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Varinska L.,University of P.J. Safarik | Gal P.,University of P.J. Safarik | Gal P.,East Slovak Institute of Cardiovascular Diseases | Gal P.,Comenius University | And 4 more authors.
International Journal of Molecular Sciences | Year: 2015

Epidemiological studies have revealed that high consumption of soy products is associated with low incidences of hormone-dependent cancers, including breast and prostate cancer. Soybeans contain large amounts of isoflavones, such as the genistein and daidzain. Previously, it has been demonstrated that genistein, one of the predominant soy isoflavones, can inhibit several steps involved in carcinogenesis. It is suggested that genistein possesses pleiotropic molecular mechanisms of action including inhibition of tyrosine kinases, DNA topoisomerase II, 5α-reductase, galectin-induced G2/M arrest, protein histidine kinase, and cyclin-dependent kinases, modulation of different signaling pathways associated with the growth of cancer cells (e.g., NF-κB, Akt, MAPK), etc. Moreover, genistein is also a potent inhibitor of angiogenesis. Uncontrolled angiogenesis is considered as a key step in cancer growth, invasion, and metastasis. Genistein was found to inhibit angiogenesis through regulation of multiple pathways, such as regulation of VEGF, MMPs, EGFR expressions and NF-κB, PI3-K/Akt, ERK1/2 signaling pathways, thereby causing strong antiangiogenic effects. This review focuses on the antiangiogenic properties of soy isoflavonoids and examines their possible underlying mechanisms. © 2015 by the authors.

Toth Jr. S.,Pavol Jozef Safarik University | Pekarova T.,Pavol Jozef Safarik University | Varga J.,Pavol Jozef Safarik University | Totha S.,Pavol Jozef Safarik University | And 5 more authors.
American Journal of Chinese Medicine | Year: 2013

Intestinal ischemia-reperfusion injury (IIRI) is a life-threatening condition requiring prompt medical intervention. Tetramethylpyrazine (TMP) is a biologically active alkaloid isolated from Ligusticum wallichii. Previously, it was shown that TMP causes vasodilatation and inhibition of platelet aggregation as well as exhibits significant antioxidant effects. Therefore, the aim of the present study was to evaluate possible therapeutic effects of TMP in the prevention of IIRI. Wistar rats (n = 80) were randomly divided into eight experimental groups and subjected to a 1 h occlusion of cranial mesenteric artery followed by 0, 1, 12, and 24 h period of reperfusion. Thirty minutes before the IIRI animals received either TMP (30 mg/kg, i.v.) or identical volume of saline. In addition, a control group of 10 animals was not exposed to IIRI. Intestine morphology was evaluated by using histopathological injury index examination (HII), goblet and Paneth cells quantification as well as by applying immunofluorescent methods such as InSitu TUNEL and caspase-3 positivity assessment. Here we showed that preconditioning with TMP prior IIRI decreases the grade of injury. Significant reduction of HII was detected in TMP pretreated groups after 0, 1, and 12 h of reperfusion where injury reduction up to 75% was found. Lower histopathological damage in preconditioned groups was accompanied with increased number of secretory epithelial cells and decreased number of apoptotic cells. These results demonstrate the protective effect of TMP on the small intestine mucosa, suggesting administration of TMP as a molecule for pharmacological intervention against IIRI. © 2013 World Scientific Publishing Company Institute for Advanced Research in Asian Science and Medicine.

Vidinsky B.,Pavol Jozef Safarik University | Gal P.,University of Veterinary Medicine in Kosice | Gal P.,East Slovak Institute of Cardiovascular Diseases | Gal P.,Charles University | And 7 more authors.
Folia Biologica (Czech Republic) | Year: 2012

Non-small cell lung cancer has one of the highest mortality rates among cancer-suffering patients. It is well known that the unwanted psychotropic effects of cannabinoids (CBs) are mediated via the CB1 receptor (R), and selective targeting of the CB2R would thus avoid side effects in cancer treatment. Therefore, the aim of our study was to evaluate the effect of selective CB2R agonist, JWH-133, on A549 cells (non-small lung cancer) and human umbilical vein endothelial cells (HUVECs). Cytotoxicity assay and DNA fragmentation assay were employed to evaluate the influence of JWH-133 (3-(1,1-dimethylbutyl)- 1-deoxy-8-tetrahydrocannabinol) on investigated cancer cells. In addition, migration assay and gelatinase zymography were performed in HUVECs to asses JWH-133 anti-angiogenic activity. Our study showed that JWH-133 exerted cytotoxiceffect only at the highest concentration used (10-4 mol/l), while inhibition of colony formation was also detected at the non-toxic concentrations (10-5-10-8 mol/l). JWH-133 was also found to be able to induce weak DNA fragmentation in A549 cells. Furthermore, JWH-133 at non-toxic concentrations inhibited some steps in the process of angiogenesis. It significantly inhibited endothelial cell migration after 17 h of incubation at concentrations of 10-4-10-6 mol/l. In addition, JWH-133 inhibited MMP-2 secretion as assessed by gelatinase zymography. The present study demonstrates the in vitro anti-proliferative and anti-angiogenic potential of CB2R agonist, JWH-133, in nonsmall lung cancer cells and HUVECs. Our results generate a rationale for further in vivo efficacy studies with this compound in preclinical cancer models.

Ivanova L.,University of P.J. Safarik | Varinska L.,University of P.J. Safarik | Pilatova M.,University of P.J. Safarik | Gal P.,East Slovak Institute of Cardiovascular Diseases | And 6 more authors.
Molecular Biology Reports | Year: 2013

In the present investigation a novel series of chalcone analogues were synthesized and evaluated for their anti-proliferative activity in human umbilical vein endothelial cells (HUVECs). Among 14 tested compounds, chalcone analogue (E)-3-(2′-methoxybenzylidene)-4-chromanone (KRP6) exhibited the most potent activity with IC50 19 μM. Moreover, HUVECs exhibited divergent, even opposing concentration-dependent responses to KRP6. This compound was the most potent inhibitor of cell proliferation and extracellular matrix formation (fibronectin and type IV collagen) at higher concentrations (20-50 μM). In contrast, KRP6 stimulated the compensatory increase in proliferative activity including extracellular matrix formation at low concentrations (1, 10 μM). KRP6 concentration-dependently modulated phosphorylation of Akt and mitogen-activated protein kinases such as extracellular signal-regulated kinase-1/-2 and p38 kinase, suggesting that these pathways play a role in the effect mediated by this compound. In addition, we found a selective effect on activated endothelial cells, in particular with resting endothelial cells. In conclusion, KRP6 is a potent modulator of selected steps of the angiogenic process in vitro. Accordingly, further in vivo research should be performed to facilitate its use in clinical practice. © 2013 Springer Science+Business Media Dordrecht.

Smetana K.,Charles University | Szabo P.,Charles University | Gal P.,Charles University | Gal P.,East Slovak Institute of Cardiovascular Diseases | And 5 more authors.
Histology and Histopathology | Year: 2015

Detailed comparative analysis of at first sight not related process cascades is a means toward this aim: to trace common effector mechanisms and hereby eventually inspire innovative routes for therapeutic management. Following this concept, promotion of tumor progression by stroma, especially cancerassociated fibroblasts and smooth muscle actin-positive myofibroblasts, and beneficial activity of respective cells in wound healing have helped to delineate the involvement of endogenous lectins of the family of galectins. In addition to initiating conversion of fibroblasts to myofibroblasts, galectin-1 instructs the cells to produce a structurally complex extracellular matrix. This bioscaffold is useful for keratinocyte culture, also apparently operative in ameliorating wound healing. These functional aspects encourage to study in detail how lectin-(glycan) counterreceptor display is orchestrated. Such insights are assumed to have potential to contribute to rationally manipulate stem/precursor cells as resource in regenerative medicine. © 2015, Histology and Histopathology. All rights reserved.

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