Lactoferrin affects in vitro and in vivo fertilization and implantation in rats.

Lactoferrin (LF) is present in the oviduct, reduces in vitro gamete interaction, and affects sperm capacitation parameters in humans. Our aim was to investigate LF actions on further stages of the reproductive process in the Wistar rat model. Motile sperm were obtained from cauda epididymis to assess LF binding by direct immunofluorescence and LF effect on acrosome reaction (AR) using a Coomassie blue staining. After ovarian hyperstimulation of female rats, oocytes were surgically recovered and coincubated with motile sperm and different doses of LF to estimate the in vitro fertilization (IVF) rate. To evaluate the LF effect on pregnancy and embryo implantation, female rats (80 days old) were placed with males and received daily intraperitoneal injections of LF during one complete estrous cycle (pregnancy experiments) or during the first 8 gestational days (implantation experiments). The number of pregnant females and live born pups was recorded after labor. Moreover, the number of implantation sites was registered during the implantation period. LF was able to bind to the sperm head, midpiece, and tail. 10 and 100 µg/ml LF stimulated the AR but reduced the IVF rate. The administration of 100 and 200 mg/kg LF significantly decreased the number of implantation sites and the litter size, whereas 100 mg/kg LF declined the pregnancy rate. The results suggest that LF might interfere with the reproductive process, possibly interfering with gamete interaction or inducing a premature AR; nevertheless, the mechanisms involved are yet to be elucidated.

Role of the RNA binding protein IGF2BP1 in cancer multidrug resistance.

The insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), a member of a conserved family of single-stranded RNA-binding proteins (IGF2BP1-3), is expressed in a broad range of fetal tissues, placenta and more than sixteen cancer types but only in a limited number of normal adult tissues. IGF2BP1is required for the transport from nucleus to cytoplasm of certain mRNAs that play essential roles in embryogenesis, carcinogenesis, and multidrug resistance (MDR), by affecting their stability, translation, or localization. The purpose of this review is to gather and present information on MDR mechanisms in cancer and the significance of IGF2BP1 in this context. Within this review, we will provide an overview of IGF2BP1, including its tissue distribution, expression, molecular targets in the context of tumorigenesis and its inhibitors. Our main focus will be on elucidating the interplay between IGF2BP1 and MDR, particularly with regard to chemoresistance mediated by ABC transporters.

Extracellular Vesicles and Cancer Multidrug Resistance: Undesirable Intercellular Messengers?

Cancer multidrug resistance (MDR) is one of the main mechanisms contributing to therapy failure and mortality. Overexpression of drug transporters of the ABC family (ATP-binding cassette) is a major cause of MDR. Extracellular vesicles (EVs) are nanoparticles released by most cells of the organism involved in cell-cell communication. Their cargo mainly comprises, proteins, nucleic acids, and lipids, which are transferred from a donor cell to a target cell and lead to phenotypical changes. In this article, we review the scientific evidence addressing the regulation of ABC transporters by EV-mediated cell-cell communication. MDR transfer from drug-resistant to drug-sensitive cells has been identified in several tumor entities. This was attributed, in some cases, to the direct shuttle of transporter molecules or its coding mRNA between cells. Also, EV-mediated transport of regulatory proteins (e.g., transcription factors) and noncoding RNAs have been indicated to induce MDR. Conversely, the transfer of a drug-sensitive phenotype via EVs has also been reported. Additionally, interactions between non-tumor cells and the tumor cells with an impact on MDR are presented. Finally, we highlight uninvestigated aspects and possible approaches to exploiting this knowledge toward the identification of druggable processes and molecules and, ultimately, the development of novel therapeutic strategies.