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Background: Grade IV gliomas are classified as glioblastoma (GBM), which is the most malignant brain cancer type. Various genetic and epigenetic mechanisms play a role in the initiation and progression of GBM. MicroRNAs (miRNAs) are small, non-coding RNA molecules that belong to the main epigenetic regulatory RNA class that plays different roles in either physiological or pathological conditions, including GBM pathogenesis regulating expression levels of the target genes. Brain Cancer Stem Cells (BCSCs) are responsible for poor prognosis, including therapy resistance and relapse. Epigenetic regulation mediated by miRNAs is also a critical component of BCSC selfrenewal and differentiation properties. Propolis is a resinous substance collected by honey bees from various plant sources. The flavonoid content of propolis varies depending on the collection region and the extraction method. Although there are studies that include the effects of different originated-propolis on the miRNA expression levels of the glioblastoma cells, the impact on the BCSCs has not been studied yet., Objective: This study aims to evaluate the effects of propolis obtained from Aydın, a city in western Turkey, on miRNA expression levels of BCSCs and GBM cells., Methods: Aydin propolis was dissolved in 60% ethanol, and after evaporation, distilled water was added to prepare the propolis stock solution. The flavonoids content of the Aydin propolis was determined by MS Q-TOF analysis. Commercially obtained U87MG and BCSCs were used as in-vitro brain cancer models. Cytotoxic and apoptotic effects of Aydın propolis were determined via WST-1 assay and Annexin V test, respectively. The miRNA expression profile was investigated using the real-time qRT-PCR method. The fold changes were calculated by the2 -ΔΔCt method. The miRNA-mRNA-pathway interactions, including significantly altered miRNAs, were determined using different bioinformatics tools and databases., Results: Quercetin 3-methyl ether was the main component of the Aydin propolis. Aydin propolis did not show significant cytotoxic and apoptotic effects on both GBM and BCSCs up to 2mg/ml concentration. Aydin propolis treatment decreased the expression of nine miRNAs in the U87MG and five miRNAs in the BCSCs. Moreover, ten miRNAs have upregulated from 2.22 to 10.56 folds in propolis treated GBM cells compared to the control group significantly (p<0.05). In the study, the potential roles of two new miRNAs, whose regulations in glioma were not previously defined, were identified. One of them was miR-30d-5p, a novel potential oncomiR in GBM, which was 2.46 folds downregulated in Aydin propolis treated GBM cells. The other one is miR-335-5p, which is a potential tumor suppressor miR in GBM, that was 5.66 folds upregulated in Aydin propolis treated GBM cells. FOXO pathway, its upstream and downstream regulators, and critically neuronal developmental regulators, NOTCH and WNT pathways, were determined as the most deregulated pathways in Aydin propolis treated cells., Conclusion: The determination of the anti-cancer effect of Aydın propolis on the miRNA expression of GBM, especially on cancer stem cells, may contribute to the elucidation of brain cancer genetics by supporting further analyses., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This review updates the information upon the chemical composition of propolis from all Mediterranean countries as well as their biological properties and applications. The non-volatile fraction of propolis was characterized by the presence of phenolic acids and their esters and flavonoids. Nevertheless, in some countries, diterpenes were also present: Sicily (Italy), Croatia, Malta, Creta (Greece), Turkey, Cyprus, Egypt, Libya, Algeria and Morocco. The volatile fraction of propolis was characterized by the presence of benzoic acid and its esters, mono- and sesquiterpenes, being the oxygenated sesquiterpene β-eudesmol characteristic of poplar propolis, whereas the hydrocarbon monoterpene α-pinene has been related with the presence of conifers. Regardless the chemical composition, there are common biological properties attributed to propolis. Owing to these attributes, propolis has been target of study for applications in diverse areas, such as food, medicine and livestock., (© 2019 Wiley-VHCA AG, Zurich, Switzerland.)

Yeasts isolated from patients with superficial mycoses were tested against propolis samples collected from different regions and honeybee races. The minimum inhibitory concentration (MIC) values obtained using the agar dilution methods were compared to the diameters of growth inhibition zones by using the disk diffusion method. The results showed that Candida albicans, C. glabrata, Trichosporon spp., and Rhodotorula sp. were susceptible to low concentrations of propolis, the latter showing a higher susceptibility. Relative to the other propolis tested, the propolis sample collected by Apis mellifera caucasica possessed the highest antifungal activity against all of the superficial mycoses. In contrast, the propolis samples collected by A.m. carnica and A.m. anatolica were the least active samples. Also, the propolis sample from the Adana region is more active than samples from other regions. An increase of MIC values was accompanied by a decrease of growth inhibition zone diameters.

Mycobacterium tuberculosis (H(37)R(v))-infected guinea-pig model was used to investigate the effect of water extract of propolis (WEP). After subcutaneous inoculation of tubercle bacilli, each animal received oral WEP (n=9), isoniazid (n=5) or saline (n=6) as placebo and were sacrificed 30 days later. Formation of necrosis was less prominent in the group treated with WEP, but was not statistically significant (P>0.05). The granuloma formation in the same group was more prominent than the placebo and isoniazid groups; however, this finding failed to reach statistical significance by the Kruskal-Wallis test (P>0.05). These findings suggest that Turkish WEP may have a limited effect on the development of tuberculosis infection in this guinea-pig model.

Antimicrobial activity of two propolis samples from Kazan and Marmaris regions in Turkey were investigated by the disc diffusion method. Antimicrobial activity was tested with four different ethanolic extracts (30, 50, 70, and 96% ethanol) of each sample against seven Gram positive, four Gram negative bacteria and one fungus culture. The activity was found to be mainly due to caffeic acid and its esters. An isomeric mixture containing 3,3-dimethylallyl caffeate, and isopent-3-enyl caffeate was isolated from Kazan propolis samples.

The antibacterial activities of propolis samples have been examined in vitro, according to the principles accepted for the determination of a similar activity of antibiotics with the use of solid and liquid media. It has been found that propolis extracts showed antibacterial activity through a range of commonly encountered gram positive cocci (S. aureus, beta hem. Streptococus), but had weak activity against gram negative bacteria (E. coli, P. aeruginosa). GC/MS analysis showed that propolis samples contain a variety of chemical compounds including aromatic compounds, fatty acid esters and sesquiterpenes.