a trend in the decrease of GFAP expression in the hippocampus and improved recognition memory in rats with CI induced by age and AlCl3 administration.

High expression of Toll-like receptor 7 is a survival factor in pediatric medulloblastoma.

PURPOSE: Medulloblastoma is an embryonal brain tumor that predominantly occurs in childhood with a wide histological and molecular variability. Our aim was to investigate the expression of Toll-like receptors (TLRs), their association with the infiltration of immune cells and with the histological subgroups, and, also, with the overall survival of patients. METHODS: Fifty-six paraffin-preserved biopsies from children with medulloblastoma of the classic, desmoplastic, and anaplastic subtypes were included. Microarrays of tissues were performed, and the infiltration of T and NK cells was quantified, as well as the expression of TLR7, TLR8, and TLR9. For all statistical analyses, significance was p < 0.05. RESULTS: CD4 + and CD8 + T lymphocytes and NK cells were found infiltrating the tumor. The infiltration of NK and CD4 + cells was greater in the classic and desmoplastic subtypes than in anaplastic. We found an important expression of TLRs in all medulloblastomas, but TLR7 and TLR8 were considerably higher in classic and desmoplastic subtypes than in anaplastic. Importantly, we observed that TLR7 was a prognostic factor for survival. CONCLUSIONS: Medulloblastomas present cellular infiltration and a differential expression of TLRs depending on the histological subtype. TLR7 is a prognostic factor of survival that is dependent on treatment and age.

NLRP3 Regulates IL-4 Expression in TOX+ CD4+ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression.

In cutaneous T cell lymphoma (CTCL), a dominant Th2 profile associated with disease progression has been proposed. Moreover, although the production and regulation of IL-4 expression during the early stages of the disease may have important implications in later stages, these processes are poorly understood. Here, we demonstrate the presence of TOX+ CD4+ T cells that produce IL-4+ in early-stage skin lesions of CTCL patients and reveal a complex mechanism by which the NLRP3 receptor promotes a Th2 response by controlling IL-4 production. Unassembled NLRP3 is able to translocate to the nucleus of malignant CD4+ T cells, where it binds to the human il-4 promoter. Accordingly, IL-4 expression is decreased by knocking down and increased by promoting the nuclear localization of NLRP3. We describe a positive feedback loop in which IL-4 inhibits NLRP3 inflammasome assembly, thereby further increasing its production. IL-4 induced a potentially malignant phenotype measured based on TOX expression and proliferation. This mechanism of IL-4 regulation mediated by NLRP3 is amplified in late-stage CTCL associated with disease progression. These results indicate that NLRP3 might be a key regulator of IL-4 expression in TOX+ CD4+ T cells of CTCL patients and that this mechanism might have important implications in the progression of the disease.