Pulmonary arterial hypertension (PH) is associated with high mortality due to right ventricular failure and hypoxia, therefore to understand the mechanism by which pulmonary vascular remodeling initiates these processes is very important. We used a well-characterized monocrotaline (MCT)-induced rat PH model, and analyzed lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, and phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-κB activation in order to elucidate the mechanisms by which sildenafil's protective effect in PH is exerted. Besides its protective effect on lung morphology, sildenafil suppressed multiple cytokines involved in neutrophil and mononuclear cells recruitment including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α/β, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1α, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, and MIP-3α. NF-κB activation and phosphorylation were also attenuated by sildenafil. Furthermore, sildenafil reduced extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation while enhanced activation of the cytoprotective Akt pathway in PH. These data suggest a beneficial effect of sildenafil on inflammatory and kinase signaling mechanisms that substantially contribute to its protective effects, and may have potential implications in designing future therapeutic strategies in the treatment of pulmonary hypertension.

Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review we summarize recent findings with different neuroprotective candidate molecules. We describe the protective effects of intravitreal treatment with: (i) urocortin 2; (ii) a mitochondrial ATP-sensitive K⁺ channel opener, diazoxide; (iii) a neurotrophic factor, pituitary adenylate cyclase activating polypeptide; and (iv) a novel poly(ADP-ribose) polymerase inhibitor (HO3089). The retinoprotective effects are demonstrated with morphological description and effects on apoptotic pathways using molecular biological techniques.

Triple-negative breast cancer (TNBC) has a poor prognosis as the therapy has several limitations, most importantly, treatment resistance. In this study we examined the different responses of triple-negative breast cancer line MDA-MB-231 and hormone receptor-positive breast cancer line MCF7 to a combined treatment including olaparib, a poly-(ADP ribose) polymerase (PARP) inhibitor, oxaliplatin, a third-generation platinum compound and LY294002, an Akt pathway inhibitor. We applied the drugs in a single, therapeutically relevant concentration individually and in all possible combinations, and we assessed the viability, type of cell death, reactive oxygen species production, cell-cycle phases, colony formation and invasive growth. In agreement with the literature, the MDA-MB-231 cells were more treatment resistant than the MCF7 cells. However, and in contrast with the findings of others, we detected no synergistic effect between olaparib and oxaliplatin, and we found that the Akt pathway inhibitor augmented the cytostatic properties of the platinum compound and/or prevented the cytoprotective effects of PARP inhibition. Our results suggest that, at therapeutically relevant concentrations, the cytotoxicity of the platinum compound dominated over that of the PARP inhibitor and the PI3K inhibitor, even though a regression-based model could have indicated an overall synergy at lower and/or higher concentrations.

Data in the literature concerning the effects of physical activity on lipid and IGF-1levels are controversial in postmenopausal women. The aim of the present study was to determine the combined effects of a 12 weeks home-based walking program aiming to achieve 10,000 steps daily and a center- based aerobic exercise training on functional capacity, some important cardio-metabolic parameters, IGF-1 level and psychological items among elderly female patients. Sixty female patients (67.4 ± 5 years) with moderate to high cardiovascular risk were randomly assigned either to an exercise training program for 12 weeks or to the control group. Our organized training program resulted in a significantly improved daily physical activity (4232 [IQR: 3162–7219] to 8455 [IQR: 6757–11,488]; p < 0.001 ft-steps), functional capacity (MET) (8.17 ± 1.57 to 8.87 ± 1.76) (p = 0.002), metabolic status including total cholesterol (5.17 ± 1.13 to 4.77 ± 1.12 mmol/l), LDL cholesterol (3.37 ± 1.05 to 2.81 ± 0.98 mmol/l), triglyceride (1.68 ± 0.71 to 1.28 ± 0.71 mmol/l) and HgbA1c (6.24 ± 0.67 to 6.06 ± 0.58 mmol/l), as well as IGF-1 (59.68 ± 27.37 to 66.79 ± 22.74 ng/ml) levels (p < 0.05) in the training group. From psychological tests only physical functionality improved significantly (p = 0.03) in the training group. The training group significantly differed from the control group in four parameters including MET (p = 0.003), LDL-cholesterol (p = 0.046), triglyceride (p = 0.001) and IGF-1 levels (p < 0.001) after the intervention. The applied home-, and- center based training program effectively increased the daily physical activity of the elderly female patients and improved several cardio-metabolic parameters. Further investigations are needed on larger patient population to establish our findings and examine how these positive changes may decrease CV events and mortality.

Mitochondria have emerged as a prospective target to overcome drug resistance that limits triple-negative breast cancer therapy. A novel mitochondria-targeted compound, HO-5114, demonstrated higher cytotoxicity against human breast cancer lines than its component-derivative, Mito-CP. In this study, we examined HO-5114′s anti-neoplastic properties and its effects on mitochondrial functions in MCF7 and MDA-MB-231 human breast cancer cell lines. At a 10 µM concentration and within 24 h, the drug markedly reduced viability and elevated apoptosis in both cell lines. After seven days of exposure, even at a 75 nM concentration, HO-5114 significantly reduced invasive growth and colony formation. A 4 h treatment with 2.5 µM HO-5114 caused a massive loss of mitochondrial membrane potential, a decrease in basal and maximal respiration, and mitochondrial and glycolytic ATP production. However, reactive oxygen species production was only moderately elevated by HO-5114, indicating that oxidative stress did not significantly contribute to the drug’s anti-neoplastic effect. These data indicate that HO-5114 may have potential for use in the therapy of triple-negative breast cancer; however, the in vivo toxicity and anti-neoplastic effectiveness of the drug must be determined to confirm its potential.