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L-3,3',5-Triiodothyronine (T3)-induced liver oxidative stress underlies significant protein oxidation, which may trigger the unfolded protein response (UPR). Administration of daily doses of 0.1mg T3 for three consecutive days significantly increased the rectal temperature of rats and liver O2 consumption rate, with higher protein carbonyl and 8-isoprostane levels, glutathione depletion, and absence of morphological changes in liver parenchyma. Concomitantly, liver protein kinase RNA-like endoplasmic reticulum (ER) kinase and eukaryotic translation initiator factor 2α were phosphorylated in T3-treated rats compared to controls, with increased protein levels of binding immunoglobulin protein and activating transcription factor 4. In addition, higher mRNA levels of C/EBP homologous protein, growth arrest and DNA damage 34, protein disulfide isomerase, and ER oxidoreductin 1α were observed, changes that were suppressed by N-acetylcysteine (0.5 g/kg) given before each dose of T3. In conclusion, T3-induced liver oxidative stress involving higher protein oxidation status has a causal role in UPR development, a response that is aimed to alleviate ER stress and promote cell survival., (Copyright © 2015 Elsevier Inc. All rights reserved.)

3,3-5-L-Triiodothyronine (T(3)) exerts significant protection against ischemia-reperfusion (IR) liver injury in rats. Considering that the underlying mechanisms are unknown, the aim of this study was to assess the involvement of inducible nitric oxide synthase (iNOS) expression and oxidative stress in T(3) preconditioning (PC). Male Sprague-Dawley rats given a single dose of 0.1 mg of T(3)/kg were subjected to 1-hour ischemia followed by 20 hours reperfusion, in groups of animals pretreated with 0.5 g of N-acetylcysteine (NAC)/kg 0.5-hour prior to T3 or with the respective control vehicles. At the end of the reperfusion period, liver samples were taken for analysis of iNOS mRNA levels (RT-PCR), liver NOS activity, and hepatic histology. T(3) protected against hepatic IR injury, with 119% enhancement in liver iNOS mRNA/18S rRNA ratios (p<0.05) and 12.7-fold increase (p<0.05) in NOS activity in T(3)-treated animals subjected to IR over values in control-sham operated rats, with a net 7.7-fold enhancement (p<0.05) in the net effect of T(3) on liver iNOS expression and a net enhancement of 0.58 units in NOS activity, changes that were abolished by NAC treatment before T(3). It is concluded that T(3)-induced liver PC is associated with upregulation of iNOS expression as a protective mechanisms against IR injury, which is achieved through development of transient and reversible oxidative stress.

Hepatic ischemia-reperfusion (IR) injury, a major clinical drawback during surgery, is abolished by L-3,3',5-triiodothyronine (T(3)) administration. Considering that the triggering mechanisms are unknown, the aim of this study is to assess the role of oxidative stress in T(3) preconditioning using N-acetylcysteine (NAC) before T(3) administration. Male Sprague-Dawley rats given a single dose of 0.1 mg of T(3)/kg were subjected to 1 h ischemia followed by 20 h reperfusion, in groups of animals pretreated with 0.5 g of NAC/kg 0.5 h before T(3) or with the respective control vehicles. At the end of the reperfusion period, blood and liver samples were taken for analysis of serum aspartate aminotransferase (AST) and hepatic histology, glutathione (GSH) and protein carbonyl contents, and nuclear factor-kappaB (NF-kappaB) and activating protein 1 (AP-1) DNA binding. The IR protocol used led to a 4.5-fold increase in serum AST levels and drastic changes in liver histology, with significant GSH depletion and enhancement of protein carbonyl levels and of the protein carbonyl/GSH content ratio, whereas NF-kappaB and AP-1 DNA binding was decreased and enhanced, respectively. In a time window of 48 h, T(3) exerted protection against hepatic IR injury, with 88% reduction in the protein carbonyl/GSH ratio and normalization of NF-kappaB and AP-1 DNA binding, changes that were suppressed by NAC administration before T(3). Data presented suggest that a transient increase in the oxidative stress status of the liver is an important trigger for T(3) preconditioning, evidenced in a warm IR injury model through antioxidant intervention.

Thyroid hormone (TH, T3) is required for the normal function of most tissues, with major effects on O2 consumption and metabolic rate. These are due to transcriptional activation of respiratory genes through the interaction of T3-liganded TH receptors with TH response elements or the activation of intermediate factors, with the consequent higher rates of mitochondrial oxidative phosphorylation and reactive O2 species (ROS) generation and antioxidant depletion. The genomic effects of TH are accompanied by redox upregulation of the liver expression of cytokines (tumor necrosis factor-alpha [TNF-alpha]), enzymes (manganese superoxide dismutase), and anti-apoptotic proteins (Bcl-2), via a cascade initiated by TNF-alpha produced by Kupffer cells and involving inhibitor of kappa-B phosphorylation and nuclear factor-kappa-B activation. Thus, TH calorigenesis triggers non-genomic effects leading to an expression pattern that may represent an adaptive mechanism to re-establish redox homeostasis and promote cell survival under conditions of ROS toxicity secondary to TH-induced oxidative stress. Mechanisms of expression of respiratory and redox-sensitive genes may be functionally integrated, which could be of importance to understand the complexities of TH action and the outcome of thyroid gland dysfunction.

Thyroid hormone (TH; 3,3',5-triiodothyronine, T3) is required for the normal function of most tissues, with major effects on O(2) consumption and metabolic rate. These are due to transcriptional activation of respiratory genes through the interaction of T3-liganded TH receptors with TH response elements or the activation of intermediate factors, with the consequent higher production of reactive O(2) species (ROS) and antioxidant depletion. T3-induced oxidative stress in the liver triggers the redox upregulation of the expression of cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin-10), enzymes (inducible nitric oxide synthase, manganese superoxide dismutase), and anti-apoptotic proteins (Bcl-2), via a cascade initiated by TNF-alpha produced by Kupffer cells, involving inhibitor of kappaB phosphorylation and nuclear factor-kappaB activation. Thus, TH calorigenesis triggers an expression pattern that may represent an adaptive mechanism to re-establish redox homeostasis and promote cell survival under conditions of ROS toxicity secondary to TH-induced oxidative stress. Mechanisms of expression of respiratory and redox-sensitive genes may be functionally integrated, which could be of importance to understand the complexities of TH action and the outcome of thyroid gland dysfunction.

Objective: This study was undertaken to evaluate whether screening through a uterine artery (UtA) Doppler and biochemical markers of oxidative stress and endothelial dysfunction predict preeclampsia., Study Design: UtA Doppler was performed at 11 to 14 and 22 to 25 weeks on 1447 asymptomatic pregnant women. Oxidative stress, endothelial dysfunction, and antiangiogenic state were assessed in women who later developed preeclampsia and normotensive controls., Results: There was a significantly increased of UtA pulsatility index (PI), plasma levels of soluble fms-like tyrosine kinase 1 (sFlt1), PAI-1/PAI-2 ratio, and F-2 isoprostane in women who subsequently developed preeclampsia compared with control pregnancies. Multivariate logistic regression showed that increased UtA PI performed at 23 weeks was the best predictor for preeclampsia., Conclusion: This study demonstrates early changes in markers of impaired placentation, antiangiogenic state, oxidative stress, and endothelial dysfunction suggesting that these derangements may play a role in the pathogenesis of preeclampsia. Our data point to UtA as the best test to predict preeclampsia at 23 weeks of gestation.

Preeclampsia (PE) is a multisystem disorder that remains a major cause of maternal and foetal morbidity and death. To date, no treatment has been found that prevents the development of the disease. Endothelial dysfunction is considered to underlie its clinical manifestations, such as maternal hypertension, proteinuria, and edema; however, the precise biochemical pathways involved remain unclear. A current hypothesis invokes the occurrence of oxidative stress as pathogenically important, as suggested by the fact that in PE, the placental and circulating levels of lipid peroxidation products (F2-isoprostanes and malondialdehyde [MDA]) are increased and endothelial cells are activated. A potential mechanism for endothelial dysfunction may occur via nuclear transcription factor kappa B (NF-kappaB) activation by oxidative stress. Alternatively, the idea that the antiangiogenic placental soluble fms-like tyrosine kinase 1 factor (sFlt1) is involved in the pathogenesis of this disease is just emerging; however, other pathophysiological events seem to precede its increased production. This review is focused on evidence providing a pathophysiological basis for the beneficial effect of early antioxidant therapy in the prevention of PE, mainly supported by the biological effects of vitamins C and E.

Nuclear factor-kappaB (NF-kappaB) is a redox-sensitive factor responsible for the transcriptional activation of cytokine-encoding genes. In this study, we show that 3,3,5-triiodothyronine (T(3)) administration to rats activates hepatic NF-kappaB, as assessed by electrophoretic mobility shift assay. This response coincides with the onset of calorigenesis and enhancement in hepatic respiration, and is suppressed by the antioxidants alpha-tocopherol and N-acetylcysteine or by the Kupffer cell inactivator gadolinium chloride. Livers from hyperthyroid rats with enhanced NF-kappaB DNA-binding activity show induced mRNA expression of the NF-kappaB-responsive genes for tumor necrosis factor-alpha (TNF-alpha) and interleukin- (IL-) 10, as evidenced by reverse transcription-polymerase chain reaction assay, which is correlated with increases in the serum levels of the cytokines. T(3) also increased the hepatic levels of mRNA for IL-1alpha and those of IL-1alpha in serum, with a time profile closely related to that of TNF-alpha. It is concluded that T(3)-induced oxidative stress enhances the DNA-binding activity of NF-kappaB and the NF-kappaB-dependent expression of TNF-alpha and IL-10 genes.

Iron- or copper-mediated catalysis leads to the generation of reactive oxygen species (ROS) that can attack biomolecules directly, with the consequent enhancement in membrane lipid peroxidation, DNA damage, and protein oxidation. Reactive nitrogen species (RNS) can also be formed, leading to nitration of aromatic structures in addition to the oxidative deterioration of cellular components. Kupffer cells, the resident macrophages of the liver, play significant roles in immunomodulation, phagocytosis, and biochemical attack. Upon stimulation, liver macrophages release biologically active products related to cell injury, namely, ROS, RNS, and both immunomodulatory and fibrogenic cytokines, with production of chemokines and adhesion molecules by other cells of the liver sinusoid. Iron and copper alter the functional status of Kupffer cells by enhancing their respiratory burst activity without modifying particle phagocytosis. This effect is probably due to extra O2 equivalents used in the oxidation of biomolecules and/or in the activating action of iron/copper on nitric oxide synthase, in addition to those employed by NADPH oxidase activity. Changes in gene expression of Kupffer cells may also be accomplished by iron and copper through modulation of the activity of transcription factors such as NF-kappaB, which signals the production of cytotoxic, proinflammatory, or fibrogenic mediators. Thus, iron/copper-induced hepatotoxicity is a multifactorial phenomenon underlying actions due to the generation of ROS and RNS that may alter essential biomolecules with loss of their biological functions, modulate gene expression of Kupffer cells with production of cytotoxic mediators, or both.

The role of Kupffer cells in the hepatocellular injury and oxidative stress induced by lindane (20 mg/kg; 24h) in hyperthyroid rats (daily doses of 0.1 mg L-3,3',5-triiodothyronine (T3)/kg for three consecutive days) was assessed by the simultaneous administration of gadolinium chloride (GdCl3; 2 doses of 10mg/kg on alternate days). Hyperthyroid animals treated with lindane exhibit enhanced liver microsomal superoxide radical (O2.-) production and NADPH cytochrome c reductase activity, with lower levels of cytochrome P450, superoxide dismutase (SOD) and catalase activity, and glutathione (GSH) content over control values. These changes are paralleled by a substantial increase in the lipid peroxidation potential of the liver and in the O2.- generation/ SOD activity ratio, thus evidencing a higher oxidative stress status that correlates with the development of liver injury characterized by neutrophil infiltration and necrosis. Kupffer cell inactivation by GdCl3 suppresses liver injury in lindane/T3-treated rats with normalization of altered oxidative stress-related parameters, excepting the reduction in the content of GSH and in catalase activity. It is concluded that lindane hepatotoxicity in hyperthyroid state, that comprises an enhancement in the oxidative stress status of the liver, is largely dependent on Kupffer cell function, which may involve generation of mediators leading to pro-oxidant and inflammatory processes.

N-3 polyunsaturated fatty acids (n-3 PUFA) affect inflammatory processes. This study evaluated the effects of dietary supplementation with fish oil on hepatic ischemia-reperfusion (IR) injury in the rat. Parameters of liver injury (serum transaminases and histology) and oxidative stress (serum 8-isoprostanes and hepatic GSH and GSSG), were correlated with NF-κB DNA binding and FA composition and inflammatory cytokine release. N-3 PUFA supplementation significantly increased liver n-3 PUFA content and decreased n-6/n-3 PUFA ratios. IR significantly modified liver histology and enhanced serum transaminases, 8-isoprotanes and inflammatory cytokines, with net reduction in liver GSH levels and net increment in those of GSSG. Early increase (3 h) and late reduction (20 h) in NF-κB activity was induced. All IR-induced changes were normalized by n-3 PUFA supplementation. In conclusion, prevention of liver IR-injury was achieved by n-3 PUFA supplementation, with suppression of oxidative stress and recovery of pro-inflammatory cytokine homeostasis and NF-κB functionality lost during IR. [ABSTRACT FROM AUTHOR]

Thyroid hormone-induced calorigenesis triggers liver oxidative stress with concomitant TNF-α production by Kupffer cells and up-regulation of gene expression. Considering that cyclin-dependent kinase-2 (CDK-2) performs essential functions for cellular proliferation, our aim was to test the hypothesis that -3,3′,5-triiodothyronine (T3) stimulates liver cell proliferation by upstream mechanisms involving CDK-2 expression dependent on Kupffer cell signaling. T3 administration induced a calorigenic response at 60–70 h after treatment, with increased TNF-α generation and hepatic oxidative stress status, as shown by enhanced protein carbonyls and decreased glutathione content compared to controls. In this time interval, liver c-jun N-terminal kinase (JNK) phosphorylation, activator protein-1 (AP-1) DNA binding, and CDK-2 expression were enhanced, with concomitantly higher levels of the proliferation markers Ki-67 and proliferating cell nuclear antigen. These changes are abolished by administration of the Kupffer cell inactivator gadolinium chloride prior to T3 treatment. We conclude that T3 administration triggers liver CDK-2 expression and cellular proliferation through a cascade associated with Kupffer cell-dependent TNF-α generation, JNK phosphorylation, and AP-1 activation. Since CDK-2 promotes phase S progression within the cell cycle, this response may constitute a major mechanism involved in T3-induced liver preconditioning to ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

Abstract: Recently, we reported that 3,3′,5-triiodothyronine (T3) induces the expression of redox-sensitive genes as a nongenomic mechanism of T3 action. In this study, we show that T3 administration to rats (daily doses of 0.1 mg/kg ip for 3 consecutive days) induced a calorigenic response and liver glutathione depletion as an indication of oxidative stress, with higher levels of interleukin (IL)-6 in serum (ELISA) and hepatic STAT3 DNA binding (EMSA), which were maximal at 48–72 h after treatment. Under these conditions, the protein expression of the acute-phase proteins haptoglobin and β-fibrinogen is significantly augmented, a change that is suppressed by pretreatment with α-tocopherol (100 mg/kg ip) or gadolinium chloride (10 mg/kg iv) before T3. It is concluded that T3 administration induces the acute-phase response in rat liver by a redox mechanism triggered at the Kupffer cell level, in association with IL-6 release and activation of the STAT3 cascade, a response that may contribute to reestablishing homeostasis in the liver and extrahepatic tissues exhibiting oxidative stress. [Copyright &y& Elsevier]

Abstract: Thyroid hormone (3,3′,5-triiodothyronine, T3) exerts significant actions on energy metabolism, with mitochondria being the major target for its calorigenic effects. Acceleration of O2 consumption by T3 leads to an enhanced generation of reactive oxygen and nitrogen species in target tissues, with a higher consumption of cellular antioxidants and inactivation of antioxidant enzymes, thus inducing oxidative stress. This redox imbalance occurring in rodent liver and extrahepatic tissues with a calorigenic response, as well as in hyperthyroid patients, is further enhanced by an increased respiratory burst activity in Kupffer cells, which may activate redox-sensitive transcription factors such as NF-κB thus up-regulating gene expression. T3 elicits an 80-fold increase in the serum levels of tumor necrosis factor-α (TNF-α), which is abolished by pretreatment with the antioxidants α-tocopherol and N-acetylcysteine, the Kupffer-cell inactivator GdCl3, or an antisense oligonucleotide against TNF-α. In addition, T3 treatment activates hepatic NF-κB, a response that is (i) inhibited by antioxidants and GdCl3 and (ii) accompanied by induced mRNA expression of the NF-κB-responsive genes for TNF-α and interleukin (IL)-10. T3 also increases the hepatic levels of mRNA for IL-1α and those of IL-1α in serum. Up-regulation of liver iNOS expression is also achieved by T3, through a cascade initiated by TNF-α and involving IκB-α phosphorylation and NF-κB activation. In conclusion, T3-induced oxidative stress in the liver enhances the DNA-binding of NF-κB and the NF-κB-dependent expression of cytokines and iNOS by actions primarily exerted at the Kupffer cell level. [Copyright &y& Elsevier]

Thyroid hormone-induced calorigenesis promotes oxidative stress in the liver with higher respiratory burst activity in Kupffer cells, which could increase the expression of redox-sensitive genes. Our aim was to test the hypothesis that L-3,3',5-triiodothyronine (T3) triggers inducible nitric oxide synthase (iNOS) expression in rat liver by upstream mechanisms involving the inhibitor of ?B (I?B) kinase activation. T3 administration (daily doses of 0.1?mg/kg for three consecutive days) induced a calorigenic response, with maximal increases in the content of hepatic thiobarbituric acid reactants or protein carbonyls and NOS activity at 48–72?h after treatment, compared to control values. In this time interval, the serum levels of tumor necrosis factor-a (TNF-a; ELISA) are enhanced, concomitantly with higher liver I?B-a phosphorylation (Western blot analysis), NF-?B DNA binding (electrophoretic mobility shift assay), and iNOS mRNA expression (reverse transcription-polymerase chain reaction). These changes and the increase in hepatic NOS activity are abolished by the administration of either a-tocopherol (100?mg/kg) or the Kupffer cell inactivator gadolinium chloride (10?mg/kg) prior to T3. It is concluded that T3-induced oxidative stress triggers the redox upregulation of liver iNOS expression through a cascade initiated by TNF-a produced by Kupffer cells and involving I?B-a phosphorylation and NF-?B activation, a response that may represent a defense mechanism by protecting the liver from cytokine-mediated lethality and ROS toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Several preconditioning strategies are used to prevent ischemia–reperfusion (IR) liver injury, a deleterious condition associated with tissue resection, transplantation or trauma. Although thyroid hormone (T3) administration exerts significant protection against liver IR injury in the rat, its clinical application is controversial due to possible adverse effects. Considering that prevention of liver IR injury has also been achieved by n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation to rats, we studied the effect of n-3 PUFA dietary supplementation plus a lower dose of T3 against IR injury. Male Sprague-Dawley rats receiving fish oil (300 mg/kg) for 3 days followed by a single intraperitoneal dose of 0.05 mg T3/kg were subjected to 1 h of ischemia followed by 20 h of reperfusion. Parameters of liver injury (serum transaminases, histology) and oxidative stress (liver contents of GSH and oxidized proteins) were correlated with fatty acid composition, NF-κB activity, and tumor necrosis factor-α (TNF-α) and haptoglobin expression. IR significantly modified liver histology; enhanced serum transaminases, TNF-α response or liver oxidative stress; and decreased liver NF-κB activity and haptoglobin expression. Although IR injury was not prevented by either n-3 PUFA supplementation or T3 administration, substantial decrease in liver injury and oxidative stress was achieved by the combined protocol, which also led to increased liver n-3 PUFA content and decreased n-6/n-3 PUFA ratios, with recovery of NF-κB activity and TNF-α and haptoglobin expression. Prevention of liver IR injury achieved by a combined protocol of T3 and n-3 PUFA supplementation may represent a novel noninvasive preconditioning strategy with potential clinical application. [Copyright &y& Elsevier]

Abstract: Aims: Liver preconditioning against ischemia–reperfusion (IR) injury is a major area of experimental research, in which regulation of gene expression with cytoprotective responses due to transient oxidative stress development has been reported. Considering that significant cytoprotection occurs after exposure to low levels of iron (Fe), we tested the hypothesis that sub-chronic administration of Fe to rats underlying transient oxidative stress preconditions the liver against IR injury. Main methods: Animals received six doses (50mg Fe–dextran/kg ip) every second day during 10days, before partial IR (vascular clamping) or sham laparotomy (control). Transient oxidative stress was defined by liver glutathione and protein carbonyl contents (24, 48, and 72h after Fe treatment). Plasma and liver Fe status and ferritin content (western blot) were assessed in animals not subjected to IR. Liver injury and inflammatory response were evaluated by serum transaminases, liver morphology and serum TNF-α. Fe preconditioning against IR injury was correlated with liver glutathione content and the redox-sensitive NF-κB signaling pathway (EMSA) and western blot analysis of haptoglobin. Key findings: Significant hepatoprotection against IR injury, underlying transient oxidative stress and enhancement in the total and labile Fe pools, was achieved by Fe administration. Abrogation of IR injury is related to reduced TNF-α response (91%), abolishment of the IR-induced liver glutathione depletion and recovery of the NF-κB signaling pathway (75%), lost during IR. Significance: Sub-chronic Fe administration protects the liver against IR injury through antioxidant and anti-inflammatory responses, with recovery of NF-κB activation and related acute-phase response signaling. [Copyright &y& Elsevier]