Induction of SK-MEL-28 Invasion by Brain Cortical Cell-Conditioned Medium Through CXCL10 Signaling.

Melanoma, an infrequent yet significant variant of skin cancer, emerges as a primary cause of brain metastasis among various malignancies. Despite recognizing the involvement of inflammatory molecules, particularly chemokines, in shaping the metastatic microenvironment, the intricate cellular signaling mechanisms underlying cerebral metastasis remain elusive. In our pursuit to unravel the role of cytokines in melanoma metastasis, we devised a protocol utilizing mixed cerebral cortical cells and SK-MEL-28 melanoma cell lines. Contrary to expectations, we observed no discernible morphological change in melanoma cells exposed to a cerebral conditioned medium (CM). However, a substantial increase in both migration and proliferation was quantitatively noted. Profiling the chemokine secretion by melanoma in response to the cerebral CM unveiled the pivotal role of interferon gamma-induced protein 10 (CXCL10), inhibiting the secretion of interleukin 8 (CXCL8). Furthermore, through a transwell assay, we demonstrated that knockdown CXCL10 led to a significant decrease in the migration of the SK-MEL-28 cell line. In conclusion, our findings suggest that a cerebral CM induces melanoma cell migration, while modulating the secretion of CXCL10 and CXCL8 in the context of brain metastases. These insights advance our understanding of the underlying mechanisms in melanoma cerebral metastasis, paving the way for further exploration and targeted therapeutic interventions.

Synthesis and In vitro and In silico Anti-inflammatory Activity of New Thiazolidinedione-quinoline Derivatives.

BACKGROUND: Inflammation is a series of complex defense-related reactions. The inflammation cascade produces various pro-inflammatory mediators. Unregulated production of these pro-inflammatory mediators can lead to a wide range of diseases, including rheumatoid arthritis, sepsis, and inflammatory bowel disease. In the literature, the anti-inflammatory action of quinoline and thiazolidinedione nuclei are well established, alone, and associated with other nuclei. The synthesis of hybrid molecules is a strategy for obtaining more efficient molecules due to the union of pharmacophoric nuclei known to be related to pharmacological activity. OBJECTIVES: Based on this, this work presents the synthesis of thiazolidinedione-quinoline molecular hybrids and their involvement in the modulation of cytokines involved in the inflammatory reaction cascade. METHODS: After synthesis and characterization, the compounds were submitted to cell viability test (MTT), ELISA IFN-γ and TNF-α, adipogenic differentiation, and molecular docking assay with PPARy and COX-2 targets. RESULTS: LPSF/ZKD2 and LPSF/ZKD7 showed a significant decrease in the concentration of IFN- γ and TNF-α, with a dose-dependent behavior. LPSF/ZKD4 at a concentration of 50 µM significantly reduced IL-6 expression. LPSF/ZKD4 demonstrates lipid accumulation with significant differences between the untreated and negative control groups, indicating a relevant agonist action on the PPARγ receptor. Molecular docking showed that all synthesized compounds have good affinity with PPARγ e COX-2, with binding energy close to -10,000 Kcal/mol. CONCLUSION: These results demonstrate that the synthesis of quinoline-thiazolidinedione hybrids may be a useful strategy for obtaining promising candidates for new anti-inflammatory agents.

Spatiotemporal transmission of SARS-CoV-2 lineages during 2020-2021 in Pernambuco-Brazil.

SARS-CoV-2 virus emerged as a new threat to humans and spread around the world, leaving a large death toll. As of January 2023, Brazil is among the countries with the highest number of registered deaths. Nonpharmacological and pharmacological interventions have been heterogeneously implemented in the country, which, associated with large socioeconomic differences between the country regions, has led to distinct virus spread dynamics. Here, we investigate the spatiotemporal dispersion of SARS-CoV-2 lineages in the Pernambuco state (Northeast Brazil) throughout the distinct epidemiological scenarios that unfolded in the first 2 years of the pandemic. We generated a total of 1,389 new SARS-CoV-2 genomes from June 2020 to August 2021. This sampling captured the arrival, communitary transmission, and the circulation of the B1.1, B.1.1.28, and B.1.1.33 lineages; the emergence of the former variant of interest P.2; and the emergence and fast replacement of all previous variants by the more transmissible variant of concern P.1 (Gamma). Based on the incidence and lineage spread pattern, we observed an East-to-West to inner state pattern of transmission, which is in agreement with the transmission of more populous metropolitan areas to medium- and small-size country-side cities in the state. Such transmission patterns may be partially explained by the main routes of traffic across municipalities in the state. Our results highlight that the fine-grained intrastate analysis of lineages and incidence spread can provide actionable insights for planning future nonpharmacological intervention for air-borne transmissible human pathogens.IMPORTANCEDuring the COVID-19 pandemic, Brazil was one of the most affected countries, mainly due its continental-size, socioeconomic differences among regions, and heterogeneous implementation of intervention methods. In order to investigate SARS-CoV-2 dynamics in the state of Pernambuco, we conducted a spatiotemporal dispersion study, covering the period from June 2020 to August 2021, to comprehend the dynamics of viral transmission during the first 2 years of the pandemic. Throughout this study, we were able to track three significant epidemiological waves of transmission caused by B1.1, B.1.1.28, B.1.1.33, P.2, and P.1 lineages. These analyses provided valuable insights into the evolution of the epidemiological landscape, contributing to a deeper understanding of the dynamics of virus transmission during the early years of the pandemic in the state of Pernambuco.