Impact of Lithium on the Immune System: An Investigation of T-Cell Subpopulations and Cytokine Responses in Rats.

The aim of this study was to investigate the dose-dependent adverse effects of long-term dietary lithium administration on specific aspects of the defense system in rats. Additionally, the study aimed to explore the inflammatory activities of lithium beyond its recognized anti-inflammatory properties. Forty Wistar Albino rats were involved, which were randomly allocated into the control and four treatment groups. The control group received standard rat feed, and the experimental groups' diet was added 1 g/kg, 1.4 g/kg, 1.8 g/kg, and 2.2 g/kg lithium bicarbonate, respectively. CD4+, CD8+, and CD161 + cells were assessed by flow cytometry. TNF-α, IFN-γ, IL-1ß, and IL-2 and IL-4, IL-6, and IL-10 levels were measured. The proportion of CD4 + cells and the CD4+/CD8 + ratio (P = 0.005 and P = 0.038, respectively) were reduced with the highest dose of lithium compared to the control group. The data regarding pro-inflammatory cytokines showed a dose-dependent increase in serum TNF-α and IFN-γ levels (P = 0.023 and P = 0.001, respectively). On the other hand, serum IL-1ß and IL-2 levels were decreased in a dose-dependent manner (P = 0. 001 and P = 0. 001, respectively). As for anti-inflammatory cytokines, a dose-dependent decrease was determined in serum IL-4 level (P = 0.002), while no significant changes were noted in IL-6 and IL-10 levels (P = 0.507 and P = 0.732, respectively). In conclusion, lithium adversely impacted the cellular defense system. Furthermore, apart from its anti-inflammatory properties, lithium exhibited cytokine-mediated inflammatory activities. Therefore, lithium's potential adverse effects on the immune system should be considered in immunodeficient patients and those with an inflammatory status treated with high doses of lithium.

Impact of chronic lithium treatment on brain oxidative stress and anxiety-like behaviors in rats: Dose-dependent effects.

Lithium (Li) is a mood-stabilizing drug. Although one of the potential mechanisms underlying the neuroprotective effects of lithium is related to its antioxidative effect, its mechanisms of action are not fully understood. Herein we aimed to investigate the impact of varied dosages of long-term lithium therapy on oxidative stress parameters in the brains of healthy rats, and on anxiety-like behaviors, and whether any changes in behavior can be attributed to modifications in oxidative stress levels within the brain. Thirty-two adult Wistar albino male rats were randomly assigned to four treatment groups. While the control (C) group was fed with a standard diet, low Li (1.4 g/kg/diet), moderate Li (1.8 g/kg/diet), and high Li (2.2 g/kg/diet) groups were fed with lithium bicarbonate (Li2CO3) for 30 days. Malondialdehyde increased, while superoxide dismutase and catalase levels decreased in the brains of the high Li group animals. In addition, anxiety-like behaviors of animals increased in the high Li group considering fewer entries to and less time spent in the open arms of the elevated plus maze test. Our findings underscore the potential adverse effects of prolonged lithium treatment, especially at doses approaching the upper therapeutic range. The induction of toxicity, manifested through heightened oxidative stress, appears to be a key mechanism contributing to the observed increase in anxiety-like behaviors. Consequently, caution is warranted when considering extended lithium therapy at higher doses, emphasizing the need for further research to delineate the precise mechanisms underlying these effects and to inform safer therapeutic practices.

Erythroid microRNA and oxidant status alterations in l-thyroxine-induced hyperthyroid rats: effects of selenium supplementation.

BACKGROUND: Hypermetabolic state in hyperthyroidism causes oxidative stress. Erythrocytes are the cells that are involved in oxidant equilibrium in an organism and contain microRNA (miRNA). Selenium, which is an essential element for an organism, has antioxidant properties. The present study was aimed at investigating the effects of selenium supplementation in hyperthyroidism, on pro- and antioxidant enzymes, and miRNA (miR-144 and miR-451) expressions in the erythrocytes. METHODS: Forty-eight Sprague-Dawley male rats were divided into 6 groups; control group, group fed with 0.5 mg/kg sodium selenite; group fed with 1 mg/kg sodium selenite; hyperthyroid group; hyperthyroid group fed with 0.5 mg/kg sodium selenite; and hyperthyroid group fed with 1 mg/kg sodium selenite. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), miR-144, and miR-451 expression levels were studied in erythrocyte hemolysates. RESULTS: MDA levels were increased in the hyperthyroid group compared to the control group, and the group fed with 0.5 mg/kg sodium selenite (P<0.001 and P<0.01, respectively). GSH levels were increased in the hyperthyroid group and the hyperthyroid group fed with 0.5 mg/kg sodium selenite compared to the control group (P<0.001, and P<0.05, respectively). GSH levels of the hyperthyroid group fed with 1 mg/kg sodium selenite were decreased when compared with the hyperthyroid group (P<0.05). SOD levels of the hyperthyroid group were increased when compared with the control group (P<0.05, and P<0.001, respectively). Similarly, SOD levels of the hyperthyroid group fed with 1 mg/kg sodium selenite were lower than the hyperthyroid group (P<0.01). miR-144 values were increased in the hyperthyroid group and the hyperthyroid group fed with 0.5 mg/kg sodium selenite compared to the control group (P<0.001, and P<0.05 respectively). miR-451 expression was increased significantly in the hyperthyroid group compared to the control group (P<0.05). CONCLUSIONS: Our findings showed that MDA, SOD and GSH levels increased, and miR-144 and miR-451 expressions changed in hyperthyroidism. Supplementation of 1 mg/kg sodium selenite was more effective than 0.5 mg/kg sodium selenite for normalizing the MDA, GSH, SOD, and miRNA levels in the hyperthyroid group.

The Effects of Lithium Administration on Oxidant/Antioxidant Status in Rats: Biochemical and Histomorphological Evaluations.

Present study was planned to determine possible dose-dependent effects of lithium (Li) on oxidant-antioxidant status and histomorphological changes in liver and kidney tissues. For this purpose, twenty-four Wistar male rats were equally divided into three groups: the rats in group I served as controls, drinking tap water without lithium. Groups II and III received 0.1 and 0.2 % lithium carbonate (Li2CO3) through their drinking water, respectively, for 30 days. At the end of the experimental period, lithium concentrations, levels of malondialdehyde (MDA) and glutathione (GSH) and superoxide dismutase (SOD) activities were measured in considered tissues. Histomorphological study was also performed on liver and kidney tissues. Compared to controls, MDA was significantly higher but GSH level lower in groups II and III. SOD activity was higher in group III, but no difference was determined in group II in liver tissue. In kidney tissue, there was no difference determined in MDA and GSH levels between control and experimental groups but SOD activity in groups II and III was significantly higher. In histologic sections of both experimental liver and kidney tissues, specific degenerations were observed. The results of the present study show that treatment with lithium carbonate may result in liver and kidney tissue abnormalities and oxidative damage.

Lithium-induced hypothyroidism: oxidative stress and osmotic fragility status in rats.

The present study was conducted to explore the possible effects of different doses of lithium carbonate on thyroid functions, erythrocyte oxidant-antioxidant status, and osmotic fragility. Twenty-four Wistar-type male rats were equally divided into three groups: groups I and II received 0.1 and0.2 % lithium carbonate in their drinking water, respectively, for 30 days. The rats in group III served as controls, drinking tap water without added lithium. At the end of the experimental period, the erythrocyte osmotic fragility and the levels of triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were measured in blood samples. Compared to controls, there was a statistically significant increase of TSH but decreases of the T3 and T4 levels in group II. Both experimental groups showed a statistically significant increase of the maximum osmotic fragility limit. The minimum osmotic fragility values of the animals in group II were statistically higher than those of controls. The standard hemolytic increment curve of both experimental groups was shifted to the right when compared to the curve obtained from the controls. Also, relative to controls, the activities of MDA and SOD were significantly higher and the GSH level lower in group II, but not so in group I. The results of the present study show that treatment with lithium carbonate may result in thyroid function abnormalities, increased oxidative damage, and possible compromise of the erythrocyte membrane integrity resulting from increased osmotic fragility.

Erythrocyte osmotic fragility and lipid peroxidation in experimental hyperthyroidism.

This study investigated the relation between erythrocyte osmotic fragility and oxidative stress and antioxidant state in primary hyperthyroidism induced experimental rats. Twenty-four Spraque-Dawley-type female rats weighing between 160 and 200 g were divided into two, as control (n = 10) and experimental (n = 12), groups. The experimental group animals have received tap water and L-Tiroksin (0.4 mg/100 g fodder) added standard fodder for 30 days to induce hyperthyroidism. Control group animals were fed tap water and standard fodder for the same period. Blood samples were drawn from the abdominal aorta of the rats under ether anesthesia. T3, T4, and TSH levels, osmotic fragility, malondialdehyde (MDA), superoxide dismutase, and glutathione levels were measured in the blood. There was a statistically significant deviation found in maximum and minimum osmotic hemolysis limit values of experimental group when compared to controls. The standard hemolytic increment curve of the hyperthyroid group shifted to the right when compared to control group's curve. There was a statistically significant increase found in MDA and superoxide dismutase, but statistically a significant decrease was detected in glutathione levels in hyperthyroid group when compared to controls. As a result of our study, it may be concluded that hyperthyroidism may led to an increase in osmotic fragility of erythrocytes and this situation may possibly originate from the increased lipid peroxidation in hyperthyroidism.

Investigation of tissue factor and other hemostatic profiles in experimental hypothyroidism.

The influence of thyroid failure on hemostasis has been studied and is still not well understood. These patients have high risk for cardiovascular diseases because of the lipid metabolism and procoagulant agents. But the influence of thyroid failure on hemostasis is controversial. Tissue factor (TF) has an important role in the thromboembolic state. Recent experiments have demonstrated that TF-dependent activation of the coagulation cascade plays an important role in the pathophysiology of intravascular thrombus formation. The purpose of the present study was to investigate the contributions of TF, factor VII:C (FVII:C), factor XII:C (FXII:C), and fibrinogen in experimental hypothyroidism. TF was obtained from the thyroid gland and lung tissue of 10 rats following experimental hypothyroidism induced for 30 d and compared with similar tissue from 10 control rats. Significantly increased TF activities were found in hypothyroid rats. By contrast, FVII:C level was significantly decreased when compared with the control group. In this respect it is interesting to note that a hypercoagulable state due to increased thromboplastic activity may occur. Based on those results, elevated tissue factor activities (TFa) of the patients with low thyroid dysfunction may have another risk factor for cardiovascular diseases.

The role of nitric oxide on bone metabolism in ovariectomized rats following chronic ethanol intake.

This experimental study was designed to examine the effect of nitric oxide (NO) on bone metabolism in ovariectomized rats following chronic ethanol treatment. Chronic ethanol intake was produced by gradual substitution (within 3 weeks) of tap water in diet with 5,10,15 and finally 20% of ethanol. Thereafter, the rats were maintained under these conditions for a duration of 4 months. The rats were divided into two groups. The first group received sham operation (SHAM) and the rats in Group II were ovariectomized (OVX). Five weeks after the SHAM and ovariectomy, the rats were treated with ethanol for 4 months. After this period of ethanol administration, the NOS inhibitor N(W)-nitro-L-arginine methyl ester (L-NAME) was given for three weeks along with ethanol to the same rats. Serum interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, NO, calcium (Ca), phosphorous (P), parathyroid hormone (PTH), 25 HydroxyvitaminD3 [25(OH)D3], alkaline phosphatase (ALP), bone alkaline phosphatase (b-ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), gamma-glutamyltransferase (GGT) levels were measured in different stages of the experiment. IL-1beta, IL-6, TNFalpha and NO levels increased after ethanol administration in SHAM and OVX rats. The decrease in serum Ca was significant while the changes in P, PTH and 25 (OH)D3 levels were not. ALP and b-ALP levels were significantly decreased; ALT, AST and GGT levels were significantly increased. In ovariectomized and SHAM rats, administration of L-NAME together with ethanol, produced a significant increase in IL-1beta, IL-6 and TNFalpha levels. In this group, Ca and P levels were significantly increased, PTH and 25 (OH)D3 levels were significantly decreased. Also, there was a significant decrease in ALT, AST, ALP, b-ALP, and GGT levels. NO increase due to alcohol intake may function as a protective mechanism preventing bone resorption in cases of estrogen insufficiency.

The effects of experimental hypothyroidism on hemorheology and plasma fibrinogen concentration.

Effects of hypothyroid on hemorheology of patients had widely attracted the attention of researchers during last decade. The present study has been planned with the purpose to determine the effects of experimental hypothyroidism on hemorheological parameters and fibrinogen concentration. To induce experimental hypothyroid methimazole (75 mg/100 g) was added to the fodder of an experimental group rats for 20 d. After experimental duration, plasma and blood viscosity, hematocrit (Hct), hemoglobin, erythrocyte rigidity index, and plasma fibrinogen concentration values of both the control and the experimental group animals were determined and evaluated. The serum T3 and T4 levels of the experimental group were found lower (p < 0.001) but TSH level higher (p < 0.001) than that of the control group. Plasma viscosity and fibrinogen concentration of hypothyroid group were found significantly higher than controls (p < 0.01). Hematocrit and hemoglobin values were also found lower in the experimental group than the control group animals (p < 0.01). However, there was no significant difference found in blood viscosity at the original Hct value but there was a significant increase at standard Hct value (p < 0.01). There was also no change in erythrocyte rigidity index between control and experimental groups. According to these results it may be said that in hypothyroidism, increased fibrinogen concentration may alter the rheological structure of blood by inducing increase in plasma viscosity.

Erythrocyte osmotic fragility and oxidative stress in experimental hypothyroidism.

The present study was planned to explain the relation between erythrocyte osmotic fragility and oxidative stress and antioxidant statue in primary hypothyroid-induced experimental rats. Twenty-four Spraque Dawley type female rats were divided into two, as control (n = 12) and experimental (n = 12), groups weighing between 160 and 200 g. The experimental group animals have received tap water methimazole added standard fodder to block the iodine pumps for 30 d (75 mg/100 g). Control group animals were fed tap water and only standard fodder for the same period. At the end of 30 d blood samples were drawn from the abdominal aorta of the rats under ether anesthesia. T3, T4, and TSH levels were measured and the animals that had relatively lower T3, T4, and higher TSH levels were accepted as hypothyroid group. Hormone levels of the control group were at euthyroid conditions. Osmotic fragility, as a lipid peroxidation indicator malondialdehyde (MDA), antioxidant defense system indicators superoxide dismutase (SOD) and glutathione (GSH) levels were measured in the blood samples. Osmotic fragility test results: There was no statistically significant difference found between maximum osmotic hemolysis limit values of both group. Minimum osmotic hemolysis limit value of hypothyroid group was found to be higher than that of control group values (p < 0.02). The standard hemolysis and hemolytic increment curve of the hypothyroid group drawn according to osmotic fragility test results was found to be shifted to the right when compared to control group's curve. This situation and hemolytic increment value, which shows maximum hemolysis ratio, is the proof of increased osmotic fragility of the erythrocytes in hypothyroidism. There is no statistically significant difference found between hypothyroid and control groups in the lipid peroxidation indicator MDA and antioxidant indicators SOD and GSH levels. As a result of our study it may be concluded that hypothyroidism may lead to an increase in osmotic fragility of erythrocytes. But the increase in erythrocyte osmotic fragility does not originate from lipid peroxidation.

Changes in leptin, plasminogen activator factor and oxidative stress in morbidly obese patients following open and laparoscopic Swedish adjustable gastric banding.

BACKGROUND: Oxidative stress is increased in obesity, leading to endothelial dysfunction, atherogenesis, and platelet aggregation. The purpose of this study was to determine the effects of weight loss after bariatric surgery on serum lipids, malondialdehyde (MDA, a marker of oxidative stress), oxidized low-density lipoprotein (oxLDL, which is increased in obesity and causes endothelial dysfunction), paraoxonase (PON-1, which inhibits lipid peroxidation), leptin and plasminogen activator inhibitor type-1 (PAI-1, which contributes to a thrombotic state). METHODS: 40 morbidly obese patients had insertion of a Swedish adjustable gastric band (SAGB). A lipid profile, MDA, oxLDL, PON-1, leptin and PAI-1 levels were drawn before and 6 months after the operation. 20 patients underwent open (Group 1) and 20 laparoscopic (Group 2) SAGB, to compare the systemic inflammatory response of the two approaches. RESULTS: Patient demographics, indications for surgery, and postoperative results were no different between the groups. Postoperative BMI and concentrations of lipid, MDA, oxLDL, leptin and PAI-1 decreased significantly in both groups. PON-1 activity increased and was negatively correlated with BMI (r=-0.618, P< 0.01), MDA (r=-0.735, P<0.001), oxLDL (r=-0.701, P< 0.01), leptin (r=-0.626, P<0.01) and PAI-1 (r=-0.461, P<0.05). There was a correlation between BMI and MDA (r=0.790, P <0.001), and also leptin (r=0.900, P<0.001) and PAI-1 (r=0.888, P=0.001). There was no correlation between BMI and oxLDL. CONCLUSION: These findings support the hypothesis that in morbid obesity, weight loss after surgery has positive effects on fibrinolytic function, oxidative stress and antioxidant activity. Both operative approaches had similar effects in this study.

Hyperuricemia in hypothyroidism: is it associated with post-insulin infusion glycemic response?

This experimental study was designed to examine whether hyperuricemia in hypothyroidism is associated with insulin resistance. For induction of hypothyroidism, rabbits (n = 12) were administered methimazole orally (75 mg/100 g food) for 30 days. T3, T4 and TSH values measured in plasma prior to and at the end of the experimentation period revealed the establishment of hypothyroidism. In the euthyroid and hypothyroid states of rabbits, crystalline porcine insulin was administered (0.1 unit/kg body weight) intraperitoneally and plasma glucose was measured at 0, 15, 30, 45 and 60 minutes. Sum of post insulin infusion glucose values was considered to reflect insulin resistance. Creatinine clearance (GFR) and uric acid clearance (CuA) were determined. Additionally, triglycerides were measured in plasma and Mg2+ both in erythrocytes and in plasma. Due to hypothyroidism: i) The glycemic response to insulin was not altered. ii) GFR and CuA were both decreased but CuA/GFR unchanged. iii) Triglycerides in plasma decreased. iv) Mg2+ concentration increased in plasma whereas decreased in erythrocytes. Several associations were observed between the variables on correlation analysis. On the basis of our data, it could be suggested that insulin resistance does not exist in hypothyroidism. Hyperuricemia observed in hypothyroidism should be considered to be secondary to decreased renal excretion but not as an indicator of insulin resistance.