[Autophagy Does Not Contribute to TKI Response in a Imatinib-resistant Chronic Myeloid Leukemia Cell Line].

Autophagy is an evolutionarily conserved cellular process in which components of the cytoplasm are delivered to lysosomes for degradation and has been proposed to play a role in imatinib resistance in chronic myeloid leukemia cells. Chronic myeloid leukemia is a clonal myeloproliferative disorder arising from the neoplastic transformation of the hematopoietic stem cell. We used a Bcr-Abl-independent and imatinib-resistant K562 subpopulation (K562-IR) that we generated earlier in our laboratory for this study. We showed that in the presence of imatinib autophagy was triggered via LC3I/II transformation, p62 protein expression and acidic vacuoles accumulation in tyrosine kinase inhibitor-sensitive K562 cells; whereas in the cell line K562-IR which is imatinib-resistant and Bcr-Abl independent, autophagy is not triggered. With ongoing research and trails to combine tyrosine kinase inhibitors with autophagy inhibitors, our results suggest a model of resistance in which treatment with a TKI inhibitor does not increase autophagy, basically because its presence does not cause cellular stress due to Bcr-Abl signaling not being required for survival.

Topiramate has protective effect on renal injury.

BACKGROUND: Topiramate (TPM) decreases tumor necrosis factor-alpha (TNF-α) and oxidative stress. We investigated protective effects of TPM on cell damage in kidney tissue during ischemia-reperfusion (I/R) damage. METHODS: A total of 30 male Wistar albino rats were divided into three groups: control, I/R, and I/R plus TPM (I/R+TPM). Laparotomy without I/R injury was performed in control group. After laparotomy, cross ligation of infrarenal abdominal aorta was applied for two hours in I/R groups which was followed by two hours of reperfusion. TPM (100 mg/kg/day) was orally administrated to animals in the I/R+TPM group for seven consecutive days before I/R. RESULTS: The I/R group's TNF-α and interleukin-1 beta (IL-1ß) levels were significantly higher (1184.2 ± 129.1 pg/mg protein; 413.1 ± 28.8 pg/mg protein, respectively) than those of the control (907.8 ± 113.0 pg/mg protein, p = 0.002; 374.7 ± 23.7 pg/mg protein, p = 0.010, respectively) and I/R+TPM groups (999.5 ± 115.2 pg/mg protein, p < 0.001; 377.9 ± 30.9 pg/mg protein, p = 0.007, respectively). CONCLUSION: TPM may partially prevent renal damage in rats. The opening of new horizons of this kind of knowledge will help understand the complex challenge in the prevention of renal I/R damage (Tab. 1, Fig. 3, Ref. 42).

Lasting hepatotoxic effects of prenatal mobile phone exposure.

OBJECTIVE: In this study, the livers of rats born to mothers exposed to electromagnetic field (EMF) were examined 60 days postpartum for biochemical and histopathological changes. METHODS: Pregnant rats were exposed to radiation (900 MHz EMF, 24 h/day for 20 days) using a digital signal generator by placing the device centrally under the cage, which formed the study (EMF) group, while untreated matching rats served as controls. Livers and blood were obtained from litters (seven males and seven females) of both groups 60 days after birth, which were used for biochemical and histopathological analyses. RESULTS: There was a significant increase in the levels of malondialdehyde (MDA) (p < 0.05) that was accompanied by a significant fall in glutathione (GSH) (p < 0.01) in the liver. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly increased (p < 0.05). Histopathologically, the liver sections of the EMF group showed intense degeneration in hepatocytes with cytoplasmic eosinophilic structures, pyknotic nuclei and fibrosis. CONCLUSION: We demonstrate that the intrauterin harmful effects of EMF on the livers of rats persist into adulthood.

Relationship between lipid peroxidation and disease activity in patients with Behçet's disease.

Behçet's disease is a chronic multi-systemic disorder which is characterized by a relapsing systemic inflammatory process. The alteration of lipid profile and lipid peroxidation resulting from the inflammatory process may he associated with an increased risk for atherosclerosis in patients with Behcet's disease. We investigated lipids, lipoprotein and lipid peroxidation and their inter-relationships considering the disease activity. Eighteen patients (11 male and 7 female) and 20 age-matched healthy subjects (10 male and 10 female) were studied. Lipid profile including total cholesterol, triacylglycerol, HDL-cholesterol, LDL-cholesterol, lipoprotein(a), apoAI and apoB, and acute phase reactants including polymorphonuclear (PMN) elastase, PMN leukocyte count, erythrocyte sedimentation rate (ESR) and complements (C3, C4) were evaluated in patients in active and inactive periods of Behçet's disease and control subjects. The levels of thiobarbituric acid reactive substance (TBARS) were assessed as an indicator of lipid peroxidation. Lipid peroxidation was found to he increased in the active period compared to the inactive period of the disease and control subjects. Also, lipid peroxidation showed correlations of various degrees with atherogenic lipid parameters in both periods of the followed-up patients. In conclusion, patients with Behçet's disease in the active period may be much more susceptible to atherogenic events than those in the inactive period of the disease and control subjects.

Decreased neutrophil antioxidative enzyme activities and increased lipid peroxidation in hyperlipoproteinemic human subjects.

Neutrophils have the capacity to produce free radicals. Free radicals are associated with hyperlipoproteinemia and atherosclerotic processes. For this reason, neutrophil superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GR), catalase (Cat) activities and thiobarbituric acid reactive substances (TBARS), as an index of lipid peroxidation, have been studied in hyperlipoproteinemic (HLP) and age-matched normolipidemic groups. Lipid parameters including triglycerides, total cholesterol, plasma TBARS, HDL-cholesterol, LDL-cholesterol, apo A-I, apo B have also been determined. Forty subjects (females 18, males 22) with HLP (mean age 43.8+/-8.7 (S.D.)) and 40 normolipoproteinemic subjects (females 17, males 23; mean age 46.4+/-11) were included in the study. Neutrophils were isolated by Percoll gradient centrifugation from venous blood samples. Methods used were as follows: INT method for SOD, UV method at 340 nm based on oxidation of NADPH for GSH-Px and GR, UV method at 240 nm based on degradation of hydrogen peroxide for catalase, and a method based on reaction with thiobarbituric acid for TBARS. Neutrophil SOD, GSH-Px, and catalase activities were found to be significantly low in the hyperlipoproteinemic group compared with the normolipoproteinemic group. GR activity did not differ between both groups. The mean TBARS level in the neutrophil fraction was found to be significantly higher in hyperlipoproteinemics than in that of the normolipoproteinemics. It was concluded that decreased neutrophil antioxidant enzyme activities in hyperlipoproteinemics may lead to insufficient detoxification of free radicals produced in these cells and contribute to increased lipid peroxidation.

Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments.

BACKGROUND: Reactive oxygen species (ROS) may play a role in some neuropsychiatric disorders. There is some evidence that the activation of immune-inflammatory process, increase of monoamines catabolism, and abnormalities in lipid compounds may cause overproduction of ROS and, in turn, antioxidative enzyme activities (AEAs) and lipid peroxidation (LP), and that these phenomena may be related to pathophysiology of major depression. METHODS: The aims of this study were (i) to examine the AEAs and LP levels of the major depressed (MD) patients, and to compare these with healthy controls; and (ii) to investigate the effect of subchronic treatment with selective serotonin reuptake inhibitors (SSRIs) on AEAs and LP levels in MD subjects. Thirty MD patients, and 32 healthy controls (HC) participated in this study. AEAs and LP levels were determined by measuring several antioxidative enzymes and malondialdehyde (MDA) levels in plasma and/or in red blood cells. RESULTS: Major depressed patients, especially melancholic patients, had higher AEA and LP levels than those of healthy controls. After treatment for 3 months with SSRIs, AEA and LP levels of the patients were significantly decreased to normal levels. CONCLUSION: These findings suggest that (i) major depression, especially with melancholia, is associated with elevated AEAs and LP, and that (ii) subchronic treatment with SSRIs may have a suppressive effect on AEA and LP. CLINICAL IMPLICATION AND LIMITATION: AEAs might be used for monitoring SSRIs effects.

Distribution of serum lipoprotein (a) concentrations in a healthy Turkish population.

Serum lipoprotein (a) [Lp (a)] concentrations are highly skewed in different populations. We measured serum Lp (a) by quantitative enzyme-linked immunosorbent assay (ELISA) in 248 healthy Turkish subjects (127 male, 121 female). The mean Lp (a) value was 0.21 g/L and values did not differ between the sexes. The Lp (a) frequency distribution showed less skewness than those of Asian and Western populations but it clearly deviated from a Gaussian distribution. Plasma Lp (a) concentration did not correlate significantly with age, total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, apolipoprotein A-1 and B or triglyceride concentration.

The effect of ATP-MgCl2 on lipid peroxidation in ischemic and reperfused rabbit kidney.

Oxygen metabolites formed during reperfusion of ischemic kidneys prevent recovery of renal function after short periods of renal ischemia. The administration of ATP-MgCl2 is beneficial to the survival of animals after hemorrhagic shock, severe burns, septicemia-peritonitis, post-ischemic hepatic failure, bowel ischemia, and endotoxic shock. In this study, the effect of ATP-MgCl2 on lipid peroxidation and its curative effect were evaluated by measuring the decomposition products of lipid peroxidation, detected as thiobarbituric-acid reactive substances in homogenized kidney tissues in ischemic and reperfused rabbit kidneys. Ischemia was performed by clamping the right renal artery for 60 minutes followed by 30 minutes of reperfusion. Thirty-six rabbits were classified into 6 groups containing 6 rabbits in each. In the first group, no renal ischemia-reperfusion (I-R) was designed (Sham group), the right kidney was removed 90 minutes later. In the second group, I-R was established but nothing given. Saline 0.25 cc/kg was given into the right renal artery in group 3 two minutes before ischemia, and in group 4 two minutes before reperfusion. ATP-MgCl2 17.5 mumol/kg (0.25 cc/kg) was given two minutes before ischemia in group 5, and before reperfusion in group 6. The right kidneys of the rabbits were removed and thiobarbituric-acid reactive substances in the homogenates were measured. In addition, histopathological evaluation was performed. High lipid peroxidation products were recorded in groups 2-5, whereas in group 6, these levels were low similar to those obtained in Sham group (76.72 +/- 1.01 nmol/g tissue). On histopathological evaluation, a considerable cell damage resulting from I-R trauma especially in proximal tubules was observed. In groups which were under saline effect, no histopathological damage was found. Histophatological preservation was better in group 6 rather than in group 5. The results of this study indicate that ATP-MgCl2 is remarkably effective for preventing the lipid peroxidation if given before reperfusion but not before ischemia in experimental I-R injury in rabbit kidneys.

Endurance training attenuates the oxidative stress due to acute exhaustive exercise in rat liver.

The aim of this study was to investigate whether an 8-week treadmill training attenuates exercise-induced oxidative stress in rat liver. Male rats were divided into untrained and trained groups. Endurance training consisted of treadmill running at a speed of 2.1 km/h, 1.5 h/day, 5 days a week for 8 weeks. To see the effects of endurance training on acute exhaustive exercise induced oxidative stress, untrained and trained rats were further devided into two groups: animals killed at rest and those killed after acute exhaustive exercise, in which the rats run at 2.1 km/h (10% uphill) until exhaustion. Acute exhaustive exercise increased malondialdehyde level in untrained but not in trained rats. It decreased the activity of glutathione peroxidase and total (enzymatic plus non-enzymatic) superoxide scavenger activity in untrained rats and catalase activity in trained rats. However, it did not affect glutathione S-transferase, glutathione reductase, superoxide dismutase and non-enzymatic superoxide radical scavenger activities in both trained and untrained rats. On the other hand, endurance training decreased glutathione peroxidase and glutathione S-transferase activities. The results suggested that endurance training attenuated exercise-induced oxidative stress in liver, probably by preventing the decreases in glutathione peroxidase and total superoxide scavenger activities during exercise.

Effects of nerve growth factor on acetylcholinesterase activity of the proximal stump of the transected sciatic nerve.

28 rats were studied. They were divided into four groups of 7 rats of each one-day control animals (Group A), seven-day control animals (Group B), one-day nerve growth factor (NGF)-treated animals (Group C) and seven-day NGF-treated animals (Group D). In all animals, the right sciatic nerve was explored and completely transected using microscissors under a microscope. In NGF-treated animals, NGF (0.1 mg/kg NGF) was injected subcutaneously. In control animals, there was a statistically significant decrease in AChE activity in the proximal stump of the transected sciatic nerve at 7-day measurements (p < 0.05). In the NGF-treated groups, mean AChE activity in the proximal stump of the transected sciatic nerve was decreased at the 7-day measurement. AChE activity difference between control and NGF-treated groups, measured on the 7th day, are statistically significant (p < 0.01). These results demonstrate the effect of NGF on the cholinergic system.

The effects of calcium channel blocker and thyrotropin releasing hormone on acute necrotizing pancreatitis in rats.

The main purpose of this study was to investigate the influence of nimodipine, a calcium channel blocker (CCB) and thyroid-releasing hormone (TRH) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. CCB decreased blood pressure in rats in the control and pancreatitis groups. TRH corrected this decrease. CCB alone had no effect on PO2 serum amylase activity, calcium concentration, liver transaminases, lactate dehydrogenase or the degree of pancreatic damage, except for the serum concentration of creatinine. CCB+TRH reduced the concentrations of serum urea and creatinine, the degree of pancreatic damage, and increased PO2 and serum calcium concentration. CCB and CCB+TRH had no effect on pancreatic myeloperoxidase activity. CCB alone had no effect on the course of ANP, but CCB+TRH had beneficial effects on the course of the ANP and various systems.