Promising Dual Anticancer and Antimetastatic Action by a Cu(II) Complex Derived from Acylhydrazone on Human Osteosarcoma Models.

Osteosarcoma cancers are becoming more common in children and young adults, and existing treatments have low efficacy and a very high mortality rate, making it pressing to search for new chemotherapies with high efficacy and high selectivity index. Copper complexes have shown promise in the treatment of osteosarcoma. Here, we report the synthesis, characterization, and anticancer activity of [Cu(N-N-Fur)(NO3)(H2O)] complex where N-N-Fur is (E)-N'-(2-hydroxy-3-methoxybenzylidene)furan-2-carbohydrazide. The [Cu(N-N-Fur)(NO3)(H2O)] complex was characterized via X-ray diffraction and electron spin resonance (ESR), displaying a copper center in a nearly squared pyramid environment with the nitrate ligand acting as a fifth ligand in the coordination sphere. We observed that [Cu(N-N-Fur)(NO3)(H2O)] binds to DNA in an intercalative manner. Anticancer activity on the MG-63 cell line was evaluated in osteosarcoma monolayer (IC50 2D: 1.1 ± 0.1 µM) and spheroids (IC50 3D: 16.3 ± 3.1 µM). Selectivity assays using nontumoral fibroblast (L929 cell line) showed that [Cu(N-N-Fur)(NO3)(H2O)] has selectivity index value of 2.3 compared to cis-diamminedichloroplatinum(II) (CDDP) (SI = 0.3). Additionally, flow cytometry studies demonstrated that [Cu(N-N-Fur)(NO3)(H2O)] inhibits cell proliferation and conveys cells to apoptosis. Cell viability studies of MG-63 spheroids (IC50 = 16.3 ± 3.1 µM) showed that its IC50 value is 4 times lower than for CDDP (IC50 = 65 ± 6 µM). Besides, we found that cell death events mainly occurred in the center region of the spheroids, indicating efficient transport to the microtumor. Lastly, the complex showed dose-dependent reductions in spheroid cell migration from 7.5 to 20 µM, indicating both anticancer and antimetastatic effects.

Anticancer activity of Ni(II) and Zn(II) complexes based on new unsymmetrical salophen-type ligands: synthesis, characterization and single-crystal X-ray diffraction.

The discovery of new coordination compounds with anticancer properties is an active field of research due to the severe side effects of platinum-based compounds currently used in chemotherapy. In the search for new agents for the treatment of cancer, unsymmetrical N2O2-tetradentate ligand (H2L1 and H2L2) and their Ni(II) and Zn(II) asymmetric complexes (NiII-L1-2 and ZnII-L1-2) have been synthesized and fully characterized. 1H NMR studies revealed that the ligands and complexes were stable in mixtures of DMSO : D2O (9 : 1). Complementary UV-Vis studies confirmed that ZnII derivatives also exhibit high stability in mixtures DMSO : buffer (6 : 4) after 24 h. Single-crystal X-ray diffraction studies confirmed the molecular structures of H2L1, H2L2, NiII-L1, and NiII-L2. At the molecular level, complexes were completely planar without significant distortions of the square-planar geometry according to τ4 parameter. Furthermore, the crystalline structures revealed non-classical intermolecular interactions of the C-H⋯O and the Ni⋯Ni type. The ligands and complexes were screened against the human osteosarcoma (MG-63), human colon cancer (HCT-116), breast cancer (MDA-MB-231) cell lines, and non-cancerous cells (L929). H2L1 and H2L2 ligands not caused cytotoxic effects at a concentration of 100 µM, while NiII-L2, ZnII-L1, and ZnII-L2 complexes induce cytotoxic effects in all cell lines. NiII-L2 was a more active complex against MG-63 (3.9 ± 1.5) and HCT-116 (3.4 ± 1.7) cell lines with IC50 values in the low micromolar range. In addition, this compound was 10-, 5-, and 11-fold more potent than cisplatin in MG-63 (39 ± 1.8), HCT-116 (17.2), and MDA-MB-231 (131 ± 18), respectively. Three complexes exhibited great selectivity for tumoral cells with SI values ranging from 1.6 to 7.4.

Anticancer and Antioxidant Activity of Water-Soluble Polysaccharides from Ganoderma aff. australe against Human Osteosarcoma Cells.

Wild mushrooms have gained great importance for being a source of biologically active compounds. In this work, we evaluate the anticancer and antioxidant activity of a water-soluble crude polysaccharide extract isolated from the fruiting bodies of the Ganoderma aff. australe (GACP). This mushroom was collected in San Mateo (Boyacá, Colombia) and identified based on macroscopic and microscopic characterization. GACP was characterized by UV-Vis spectroscopy, Fourier-transform infrared spectroscopy, high-performance liquid chromatography-diode array detector, and nuclear magnetic resonance. The antiradical and antioxidant activity were evaluated by different methods and its anticancer activity was verified in the osteosarcoma MG-63 human cell line. Chemical and spectroscopic analysis indicated that GACP consisted of ß-D-Glcp-(1→, →3)-ß-D-Glcp-(1→ and α-D-Glcp-(1→ residues. The results of the biological activity showed that GACP exhibited high antioxidant activity in the different methods and models studied. Moreover, the results showed that GACP impaired cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay) and cell proliferation (clonogenic assay) in a dose-response manner on MG-63 cells. The findings of this work promote the use of mushroom-derived compounds as anticancer and antioxidant agents for potential use in the pharmaceutical and food industries.

Cyclic di-GMP Signaling Links Biofilm Formation and Mn(II) Oxidation in Pseudomonas resinovorans.

Bioaugmentation of biological sand filters with Mn(II)-oxidizing bacteria (MOB) is used to increase the efficiency of Mn removal from groundwater. While the biofilm-forming ability of MOB is important to achieve optimal Mn filtration, the regulatory link between biofilm formation and Mn(II) oxidation remains unclear. Here, an environmental isolate of Pseudomonas resinovorans strain MOB-513 was used as a model to investigate the role of c-di-GMP, a second messenger crucially involved in the regulation of biofilm formation by Pseudomonas, in the oxidation of Mn(II). A novel role for c-di-GMP in the upregulation of Mn(II) oxidation through induction of the expression of manganese-oxidizing peroxidase enzymes was revealed. MOB-513 macrocolony biofilms showed a strikingly stratified pattern of biogenic Mn oxide (BMnOx) accumulation in a localized top layer. Remarkably, elevated cellular levels of c-di-GMP correlated not only with increased accumulation of BMnOx in the same top layer but also with the appearance of a second BMnOx stratum in the bottom region of macrocolony biofilms, and the expression of mop genes correlated with this pattern. Proteomic analysis under Mn(II) conditions revealed changes in the abundance of a PilZ domain protein. Subsequent analyses supported a model in which this protein sensed c-di-GMP and affected a regulatory cascade that ultimately inhibited mop gene expression, providing a molecular link between c-di-GMP signaling and Mn(II) oxidation. Finally, we observed that high c-di-GMP levels were correlated with higher lyophilization efficiencies and higher groundwater Mn(II) oxidation capacities of freeze-dried bacterial cells, named lyophiles, showing the biotechnological relevance of understanding the role of c-di-GMP in MOB-513. IMPORTANCE The presence of Mn(II) in groundwater, a common source of drinking water, is a cause of water quality impairment, interfering with its disinfection, causing operation problems, and affecting human health. Purification of groundwater containing Mn(II) plays an important role in environmental and social safety. The typical method for Mn(II) removal is based on bacterial oxidation of metals to form insoluble oxides that can be filtered out of the water. Evidence of reducing the start-up periods and enhancing Mn removal efficiencies through bioaugmentation with appropriate biofilm-forming and MOB has emerged. As preliminary data suggest a link between these two phenotypes in Pseudomonas strains, the need to investigate the underlying regulatory mechanisms is apparent. The significance of our research lies in determining the role of c-di-GMP for increased biofilm formation and Mn(II)-oxidizing capabilities in MOB, which will allow the generation of super-biofilm-elaborating and Mn-oxidizing strains, enabling their implementation in biotechnological applications.

Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth.

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosine kinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinical biomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for early and metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interference strategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or the non-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in the nucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumor growth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but also isoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2 correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins, which conserve the canonical domains and are located in their classical cellular compartments.

Respuesta a la prueba de desmopresina: estudio de cohorte en un hospital de Bogotá / Response to the desmopressin test: cohort study in a Bogota hospital

Introducción: La desmopresina es un análogo sintético de la vasopresina que aumenta los niveles plasmáticos del factor VIII y del factor de von Willebrand. Algunos autores señalan el tiempo de mantenimiento del efecto hemostático entre 6 y 8 h, por lo que es necesario estudiar su efecto en el tiempo. Objetivo: Determinar la variación de las variables de laboratorio de pacientes con enfermedad de von Willebrand y hemofilia tipo A posterior a la administración de desmopresina. Métodos: Estudio de cohorte retrospectivo en un hospital universitario en Bogotá. Se realizó un muestreo no aleatorio, se incluyeron 24 pacientes mayores de 18 años con diagnóstico de enfermedad de von Willebrand (67 por ciento) y hemofilia tipo A no grave (33 por ciento), a quienes se les realizó la prueba de desmopresina. Se conformaron dos grupos de pacientes, independientemente del diagnóstico: 15 pacientes con valores basales de factor VIII ; 50 UI y 13 pacientes con valores basales de antígeno von Willebrand lt; 50 UI. Se efectúo análisis estadístico descriptivo y correlacional en Stata 13. Resultados: El 87 por ciento de los pacientes del grupo I alcanzó el valor terapéutico a las 2 h de administrada la desmopresina (p= 0,000), el cual se mantuvo hasta 6 h en el 77 por ciento (p= 0,000). En el grupo II el 92 por ciento logró el valor terapéutico en 2 h (p= 0,003), que continuó hasta las 6 h en el 83 por ciento (p= 0,000). Conclusiones: La respuesta a la administración de desmopresina fue máxima a las 2 h posteriores, cuando comenzó a disminuir progresivamente, pero mantuvo el efecto terapéutico. Aunque no se encontraron efectos adversos, existe variabilidad de respuesta entre pacientes(AU)

Introduction: Desmopressin is a synthetic analog for vasopressin that increases the plasma levels of factor VIII and of von Willebrand factor. Some authors indicate maintenance time of hemostatic effect between 6 and 8 hours, so it is necessary to study its effect over time. Objective: To determine the variation of laboratory variables in patients with von Willebrand disease and type A hemophilia after desmopressin administration. Methods: Retrospective cohort study carried out in a university hospital in Bogotá. Nonrandomized sampling was used, including 24 patients older than 18 years and with a diagnosis of von Willebrand disease (67 percent) and non-severe type A hemophilia (33 percent), who underwent the desmopressin test. Two groups of patients were created, regardless of diagnosis: 15 patients with baseline values of factor-VIII 8203; #8203;lower than 50 IU and 13 patients with baseline values of von Willebrand antigen8203;8203;lower than 50 IU. Descriptive and correlational statistical analysis was performed in Stata 13. Results: 87 percent of patients in group I reached the therapeutic value two hours after desmopressin administration (p=0.000), which was maintained for up to six hours in 77 percent (p=0.000). In group II, 92 percent achieved the therapeutic value in two hours (p=0.003), which continued until six hours in 83 percent (p=0.000). Conclusions: Response to desmopressin administration was maximum at two hours, when it began to decrease progressively, but maintained the therapeutic effect. Although no adverse effects were found, there is variability of response among patients(AU)

Anticancer and antimetastatic activity of copper(II)-tropolone complex against human breast cancer cells, breast multicellular spheroids and mammospheres.

The goal of this work was to display the anticancer and antimetastatic activity of a copper(II) with tropolone (trp), complex [Cu(trp)2] toward human breast cancer cells in monolayer (2D) and spheroids (3D). Cytotoxicity assays against MCF7 (IC50(complex) = 5.2 ± 1.8 µM, IC50(CDDP) = 19.3 ± 2.1 µM) and MDA-MB-231 (IC50(complex) = 4.0 ± 0.2 µM, IC50(CDDP) = 27.0 ± 1.9 µM) demonstrate that [Cu(trp)2] exert greater antitumor potency than cisplatin (CDDP) on 2D and 3D human breast cancer cell models. Besides, [Cu(trp)2] inhibits cell migration by reducing the metalloproteinases activities and the compound undergoes the breast cancer cells to apoptosis at lower concentrations (2.5-10 µM). Moreover, [Cu(trp)2] overcame CDDP presenting an IC50 value 26-fold more lower against breast multicellular spheroids ((IC50(complex) = 4.9 µM, IC50(CDDP) = 130 µM)). Also, our results showed that [Cu(trp)2] inhibited the cell migration and cell invasion of breast multicellular spheroids, showing that [Cu(trp)2] exhibited antimetastatic properties. On the other hand, [Cu(trp)2] reduced mammosphere forming capacity affecting the size and number of mammospheres. Taken together, [Cu(trp)2] exhibited anticancer and antimetastatic properties on monolayer (2D) and spheroids (3D) derived from human breast cancer cells.

Los síndromes de lesión talámica

En la unidad de Neurología del Centro Hospitalario San Juan de Dios de Bogotá, durante cuatro años (1986 a 1989), se estudiaron en forma consecutiva 25 pacientes con lesiones talámaticas no fatales. Se registraron los hallazgos neurológicos, neurosicológicos y neurooftalmológicos y los diagnósticos se confirmaron por tomografía computarizada (TC). Fueron 14 mujeres y 11 varones con una edad promedio de 52.5 y un rango de 25 a 84 años. La lesión talámica fue de origen vascular en 24 casos, ocho por infarto isquémico, cuatro por infarto hemorrágico y 12 con hematomas parenquimatosos. Diecisiete pacientes tenían hipertensión arterial sistémica y el único factor de riesgo en otros dos era el consumo de cocaína base (basuco). Ocho infartos se presentaron en el tálamo derecho, 12 en el izquierdo y cinco pacientes tuvieron lesiones bilaterales, uno de ellos con un glioma complobado por biopsia. En 5 pacientes con lesiónes bilateral se observó el síndrome del "Tope" de la arteria basilar, por compromiso del pedículo retromamilar; en todos ellos encontramos alteraciones sensitivomotoras, cerebelosas, oculomotoras bilaterales y demencia. Solamente un paciente presentó el clasicó síndrome de hiperpatía (Dejerine-Roussy). En los restantes se observaron asociaciones de síndromes sensitivomotores, cerebelosos, neurooftalmológicos, neuropsicológicos, y del comportamiento motor que remedan con frecuencia los hallazgos clínicos de la alteración cortical frontal, temporal o parietal.