131I-C19 Iodide Radioisotope and Synthetic I-C19 Compounds as K-Ras4B-PDE6δ Inhibitors: A Novel Approach against Colorectal Cancer-Biological Characterization, Biokinetics and Dosimetry.

In 40-50% of colorectal cancer (CRC) cases, K-Ras gene mutations occur, which induce the expression of the K-Ras4B oncogenic isoform. K-Ras4B is transported by phosphodiesterase-6δ (PDE6δ) to the plasma membrane, where the K-Ras4B-PDE6δ complex dissociates and K-Ras4B, coupled to the plasma membrane, activates signaling pathways that favor cancer aggressiveness. Thus, the inhibition of the K-Ras4B-PDE6δ dissociation using specific small molecules could be a new strategy for the treatment of patients with CRC. This research aimed to perform a preclinical proof-of-concept and a therapeutic potential evaluation of the synthetic I-C19 and 131I-C19 compounds as inhibitors of the K-Ras4B-PDE6δ dissociation. Molecular docking and molecular dynamics simulations were performed to estimate the binding affinity and the anchorage sites of I-C19 in K-Ras4B-PDE6δ. K-Ras4B signaling pathways were assessed in HCT116, LoVo and SW620 colorectal cancer cells after I-C19 treatment. Two murine colorectal cancer models were used to evaluate the I-C19 therapeutic effect. The in vivo biokinetic profiles of I-C19 and 131I-C19 and the tumor radiation dose were also estimated. The K-Ras4B-PDE6δ stabilizer, 131I-C19, was highly selective and demonstrated a cytotoxic effect ten times greater than unlabeled I-C19. I-C19 prevented K-Ras4B activation and decreased its dependent signaling pathways. The in vivo administration of I-C19 (30 mg/kg) greatly reduced tumor growth in colorectal cancer. The biokinetic profile showed renal and hepatobiliary elimination, and the highest radiation absorbed dose was delivered to the tumor (52 Gy/74 MBq). The data support the idea that 131I-C19 is a novel K-Ras4B/PDE6δ stabilizer with two functionalities: as a K-Ras4B signaling inhibitor and as a compound with radiotherapeutic activity against colorectal tumors.

Evaluation of hydrocarbons and organochlorine pesticides and their tolerant microorganisms from an agricultural soil to define its bioremediation feasibility.

The concentrations of hydrocarbons and organochlorine pesticides (OCPs), nutrients and tolerant microorganisms in an agricultural soil from a locality in Tepeaca, Puebla, Mexico, were determined to define its feasibility for bioremediation. The OCPs detected were heptachlor, aldrin, trans-chlordane, endosulfán I, endosulfán II, 1,1,1-bis-(4-chlorophenyl)-2,2-trichloroethane (4,4'-DDT), 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (4,4'-DDE) and endrin aldehyde, with values of 0.69-30.81 ng g(-1). The concentration of hydrocarbons in the soil of Middle Hydrocarbons Fraction (MHF), C10 to C28, was 4608-27,748 mg kg(-1) and 1117-19,610 mg kg(-1) for Heavy Hydrocarbons Fraction (HHF), C28 to C35, due to an oil spill from the rupture of a pipeline. The soil was deficient in nitrogen (0.03-0.07%) and phosphorus (0 ppm), and therefore it was advisable to fertilize to bio-stimulate the native microorganisms of soil. In the soil samples, hydrocarbonoclast fungi 3.72 × 10(2) to 44.6 × 10(2) CFU g(-1) d.s. and hydrocarbonoclast bacteria (0.17 × 10(5) to 8.60 × 10(5) CFU g(-1) d.s.) were detected, with a tolerance of 30,000 mg kg(-1) of diesel. Moreover, pesticideclast fungi (5.13 × 10(2) to 42.2 × 10(2) CFU g(-1) d.s.) and pesticideclast bacteria (0.15 × 10(5) to 9.68 × 10(5) CFU g(-1) d.s.) were determined with tolerance to 20 mg kg(-1) of OCPs. Fungi and bacteria tolerant to both pollutants were also quantified. Therefore, native microorganisms had potential to be stimulated to degrade hydrocarbons and pesticides or both pollutants. The concentration of pollutants and the microbial activity analyzed indicated that bioremediation of the soil contaminated with hydrocarbons and pesticides using bio-stimulation of native microorganisms was feasible.

Direct Polyphenol Attachment on the Surfaces of Magnetite Nanoparticles, Using Vitis vinifera, Vaccinium corymbosum, or Punica granatum.

This study presents an alternative approach to directly synthesizing magnetite nanoparticles (MNPs) in the presence of Vitis vinifera, Vaccinium corymbosum, and Punica granatum derived from natural sources (grapes, blueberries, and pomegranates, respectively). A modified co-precipitation method that combines phytochemical techniques was developed to produce semispherical MNPs that range in size from 7.7 to 8.8 nm and are coated with a ~1.5 nm thick layer of polyphenols. The observed structure, composition, and surface properties of the MNPs@polyphenols demonstrated the dual functionality of the phenolic groups as both reducing agents and capping molecules that are bonding with Fe ions on the surfaces of the MNPs via -OH groups. Magnetic force microscopy images revealed the uniaxial orientation of single magnetic domains (SMDs) associated with the inverse spinel structure of the magnetite (Fe3O4). The samples' inductive heating (H0 = 28.9 kA/m, f = 764 kHz), measured via the specific loss power (SLP) of the samples, yielded values of up to 187.2 W/g and showed the influence of the average particle size. A cell viability assessment was conducted via the MTT and NRu tests to estimate the metabolic and lysosomal activities of the MNPs@polyphenols in K562 (chronic myelogenous leukemia, ATCC) cells.

Processing and Physicochemical Properties of Magnetite Nanoparticles Coated with Curcuma longa L. Extract.

In this work, Curcuma longa L. extract has been used in the synthesis and direct coating of magnetite (Fe3O4) nanoparticles ~12 nm, providing a surface layer of polyphenol groups (-OH and -COOH). This contributes to the development of nanocarriers and triggers different bio-applications. Curcuma longa L. is part of the ginger family (Zingiberaceae); the extracts of this plant contain a polyphenol structure compound, and it has an affinity to be linked to Fe ions. The nanoparticles' magnetization obtained corresponded to close hysteresis loop Ms = 8.81 emu/g, coercive field Hc = 26.67 Oe, and low remanence energy as iron oxide superparamagnetic nanoparticles (SPIONs). Furthermore, the synthesized nanoparticles (G-M@T) showed tunable single magnetic domain interactions with uniaxial anisotropy as addressable cores at 90-180°. Surface analysis revealed characteristic peaks of Fe 2p, O 1s, and C 1s. From the last one, it was possible to obtain the C-O, C=O, -OH bonds, achieving an acceptable connection with the HepG2 cell line. The G-M@T nanoparticles do not induce cell toxicity in human peripheral blood mononuclear cells or HepG2 cells in vitro, but they can increase the mitochondrial and lysosomal activity in HepG2 cells, probably related to an apoptotic cell death induction or to a stress response due to the high concentration of iron within the cell.