Özge Uzun

Effect of metformin on the human T98G glioblastoma multiforme cell line

Metformin is a guanidine derivative found in Galega officinalis that is commonly used to treat diabetes mellitus. The mechanism of action of metformin involves regulation of the adenosine monophosphate-activated protein kinase/mammalian target of rapamycin signaling pathway, which is implicated in the control of protein synthesis and cell proliferation. This led to the hypothesis that metformin reduces the risk of cancer and slows tumor growth. Thus, in the present study, the effectiveness of metformin as an antiglioma agent was evaluated using the human T98G glioblastoma multiforme cell line. The viability of the T98G cells was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was monitored by measuring caspase-3 levels, as well as by terminal deoxynucleotidyl transferase dUTP nick end labeling and staining with acridine orange and ethidium bromide. The results demonstrate that metformin reduced cell viability and caused apoptotic morphological changes in the T98G cells. Furthermore, the caspase-3 levels in the metformin-treated T98G cells were higher than those in the control cells. Metformin induced apoptosis in the T98G cell line in a concentration-dependent manner. Metformin may provide an important contribution to the treatment of glioblastoma multiforme.

Involvement of tyrosine kinase pathway in acute hypoxic vasoconstriction in sheep isolated pulmonary vein.

Tyrosine kinase pathway has been shown to be involved in the effects of hypoxia in pulmonary arteries, but its role in pulmonary vein is not known. The aims of this study were to determine the effect of hypoxia in sheep isolated pulmonary veins and to identify the role of tyrosine kinase pathway in hypoxic response. Genistein and tyrphostin were used as selective tyrosine kinase inhibitors, and sodium orthovanadate was administered for tyrosine kinase activation. Hypoxia (95% N(2) to 5% CO(2)) caused a vasoconstriction either under resting tone or in U46619-precontracted pulmonary veins. Genistein and tyrphostin inhibited hypoxia-induced vasoconstriction both under resting tone and in precontracted veins, while sodium orthovanadate increased these hypoxic contractions. Our findings suggest that tyrosine kinase pathway is involved in hypoxic pulmonary vasoconstriction in sheep isolated pulmonary vein rings.

Nuclear factor-κB inhibitors abolish hypoxic vasoconstriction in sheep-isolated pulmonary arteries

The aim of this study was to determine the role of nuclear factor-kappaB (NF-kappaB) in hypoxic constriction of isolated pulmonary arteries. Rings were suspended in an organ bath filled with Krebs-Henseleit solution and isometric contractions were recorded continuously. Hypoxia (%95 N(2)-%5 CO(2)) had no marked effect on resting force in artery rings. However, hypoxia caused further contractions in serotonin-precontracted arteries. Hypoxia-induced vasoconstrictions were abolished by preincubation with NF-kappaB inhibitors, pyrrolidine dithiocarbamate (100 microM) or pyrithione (10 microM). These results suggest that reactive oxygen species and/or NF-kappaB activation may be involved in the hypoxia-induced vasoconstriction in sheep-isolated pulmonary arteries.

Erdosteine protects rat testis tissue from hypoxic injury by reducing apoptotic cell death

The purpose of this study was to examine the effects of hypobaric hypoxia on testis morphology and the effects of erdosteine on testis tissue. Caspase‐3 and hypoxia‐inducible factor 1α expressions were detected by immunohistochemistry. Adult male Wistar rats were placed in a hypobaric hypoxic chamber. Rats in the erdosteine group were exposed to the same conditions and treated orally with erdosteine (20 mg kg−1 daily) at the same time from the first day of hypoxic exposure for 2 weeks. The normoxia group was evaluated as the control. The hypoxia group showed decreased height of spermatogenic epithelium in some seminiferous tubules, vacuolisation in spermatogenic epithelial cells, deterioration and gaps in the basal membrane and an increase in blood vessels in the interstitial area. The erdosteine group showed amelioration of both epithelial cell vacuolisation and basal membrane deterioration. Numbers of hypoxia‐inducible factor 1α–immunostained Sertoli and Leydig cells were significantly higher in the hypoxia group than in the erdosteine group. The number of seminiferous tubules with caspase‐3–immunostained germ cells was highest in the hypoxia group and decreased in the erdosteine and normoxia groups respectively. Based on these observations, erdosteine protects testis tissue from hypoxic injury by reducing apoptotic cell death.

Pyrrolidine dithiocarbamate attenuates the development of monocrotaline-induced pulmonary arterial hypertension

We aimed to demonstrate the potential protective effects of pyrrolidine dithiocarbamate (PDTC) on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Adult male rats were randomly assigned to 4 groups: control group, MCT-treated rats only, MCT-injected rats treated with PDTC, and PDTC-treated rats only. Blood and tissue samples were collected after the sacrifice. Levels of malondialdehyde (MDA) were measured by using the thiobarbituric acid method. Total antioxidant status (TAS) was determined using a commercially available ImAnOx kit. A histopathological evaluation was accomplished by scoring the degree of severity. Endothelial damage of the main pulmonary artery was evaluated by immunohistochemical labeling of endothelial cells using anti-rat endothelial cell antigen 1 (RECA-1) antibody. MCT-induced right ventricular hypertrophy (RVH) was reduced significantly in the MCT+PDTC-treated group. MDA levels were significantly lowered in the MCT+PDTC-treated group. TAS was significantly higher in the MCT+PDTC-treated group when compared with the rats with PAH. Histopathological examination demonstrated that PDTC treatment reduced the development of inflammation, hemorrhage and congestion, and collagen deposition. In conclusion, PDTC attenuated PAH and protected pulmonary endothelium in rats administered MCT. These findings suggest that PDTC treatment may provide a new effective therapeutic approach in the treatment of PAH.

Role of GS Proteins in Hypoxic Constriction of Sheep Pulmonary Artery Rings

The introduction of hypoxia is well known to cause contraction of pulmonary artery rings in vitro. Despite intensive studies, the cellular mechanisms of hypoxic pulmonary vasoconstriction are still not well defined. In this study, we aimed to determine the contribution of GS proteins in hypoxia-induced vasoconstriction in large-diameter sheep pulmonary arteries using cholera toxin (CT). Hypoxia caused further contractions in serotonin but not in NaF-precontracted pulmonary artery rings. However, hypoxic vasoconstriction due to lowering of pO2 from 97 to 5 mm Hg was totally abolished by preincubation with CT in serotonin-precontracted arteries. These preliminary results indicate that signal transduction mediated by Gs proteins may be an important mechanism in the hypoxic vasoconstriction of isolated pulmonary arteries of sheep.

Role of NO and Prostaglandins in Acute Hypoxic Vasoconstriction in Sheep Pulmonary Veins

The aim of this study was to investigate the effect of hypoxia on and the role of nitric oxide (NO) and cyclooxgenase inhibition in hypoxia-induced vasoconstriction in sheep isolated pulmonary veins. We used the potent pulmonary vasoconstrictor U46619, a thromboxane analog, as a precontractile agent. Our results showed that hypoxia caused a vasoconstriction both under resting tone and in U46619 (10–6 mol/l) precontracted pulmonary veins. In the presence of the nonselective NO synthase inhibitior Nω-nitro-L-arginine methyl ester (L-NAME; 3 × 10–5 mol/l), the hypoxic pulmonary vasoconstriction (HPV) was significantly increased in veins under resting force. However, there was a decrease in HPV in pulmonary veins precontracted with U46619 in the presence of L-NAME. Moreover, L-NAME markedly augmented the U46619-induced pulmonary contractions under normoxic conditions. Cyclooxygenase inhibition with indomethacin (10–5 mol/l) significantly reduced the HPV both under resting tone and in precontracted veins. Indomethacin also significantly decreased the U46619-induced pulmonary contractions prior to the induction of hypoxia. Our findings suggest that NO and prostaglandins can act as a modulators of the hypoxic vasoconstriction in isolated pulmonary veins.

Re: Dasanu et al. Muehrcke's lines (Leukonychiastriata) due to transretinoic acid therapy for acute promyelocytic leukemia.

We wrote for the case report entitled ‘Muehrcke’s lines (Leukonychia striata) due to transretinoic acid therapy for acute promyelocytic leukemia’ presented by Dasanu et al. Our assessment is based on clinical photographs submitted by the researchers. It is well known that drug-induced nail abnormalities may result from toxicity to the matrix, the nail bed, or the periungual tissues. The most common symptoms include Beau’s lines, onychomadesis, melanonychia, onycholysis, periungual pyogenic granulomas, and Muehrcke’s lines. Nail changes usually affect several nails and in most cases are asymptomatic. Drugs that most frequently produce nail abnormalities include retinoids, indinavir, and cancer chemotherapeutic agents. In this case, it should be considered all differential diagnosis such as Muehrcke’s lines, Beau’s lines, or onychomadesis occurs due to drugs. In the presented case, we saw transverse white band on her nail plates after receiving 16-week transretinoic acid therapy for acute promyelocytic leukemia. But this cannot identify as a Muehrcke’s line. Because it does not appear the two horizontal white lines that run parallel to the lunula across the width of the nail which are specific for Muehrcke’s lines. Otherwise Muehrcke’s lines are nonpalpable. Moreover, we detected broken nail and grooves or furrows on the white nail plate. As a result, these are characteristic of Beau’s lines or onychomadesis not Muehrcke’s lines.