Potential Therapeutic Targets of Quercetin in the Cutaneous Melanoma Model and Its Cellular Regulation Pathways: A Systematic Review.

Melanoma is a skin cancer with a high mortality rate due to its invasive characteristics. Currently, immunotherapy and targeted therapy increase patient survival but are ineffective in the advanced stages of the tumor. Quercetin (Que) is a natural compound that has demonstrated chemopreventive effects against different types of tumors. This review provides evidence for the therapeutic potential of Que in melanoma and identifies its main targets. The Scopus, Web of Science, and PubMed databases were searched, and studies that used free or encapsulated Que in melanoma models were included, excluding associations, analogs, and extracts. As a result, 73 articles were retrieved and their data extracted. Que has multiple cellular targets in melanoma models, and the main regulated pathways are cell death, redox metabolism, metastasis, and melanization. Que was also able to regulate important targets of signaling pathways, such as PKC, RIG-I, STAT, and P53. In murine models, treatment with Que reduced tumor growth and weight, and decreased metastatic nodules and angiogenic vasculature. Several studies have incorporated Que into carriers, demonstrating improved efficacy and delivery to tumors. Thus, Que is a promising therapeutic agent for the treatment of melanoma; however, further studies are needed to evaluate its effectiveness in clinical trials.

C-phycocyanin decreases proliferation and migration of melanoma cells: In silico and in vitro evidences.

The incidence and number of deaths caused by melanoma have been increasing in recent years, and the pigment C-phycocyanin (C-PC) appears as a possible alternative to treat this disease. So, the objective of this study was to combine in silico and in vitro analysis to understand the main anti-melanoma pathways exerted by C-PC. We evaluated the ability of C-PC to bind to the main cellular targets related in the progression of melanoma through molecular docking, and the reflection of this bind in the biological effects in the B16F10 cell line through in vitro analysis. Our results showed that C-PC was able to bind BRAF and MEK, which are related to the signal transduction pathway for proliferation and survival. There was also an interaction between C-PC and cyclin-dependent kinase 4 and 6. In vitro analysis demonstrated that C-PC decreased B16F10 cell proliferation, as observed by cell viability and mitotic index assays. C-PC also interacted with matrix metalloproteinase 2 and 9 and N-cadherin, which may have caused the decrease in cell migration observed in vitro. Besides that, C-PC interacts with VEGF, a factor responsible for regulating the proliferation and cellular invasion pathways. Finally, C-PC did not alter the cell viability of the non-tumoral melanocytes. Therefore, C-PC is a strong anti-tumor candidate for the treatment of melanoma, since it acts in different cellular pathways of melanoma, without causing damage to non-tumoral cells.

Relation between ABCB1 overexpression and COX2 and ALOX5 genes in human erythroleukemia cell lines.

This study aimed to characterize the relationship between the COX2 and ALOX5 genes, as well as their link with the multidrug resistance (MDR) phenotype in sensitive (K562) and MDR (K562-Lucena and FEPS) erythroleukemia cells. For this, the inhibitors of 5-LOX (zileuton) and COX-2 (acetylsalicylic acid-ASA) and cells with the silenced ABCB1 gene were used. The treatment with ASA caused an increase in the gene expression of COX2 and ABCB1 in both MDR cell lines, and a decrease in the expression of ALOX5 in the FEPS cells. Silencing the ABCB1 gene induced a decrease in COX2 expression and an increase in the ALOX5 gene. Treatment with zileuton did not alter the expression of COX2 and ABCB1. Cytometry data showed that there was an increase in ABCB1 protein expression after exposure to ASA. In addition, the increased activity of ABCB1 in the K562-Lucena cell line indicates that ASA may be a substrate for this efflux pump, corroborating the molecular docking that showed that ASA can bind to ABCB1. Regardless of the genetic alteration in COX2 and ABCB1, the direct relationship between these genes and the inverse relationship with ALOX5 remained in the MDR cell lines. We assume that ABCB1 can play a regulatory role in COX2 and ALOX5 during the transformation of the parental cell line K562, explaining the increased gene expression of COX2 and decreased ALOX5 in the MDR cell lines.

Anti-MDR Effects of Quercetin and its Nanoemulsion in Multidrug-Resistant Human Leukemia Cells.

BACKGROUND: Quercetin has potential against the Multidrug Resistance (MDR) phenotype, but with low bioavailability. The increase in the bioavailability can be obtained with nanostructures. OBJECTIVE: To analyze the effects of quercetin and its nanoemulsion on MDR and non-MDR cells. METHODS: We used high-pressure homogenization for nanoemulsion production; Trypan Blue for cytostatic/cytotoxicity assays; Epifluorescence microscope (with specific probes) for apoptosis and DNA damage; Real-Time PCR for gene expression; AutoDock Vina for docking and Flow Cytometry for efflux analysis. Quercetin exerted antiproliferative impact, induced apoptosis, necrosis and DNA damage on cells. RESULTS: Quercetin combined with vincristine showed an effect similar to verapamil (an ABCB1 inhibitor), and docking showed that it binds to ABCB1 in a similar region. Quercetin was also capable of altering ABCB1 gene expression. Quercetin in nanoemulsion maintained the cytotoxic and cytostatic effects of quercetin, which may increase bioavailability. Besides, the unloaded nanoemulsion was able to inhibit per se the efflux activity of ABCB1, demonstrating pharmacological action of this structure. CONCLUSION: Quercetin may be considered as a prospective drug to overcome resistance in cancer cells and its nanoemulsion can be an alternative for in vivo application.

C-Phycocyanin: Cellular targets, mechanisms of action and multi drug resistance in cancer.

C-Phycocyanin (C-PC) has been shown to be promising in cancer treatment; however, although several articles detailing this have been published, its main mechanisms of action and its cellular targets have not yet been defined, nor has a detailed exploration been conducted of its role in the resistance of cancer cells to chemotherapy, rendering clinical use impossible. From our extensive examination of the literature, we have determined as our main hypothesis that C-PC has no one specific target, but rather acts on the membrane, cytoplasm, and nucleus with diverse mechanisms of action. We highlight the cell targets with which C-PC interacts (the MDR1 gene, cytoskeleton proteins, and COX-2 enzyme) that make it capable of killing cells resistant to chemotherapy. We also propose future analyses of the interaction between C-PC and drug extrusion proteins, such as ABCB1 and ABCC1, using in silico and in vitro studies.

Criopreservação de sêmen suíno: avanços tecnológicos e perspectivas / Cryopreservation of boar semen: progress and perspectives / Criopreservación de semen de verraco: avances y perspectivas tecnológicas

Resumo A criopreservação de sêmen suíno é uma técnica ainda não consolidada devido à alta sensibilidade do espermatozoide da espécie ao processo de congelamento e descongelamento. Ainda assim, a utilização do sêmen criopreservado é altamente desejável para o intercâmbio genético e manutenção da biossegurança. Esta revisão tem como objetivo ressaltar alguns fatores limitantes do processo e apontar os consideráveis avanços desenvolvidos nos últimos anos, principalmente devido ao aperfeiçoamento das técnicas já existentes, como caracterização das proteínas do ejaculado, ajustes na remoção do plasma seminal e uso de adjuvantes na confecção dos diluentes. Todas estas técnicas tornarão a criopreservação do sêmen suíno mais aplicável nos próximos anos para que possa ser finalmente uma técnica de uso comercial.

Abstract Biotechnology of boar semen cryopreservation has not succeeded due to the high sensitivity of swine sperm to the freezing and thawing process. However, its use is highly desirable for genetic improvement and maintenance of biosecurity. This review aims to highlight some limitations of the process and point out important advances obtained in recent years, including the improvement of existing techniques, such as protein characterization of the ejaculate, adjustments in the removal of seminal plasma, and use of adjuvants in the manufacture of diluents; all of which will make cryopreservation commercially available in the near future.

Resumen La criopreservación del semen de porcino es una técnica aún no consolidada debido a la alta sensibilidad del espermatozoide de esta especie al proceso de congelación y descongelación, aun así, el uso de semen criopreservado es altamente deseable para el intercambio genético y el mantenimiento de la bioseguridad. Esta revisión tiene por objeto poner de relieve algunos factores limitantes del proceso y señalar las importantes avances desarrollados en los últimos años, debido principalmente al mejoramiento de las técnicas existentes, entre ellas, la caracterización de las proteínas de la eyaculación, los ajustes de extracción del plasma seminal y el uso de adyuvantes en la producción de los diluyentes. Todas estas técnicas harán que la criopreservación del semen de porcino sea más aplicable en los próximos años, para ser finalmente una técnica de uso comercial.