Design, Synthesis and Biological Evaluation of Novel Gypsogenin Derivatives as Potential Anticancer and Antimicrobial Agents.

Natural compounds are important sources for the treatment of chronic disorders such as cancer and microbial infectious disorders. In this research, Gypsogenin and its derivatives (2 a-2 f) have been tested against different cancer cell lines (MCF-7, HeLa, Jurkat and K562 cell lines) and further analyzed for cell proliferation, cell death type, and for act of the mechanism. Cell proliferation was determined by the MTT method and cell death types were analyzed with HO/PI staining. Fibroblast Growth Factor 1 (FGF-1), Interleukin 1 (IL-1), Interleukin 6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α), key players in breast cancer development and progression, were determined by Elisa kits. Results showed that compound 2 e inhibited the MCF-7 cell line proliferation with an IC50 value of 0.66±0.17 µM with 93.38 % apoptosis rate. Compound 2 e also decreased FGF-1, IL-1, IL-6, and TNF-α levels. Molecular docking studies performed in the binding site of FGFR-1 indicated that compound 2 e formed key hydrogen bonding with Arg627 and Asn568. Besides, compounds 2 a-2 f were evaluated for their antimicrobial activities against gram-negative and gram-positive bacteria and C. albicans via the microdilution method. Overall, compound 2 e stands out as a potential anticancer agent for future studies.

Comparison of sonodynamic, photodynamic and sonophotodynamic therapy activity of fluorinated pyridine substituted silicon phthalocyanines on PC3 prostate cancer cell line.

BACKGROUND: Sonophotodynamic therapy (SPDT), a combination of photodynamic therapy (PDT) and sonodynamic therapy (SDT), may offer theraputic advantage. The therapeutic effects of sonodynamic, photodynamic, and sonophotodynamic of 5-(trifluoromethyl)-2-thiopyridine substituted silicon phthalocyanine (gy3) and its quaternized derivative (gy3q) were examined in vitro on prostate cancer using PC3 cells. METHODS: The SDT, PDT and SPDT efficiency was determined by using MTT test.Apoptosis mechanism was evaluated by HOPI staining. RESULTS AND DISCUSSIONS: According to MTT results, the phthalocyanines decreased cell viability when compared with a control group. Also, apoptosis measurement data represents that the phthalocyanines would produce much better therapeutic outcomes compare to PDT and SDT by utilizing SPDT. Further studies should be performed to understand the effectiveness of SPDT.

Design, semi-synthesis and examination of new gypsogenin derivatives against leukemia via Abl tyrosine kinase inhibition and apoptosis induction.

Chronic myelogenous leukemia (CML) is characterized by Philadelphia translocation arising from Bcr-Abl fusion gene, which encodes abnormal oncoprotein showing tyrosine kinase (TK) function. Certain mutations in kinase domain, off-target effects and resistance problems of current TK inhibitors require the discovery of novel Abl TK inhibitors. For this purpose, herein, we synthesized new gypsogenin derivatives (6a-l) and evaluated their anticancer effects towards CML cells along with healthy cell line and different leukemic cells. Among these compounds, compound 6l was found as the most active anti-leukemic agent against K562 CML cells compared to imatinib exerting less cytotoxicity towards PBMCs (healthy). This compound also revealed significant anti-leukemic effects against Jurkat cell line. Besides, compound 6l enhanced apoptosis in CML cells with 52.4 % when compared with imatinib (61.8 %) and inhibited Abl TK significantly with an IC50 value of 13.04 ± 2.48 µM in a large panel of kinases accentuating Abl TK-mediated apoptosis of compound 6l in CML cells. Molecular docking outcomes showed that compound 6l formed mainly crucial interactions in the ATP-binding cleft of Abl TK similar to that of imatinib. Ultimately, in silico pharmacokinetic evaluation of compound 6l indicated that this compound was endowed with anti-leukemic drug candidate features.

Titaniumdioxide mediated sonophotodynamic therapy against prostate cancer.

In this study, we aimed to investigate of antitumor efficiency of titanium dioxide mediated photodynamic (PDT), sonodynamic (SDT), and sonophotodynamic (SPDT) therapies with a possible mechanism against the PC3 prostate cancer cell line. SPDT is a new approach to cancer treatment that combines sonodynamic and photodynamic therapies. On the other hand, Titanium dioxide (TiO2) has been used in many applications in pharmaceutical products and cosmetics, industrial products, and medicines. TiO2 nanoparticles will be useful for the treatment of cancer with PDT and SDT as the sensitizers in medicine. In this study, TiO2 nanoparticles were used for an in vitro comparison between the PDT, SDT, SPDT damages on prostate cancer cell lines. For this purpose, the cells were incubated in RPMI-1640 media with various concentrations of TiO2 and subjected to 0,5 W/cm2 ultrasound and/or 0,5 mJ/cm2 light irradiation. The prostate cancer cells were irradiated with light and exposed with the US and both for SPDT in the presence and/or absence of TiO2. Cell viability was measured using by MTT test after treatments. Investigate to apoptosis mechanism, Propidium iodide and Hoechst 33342 staining were used and the results showed that apoptotic cell bodies were increased compared with other groups. According to western blot analyses, caspase-3, caspase-8, PARP, and Bax levels were decreased after treatments, whereas the expression levels of caspase-9 were increased. Biochemical results showed that after treatments MDA levels were increased while SOD, CAT, GSH levels were decreased. In conclusion, TiO2-mediated SPDT may provide a promising approach for prostate cancer therapy and might play a key role in the apoptotic mechanism of these treatments.

Pheophorbide a-mediated sonodynamic, photodynamic and sonophotodynamic therapies against prostate cancer.

Anticancer efficiencies and mechanisms of Pheophorbide-a-mediated photodynamic, sonodynamic and sonophotodynamic therapies were investigated in vitro using androgen-sensitive (LNCaP) and androgen insensitive (PC3) prostate cancer cell lines. The cells were incubated in RPMI-1640 media at various concentrations of Pheophorbide-a. The media was treated with 0.5 W/cm2 ultrasound and/or 0.5 mJ/cm2 light irradiation. Cell proliferation in both cell lines was inhibited most effectively by sonophotodynamic therapy in comparison to that of both monotherapies. LNCaP cells were more sensitive to the applied treatments and the cell survival in LNCaP cell line was observed to be less than that of PC3 cell line. The results of histochemical analysis showed that there were more apoptotic cells in the treatment groups in comparison to control group. Additionally, the treatments induced apoptosis deduced by the overexpressed levels of caspase-3, caspase-8, PARP, and Bax proteins, while the expression levels of caspase-9 and Bcl-2 proteins were observed to be lower than those of control group. Treatments led to an increase in the oxidative stress markers, ROS and MDA, but a decrease in the activities of antioxidant enzymes, SOD, CAT and GSH. The results of this study revealed that Pheophorbide a-mediated sonophotodynamic therapy more efficiently activates the apoptotic mechanisms in prostate cancer cells and thus may provide a promising approach for treatment.

Green synthesis of silver nanoparticles via Cynara scolymus leaf extracts: The characterization, anticancer potential with photodynamic therapy in MCF7 cells.

In this study, we report on the synthesis of silver nanoparticles (AgNPs) from the leaf extracts of Cynara scolymus (Artichoke) using microwave irradiation and the evaluation of its anti-cancer potential with photodynamic therapy (PDT). Silver nanoparticles formation was characterized by scanning electron microscopy with energy dispersive x-ray spectroscopy and Fourier transform infrared (FTIR) spectroscopy. Silver nanoparticles formation was also investigated the surface charge, particle size and distribution using zetasizer analysis. The cytotoxic effect of AgNPs and/or PDT was studied by MTT assay and migration by the scratch assay. The apoptotic inducing ability of the AgNPs and/or PDT was investigated by intracellular ROS analysis, antioxidant enzyme levels (SOD, CAT, GPx and GSH), Hoechst staining and Bax/Bcl-2 analysis using western blotting. The mean particle size of produced AgNPs was found 98.47±2.04 nm with low polydispersity (0.301±0.033). Zeta potential values of AgNPs show -32.3± 0.8 mV. These results clearly indicate the successful formation of AgNPs for cellular uptake. Mitochondrial damage and intracellular ROS production were observed upon treatment with AgNPs (10µg/mL) and PDT (0.5 mJ/cm2) showed significant reducing cell migration, expression of Bax and suppression of Bcl-2. Significantly, biosynthesized AgNPs showed a broad-spectrum anti-cancer activity with PDT therapy and therefore represent promoting ROS generation by modulating mitochondrial apoptosis induction in MCF7 breast cancer cells.

Ozone Partially Decreases Axonal and Myelin Damage in an Experimental Sciatic Nerve Injury Model.

AIM: To investigate the effects of ozone in experimental acute sciatic nerve injury. MATERIAL AND METHODS: Twenty-eight male rats were divided into four groups (n = 7): control (C), ozone (O), injury (SNI), and treatment with ozone after injury (SNI + Ozone). Sciatic nerve injury was generated by compressing the right sciatic nerve for 90 s using a Yasargil aneurysm clip in groups SNI and SNI + Ozone. A 70 µg/ml concentration of ozone was given four times (once a day at 1st, 24th, 48th, and 72th h) at a dose of 0.5 mg/kg to groups O and SNI + Ozone after injury by an intraperitoneal injection. Nerve conduction velocities of all rats were measured by in vivo electrophysiological tests at the end of the day 4. Then, plasma malondialdehyde, total oxidant and antioxidant status were measured and also axonal and myelin changes in sciatic nerves of histopathological examination were performed. The data were analyzed by Kolmogorov Smirnov test, Mann-Whitney U-test, and Chi square test. p <.05 was considered statistically significant. RESULTS: The proximal and distal latency difference were higher and nerve conduction velocity were lower in SNI group than C and O groups, and the myelin structure was found to be broken in group SNI compared to groups C and O. However, the amplitude of the compound action potential, the nerve conduction velocity were significantly higher in group SNI + Ozone than in group SNI. Moreover, myelin injury was significantly lower in group SNI + Ozone compared to group SNI. Total oxidant status in group SNI was significantly higher than in groups C, O, and SNI + Ozone. But, total antioxidant status in group SNI was significantly lower than in groups C, O, and SNI + Ozone. CONCLUSION: This study showed that the administration of ozone at a dose of 0.5 mg/kg after peripheral nerve injury in rats reduces myelin and axonal injury.

The effect of inclination angle on the strength of vertical mattress configuration for meniscus repair.

PURPOSE: Vertical mattress configuration is the strongest of all other configurations and the repairing devices of meniscus repair. The purpose was whether increasing the inclination angle between two strands of the vertical mattress configuration by increasing the amount of meniscus tissue captured would enhance the initial strength of the construction. METHODS: A 2-cm long anteroposterior vertical longitudinal incision was created in two groups of bovine medial menisci. In the first group, the distance between the two vertical suture strands and the vertical horizontal sutures on the capsular side of the meniscal lesion was 2 mm (Group 1). In the second group, the distance was 5 mm (Group 2). The following repair specimens underwent cyclic loading prior to loading the failure testing. The endpoints included ultimate failure load (N), stiffness (N/mm) and cyclic displacement (mm) after the 100 cycles and the mode of failure. RESULTS: Group 1 (2 mm) (90.7 (±19.9) N) had lower ultimate load than Group 2 (5 mm) (120.8 (±24.5)) (P < 0.05). Stiffness and displacements during the cycling were not different between the groups (n.s.). All specimens failed by suture rupture. CONCLUSION: Increased inclination angle with increased distance between the two vertical suture strands on the capsular side of the meniscal lesion resulted in higher failure load compared to control group with lower inclination angle and distance on the capsular side.