Study of endocrine disruptor effects in AVP and OT mediated behavioral and reproductive processes in female rat models.

Environmental exposures may have endocrine disruptor (ED) effects, e.g., a role for halogenated hydrocarbon chlorobenzenes in increasing vasopressin (AVP), oxytocin (OT) secretion and, in association, anxiety and aggression in male rats has been shown. Our aim is to investigate whether 1,2,4-trichlorobenzenehexachlorobenzene= 1:1 (mClB) treatment of female rats also shows ED effects and reproductive biology differences, and whether AVP may have a mediator role in this? Female Wistar rats were treated (0.1; 1.0; 10.0 µg/bwkg/day) with mClB (by gastrictube) and then 30; 60; 90 days after treatment anxiety (open field test) and aggressive (resident intruder test) behaviors AVP, OT concentrations from blood plasma samples were detected by radioimmunoassay on 30; 60; 90 days. Treated female rats were mated with untreated males. Mating success, number of newborn and maternal aggression on the neonates were monitored. Results showed that AVP, OT levels; and anxiety, aggressive behaviors; and mothers' aggression towards their offspring increased significantly in relation to the duration and the dose of mClB treatment. But mating propensity and number of offspring decreased. Patterns of AVP, OT release and anxiety, aggression behaviors, and reproductive-related behaviors were correlated. Consistent with the literature, our studies confirmed the role of AVP and OT in different behavioral effects.

A Comprehensive Overview on Chemotherapy-Induced Cardiotoxicity: Insights into the Underlying Inflammatory and Oxidative Mechanisms.

While oncotherapy has made rapid progress in recent years, side effects of anti-cancer drugs and treatments have also come to the fore. These side effects include cardiotoxicity, which can cause irreversible cardiac damages with long-term morbidity and mortality. Despite the continuous in-depth research on anti-cancer drugs, an improved knowledge of the underlying mechanisms of cardiotoxicity are necessary for early detection and management of cardiac risk. Although most reviews focus on the cardiotoxic effect of a specific individual chemotherapeutic agent, the aim of our review is to provide comprehensive insight into various agents that induced cardiotoxicity and their underlying mechanisms. Characterization of these mechanisms are underpinned by research on animal models and clinical studies. In order to gain insight into these complex mechanisms, we emphasize the role of inflammatory processes and oxidative stress on chemotherapy-induced cardiac changes. A better understanding and identification of the interplay between chemotherapy and inflammatory/oxidative processes hold some promise to prevent or at least mitigate cardiotoxicity-associated morbidity and mortality among cancer survivors.

Voluntary Exercise-Mediated Protection in TNBS-Induced Rat Colitis: The Involvement of NETosis and Prdx Antioxidants.

Inflammatory bowel diseases (IBDs) are autoimmune disorders of the gut. It is increasingly clear that voluntary exercise (VE) may exert protection against IBDs, but the exact background mechanism needs to be elucidated. In the present study, we aimed to investigate the possible role of NETosis and the antioxidant peroxiredoxin (Prdx) enzyme family in VE-induced protection. Wistar Han rats were randomly divided into two groups: sedentary (SED) and VE. After the 6-week voluntary wheel running, animals were treated with 2,4,6-trinitrobenzene sulphonic acid (TNBS) as a model of colitis. Here, we found that VE significantly decreased inflammation and ulceration of the colon in the VE TNBS group compared with SED TNBS. We also found that VE significantly decreased the expression of protein arginine deiminase 4 (PAD4) and myeloperoxidase (MPO), and markedly reduced citrullinated histone H3 (citH3) compared with SED TNBS. Furthermore, VE caused a significant increase in the levels of Prdx6 in the control and TNBS groups. Taken together, we found that a prior 6-week VE effectively reduces inflammation in TNBS-induced colitis, and we suggest that the protective effect of VE may be mediated via the inhibition of NETosis and upregulation of Prdx6 antioxidant.

The Interplay of Lifestyle and Adipokines in the Non-Obese Stroke-Prone Spontaneously Hypertensive Rats.

Although the morphological features and functions of adipose tissue are well-described in obesity-prone animal models, less information is available on animals such as the stroke-prone spontaneously hypertensive (SHRSP) strain with cardiovascular abnormalities, which is not characterized by excessive adiposity. Our aim was to focus on lifestyle-induced (type of diet and physical exercise) effects on adipokine profile and lipid peroxidation in SHRSP rats. In our study, male Wistar-kyoto (control) and SHRSP rats were used. SHRSP rats were fed either standard chow or a high-fat diet with 40% fat content (HFD). One group of the animals was placed into cages fitted with a running-wheel; thus, the dietary and training period started at the same time and lasted for 12 weeks. At the end of the experimental period, adiponectin, leptin, omentin, and chemerin concentrations were determined from adipose tissue and serum. Besides adipokines, malondialdehyde (MDA) levels were also measured. Twelve weeks of HFD significantly decreased adiponectin and omentin concentrations of both adipose tissue and serum, which were ameliorated by physical exercise. Serum leptin, chemerin, and MDA values were elevated in HFD groups; however, physical exercise was able to mitigate these adverse changes. Our results underpin the crosstalk between lifestyle changes and dysfunctional adipose tissue in SHRSP rats.

Protective Effects of H2S Donor Treatment in Experimental Colitis: A Focus on Antioxidants.

Inflammatory bowel diseases (IBD) are chronic, inflammatory disorders of the gastrointestinal (GI) system, which have become a global disease over the past few decades. It has become increasingly clear that oxidative stress plays a role in the pathogenesis of IBD. Even though several effective therapies exist against IBD, these might have serious side effects. It has been proposed that hydrogen sulfide (H2S), as a novel gasotransmitter, has several physiological and pathological effects on the body. Our present study aimed to investigate the effects of H2S administration on antioxidant molecules in experimental rat colitis. As a model of IBD, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used intracolonically (i.c.) to induce colitis in male Wistar-Hannover rats. Animals were orally treated (2 times/day) with H2S donor Lawesson's reagent (LR). Our results showed that H2S administration significantly decreased the severity of inflammation in the colons. Furthermore, LR significantly suppressed the level of oxidative stress marker 3-nitrotyrosine (3-NT) and caused a significant elevation in the levels of antioxidant GSH, Prdx1, Prdx6, and the activity of SOD compared to TNBS. In conclusion, our results suggest that these antioxidants may offer potential therapeutic targets and H2S treatment through the activation of antioxidant defense mechanisms and may provide a promising strategy against IBD.

Resveratrol as a Promising Polyphenol in Age-Associated Cardiac Alterations.

According to a widely accepted theory, oxidative stress is considered to be the number one trigger of aging-associated degenerative processes including cardiovascular diseases. In the context of aging-research, resveratrol receives special attention with its surprising number of health benefits. The aim of our study was to examine the anti-inflammatory and antioxidant effects of this dietary polyphenol in aging rat heart. 20-month-old female and male Wistar rats were divided into control (untreated) and resveratrol-treated groups. Resveratrol was administered at a dose of 0.05 mg/ml for 12 weeks dissolved in drinking water, while the control rats received ad libitum water. Cardiac level of reactive oxygen species (ROS), nuclear factor kappa B (NFκB), tumor necrosis factor alpha (TNF-α), and glutathione (GSH) parameters, as well as the activity of myeloperoxidase (MPO) and heme oxygenase (HO) enzymes were detected. Together with the biochemical measurements, hearts were isolated and used for an exposure of ischemic-reperfusion injury via Langendorff perfusion system. 12 week of resveratrol treatment suppressed the age-related inflammatory pathways including the expression of TNF-α, NFκB, and the activity of MPO while intensified the endogenous antioxidant defenses through the induction of GSH and HO system. Presumably, as a result of these processes, the necrotic area of the heart in response to an acute injury was also significantly reduced in the resveratrol-treated groups. Our findings confirmed that resveratrol has cardioprotective effects at several points by counteracting the aging-associated cellular malfunctions in the heart.

Andrological Aspects of Exercise: Moderate Swimming Protects against Isoproterenol Induced Testis and Semen Abnormalities in Rats.

The development and progression of male infertility are closely linked to a sedentary lifestyle; however, its underlying mechanisms are not fully elucidated. Our aim was to assess the protective effects of moderate swimming exercise on the male reproductive system in isoproterenol-treated rats. Male Wistar rats were divided into five groups as follows: (1) non-interventional controls (CTRL), (2) isoproterenol-treated (ISO), (3) pre-treatment swimming training + ISO (PRE + ISO), (4) ISO + post-treatment swimming training (ISO+POST), (5) pre-treatment swimming training + ISO + post-treatment swimming training (PRE + ISO + POST) groups. Testicular oxidative stress was induced by ISO injection (1.0 mg/kg). Rats in the pre- or post-training groups were trained five days a week. At the end of the experimental period, serum testosterone levels, sperms' hyaluronan binding, and total glutathione (GSH) content, as well as myeloperoxidase activity (MPO), TNF alpha and IL6 concentrations in the testis and semen, were measured. Serum testosterone levels, sperms' hyaluronan binding, and GSH content were found to be significantly reduced, while MPO, TNF alpha and IL6 concentrations in the testis and semen were elevated after the ISO treatment compared to the CTRL group. Moderate-intensity swimming exercise effectively alleviated the negative effects of high oxidative stress. Our findings provide the first evidence that moderate-intensity swimming exercise confers sustained protection from isoproterenol-induced adverse effects on testicular inflammation.

Hormone Replacement Therapy and Aging: A Potential Therapeutic Approach for Age-Related Oxidative Stress and Cardiac Remodeling.

Advanced age is an independent risk factor for cardiovascular diseases, which might be further exacerbated by estrogen deficiency. Hormone replacement therapy (HRT) decreases cardiovascular risks and events in postmenopausal women; however, its effects are not fully elucidated in older individuals. Thus, the aim of our study is to examine the impact of HRT on oxidant/antioxidant homeostasis and cardiac remodeling. In our experiment, control (fertile) and aging (~20-month-old) female Wistar rats were used. Aging rats were further divided into estrogen- (E2, 0.1 mg/kg/day per os) or raloxifene- (RAL, 1.0 mg/kg/day per os) treated subgroups. After 2 weeks of treatment, cardiac heme oxygenase (HO) activity, total glutathione (GSH) content, matrix metalloproteinase-2 (MMP-2) activity, and the concentrations of collagen type I and tissue inhibitor of metalloproteinase (TIMP-2), as well as the infarct size, were determined. The aging process significantly decreased the antioxidant HO activity and GSH content, altered the MMP-2/TIMP-2 signaling, and resulted in an excessive collagen accumulation, which culminated in cardiovascular injury. However, 2 weeks of either E2 or RAL treatment enhanced the antioxidant defense mechanisms and attenuated cardiac remodeling related to aging. Our findings clearly show that 2-week-long HRT is a potential intervention to bias successful cardiovascular aging via reducing oxidative damage and cardiovascular dysfunction.

Distinct Approaches of Raloxifene: Its Far-Reaching Beneficial Effects Implicating the HO-System.

Selective estrogen receptor modulators (SERMs) were discovered in the mid-1900s in connection with estrogen-related pathological conditions. They were developed to antagonize the adverse effects of estrogen and have been shown to be effective against postmenopausal disorders manifested by estrogen deficiency. Raloxifene (RAL), one of the most widely used SERMs, expresses estrogen-like effects on bones, while it is found to be an antagonist on breast and uterus. RAL has multiple beneficial effects throughout the body, including antioxidant and anti-inflammatory properties, because of which it gains particular attention. Additionally, previous studies have revealed that RAL is an efficient modulator of heme-oxygenase (HO) expression. HO, through its general activity, participates in comprehensive cell defense processes, thus the induction of HO by RAL administration indicates a major role in its therapeutic efficacy. In this review, we compile the current knowledge about the overall metabolic, neurocognitive, and cardiovascular effects of RAL involving the cytoprotective HO-system.

Postconditioning-like effect of exercis: new paradigm in experimental menopause.

The progression of coronary artery diseases in premenopausal women is lower than in age-matched men; however, its probability increases rapidly after menopause. The aim of our study was to investigate the postconditioning-like effects of voluntary physical exercise on postmenopausal cardiovascular outcomes after myocardial infarction. We used fertile Wistar females [control (CTRL)] and pharmacologically induced estrogen-deficient (POVX; 750 µg/kg triptorelin im, every 4th week) rats. CTRL and POVX animals were randomly assigned to receive an injection of 0.1 mg isoproterenol (ISO)/kg. At the 20th hour after ISO injection, serum markers of myocardial injury, such as lactate dehydrogenase (LDH) and myoglobin, were measured. After a 3-wk resting period, ISO-treated and untreated animals were further divided into subgroups on the basis of 6 wk of physical exercise. At the end of the experiment, cardiac activity and content of the antioxidative heme oxygenase (HO) enzyme, levels of GSH and GSH + GSSG, activity of myeloperoxidase, as well as the concentration of TNF-α were determined. At the end of the experimental period, we observed a significant decrease in the activity and content of HO enzymes in POVX and POVX/ISO rats, whereas physical exercise significantly improved HO and GSH values in both CTRL and POVX rats. Furthermore, our training protocol significantly reduced the pathological levels of myeloperoxidase and TNF-α. Our findings clearly demonstrate that modulation of the HO system by voluntary physical exercise is a key process to decrease inflammatory parameters and ameliorate the antioxidative status in estrogen-deficient conditions postmyocardial injury. NEW & NOTEWORTHY We used a noninvasive rat model of estrogen deficiency and myocardial infarction. The long-term effects of isoproterenol treatment revealed reduced heme oxygenase enzyme activity and expression and decreased glutathione levels. Isoproterenol treatment enhanced the myeloperoxidase enzyme activity. Voluntary physical exercise ameliorated the antioxidative status by increasing of the heme oxygenase enzyme system. Voluntary physical exercise is a potential therapeutic tool to improve cardiac antioxidant status in menopausal women postmyocardial injury.

The Effects of Exercise Training and High Triglyceride Diet in an Estrogen Depleted Rat Model: The Role of the Heme Oxygenase System and Inflammatory Processes in Cardiovascular Risk.

Cardiovascular morbidity and mortality of premenopausal women are significantly lower compared to men of similar age. However, this protective effect evidently decreases after the onset of menopause. We hypothesized that physical exercise could be a potential therapeutic strategy to improve inflammatory processes and cardiovascular antioxidant homeostasis, which can be affected by the loss of estrogen and the adverse environmental factors, such as overnutrition. Ovariectomized (OVX, n= 40) and sham-operated (SO, n= 40) female Wistar rats were randomized to exercising (R) and non-exercising (NR) groups. Feeding parameters were chosen to make a standard chow (CTRL) or a high triglyceride diet (HT) for 12 weeks. Aortic and cardiac heme oxygenase (HO) activity and HO-1 concentrations significantly decreased in all of the NR OVX and SO HT groups. However, the 12-week physical exercise was found to improve HO-1 values. Plasma IL-6 concentrations were higher in the NR OVX animals and rats fed HT diet compared to SO CTRL rats. TNF-α concentrations were significantly higher in the NR OVX groups. 12 weeks of exercise significantly reduced the concentrations of both TNF-α and IL-6 compared to the NR counterparts. The activity of myeloperoxidase enzyme (MPO) was significantly increased as a result of OVX and HT diet, however voluntary wheel-running exercise restored the elevated values. Our results show that estrogen deficiency and HT diet caused a significant decrease in the activity and concentration of HO enzyme, as well as the concentrations of TNF-α, IL-6, and the activity of MPO. However, 12 weeks of voluntary wheel-running exercise is a potential non-pharmacological therapy to ameliorate these disturbances, which determine the life expectancy of postmenopausal women.

Cardioprotective Effect of Selective Estrogen Receptor Modulator Raloxifene Are Mediated by Heme Oxygenase in Estrogen-Deficient Rat.

Estrogens and raloxifene (RAL) have beneficial effects on certain cardiovascular indices in postmenopausal women characterized by estrogen deficiency. Heme oxygenase (HO) activity is increased by 17ß-estradiol (E2) and RAL in estrogen-deficient rat resulting in vasorelaxation mediated by carbon monoxide. We determined the expressions of HO in cardiac and aortic tissues after ovariectomy (OVX) and subsequent RAL or E2 treatment. We investigated the effects of pharmacological inhibition of HO enzyme on the arginine vasopressin- (AVP-) induced blood pressure in vivo, the epinephrine- and phentolamine-induced electrocardiogram ST segment changes in vivo, and the myeloperoxidase (MPO) enzyme activity. When compared with intact females, OVX decreased the HO-1 and HO-2 expression, aggravated the electrocardiogram signs of heart ischemia and the blood pressure response to AVP, and increased the cardiac MPO. E2 and RAL are largely protected against these negative impacts induced by OVX. The pharmacological inhibition of HO in E2- or RAL-treated OVX animals, however, restored the cardiovascular status close to that observed in nontreated OVX animals. The decreased expression of HO enzymes and the changes in blood pressure ischemia susceptibility and inflammatory state in OVX rat can be reverted by the administration of E2 or RAL partly through its antioxidant and anti-inflammatory roles.

Experimental Diabetes Mellitus in Different Animal Models.

Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology and target identification and in the evaluation of novel therapeutic agents and treatments in vivo. Diabetes mellitus disease, commonly known as diabetes, is a group of metabolic disorders characterized by high blood glucose levels for a prolonged time. To avoid late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic symptoms, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. We overviewed the pathophysiological features of diabetes in relation to its complications in type 1 and type 2 mice along with rat models, including Zucker Diabetic Fatty (ZDF) rats, BB rats, LEW 1AR1/-iddm rats, Goto-Kakizaki rats, chemically induced diabetic models, and Nonobese Diabetic mouse, and Akita mice model. The advantages and disadvantages that these models comprise were also addressed in this review. This paper briefly reviews the wide pathophysiological and molecular mechanisms associated with type 1 and type 2 diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans.

Consequences of exercising on ischemia-reperfusion injury in type 2 diabetic Goto-Kakizaki rat hearts: role of the HO/NOS system.

BACKGROUND: It is well established that physical exercise continues to be one of the most valuable forms of non-pharmacological therapy against diabetes mellitus; however, the precise mechanism remains unknown. The aim of this study was to investigate the cardioprotective effect of voluntary exercise in the Goto-Kakizaki type 2 diabetic rat heart against ischemia-reperfusion injury and to clarify its biochemical background, focusing on the nitric oxide synthase/heme oxygenase system. METHODS: One group of male Goto-Kakizaki rats were allowed voluntary exercise, whereas others were kept sedentary for 6 weeks. At the end of the 6th week the hearts were isolated from both groups and subjected to 45-min coronary occlusion followed by 120-min reperfusion. The infarct size was evaluated by means of triphenyltetrazolium chloride staining. The cardiac and aortic nitric oxide synthase/heme oxygenase activities, plasma leptin and glucose concentrations were also assessed. RESULTS: The sedentary state prior to the ischemia-reperfusion injury was associated with a significantly higher infarct size (24.56 ± 2.21 vs. 16.66 ± 1.87 %) as compared with that in the voluntary wheel-running group. Exercise altered the constitutive nitric oxide synthase activity; an enhancement was evident in the cardiac (42.5 ± 2.72 vs. 75.6 ± 13.34 pmol/min/mg protein) and aortic tissues (382.5 ± 66.57 vs. 576.9 ± 63.16 pmol/min/mg protein). Exercise lead to a higher heme oxygenase activity (0.68 ± 0.08 vs. 0.92 ± 0.04 nmol bilirubin/h/mg protein) in the diabetic rat hearts. Exercise was associated with lower plasma leptin (192.23 ± 7.22 vs. 169.65 ± 4.6 ng/L) and blood glucose (19.61 ± 0.76 vs. 14.58 ± 0.88 mmol/L) levels. CONCLUSIONS: These results indicate the beneficial role of exercise against myocardial ischemia-reperfusion injury in diabetic rats. These observations in experimental diabetes suggest that the cytoprotective mechanism of exercise involves modulation of the nitric oxide synthase/heme oxygenase system and metabolic parameters that may be responsible for cardioprotection.

Endogenous Estrogen-Mediated Heme Oxygenase Regulation in Experimental Menopause.

Estrogen deficiency is one of the main causes of age-associated diseases in the cardiovascular system. Female Wistar rats were divided into four experimental groups: pharmacologically ovariectomized, surgically ovariectomized, and 24-month-old intact aging animals were compared with a control group. The activity and expression of heme oxygenases (HO) in the cardiac left ventricle, the concentrations of cardiac interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the myeloperoxidase (MPO) activity in the cardiac left ventricle, and the effects of heme oxygenase blockade (by 24-hour and 1-hour pretreatment with tin-protoporphyrin IX, SnPP) on the epinephrine and phentolamine-induced electrocardiogram ST segment changes in vivo were investigated. The cardiac HO activity and the expression of HO-1 and HO-2 were significantly decreased in the aged rats and after ovariectomy. Estrogen depletion was accompanied by significant increases in the expression of IL-6 and TNF-α. The aged and ovariectomized animals exhibited a significantly elevated MPO activity and a significant ST segment depression. After pretreatment with SnPP augmented ST segment changes were determined. These findings demonstrate that the sensitivity to cardiac ischemia in estrogen depletion models is associated with suppression of the activity and expression of the HO system and increases in the secretion of proinflammatory cytokines and biomarkers.

Exercise training and calorie restriction influence the metabolic parameters in ovariectomized female rats.

The estrogen deficiency after menopause leads to overweight or obesity, and physical exercise is one of the important modulators of this body weight gain. Female Wistar rats underwent ovariectomy surgery (OVX) or sham operation (SO). OVX and SO groups were randomized into new groups based on the voluntary physical activity (with or without running) and the type of diet for 12 weeks. Rats were fed standard chow (CTRL), high triglyceride diet (HT), or restricted diet (CR). The metabolic syndrome was assessed by measuring the body weight gain, the glucose sensitivity, and the levels of insulin, triglyceride, leptin, and aspartate aminotransferase transaminase (AST) and alanine aminotransferase (ALT). The exercise training combined with the CR resulted in improvements in the glucose tolerance and the insulin sensitivity. Plasma TG, AST, and ALT levels were significantly higher in OVX rats fed with HT but these high values were suppressed by exercise and CR. Compared to SO animals, estrogen deprivation with HT caused a significant increase in leptin level. Our data provide evidence that CR combined with voluntary physical exercise can be a very effective strategy to prevent the development of a metabolic syndrome induced by high calorie diet.

Cardioprotective effects of voluntary exercise in a rat model: role of matrix metalloproteinase-2.

BACKGROUND: Regular exercise at moderate intensity reduces cardiovascular risks. Matrix metalloproteinases (MMPs) play a major role in cardiac remodeling, facilitating physiological adaptation to exercise. The aim of this study was to examine the influence of voluntary physical exercise on the MMP-2 enzyme activity and to investigate the cardiac performance by measurement of angina susceptibility of the heart, the basal blood pressure, the surviving aorta ring contraction, and the cardiac infarct size after I/R-induced injury. METHODS: Male Wistar rats were divided into control and exercising groups. After a 6-week period, the serum level of MMP-2, basal blood pressure, cardiac angina susceptibility (the ST segment depression provoked by epinephrine and 30 s later phentolamine), AVP-induced heart perfusion and aorta ring contraction, infarct size following 30 min ischemia and 120 min reperfusion, and coronary effluent MMP-2 activity were measured. RESULTS: Voluntary wheel-running exercise decreased both the sera (64 kDa and 72 kDa) and the coronary effluent (64 kDa) MMP-2 level, reduced the development of ST depression, improved the isolated heart perfusion, and decreased the ratio of infarct size. CONCLUSION: 6 weeks of voluntary exercise training preserved the heart against cardiac injury. This protective mechanism might be associated with the decreased activity of MMP-2.