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OBJECTIVE Maternal mood disorders such as postpartum depression (PPD) can negatively affect the lives not only of mothers but also of partners. The purpose of this study investigates emotional behavior and hippocampal apoptosis alterations of the male live with a postpartum depressed female. METHODS Pregnant rats in the stress group were exposed to restraint stress (RS). The male rats who shared the same cages were not exposed to RS. To explain the consequences of depressive-like behavior and anxiety, animals were exposed to the forced swim test (FST), open-field test (OFT), and elevated plus maze (EPM). The apoptotic cell number was detected by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP biotin nick-end labeling (TUNEL) staining. RESULTS According to FST, PPD caused more immobility, reduced swimming, and climbing compared to control groups in the stressed female and male (p

The present study investigates the toxicity of the herbicide tribenuron methyl (TBM) as an anthropogenic agent and ammonia as an abiotic factor on Daphnia magna at environmentally relevant concentrations. These stressors may coexist in surface waters in agricultural regions. To achieve this objective, D. magna were exposed to TBM at a nominal concentration of 0.81 μg/L in association with a low ammonia (LA) concentration of 0.65 mg/L and a high ammonia (HA) concentration of 1.61 mg/L in acute toxicity tests of 96-h duration and chronic toxicity tests of 21-day duration. The D. magna also were exposed to TBM, HA, and LA singly. The D. magna were analysed for various biomarkers of sublethal toxicity. Glutathione peroxidase (GPx), glutathione S-transferase (GST), cholinesterase (ChE) enzyme activities, and levels of thiobarbituric acid reactive substances (TBARS) and total protein were determined spectrophotometrically. Mitochondrial membrane potential (MMP) was analysed by microscopy with fluorescence staining. Cytochrome c and 5' AMP-activated protein kinase (AMPK) were analysed by Western blotting. Morphometric properties were examined microscopically. This is the first study in which AMPK, an indicator of intracellular energy, was measured in D. magna. GST and ChE enzyme activities and TBARS and total protein levels did not change during acute exposures (i.e., 96 h) in all treatments. GPx activity increased in D. magna from the HA + TBM treatment compared with single-exposure groups. The level of cytochrome c protein was elevated in D. magna from the LA and LA + TBM treatments. AMPK protein levels increased in all treatments with daphnids, except in the LA group. MMP was depolarised in D. magna from all treatments, whereas the most notable change was observed in HA + TBM mixture group in chronic exposures. The results show that GST and ChE may not be sensitive biomarkers for evaluating the sublethal toxic effects to D. magna exposed to environmentally relevant concentrations of ammonia and TBM. Acute and chronic exposure to ammonia and TBM probably caused an energetic crisis in D. magna. Therefore, AMPK and MMP are promising biomarkers for these toxicants.

The aim of this study was to investigate the oxidative and apoptotic potential of fluoxetine, a widely used antidepressant in Turkey and the world, and of its metabolite norfluoxetine on a model non-target organism, Daphnia magna to see how exposure to this group of antidepressants (specific serotonin reuptake inhibitors) could affect the aquatic environment in which they end up. Juvenile D. magna specimens were chronically exposed to fluoxetine and norfluoxetine alone and in combination at concentrations found in the aquatic environment (0.091 and 0.011 μg/L, respectively) and to their 10-fold environmental concentrations for 21 days. Another group of 17-day-old animals were subacutely exposed to 100-fold environmental concentrations for four days. After exposure, we measured their glutathione peroxidase (GPx) and cholinesterase (ChE) activities, thiobarbituric acid-reactive substances (TBARS), and total protein content spectrophotometrically, while mitochondrial membrane potential (MMP) was analysed by fluorescence staining, and cytochrome c and ERK1/2 protein content by Western blotting. This is the first-time cytochrome c and ERK1/2 were determined at the protein level in D. magna. We also measured their carapace length, width, and caudal spine length microscopically. At environmental concentrations fluoxetine and norfluoxetine caused an increase in ChE activity and brood production. They also caused a decrease in juvenile carapace length, width, and caudal spine length and depolarised the mitochondrial membrane. At 10-fold environmental concentrations, GPx activity, lipid peroxidation levels, cytochrome c, and ERK1/2 protein levels rose. The most pronounced effect was observed in D. magna exposed to norfluoxetine. Norfluoxetine also decreased brood production. Similar effects were observed with subacute exposure to 100-fold environmental concentrations. However, total protein content decreased. All this confirms that fluoxetine and norfluoxetine have oxidative and apoptotic potential in D. magna. Daphnia spp. have a great potential to give us precious insight into the mechanisms of environmental toxicants, but there is still a long way to go before they are clarified in these organisms.

The aim of this study was to investigate the protective and therapeutic effects of thymoquinone against the negative effects of varicocele on testicular tissue and sperm morphology. Five groups were formed by random selection from a total of 40 adult male Wistar rats (n = 8). Thymoquinone (5 mg/kg/day) was administered intraperitoneally to the varicocele-dimethyl sulfoxide-olive oil-thymoquinone (VT) group and the sham-thymoquinone group. At the end of the 60th day, all groups were anaesthetised and the left testis was removed from the body quickly. One half of the testis tissue, which was divided into two, was separated for biochemical and Western blot analysis, while the other half were fixed in Bouin's fixative. As a result of biochemical, molecular and histopathological analyses, a statistically significant increase was found in the varicocele group testicular tissues in the malondialdehyde level, apoptotic index, Bax expression, cytochrome c expression and Bax/Bcl-2 ratio compared with the sham group. In addition, histopathological changes characterised by partial or complete degeneration of the germinal epithelium were observed in the seminiferous tubules in the same group. Total oxidant status level and sperm count with abnormal morphology increased in varicocele group, whereas total antioxidant status level decreased. In the VT group, all of the biochemical, molecular and histopathological changes detected in the varicocele group were statistically significantly reduced. When the findings obtained in this study are evaluated, it can be said that thymoquinone has the potential to be used as a preventive and therapeutic pharmacological agent in the medical treatment of varicocele. Although the exact mechanism of action of thymoquinone has not been fully elucidated, the findings obtained in this study support the view that thymoquinone showed a cytoprotective effect by reducing apoptosis, oxidative stress and lipid peroxidation.

Vulnerable areas like the hippocampus are sensitive to insults such as sleep deprivation (SD); they are also susceptible to environmental enrichment. Much evidence is accumulating that chronic sleep deprivation causes alterations in the hippocampus that responsible for spatial memory. However, there is conflicting about the differences between acute and chronic SD results. The purpose of this study was to determine the protective effects of mild treadmill exercise on acute SD rats. Four groups were created as control, exercise, sleep deprivation, exercise + sleep deprivation. Multiple platforms method was used to induce REM sleep deprivation (RD) for 48 h. The exercise was applied five days per week for four weeks (5 × 4). For the first and second weeks, the length of the exercise was 15 min in two sessions (5 min interval) followed by 15 min in three, 15 min in four sessions. Morris water maze (MWM) was used as a spatial memory test. Gene level was determined by using the qPCR technique. Malondialdehyde (MDA) content in the hippocampus was measured as an extent of peroxidative damage to lipids by using the ELISA method. 48 h RD impaired long-term spatial memory significantly. Mild, regular treadmill exercise ameliorated the detrimental effects of acute sleep deprivation on memory. There was no significant difference in MDA between groups. Hippocampal gene expression did not show any changes in all groups. Lack of correlation between memory impairment and levels of genes in the hippocampus is likely to be related to the differences in behavioral and genetic mechanisms.

Adriamycin (ADR) is a commonly used anti-cancer drug. ADR has toxic effects on cardiomyocytes and leads to heart failure. However, the underlying mechanism(s) by which ADR causes heart failure is still not clarified exactly. The aim of present study is to investigate whether ADR-induced heart failure is mediated via HMGB1/TLR4 to initiate the apoptosis through MAPK/AMPK pathways.H9c2 cell line was used to create four groups as a control, HMGB1 inhibition, ADR, ADR+HMGB1 inhibition. Silencing HMGB1 was performed with specific small interfering RNA. ADR was used at 2 µM concentration for 36 and 48 hours. Protein and genes expressions, apoptosis was measured.Although ADR decreased AMPK, pAMPK, ERK1/2, pERK1/2, p38, JNK protein expression, ADR+HMGB1 inhibition led to change those protein expressions. The effect of silencing of HMGB1 prevented apoptosis induced by ADR in the cells. HMGB1 caused changes a kind of posttranscriptional modification on the TLR4 receptor. This posttranscriptional modification of TLR4 receptor led to decreased AMPK protein level, but phosphorylated-AMPK. This alternation of AMPK protein caused enhancing of JNK protein, resulting from the decline of p38 and ERK protein levels. Eventually, JNK triggered apoptosis by a caspase-dependent pathway. The number of TUNEL positive and active caspase 8 cells at ADR was high, although HMGB1 silencing could decrease the cell numbers.Inhibition of HMGB1 might prevent the lose of the cardiac cell by inhibition of apoptotic pathway, therefore HMGB1 plays an essential role as amplifying on ADR toxicity on the heart by TLR4.

Diabetic patients are more susceptible to cardiovascular diseases than nondiabetic patients. In addition, cardiovascular diseases associated with diabetes are a major cause of mortality and morbidity among diabetic people in the world. Diabetes has alarmingly continued to affect human beings around the world, and still continues especially in developed or developing countries with an increasing pace. There is a growing need for innovative and effective therapies for the management of hyperglycemia and the improvement of cardiovascular complications in diabetic patients as well. Herein, herbal medicine or products play an essential role in developing a new cure or improving the efficiency of the antidiabetic drugs with the features of cardioprotective effects. This chapter highlights some promising herbal remedies, including resveratrol, berberine, ginseng, curcumin, and ginkgo in the therapeutic usage for controlling of hyperglycemia as well as in either preventing or decreasing the susceptibility of diabetic patients to cardiovascular diseases with a focus on possible underlying mechanisms of their effects.

Sevgiler, Yusuf/0000-0002-4373-2389 WOS: 000484035300029 PubMed: 31369761 Aims: Doxorubicin, an anticancer drug, has a toxic effect on many tissues such as heart, pancreas, liver, kidney, and testis. The aim of current study is to investigate whether melatonin would be protective in doxorubicin-induced beta (beta) cell toxicity via HMGB1/TLR2/TLR4/MAPK/NF-kappa B signaling pathway. Main methods: Human pancreatic beta cell (1.1B4) was used in the present study. Four experimental groups were created as control, melatonin (10 mu M), doxorubicin (2 mu M) and the combination of melatonin with doxorubicin. Following 24-h treatment, Mitogen-activated protein kinase (MAPKs), Toll like receptors (TLRs) including TLR2 and TLR4, pro-and anti-apoptotic protein expression levels were determined by western blotting. Total antioxidant (TAS), oxidant status (TOS) and oxidative stress index (OSI) of the cells as well as superoxide dismutase (SOD) levels were determined. Active caspase-8 activity was measured and TUNEL staining was performed to study apoptotic pathways. Mitochondrial membrane potential (MMP), some protein expressions and F-actin distribution were analyzed. Key findings: Doxorubicin caused to depolarize MMP, resulting in enhancing apoptosis by activation of caspase-8 via MAPKs/NF-kappa B pathway via elevation of TOS and decreasing TAS. Also, doxorubicin destroyed F-actin distribution and elevated TLR2 and some apoptotic proteins, including Bax. However, co-treatment of melatonin with doxorubicin could reverse depolarization of MMP and inhibition of apoptosis through MAPK/NF-kappa B signaling by decreasing TOS and increasing TAS. The co-treatment reversed the alternations of TLR2, TLR4, MAPKs and apoptotic protein expressions induced by doxorubicin. Significance: Melatonin could be a good candidate against pancreatic beta cell toxicity-induced by doxorubicin through TLR2/TLR4/MAPK/NF-kappa B pathways. Nigde Omer Halisdemir University Scientific Research Projects Coordination Unit, Nigde/Turkey [SSB2017/01-BAGEP] This work was supported by the Nigde Omer Halisdemir University Scientific Research Projects Coordination Unit, Nigde/Turkey [grant number SSB2017/01-BAGEP]

Phthalate plasticizers used in a wide range of common plastic products are released into the environment and may pose a risk of increased incidence of type 2 diabetes. In this work, we studied the effects of monoethyl phthalate (MEP), the metabolite of diethyl phthalate, exposure on 1.1B4 human pancreatic beta cells at low doses (1–1000 nM). We showed that MEP treatment induced proliferation in 1.1B4 cells. Also PCNA protein expression levels were increased related to proliferation induction. It has been noted that phthalates can exert estrogen mediated response by interacting with ER. In our study 24 h MEP treatment decreased ERα protein expression level conversely it increased the same protein expression level after 72 h treatment. Also MEP treatment decreased ERβ expression after 72 h at 1.1B4 cells. Our results further show that insulin content of 1.1B4 cells were increased with low dose MEP treatment. Along with our insulin content results, PDX- 1 expression levels were also increased at 1.1B4 cells with MEP treatment. These findings suggest that MEP acts as an estrogenic compound and PPARγ agonist at lower concentrations. Also it should be noted that PDX-1 may be a critical regulator of 1.1B4 cells treated with MEP.

BACKGROUND Doxorubicin (brand name: Adriamycin®) is used to treat solid tissue cancer but it also affects noncancerous tissues. Its mechanism of cytotoxicity is probably related to increased oxidation, mitochondrial dysfunction, and apoptosis. Melatonin is reported to have antiapoptotic and antioxidative effects. The aim of this study was to determine whether melatonin would counteract in vitro cytotoxicity of doxorubicin in mouse fibroblasts and determine the pathway of its action against doxorubicin-induced apoptosis. MATERIAL AND METHODS We measured markers of apoptosis (cytochrome-c, mitochondrial membrane potential, and apoptotic cell number) and oxidative stress (total oxidant and antioxidant status) and calculated oxidant stress index in 4 groups of fibroblasts: controls, melatonin-treated, doxorubicin-treated, and fibroblasts concomittantly treated with a combination of melatonin and doxorubicin. RESULTS Melatonin given with doxorubicin succesfully countered apoptosis generated by doxorubicin alone, which points to its potential as a protective agent against cell death in doxorubicin chemotherapy. This also implies that patients should be receiving doxorubicin treatment when their physiological level of melatonin is at its highest, which is early in the morning. CONCLUSIONS This physiological level may not be high enough to overcome doxorubicin-induced oxidative stress, but adjuvant melatonin treatment may improve quality of life. Further research is needed to verify our findings.

Diabetes mellitus is a global disease, of which prevalence increases rapidly. It causes severe microvascular and macrovascular complications such as retinopathy, nephropathy, cardiomyopathy, neuropathy etc. These contribute to morbidity and mortality in diabetic patients. Therefore, it is important to find an effective therapy method(s) for the protection of body from diabetes-related complications. In this sense, herbal products are of great importance. Herein, this review will highlight the potential usage of some herbals as a preventive and/or therapeutic approach in diabetes and discusses the possible underlying mechanisms of anti-diabetic actions.&nbsp

PubMedID: 28635325 Background: High dietary salt, as well as renal mass reduction, is known to decrease baroreflex sensitivity in rats. However, the effect of high salt intake on baroreflex sensitivity is unknown in reduced renal mass (RRM) hypertension; therefore, the aim of this study was to investigate the effects of salt loading on arterial baroreflex sensitivity and mean arterial pressure (MAP) in RRM hypertension. Methods: Both RRM and sham-operated control (SO) rats were loaded with 0.25 or 0.5% NaCl for five weeks. Plasma Na+, K+, and creatinine levels were measured, and baroreflex sensitivity was evaluated before and after ß1 blockade. In addition, cardiac vagal tone and intrinsic heart rate (IHR) were measured. RESULTS: RRM decreased full baroreflex sensitivity of the tachycardic response under 0.5% NaCl loading and the parasympathetic bradycardic response under 0% NaCl loading. The NaCl loading did not affect the severity of RRM hypertension. Cardiac vagal tone and IHR decreased in RRM rats versus SO controls under all NaCl loading conditions. RRM decreased plasma K+ under 0% NaCl loading and increased plasma Na+ under 0.5% NaCl loading. High (0.5%) NaCl loading decreased IHR and increased plasma creatinine and left ventricular weight in RRM rats. CONCLUSIONS: RRM in combination with 0.5% NaCl loading led to a decrease in the sensitivity of full baroreflex and of the parasympathetic component of baroreflex. Changes in plasma Na+ and K+ levels, due to NaCl loading, may have contributed to the decrease in baroreflex sensitivities and IHR but had no effect upon MAP in RRM rats. © 2017 Taylor & Francis.

Adriamycin (ADR) is a chemotherapeutic drug. Its toxicities may associate with mitochondriopathy. Selenium (Se) is a trace element for essential intracellular antioxidant enzymes. However, there is lack of data related to the effect of selenium on the liver tissue of ADR-induced mitochondrial dysfunction. The study was to investigate whether Se could restore mitochondrial dysfunction of liver-exposed ADR. Rats were divided into four groups as a control, ADR, Se, co-treated ADR with Se groups. The biochemical measurements of the liver were made in mitochondrial and cytosol. ATP level and mitochondria membrane potential (MMP) were measured. Total oxidant (TOS), total antioxidant (TAS) status were determined and oxidative stress index (OSI) was calculated by using TOS and TAS. ADR increased TOS in mitochondria and also oxidative stress in mitochondria. ADR sligtly decreased MMP, and ATP level. Partial recovery of MMP by Se was able to elevate the ATP production in cotreatment of ADR with Se. TOS in mitochondria and cytosol was diminished, as well as OSI. We concluded that selenium could potentially be used against oxidative stress induced by ADR in liver, resulting from the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.

Background Chronic kidney disease (CKD) is a major health problem worldwide. Oxidative stress is one of the mediators of this disease. Systemic complications of oxidative stress are involved in the pathogenesis of hypertension, endothelial dysfunction, shortened erythrocyte lifespan, deformability, and nitric oxide (NO) dysfunction. L-carnosine is known as an antioxidant. In this study, our aim was to investigate the effect of carnosine on hemorheologic and cardiovascular parameters in CKD-induced rats. Material/Methods We used 4-month-old male Sprague-Dawley rats divided into 4 groups of 6 rats each. Three days after subtotal nephrectomy and sham operations, the surviving rats were divided into the 4 groups; 1) Sham (S), 2) Sham+Carnosine (S-C), 3) Subtotal nephrectomy (Nx), and 4) Subtotal nephrectomy + Carnosine (N-C). Carnosine was injected intraperitoneally (i.p.) (50 mg/kg) for 15 days. The control group received the same volume of physiological saline. Results In CKD rats, malondialdehyde (MDA) levels were increased, and NO and RBC deformability were decreased compared to Sham. Carnosine treatment decreased MDA levels, improved RBC (red blood cell) ability to deform, and increased NO levels. However, carnosine did not affect blood pressure levels in these rats. Conclusions We found that carnosine has beneficial effects on CKD in terms of lipid peroxidation and RBC deformability. Carnosine may have a healing effect in microcirculation level, but may not have any effect on systemic blood pressure in CKD-induced rats.

Guven, Celal/0000-0003-0499-7787 WOS: 000388507800001 PubMed: 27889788 Background: Myocardial ischemia and reperfusion lead to impairment of electrolyte balance and, eventually, lethal arrhythmias. The aim of this study was to investigate the effects of pharmacological inhibition of angiotensin-II (Ang-II) production on heart tissue with ischemia-reperfusion damage, arrhythmia, and oxidative stress. Material/Methods: Rats were divided into 4 groups: only ischemia/reperfusion (MI/R), captopril (CAP), aliskiren (AL), and CAP+AL. The drugs were given by gavage 30 min before anesthesia. Blood pressure and electrocardiography (ECG) were recorded during MI/R procedures. The heart tissue and plasma was kept so as to evaluate the total oxidant (TOS), antioxidant status (TAS), and creatine kinase-MB (CK-MB). Results: Creatine kinase-MB was not different among the groups. Although TAS was not affected by inhibition of Ang-II production, TOS was significantly lower in the CAP and/or AL groups than in the MI/R group. Furthermore, oxidative stress index was significantly attenuated in the CAP and/or AL groups. Captopril significantly increased the duration of VT during ischemia; however, it did not have any effect on the incidence of arrhythmias. During reperfusion periods, aliskiren and its combinations with captopril significantly reduced the incidence of other types of arrhythmias. Captopril alone had no effect on the incidence of arrhythmias, but significantly increased arrhythmias score and durations of arrhythmias during reperfusion. MAP and heart rate did not show changes in any groups during ischemic and reperfusion periods. Conclusions: Angiotensin-II production appears to be associated with elevated levels of reactive oxygen species, but Ang-II inhibitions increases arrhythmia, mainly by initiating ventricular ectopic beats. Research Foundation of Erciyes UniversityErciyes University [TSY-09-734] This study was financially supported by the Research Foundation of Erciyes University (TSY-09-734)

Doxorubicin and cyclophosphamide are widely used anticancer drugs with substantial toxicity in noncancerous tissue resulting from oxidative damage. Quercetin is a potent antioxidant compound. We hypothesized that quercetin administration would ameliorate the toxic effects of doxorubicin and cyclophosphamide prior to pregnancy.Cyclophosphamide, 27 mg/kg, and doxorubicin, 1.8 mg/kg, were administered to rats as intraperitoneal doses once every 3 weeks for a total of 10 weeks with or without concurrent treatment with quercetin, 10 mg/kg/d. Oxidative stress parameters were evaluated in maternal kidney and liver tissues after gestation.Doxorubicin was associated with elevated kidney tissue malondialdehyde relative to the controls and quercetin only treatment (P.05). Both cyclophosphamide and doxorubicin were associated with elevated malondialdehyde levels in the liver tissue (P.05). Doxorubicin treatment was associated with decreased liver glutathione peroxidase (P.05). Quercetin treatment suppressed the accumulation of malondialdehyde and increased glutathione peroxidase levels during doxorubicin and cyclophosphamide treatment (P.05) Conclusions. Treatment with quercetin in patients receiving doxorubicin and cyclophosphamide results in therapeutic restoration of homeostatic expression of the antioxidant parameters, reducing oxidative damage to the liver and kidney.

Ventricular ATP-sensitive potassium (KATP) channels link intracellular energy metabolism to membrane excitability and contractility. Our recent proteomics experiments identified plakoglobin and plakophilin-2 (PKP2) as putative KATP channel-associated proteins. We investigated whether the association of KATP channel subunits with junctional proteins translates to heterogeneous subcellular distribution within a cardiac myocyte. Co-immunoprecipitation experiments confirmed physical interaction between KATP channels and PKP2 and plakoglobin in rat heart. Immunolocalization experiments demonstrated that KATP channel subunits (Kir6.2 and SUR2A) are expressed at a higher density at the intercalated disk in mouse and rat hearts, where they co-localized with PKP2 and plakoglobin. Super-resolution microscopy demonstrate that KATP channels are clustered within nanometer distances from junctional proteins. The local KATP channel density, recorded in excised inside-out patches, was larger at the cell end when compared with local currents recorded from the cell center. The KATP channel unitary conductance, block by MgATP and activation by MgADP, did not differ between these two locations. Whole cell KATP channel current density (activated by metabolic inhibition) was ∼40% smaller in myocytes from mice haploinsufficient for PKP2. Experiments with excised patches demonstrated that the regional heterogeneity of KATP channels was absent in the PKP2 deficient mice, but the KATP channel unitary conductance and nucleotide sensitivities remained unaltered. Our data demonstrate heterogeneity of KATP channel distribution within a cardiac myocyte. The higher KATP channel density at the intercalated disk implies a possible role at the intercellular junctions during cardiac ischemia.

Since ion channels move electrical charge during their activity, they have traditionally been studied using electrophysiological approaches. This was sometimes combined with mathematical models, for example with the description of the ionic mechanisms underlying the initiation and propagation of action potentials in the squid giant axon by Hodgkin and Huxley. The methods for studying ion channels also have strong roots in protein chemistry (limited proteolysis, the use of antibodies, etc.). The advent of the molecular cloning and the identification of genes coding for specific ion channel subunits in the late 1980s introduced a multitude of new techniques with which to study ion channels and the field has been rapidly expanding ever since (e.g. antibody development against specific peptide sequences, mutagenesis, the use of gene targeting in animal models, determination of their protein structures) and new methods are still in development. This review focuses on techniques commonly employed to examine ion channel function in an electrophysiological laboratory. The focus is on the K ATP channel, but many of the techniques described are also used to study other ion channels.

Manipulations of thyroid hormones have been shown to influence learning and memory. Although a large body of literature is available on the effect of thyroid hormone deficiency on learning and memory functions during the developmental stage, electrophysiological and behavioural findings, particularly on propylthiouracil administration to adult normothyroid animals, are not satisfactory. The experiments in the present study were carried out on 12 adult male Wistar rats aged 6-7 months. Hypothyroidism was induced by administering 6-n-propyl-2-thiouracil in their drinking water for 21 days at a concentration of 0.05%. The spatial learning performance of hypothyroid and control rats was studied on a Y-maze. The rats were then placed in a stereotaxic frame under urethane anaesthesia. A bipolar tungsten electrode was used to stimulate the medial perforant path. A glass micropipette was inserted into the granule cell layer of the ipsilateral dentate gyrus to record field excitatory post-synaptic potentials. After a 15-min baseline recording of field potentials, long-term potentiation was induced by four sets of tetanic trains. The propylthiouracil-treated rats showed a significantly attenuated input-output (I/O) relationship when population spike (PS) amplitudes and field excitatory post-synaptic potentials (fEPSP) were compared. fEPSP and PS latencies were found to be longer in the hypothyroid group than in the control group. The PS amplitude and fEPSP slope potentiations in the hypothyroid rats were not statistically different from those in the control rats, except for the field EPSP slope measured in the post-tetanic and maintenance phases. The hypothyroid rats also showed lower thyroxine levels and poor performance in the spatial memory task. The present study provides in vivo evidence for the action of propylthiouracil leading to impaired synaptic plasticity, which might explain deficit in spatial memory tasks in adult hypothyroid rats.

Although adriamycin (ADR) exhibits high anti-tumor efficacy in vitro, its clinical use in cancer chemotherapy is limited due to its high renal toxicity. This study investigated the mechanism of ADR nephropathy and the protective effect of selenium on ADR-induced kidney damage by analyzing of the relationship between selenium and mitochondria. Rats were divided into four groups. The first group was injected with saline i.p. for 21 days, the second group received the 4 mg/kg i.p. ADR every alternate day for 8 days, the third group received the 50 mu g/kg i.p. Se for 21 days, and the fourth group received the Se. ADR co-administration i.p. blood pressures were assessed, the mitochondrial membrane potential (MMP) was assessed, and the adenosine triphosphate (ATP) levels were determined. The total antioxidant (TAS) and oxidant status (TOS) in cytosol, the mitochondria of kidney cells, and plasma were measured. Mitochondrial TAS decreased and TOS increased in the ADR group compared to the Se group. ADR-treated rats showed significantly lower MMP than did the control and Se groups. MMP was significantly restored in the Se + ADR group through selenium treatment compared to the ADR group (p < 0.01). In the ADR group, a reduction in ATP content was seen compared to the control and Se groups (p < 0.01). ATP level was significantly restored through treatment with selenium in the Se + ADR group compared to the ADR group (p < 0.01). We concluded that selenium is effective in vivo against ADR-induced kidney damage via the restoration of TAS and TOS, which prevented mitochondrial damage.

The aim of this study was to investigate the effects of carnosine, a biological antioxidant, on the acute cardiac damage induced by a single dose of adriamycin in rats. The experimental design consisted of four groups: Control (saline, i.p.); carnosine (CAR; 10 mg/kg/day, i.p.); adriamycin (ADR; 16 mg/kg on the 14th day, i.p.); carnosine with adriamycin. Carnosine was given 2 weeks before and following adriamycin treatment. Blood samples were collected for analysis of plasma creatine kinase (CK) and plasma antioxidant enzymes, glutathione peroxidase (GSH-Px), Cu, Zn-superoxide dismutase (SOD), and catalase (CAT). The rats were then sacrificed, and the hearts were autopsied for hemodynamic study, ECG, and histopathological examination. Results showed that adriamycin produced evident cardiac damage revealed by hemodynamic change, histological alterations, decreased plasma antioxidant enzymes activities, and increased lipid peroxidation to the control value. Carnosine treatment led to significant attenuation of adriamycin-induced cardiomyopathy revealed by normalization of the LVDP, ST interval, CK, SOD, GSH-Px, CAT, and lipid peroxidation. An increase in oxidative stress and inactivation of SOD, GSH-Px, CAT by a single dose of adriamycin were prevented when carnosine was given 2 weeks before and on the same day adriamycin treatment was administered.

Adriamycin (ADR) increases the production of reactive oxygen species (ROS), which diminishes mitochondrial function. Angiotensin-II stimulates mitochondrial ROS generation. The aim of the study was to examine whether angiotensin converting enzyme (ACE) or renin inhibitors protect against ADR-induced mitochondrial function impairment. Rats were divided into five groups as control, ADR, co-treatment ADR with captopril, co-treatment ADR with aliskiren, co-treatment ADR with both captopril and aliskiren. Left ventricular function and blood pressures were assessed at the end of treatment period. Mitochondrial membrane potential (MMP) and ATP levels were determined. ADR treatment decreased the left ventricular pressure and increased the left ventricular end-diastolic pressure. ADR decreased MMP and ATP levels in myocyte mitochondria due to increasing oxidative stress. ADR decreased MMP and ATP levels due to increased oxidative stress in the heart. Inhibitors of ACE and renin caused the elevation of the decreased of MMP and ATP levels. The pathologic changes in electrocardiogram, blood pressure and left ventricular function were decreased by inhibition of Ang-II production. We concluded that inhibitors of angiotensin II are effective against ADR cardiotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo., Adriamycin (ADR) increases the production of reactive oxygen species (ROS), which diminishes mitochondrial function. Angiotensin-II stimulates mitochondrial ROS generation. The aim of the study was to examine whether angiotensin converting enzyme (ACE) or renin inhibitors protect against ADR-induced mitochondrial function impairment.Rats were divided into five groups as control, ADR, co-treatment ADR with captopril, co-treatment ADR with aliskiren, co-treatment ADR with both captopril and aliskiren. Left ventricular function and blood pressures were assessed at the end of treatment period. Mitochondrial membrane potential (MMP) and ATP levels were determined. ADR treatment decreased the left ventricular pressure and increased the left ventricular end-diastolic pressure. ADR decreased MMP and ATP levels in myocyte mitochondria due to increasing oxidative stress. ADR decreased MMP and ATP levels due to increased oxidative stress in the heart. Inhibitors of ACE and renin caused the elevation of the decreased of MMPand ATP levels. The pathologic changes in electrocardiogram, blood pressure and left ventricular function were decreased by inhibition of Ang-II production. We concluded that inhibitors of angiotensin II are effective against ADR cardiotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.&nbsp

Adriamycin (ADR) is commonly used for many solid tumor treatments. Its clinical utility is, however, largely limited by the adverse reactions, are known to be nephrotoxic. The mechanism by which it induces kidney damage is still not completely understood, but its nephrotoxicity might relate to increase reactive oxidant status (ROS), mitochondrial dysfunction. Until now, neurohormonal activation of it is unclear. ADR might activate the renin angiotensin system. Angiotensin-II also induced ROS and mitochondrial dysfunction. The aim of this study was to investigate whether angiotensin-II production inhibition has the protective effect on attenuation of mitochondrial function in rats with acute ADR-nephrotoxicity or not. Rats were divided into five groups as a control, ADR, co-treated ADR with captopril (CAP), co-treated ADR with Aliskren, co-treated ADR with both CAP and Aliskren groups. Creatinine kinase (CK) levels were measured at the end of treatment period. The kidneys were homogenized and biochemical measurements were made in mitochondria, cytosol. Mitochondria membrane potential (MMP) and ATP levels were determined. ADR increased CK levels and oxidative stress in mitochondria too (p

Coronary heart disease remains the principle cause of mortality in the United States. During aging, the efficiency of the cardiovascular system is decreased and the aged heart is less tolerant to ischemic injury. ATP-sensitive K(+) (K(ATP)) channels protect the myocardium against ischemic damage. We investigated how aging affects cardiac K(ATP) channels in the Fischer 344 rat model. Expression of K(ATP) channel subunit mRNA and protein levels was unchanged in hearts from 26-month-old vs. 4-month-old rats. Interestingly, the mRNA expression of several other ion channels (> 80) was also largely unchanged, suggesting that posttranscriptional regulatory mechanisms occur during aging. The whole-cell K(ATP) channel current density was strongly diminished in ventricular myocytes from aged male rat hearts (also observed in aged C57BL/6 mouse myocytes). Experiments with isolated patches (inside-out configuration) demonstrated that the K(ATP) channel unitary conductance was unchanged, but that the inhibitory effect of cytosolic ATP on channel activity was enhanced in the aged heart. The mean patch current was diminished, consistent with the whole-cell data. We incorporated these findings into an empirical model of the K(ATP) channel and numerically simulated the effects of decreased cytosolic ATP levels on the human action potential. This analysis predicts lesser activation of K(ATP) channels by metabolic impairment in the aged heart and a diminished action potential shortening. This study provides insights into the changes in K(ATP) channels during aging and suggests that the protective role of these channels during ischemia is significantly compromised in the aged individual.

AMPK is an important sensor of cellular energy levels. The aim of these studies was to investigate whether cardiac K(ATP) channels, which couple cellular energy metabolism to membrane excitability, are regulated by AMPK activity. We investigated effects of AMPK on rat ventricular K(ATP) channels using electrophysiological and biochemical approaches. Whole-cell K(ATP) channel current was activated by metabolic inhibition; this occurred more rapidly in the presence of AICAR (an AMPK activator). AICAR had no effects on K(ATP) channel activity recorded in the inside-out patch clamp configuration, but ZMP (the intracellular intermediate of AICAR) strongly activated K(ATP) channels. An AMPK-mediated effect is demonstrated by the finding that ZMP had no effect on K(ATP) channels in the presence of Compound C (an AMPK inhibitor). Recombinant AMPK activated Kir6.2/SUR2A channels in a manner that was dependent on the AMP concentration, whereas heat-inactivated AMPK was without effect. Using mass-spectrometry and co-immunoprecipitation approaches, we demonstrate that the AMPK α-subunit physically associates with K(ATP) channel subunits. Our data demonstrate that the cardiac K(ATP) channel function is directly regulated by AMPK activation. During metabolic stress, a small change in cellular AMP that activates AMPK can be a potential trigger for K(ATP) channel opening. This article is part of a Special Issue entitled "Local Signaling in Myocytes".

Adriamycin (ADR) causes morphological and functional alterations in mitochondrial structure in the heart. The study's aim was to determine whether there is a protective effect of selenium (Se) on ADR-induced cardiac damage. Rats were divided into four groups: The first group was injected saline intraperitoneally (i.p.) for 21 days; the second group received 4 mg/kg i.p. ADR every alternate day for 8 days; the third group received 50 mu g/kg i.p. Se for 21 days; and the fourth received the Se (for 21 days) and ADR (for 8 days) coadministration i.p. Left ventricular functions, electrocardiography parameters, and blood pressures were assessed. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) level, and thioredoxin reductase (TrxR) activity were determined. Total antioxidant (TAS) and oxidant status (TOS) in cytosol, mitochondria of myocytes, and plasma were measured. Left ventricular data demonstrated left ventricular systolic pressure (LVSP) decreased, left ventricular developed pressure (LVDP) decreased, and left ventricular end-diastolic pressure (LVEDP) increased in ADR-treated animals, compared to the control and Se groups. ADR decreased the membrane potential and ATP level in myocyte mitochondria. TrxR activity decreased in the ADR group, compared to the Se group. Cytosolic and mitochondrial TAS decreased and mitochondrial and plasma TOS increased in the ADR group, compared to the control. The coadministration of Se with ADR attenuated left ventricular dysfunction, improved MMP and ATP levels, and prevented oxidative stress by increasing antioxidants (especially TrxR) and decreasing oxidants. We concluded that Se is effective against ADR-induced cardiac damage via the restoration of TAS and TOS, which prevented mitochondrial damage.

Amaç: Oksidatif stres, adriamisinin (ADR) neden olduğu kardiyak fonksiyon bozukluğu patogenezinde, önemli faktörlerden birisidir. Bu çalışmadasıçanlarda adriamisin ile oluşturulan kalp hasarı üzerine karnozinin antioksidan savunma etkisi araştırılmıştır.Yöntemler: Dişi Spraque Dawley sıçanlar 4 gruba ayrıldı; kontrol (KONT, n=8, serum fizyolojik i.v.); karnozin (KAR, n=8, 10 mg/kg/gün, i.v.) sadeceadriamisin (ADR, n=10, 4 mg/kg dört defa, iki gün ara ile toplam 8 gün, i.v.); karnozin ile adriamisin (KAR+ADR, n=10). Karnozin, adriamisinden birhafta önce verilmeye başlandı ve sonraki bir hafta adriamisinle birlikte verildi. Fizyolojik fonksiyon değerlendirmelerinden sonra biyokimyasaltayinler için kan örnekleri alındı. Kalpler hemodinamik çalışma için izole edildi. Gruplar arası farklılıkların belirlenmesi için ANOVA ve posthocTukey testi kullanıldı.Bulgular: Adriamisin, belirgin bir şekilde kalp hasarı yapmış olup; karnozin ve kontrol grubuna göre, hemodinamik değişiklikler [azalmış solventrikül basınç gelişimi (p, Objective: Oxidative stress is one of the major factors involved in the pathogenesis of adriamycin (ADR)-induced cardiac dysfunction. Thepresent study examined the antioxidant protective effects of carnosine (CAR) on adriamycin-induced cardiac damage in rats.Methods: Female Sprague Dawley rats were divided into four groups. Control (CONT, n=8, saline only i.v.); carnosine (CAR, n=8.10 mg/kg/day,i.v.); adriamycin (ADR, n=10.4 mg/kg four times every 2 days for 8 days, i.v.) alone and carnosine with adriamycin (CAR+ADR, n=10). Carnosinewas given one week before adriamycin treatment and following one week with adriamycin treatment. After measurement of physiological functions,blood samples were collected for biochemical assays. The hearts were excised for hemodynamic study. Comparisons between differentgroups were made using ANOVA and posthoc Tukey test.Results: Adriamycin produced evident cardiac damage revealed by; hemodynamic changes - decreased left ventricular developed pressure(p

Background: Manipulating thyroid hormones has been shown to influence learning and memory. Although a large body of literature is available on the effects of thyroid hormone deficiency on learning and memory functions during developmental or adult-onset hypothyroidism, electrophysiological findings are limited. This limitation is especially notable with respect to thyroxine administration in adult, normothyroid animals. Methods: Experiments were carried out on 12 adult male Wistar rats, each 9–10 months of age. Rats were randomly divided into hyperthyroid (0.2 mg/kg/day intraperitoneal thyroxine injection, for 21 days) and control groups (n = 6 animals in each group). Following spatial learning performance tests on hyperthyroid and control groups, rats were anesthetized with urethane and placed in a stereotaxic frame. A bipolar, tungsten electrode was used to stimulate the medial perforant path. A glass micropipette was inserted within the granule cell layer of the ipsilateral dentate gyrus to record field excitatory postsynaptic potentials (fEPSP). Following a 15-min baseline recording of fEPSPs, long-term potentiation (LTP) was induced by four sets of tetanic pulse trains. Results: Thyroxine-treated rats showed significantly worse performance in the spatial memory task and attenuated input-output relationships in the electrophysiological analyses. Treated rats also showed a lower efficacy of LTP induction when compared with controls. Conclusion: The present study provides clear in vivo evidence for the action of L-thyroxine in the impairment of synaptic plasticity and in inducing spatial memory task deficits in adult rats. These findings may explain the complaints of cognitive function reductions in hyperthyroid patients.

Adriamycin (ADR) increases the production of reactive oxygen species, which diminishes mitochondrial function. Angiotensin-II stimulates mitochondrial-ROS generation. The aim of the study was to examine whether angiotensin converting enzyme (ACE) or renin inhibitors (captopril and/or aliskiren) protect against ADR-induced mitochondrial function impairment.Rats were divided into five groups (n=14 each). The control group was treated with saline. ADR was administered to the four other groups every 2 days (4 mg/kg i.p). One of these was co-administered captopril (10 mg/kg/daily) and the other was co-treated with aliskiren (50 mg/kg/daily), while another was co-treated with both captopril and aliskiren (captopril and aliskiren were gavage administration daily for 8 days). Left ventricular function, ECG variables and blood pressure were assessed at the end of treatment period. The hearts were homogenized and biochemical measurements were made in mitochondria, cytosol and plasma. Mitochondria membrane potential (MMP), ATP levels were determined.ADR decreased in the left ventricular developed pressure (LVDP), the maximal rate of rise of pressure (+dP/dt), and increased in the left ventricular end-diastolic pressure (LVEDP). ADR increased ST interval and decreased mean blood pressure. ADR increased oxidative stress in mitochondrial, cytosolic and plasma. ADR decreased MMP and ATP level in myocyte mitochondria. ADR co-administration with renin and ACE inhibitors improved the dissipation of MMP. The decreased in ATP level was restored by treatment with inhibitors of ACE and renin. By maintaining normal levels of mitochondrial MMP and ATP, captopril and aliskiren treatment prevented the pathologic changes in ECG, blood pressure and left ventricular function.We concluded that inhibitors of angiotensin II are effective against ADR cardiotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.