Local Renin-Angiotensin System at Liver and Crosstalk with Hepatic Diseases

The systemic renin-angiotensin system mainly regulates blood pressure and maintains kidney function. Recent studies have realized that renin-angiotensin system (RAS) has been found in many tissues, such as heart, liver, and kidney. Although RAS in heart and kidney has been well documented, the RAS in the liver has been evaluated in a few studies. Therefore, this chapter will be assessed it. Based on findings, RAS in the liver has presented almost all of its components, such as angiotensin-I (Ang-I), angiotensin-II (Ang-II), angiotensin-converting enzyme (ACE), angiotensin type-1 receptor (AT1), angiotensin type-2 receptor (AT2), named as classical RAS. Expect these components, the local RAS has had alternative pathway components, including angiotensin-converting enzyme 2 (ACE2) and chymase. Classical RAS has an opposite effect of alternative RAS. Although these local RAS might not be such a crucial for the tissue, it could be a more vital function under pathophysiologic conditions. The chapter the local RAS in the liver the under both physiologic and pathophysiologic conditions is highlighted

Mitochondrial Dysfunction Associated with Doxorubicin

Cancer prevalence is scaling up each year. Anthracycline groups are still the best chemotherapeutic agent. The most popular anticancer drug in the group is doxorubicin (DOX). Unfortunately, DOX has potent toxicity on noncancerous tissues, e.g., heart, kidneys, etc. However, it is well documented that the severest toxicity of the drug affects heart tissue. Of course, some reasons have been suggested why and/or how the heart is so vulnerable to toxicity. The primary mechanism responsible for DOX’s cardiospecific toxicity remains unidentified so far; however, mitochondrial dysfunction induced by DOX is now considered one of the leading reasons for DOX’s toxicities and undesired side effects. Mitochondrial reactive oxygen production in the heart is a significant contributor to developing mitochondrial dysfunction-exposed DOX based on a variety of evidence. The objective of this review chapter is to critically evaluate and highlight the role of mitochondria in the development of DOX-induced cardiotoxicity

Pyrethroid Insecticides as the Mitochondrial Dysfunction Inducers

Pyrethroids are used to decrease vector-based health concerns and to increase field yield against agricultural pests. Their metabolism is a concern to disrupt a cell’s homeostatic machinery via reactive oxygen species (ROS) production. They interact with lipid membranes to damage the fine balance between membrane lipids and membrane proteins, especially mitochondrial substrate transporters and electron carriers. Pyrethroids cause a shift in the metabolic energy production strategy, resulting in ROS production and intracellular lipid deposition. The change of open/closed conformation of some mitochondrial membrane proteins increases the vulnerability of mitochondria to Ca2+ ions. Membrane lipid fluidity change is also a concern because of permeability to the substrates and ions to produce energy and other substrates necessary for the cell. Pyrethroids can change the Ca2+ signaling and its interaction with ROS signals via disruption of the fine balance between endoplasmic reticulum and mitochondria. They can disrupt the mitochondrial DNA (mtDNA) via their hydrophobic nature or their ROS production capacity. In conclusion, mitochondria are the center of pyrethroid toxicity, and dysfunction of this organelle via pyrethroid toxicity plays an important role in the fate of cell. Their lipophilic and pro-oxidative nature together with Ca2+ homeostasis plays a synergistic role in this mitochondrial effect

Oksidacijski i apoptotski učinci fluoksetina i njegova metabolita norfluoksetina u vodenbuhe Daphnia magna

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 depolarized 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.Cilj je ovoga istraživanja bio utvrditi oksidacijski i apoptotski potencijal fluoksetina, antidepresiva raširenoga u Turskoj i svijetu, i njegova metabolita norfluoksetina na modelu vodenbuhe Daphnia magna koji nije ciljani organizam djelovanja spojeva. Također smo željeli vidjeti kako izloženost toj skupini antidepresiva (specifičnih inhibitora ponovne pohrane serotonina) može utjecati na vodeni okoliš u kojem oni završe. Mlade jedinke vodenbuhe bile su izložene fluoksetinu (0,091 μg/L) i norfluoksetinu (0,011 μg/L), odvojeno i u kombinaciji, pri koncentracijama zamijećenima u okolišu I deseterostrukim okolišnim koncentracijama u trajanju od 21 dan (kronična izloženost). Jedna je skupina 17 dana starih vodenbuha također bila izložena stostrukoj okolišnoj koncentraciji u trajanju od četiri dana (subakutna izloženost). Potom su u životinja spektrofotometrijom izmjerene aktivnosti enzima glutation peroksidaze (GPx) i kolinesteraza (ChE) te razine reaktivnih tvari tiobarbituratne kiseline (TBARS) i ukupnih proteina. Potencijal mitohondrijske membrane (MMP) utvrđen je fluorescencijom, a proteini citokrom c i ERK1/2 Western blot metodom. Ovo je prvi put da su se u vodenbuhi citokrom c i ERK1/2 utvrđivali na razini proteina. Također je mikroskopski izmjerena dužina i širina oklopa i dužina repne bodlje vodenbuha. Pri okolišnim koncentracijama fluoksetin i norfluoksetin doveli su do povišene aktivnost ChE i većeg razmnožavanja te smanjenja (dužine i širine) karapaksa i repne bodlje u podmlatka i depolarizacije mitohondrijske membrane. Pri deseterostrukim okolišnim koncentracijama porasle su razine aktivnosti GPx, lipidne peroksidacije, citokroma c i ERK1/2 proteina. Norfluoksetin je pritom iskazao najsnažnije djelovanje te doveo do pada razmnožavanja. Slični su učinci primijećeni kod subakutne izloženosti stostrukim okolišnim koncentracijama fluoksetina i norfluoksetina, osim što je ona dovela i do pada ukupnih proteina. Naši rezultati potvrđuju da fluoksetin i norfluoksetin imaju oksidacijski i apoptotski učinak u vodenbuhe. Taj životinjski model može odlično poslužiti za stjecanje uvida u mehanizme toksičnoga djelovanja tvari u okolišu, no potrebna su daljnja istraživanja prije nego što ti mehanizmi postanu potpuno jasni

Mild regular treadmill exercise ameliorated the detrimental effects of acute sleep deprivation on spatial memory

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 x 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

Effects of Different Ammonia Levels on Tribenuron Methyl Toxicity in Daphnia magna

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 mu g/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.Adyaman University Scientific Research Commission [FBEYL/2014-0003]Adyaman University Scientific Research Commission supported this project (FBEYL/2014-0003). The authors thank Dr. Serdar Sonmez for his precious help in microscopic analysis. They also thank Dr. Muhsin Aydn for editing the manuscript to read better

Silencing HMGB1 expression inhibits adriamycin's heart toxicity via TLR4 dependent manner through MAPK signal transduction

Purpose: Adriamycin (APR) 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. Methods: 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 mu M concentration for 36 and 48 hours. Protein and genes expressions, apoptosis was measured. Results: 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. Conclusions: 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.Scientific and Technological Research Council of Turkey (TUBITAK) [114S118]This study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK) as a Project No: 114S118

EFFECT OF ELAMIPRETIDE ON MITOCHONDRIAL FUNCTIONS IN MICE WITH OXALATE NEPHROPATHY

[Abstract Not Available]Erciyes University Scientific Research Center [TDK-2019-9184]This study supported by the Erciyes University Scientific Research Center (TDK-2019-9184)

The Identification of Intracellular Signalling Pathway Through DHMGB1/TLR2 Axis on Myocardial Ischemia/Reperfusion Injury-Induced Apoptosis

[Abstract Not Available

Living with female rats exposed to restraint stress during pregnancy caused depressive-like behavior in male rats and stress-induced apoptosis

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 < 0.05). For the crossing number of squares in the center area, the main effect of the group was significant (p < 0.05). Stressed groups have a higher crossing number of squares in the center area compared to control groups. In the OFT, there was a significant increase in the time spent in the center area in the stress female and male group compared to the control female and male group (p < 0.05). For the EPM, time spent in the close arms was increased in the control male and stress male compared to the stress female group (p < 0.05). Female and male rats with PPD demonstrated apoptosis in neuron and glial cells in the hippocampus. Conclusions The present study demonstrates that RS results in PPD in females. Furthermore, it implicates RS as a potential risk factor for the development of postpartum mood disorder in males. Most of the studies on paternal PPD have been done by using self-report questionnaires. Studies on physiological and hormonal changes during the postpartum period among fathers would provide information on biological factors of depression.Adiyaman University Research Foundation [TIPFBAP/2013-0002]Adiyaman University Research Foundation, Grant/Award Number: TIPFBAP/2013-000