Medicines, Volume 8, Issue 5 (May 2021) – 4 articles

Background: Eukaryotic elongation factor 2 kinase (eEF2K) regulates the elongation stage of protein synthesis by phosphorylating eEF2, a process related to various diseases including cancer and cardiovascular and neurodegenerative diseases. In this study, we describe the identification of novel eEF2K inhibitors using high-throughput screening fingerprints (HTSFP) generated from predicted profiling of compound-protein interactions (CPIs). Methods: We utilized computationally generated HTSFPs referred to as chemical genomics-based fingerprint (CGBFP). Generally, HTSFPs are generated from multiple biochemical or cell-based assay data. On the other hand, CGBFPs are generated from computational prediction of CPIs using the Chemical Genomics-Based Virtual Screening (CGBVS) method. Therefore, CGBFPs do not have missing information mainly caused by the absence of assay data. Results: Chemogenomics-Based Similarity Profiling (CGBSP) of the screening library (2.6 million compounds) yielded 27 compounds which were evaluated for in vitro eEF2K inhibitory activity. Three compounds with interesting results were identified. Compounds 2 (IC${}_{50}$ = 11.05 μM) and 4 (IC${}_{50}$ = 43.54 μM) are thieno[2,3-b]pyridine derivatives that have the same scaffolds with a known eEF2K inhibitor, while compound 13 (IC${}_{50}$ = 70.13 μM) was a new thiophene-2-amine-type eEF2K inhibitor. Conclusions: CGBSP supplied an efficient strategy in the identification of novel eEF2K inhibitors and provided useful scaffolds for optimization. Full article

Background: Angiogenesis is well known to be an important event in the tissue remodeling observed in allergic diseases. Although there is much evidence that quercetin, one of the most abundant dietary flavonoids, exerts anti-allergic effects in both human and experimental animal models of allergic diseases, the action of quercetin on angiogenesis has not been defined. Therefore, in this study, we first examined the action of quercetin on the secretion of angiogenic factors from murine mast cells in vitro. We also examined the action of quercetin on angiogenic factor secretion in the murine allergic rhinitis model in vivo. Methods: Mast cells (1 × 105 cells/mL) sensitized with ovalbumin (OVA)-specific murine IgE were stimulated with 10.0 ng/mL OVA in the presence or the absence of quercetin for 24 h. The concentrations of angiogenic factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis factor-α, IL-6 and IL-8 in the supernatants were examined by ELISA. BALB/c male mice immunized with OVA were challenged intranasally with OVA every other day, starting seven days after the final immunization. These mice were then orally administered quercetin once a day for five days, starting seven days after the final immunization. Clinical symptoms were assessed by counting the number of sneezes and nasal rubbing behaviors during the 10 min period just after OVA nasal provocation. The angiogenic factor concentrations in the nasal lavage fluids obtained 6 h after nasal antigenic provocation were examined by ELISA. Results: Quercetin significantly inhibited the production of angiogenetic factors induced by IgE-dependent mechanisms at 5.0 µM or more. Oral administration of 25.0 mg/kg quercetin into the mice also suppressed the appearance of angiogenetic factors in nasal lavage fluids, along with the attenuation of nasal symptoms. Conclusions: These results strongly suggest that the inhibitory action of quercetin on angiogenic factor secretion may be implicated in the therapeutic action of quercetin on allergic diseases, especially allergic rhinitis. Full article

Background: This study aimed to determine the rates of inpatient palliative care service use and assess the impact of palliative care service use on in-hospital treatments and resource utilization in hospital admissions for hepatorenal syndrome. Methods: Using the National Inpatient Sample, hospital admissions with a primary diagnosis of hepatorenal syndrome were identified from 2003 through 2014. The primary outcome of interest was the temporal trend and predictors of inpatient palliative care service use. Logistic and linear regression was performed to assess the impact of inpatient palliative care service on in-hospital treatments and resource use. Results: Of 5571 hospital admissions for hepatorenal syndrome, palliative care services were used in 748 (13.4%) admissions. There was an increasing trend in the rate of palliative care service use, from 3.3% in 2003 to 21.1% in 2014 (p < 0.001). Older age, more recent year of hospitalization, acute liver failure, alcoholic cirrhosis, and hepatocellular carcinoma were predictive of increased palliative care service use, whereas race other than Caucasian, African American, and Hispanic and chronic kidney disease were predictive of decreased palliative care service use. Although hospital admission with palliative care service use had higher mortality, palliative care service was associated with lower use of invasive mechanical ventilation, blood product transfusion, paracentesis, renal replacement, vasopressor but higher DNR status. Palliative care services reduced mean length of hospital stay and hospitalization cost. Conclusion: Although there was a substantial increase in the use of palliative care service in hospitalizations for hepatorenal syndrome, inpatient palliative care service was still underutilized. The use of palliative care service was associated with reduced resource use. Full article

Background: Cutaneous melanoma is the most aggressive form of skin cancer, with the worst prognosis, and it affects a younger population than most cancers. The high metastatic index, in more advanced stages, and the high aggressiveness decrease the effectiveness of currently used therapies, such as surgical removal, radiotherapy, cryotherapy, and chemotherapy, used alone or in combination. Based on these disadvantages, research focused on alternative medicine offers great potential for therapeutic innovation. Medicinal plants represent a remarkable source of compounds for the treatment of various diseases. Methods: In this study, we investigated the tumoral behavior of melanoma under treatment with the compounds baccharin and p-coumaric acid, extracted from green propolis, in mice inoculated with B16F10 cells for 26 days. Results: A significant modulation in the number of inflammatory cells recruited to the tumor region and blood in the groups treated with the compounds was observed. In addition, a significant reduction in the amount of blood vessels and mitosis in the neoplastic area was noticed. Conclusions: Through our research, we confirmed that baccharin and coumaric acid, isolated substances from Brazilian green propolis, have a promising anticarcinogenic potential to be explored for the development of new antitumor agents, adhering to the trend of drugs with greater tolerance and biological effectiveness. Full article