Fabiola González-Herrera

Major histocompatibility complex class I chain-related gene A (MICA) is a non-classical MHC-I molecule essential for immune surveillance, yet its intracellular maturation remains poorly understood. We show that MICA is predominantly retained intracellularly in melanoma cells and colocalizes with the endoplasmic reticulum chaperone calreticulin (CRT). Notably, MICA also colocalizes with CRT in healthy skin. Immunoprecipitation assays reveal that CRT preferentially associates with a low-molecular-weight form of MICA. Recombinant protein assays and in silico analyses support direct interaction between CRT and non-glycosylated MICA, but not with fully glycosylated eukaryotic MICA. These findings identify CRT-dependent retention of MICA as a physiological checkpoint that may be dysregulated in melanoma to promote immune evasion.

The neglected Chagas disease, a zoonosis caused by the Trypanosoma cruzi parasite, has limited treatment options like nifurtimox and benznidazole, known for their toxic effects and controversial efficacy. Natural products present opportunities for therapeutic alternatives, particularly in Chile, which has a rich variety of endemic flora. This study focused on the Chilean Buddleja globosa, evaluating the antioxidant activities and biological effects of its methanolic extract (MET) and BG500, an enriched iridoid fraction (6-O-methylcatalpol), against T. cruzi trypomastigotes. Although the trypanocidal activity of the extract was significantly lower than that of nifurtimox (280 ± 3.5 vs. 5.0 ± 0.5), its selectivity was comparable (selectivity index > 15). The MET and enriched fraction also induced hyperpolarization of mitochondrial membrane potential (ΔΨm). In silico docking studies suggested that T. cruzi’s Old Yellow (OYE) could be a potential target for 6-O-methylcatalpol. This work provides the first report on the potential trypanocidal activity of a B. globosa extract, highlighting the need for further studies to connect ΔΨm and OYE inhibition to the effects of 6-O-methylcatalpol.

Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC—such as 5-fluorouracil (5FU)—remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP⁺C₁₀), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP⁺C₁₀), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP⁺C₁₀ with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP⁺C₁₀ and TPP⁺C₁₀ using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP⁺C10 and TPP⁺C₁₀, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP⁺C₁₀ and GA-TPP⁺C₁₀ increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity.