RESUMEN
BACKGROUND: Vanillic acid (VA; 4-hydroxy-3-methoxybenzoic acid) is a flavouring agent found in various natural sources such as olives, fruits, and green tea. While VA exhibits numerous pharmacological effects, its potential protective effects against gastric injury warrants further investigation. Therefore, the primary objective of this study is to elucidate investigate the gastroprotective properties of VA against ethanol-induced gastric injury. METHODS AND RESULTS: Rats were orally administered either saline or VA at different doses (50, 100, and 200 mg/kg/day), with omeprazole (20 mg/kg) serving as a positive control, for fourteen consecutive days before ethanol administration. Blood and gastric tissue samples were collected one hour after ethanol administration for biochemical, molecular, and histological analyses. Pre-treatment with VA before ulcer induction alleviated both macroscopic and microscopic damage. It also increased antioxidant glutathione levels and decreased malondialdehyde and myeloperoxidase activity, along with reducing inflammatory markers such as tumour necrosis factor (TNF)-α, interleukin (IL)-6, and nuclear factor kappa B (NF-κB). Additionally, VA pre-treatment reversed the elevation of Bax mRNA expression and gastric caspase-3 levels induced by gastric damage. It also mitigated the reduction in Bcl-2 mRNA expression. CONCLUSION: These findings suggest that VA exerts protective effects against ethanol-induced gastric injury in rats. It achieves this by augmenting gastric antioxidant capacity and mitigating oxidative, inflammatory, and apoptotic damage.
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Apoptosis , Etanol , FN-kappa B , Transducción de Señal , Úlcera Gástrica , Ácido Vanílico , Animales , FN-kappa B/metabolismo , Etanol/toxicidad , Etanol/efectos adversos , Ratas , Apoptosis/efectos de los fármacos , Ácido Vanílico/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/lesiones , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/metabolismo , Sustancias Protectoras/farmacología , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Glutatión/metabolismoRESUMEN
OBJECTIVES: The aim of this study was to investigate the protective effect of neuropeptide W (NPW) on ovarian ischemia-reperfusion-induced oxidative injury and ovarian steroid metabolism. METHODS: Rats were randomly divided into control and ischemia groups that received either saline or NPW (0.1 or 5 µg/kg/day). Bilateral ovarian ischemia was performed for 3 h followed by a 72-h reperfusion. Blood, ovary, and uterus samples were collected for biochemical and histological assessments. KEY FINDINGS: Treatment with either dose of NPW alleviated oxidative injury of the ovaries with a significant suppression in free radical formation and decreased histopathological injury in both the ovarian and uterine tissues, along with reduced lipid peroxidation and neutrophil accumulation in the uterus. Moreover, NPW treatment reversed the decrease in aromatase expression with a concomitant reduction in the expression of the inactivity enzyme estrogen sulfotransferase. Also, downregulation of estrogen receptor-α (ERα) expression in the injured ovarian tissue was abolished by NPW treatment, which implicates that the protective effect of NPW on the female reproductive system may involve the upregulation of the ERα-mediated signaling pathway. CONCLUSIONS: Our study demonstrated for the first time that NPW protects against ovarian oxidative injury and reinforces ovarian steroidogenic activity, which is accompanied by the upregulation of ERα expression in the ovaries.
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Receptor alfa de Estrógeno , Ovario , Estrés Oxidativo , Daño por Reperfusión , Regulación hacia Arriba , Animales , Femenino , Ovario/metabolismo , Ovario/efectos de los fármacos , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Receptor alfa de Estrógeno/metabolismo , Estrés Oxidativo/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Peroxidación de Lípido/efectos de los fármacos , Útero/efectos de los fármacos , Útero/metabolismo , Neuropéptidos/metabolismo , Aromatasa/metabolismo , Transducción de Señal/efectos de los fármacos , Sustancias Protectoras/farmacologíaRESUMEN
AIMS: Putative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were investigated in an acetic acid-induced gastric ulcer model. MAIN METHODS: In anesthetized male Sprague-Dawley rats, acetic acid was applied surgically on the serosa and then a COX-inhibitor (COX-2-selective NS-398, COX-1-selective ketorolac, or non-selective indomethacin; 2 mg/kg/day, 3 mg/kg/day or 5 mg/kg/day; respectively) or saline was injected intraperitoneally. One h after ulcer induction, omeprazole (20 mg/kg/day), NPW (0.1 µg/kg/day) or saline was intraperitoneally administered. Injections of NPW, COX-inhibitors, omeprazole or saline were continued for the following 2 days until rats were decapitated at the end of the third day. KEY FINDINGS: NPW treatment depressed gastric prostaglandin (PG) I2 level, but not PGE2 level. Similar to omeprazole, NPW treatment significantly reduced gastric and serum tumor necrosis factor-alpha and interleukin-1 beta levels and depressed the upregulation of nuclear factor kappa B (NF-κB) and COX-2 expressions due to ulcer. In parallel with the histopathological findings, treatment with NPW suppressed ulcer-induced increases in myeloperoxidase activity and malondialdehyde level and replenished glutathione level. However, the inhibitory effect of NPW on myeloperoxidase activity and NPW-induced increase in glutathione were not observed in the presence of COX-1 inhibitor ketorolac or the non-selective COX-inhibitor indomethacin. SIGNIFICANCE: In conclusion, NPW facilitated the healing of gastric injury in rats via the inhibition of pro-inflammatory cytokine production, oxidative stress and neutrophil infiltration as well as the downregulation of COX-2 protein and NF-κB gene expressions.
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Neuropéptidos , Transducción de Señal , Úlcera Gástrica , Animales , Masculino , Ratas , Acetatos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/uso terapéutico , Mucosa Gástrica , Glutatión/metabolismo , Indometacina/uso terapéutico , Ketorolaco/efectos adversos , Neuropéptidos/uso terapéutico , FN-kappa B/metabolismo , Omeprazol/farmacología , Omeprazol/uso terapéutico , Peroxidasa/metabolismo , Ratas Sprague-Dawley , Úlcera Gástrica/tratamiento farmacológico , Úlcera/metabolismo , Úlcera/patologíaRESUMEN
Neuropeptide W (NPW), a novel hypothalamic peptide, contributes to the central regulation of food intake and energy balance, and suppresses feeding behavior when administered centrally. The aim of our study was to investigate the role of peripherally administered NPW in the modulation of gastric emptying, and to evaluate the participation of afferent fibers, cholecystokinin (CCK) receptors and gastric smooth muscle contractility in the regulatory effects of NPW on gastric motility. In Sprague-Dawley male rats equipped with gastric fistula, gastric emptying rate of the saline and peptone solutions was measured following subcutaneous administration of NPW (0.1 or 5 µg/kg) preceded by subcutaneous injections of saline, CCK-1 or CCK-2 receptor antagonists. Another group of rats with cannulas were injected subcutaneously with capsaicin for afferent denervation before commencing emptying trials. The effect of NPW on carbachol-induced gastric contractility and the role of CCK receptors in gastric smooth muscle contractility were also assessed in gastric strips. Peripheral injection of NPW delayed gastric emptying rate of both caloric and non-caloric liquid test meals, while administration of CCK-1 or CCK-2 receptor antagonists or denervation of small diameter afferents reversed NPW-induced delay in gastric emptying. Moreover, NPW inhibited antrum contractility in the organ bath. Our results revealed that peripherally administered NPW delayed liquid emptying from the stomach via the involvement of small diameter afferent neurons and CCK receptors, and thereby this regulatory role may contribute to its central regulatory role in controlling food intake and energy balance.
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Neuropéptidos , Receptores de Colecistoquinina , Ratas , Masculino , Animales , Receptores de Colecistoquinina/fisiología , Ratas Sprague-Dawley , Vaciamiento Gástrico , Estómago , ColecistoquininaRESUMEN
BACKGROUND: The novel peptide neuropeptide W (NPW) was originally shown to function in the control of feeding behavior and energy homeostasis. The aim of this study was to elucidate the putative preventive and therapeutic effects of NPW on colitis-associated oxidative injury and the underlying mechanisms for its action. METHODS: Sprague-Dawley rats in the acute colitis groups received NPW (0.5, 1 or 5 µg/kg/day) injections prior to induction of colitis with acetic acid, while the chronic colitis groups were treated after the induction of colitis. In both acute and chronic colitis (CC) groups, treatments were continued for 5 days and the rats were decapitated at the 24th hour of the last injections and colon tissues were collected for assessments. RESULTS: NPW pretreatment given for 5 days before colitis induction, as well as treating rats with NPW during the 5-day course of CC, abolished colonic lipid peroxidation. NPW treatment prevented colitis-induced reduction in blood flow, diminished neutrophil infiltration, and pro-inflammatory cytokine responses. NPW pretreatment only at the higher dose reduced colonic edema and microscopic score and preserved colonic glutathione stores. Elevations in cyclooxygenase (COX) enzyme activity and COX-1 protein level during the acute phase of colitis as well as reduction in COX-2 were all reversed with NPW pretreatment. In contrast, NPW treatment was effective in reducing the elevated COX-2 concentration during the chronic phase. CONCLUSIONS: NPW alleviates acetic acid-induced oxidative colonic injury in rats through the upregulation of colonic blood flow as well as the inhibition of COX-2 protein expression and pro-inflammatory cytokine production.
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Colitis , Neuropéptidos , Ratas , Animales , Ciclooxigenasa 2/metabolismo , Ácido Acético/farmacología , Ratas Sprague-Dawley , Colitis/inducido químicamente , Colitis/prevención & control , Colitis/metabolismo , Colon/metabolismo , Citocinas/metabolismo , Peroxidasa/metabolismoRESUMEN
We aimed to evaluate the impact of hormone replacement, melatonin, or exercise alone or their combination on oxidative damage and functional status of heart, brain, and aorta of ovariectomized (OVX) rats and to determine whether the signaling pathway is dependent on sirtuin-1 (SIRT1). Ovariectomized Sprague Dawley rats were orally given either a hormone replacement therapy (1 mg/kg/day,17ß estradiol; HRT) or melatonin (4 mg/kg/day) or HRT + melatonin treatments or tap water, while each group was further divided into sedentary and exercise (30 min/5 days/week) groups. After the heart rate measurements and memory tests were performed, trunk blood was collected at the end of the 10th week to determine metabolic parameters in serum samples. Tissue samples of abdominal aorta, heart, and brain were taken for biochemical measurements and histopathological evaluation. Heart rates and memory performances of the OVX rats were not changed significantly by none of the applications. Melatonin treatment or its co-administration with HRT upregulated the expressions of IL-10 and SIRT1, reduced the expressions of IL-6 and TNF-α, and reduced DNA damage in the hearts and thoracic aortae of non-exercised rats. Co-administration of melatonin and HRT to exercised OVX rats reduced inflammatory response and upregulated SIRT1 expression in the aortic and cardiac tissues. The present study suggests that melatonin treatment, either alone or in combination with exercise and/or HRT, upregulates SIRT1 expression and alleviates oxidative injury and inflammation in the hearts and aortas of OVX rats. Melatonin should be considered in alleviating cardiovascular disease risk in postmenopausal women.
Asunto(s)
Sistema Cardiovascular , Melatonina , Condicionamiento Físico Animal , Sirtuina 1 , Animales , Femenino , Ratas , Inflamación/tratamiento farmacológico , Melatonina/uso terapéutico , Ovariectomía , Ratas Sprague-Dawley , Sirtuina 1/metabolismo , Sistema Cardiovascular/patología , Terapia de Reemplazo de HormonasRESUMEN
AIMS: We aimed to investigate putative neuroprotective effects of nesfatin-1 on oxidative brain injury and memory dysfunction induced by a single epileptic seizure and to compare these effects with those of antiepileptic phenytoin. MAIN METHODS: Wistar albino rats were randomly divided into a control group and pentylenetetrazole (PTZ)-seizure groups pretreated intraperitoneally (ip) with saline or nesfatin-1 (NES-1; 0.3, 1 or 3 µg/kg/day) or phenytoin (PHE; 40 mg/kg/day) or PHE + NES-1 (0.3 µg/kg/day) at 30 min before the single-dose PTZ injection (45 mg/kg; ip). All treatments were repeated at the 24th and 48th h of the provoked epileptic seizure. Passive-avoidance test was performed to assess memory function. The rats were decapitated at the 72nd hour of seizures and brain tissues were analyzed for histopathological changes and for measuring levels of malondialdehyde, glutathione, myeloperoxidase activity and reactive oxygen/nitrogen species. KEY FINDINGS: In parallel to the effects of phenytoin, NES-1 reduced seizure score, elevated antioxidant glutathione content, depressed generation of nitric oxide and protected against seizure-induced neuronal damage. Additionally, increased malondialdehyde levels and elevated glial fibrillary acidic protein immunoreactivity in the cortex and hippocampus were decreased and memory dysfunction was improved by NES-1. However, NES-1 had no impact on myeloperoxidase activity or production of reactive oxygen species in the brain. SIGNIFICANCE: The findings of the present study demonstrate that nesfatin-1 treatment provides neuroprotection against seizure-induced oxidative damage and memory dysfunction by inhibiting reactive nitrogen species and upregulating antioxidant capacity, indicating its potential in alleviating memory deficits and increasing the effectiveness of conventional anti-convulsant therapies.
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Lesiones Encefálicas/prevención & control , Epilepsia/complicaciones , Trastornos de la Memoria/prevención & control , Fármacos Neuroprotectores/farmacología , Nucleobindinas/metabolismo , Estrés Oxidativo , Convulsiones/complicaciones , Animales , Anticonvulsivantes/farmacología , Lesiones Encefálicas/etiología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Epilepsia/patología , Glutatión/metabolismo , Masculino , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Óxido Nítrico/metabolismo , Nucleobindinas/genética , Fenitoína/farmacología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Convulsiones/patologíaRESUMEN
Sepsis leads to systemic hypotension, disturbed perfusion, inflammation, and tissue toxicity in vital organs. Neuropeptide W (NPW) has modulatory effects in the control of blood pressure and inflammatory processes, implicating a potential beneficial effect against sepsis-induced oxidative damage. Under anesthesia, male Sprague Dawley rats underwent cecal ligation and puncture. Immediately after surgery, either saline or TNF-alpha inhibitor (etanercept; 1 mg/kg) antibiotic (ceftriaxon; 10 mg/kg) combination or NPW (0.1, 1, or 3 µg/kg) was given subcutaneously, and injections were repeated on the 12th and 24th h. The sham-operated control group was treated with saline at the same time points. All rats were euthanized on the 25th h of surgery. Sepsis resulted in oxidative damage of the brain, heart, lung, liver, and kidney. Elevations in blood urea nitrogen and alkaline phosphatase, showing renal and hepatic dysfunction, were not evident when septic rats were treated with NPW. NPW reduced serum levels of C-reactive protein, corticosterone, and interleukin-6, while histopathologically verified tissue damage in all the studied tissues was ameliorated. NPW treatment suppressed lipid peroxidation in the heart, lung, and brain, and the depleted antioxidant GSH levels of the brain and heart were replenished by NPW. Moreover, sepsis-related neutrophil recruitment to the liver and lung was also suppressed by NPW. Although the survival rate of the rats was not significantly prolonged by NPW, most of these improvements in systemic and local inflammatory events were comparable with those reached by the etanercept and antibiotic combination, suggesting the therapeutic impact of NPW during the acute period of sepsis.
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Antiinflamatorios/farmacología , Insuficiencia Multiorgánica/prevención & control , Neuropéptidos/farmacología , Estrés Oxidativo/efectos de los fármacos , Sepsis/tratamiento farmacológico , Animales , Antiinflamatorios/uso terapéutico , Biomarcadores/metabolismo , Masculino , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/metabolismo , Neuropéptidos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Sepsis/metabolismo , Sepsis/fisiopatología , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: Gastrointestinal motility changes contribute to development and maintenance of obesity. Nesfatin-1 (NES-1) is involved in central appetite control. The aim is to elucidate effects of NES-1 and high-fat diet (HFD) on gastrointestinal motility and to explore myenteric neuron expressions of tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), and neuronal nitric oxide synthase (nNOS) in HFDinduced oxidative injury. METHODS: Sprague-Dawley rats were fed with normal diet (ND) or HFD. Gastric emptying rate was measured following NES-1 (5 pmol/rat, intracerebroventricular) preceded by subcutaneous injections of glucagon-like peptide 1 (GLP-1), cholecystokinin 1 (CCK-1), and gastrin/CCK-2 receptor antagonists. In carbachol-contracted gastric and ileal strips, contractile changes were recorded by adding NES- 1 (0.3 nmol/L), GLP-1, CCK-1, and gastrin/CCK-2 antagonists. RESULTS: Neither HFD nor NES-1 changed methylcellulose emptying, but NES-1 delayed saline emptying in cannulated ND-rats. Inhibitory effect of NES-1 on gastric emptying in ND-rats was reversed by all antagonists, and abolished in HFD-rats. In HFD-rats, carbachol-induced contractility was enhanced in gastric, but inhibited in ileal strips. HFD increased body weight, while serum triglycerides, alanine transaminase, aspartate aminotransferase, glucose, and levels of malondialdehyde, glutathione, myeloperoxidase activity, and luminolchemiluminescence in hepatic, ileal, and adipose tissues were similar in ND- and HFD-rats, but only lucigenin-chemiluminescence was increased in HFD-rats. Vasoactive intestinal peptide (VIP) and TH immunoreactivities were depressed and nNOS immunoreactivity was increased in gastric tissues of HFD-rats, while VIP and TH were enhanced, but nNOS was reduced in their intestines. CONCLUSIONS: HFD caused mild systemic inflammation, disrupted enteric innervation, enhanced gastric contractility, inhibited ileal contractility, and eliminated inhibitory effect of NES-1 on gastric motility.
RESUMEN
BACKGROUND: Although alterations in the plasma levels of leptin, glucagon-like peptide-1, and gastrin were linked with bariatric surgery outcomes, gastric production of these peptides was not elucidated before. OBJECTIVE: The aim was to evaluate the impact of estrogen depletion and estrogen receptors (ERs) on sleeve gastrectomy (SG)-induced alterations in gastric hormone production, gastric mucosal integrity, and bone mass. SETTING: Physiology Research Lab at the University. METHODS: Female Sprague-Dawley rats underwent ovariectomy or sham operation (control), and 2 months later SG or sham SG was performed. Rats received either nonselective agonist 17 ß, ER-α agonist, ER-ß agonist, or vehicle for 3 weeks. Trunk blood and gastric tissues were collected for biochemical measurements, while histopathologic examination was performed in gastric and femur samples. RESULTS: In the presence of intact ovaries, SG-induced weight loss was accompanied by reductions in the gastric synthesis of leptin and gastrin, while gastric glucagon-like peptide-1 was additionally decreased when SG was performed at the postmenopausal state. SG elevated the depleted serum estradiol levels of menopause, implicating a beneficial effect, but the occurrence of severe gastric mucosal injury was triggered. On the other hand, using ER agonists upregulated gastrin-expressing cells, ameliorated gastric injury, and improved bone loss. CONCLUSIONS: SG, either at premenopausal or postmenopausal state, resulted in considerable loss in bone mass, along with reductions in the gastric levels of gastrin and leptin. Functional status of the ovaries needs to be taken into consideration when monitoring the outcomes of SG, and ER agonists could be of value in controlling SG-induced complications.
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Gastrectomía , Muñón Gástrico , Receptores de Estrógenos/fisiología , Animales , Estrógenos , Femenino , Gastrinas , Leptina , Osteoporosis , Ovariectomía , Ratas , Ratas Sprague-DawleyRESUMEN
KEY POINTS: A moderate level of exercise has beneficial effects for the prevention of gastric ulcers. Although regular aerobic exercise was shown to elevate serum oxytocin levels and exogenously administered oxytocin exerts an anti-ulcer activity, the role of endogenous oxytocin in the gastroprotective effects of exercise has not yet been elucidated. We showed that increased anxiety and oxidative gastric damage induced by gastric ulcers were reversed in pre-exercised rats, while reduced hypothalamic oxytocin expression and decreased myenteric oxytocin receptor expression due to gastric ulcers were abolished by exercise. We also reported that the blockade of oxytocin receptors exaggerated gastric damage in exercised rats with ulcers. Our data establish that endogenous oxytocin is the key mediator in the beneficial effects of regular physical activity in alleviating gastric injury. ABSTRACT: Exercise increases serum oxytocin levels and exogenous oxytocin exerts an anti-ulcer activity; but the role of oxytocin in the protective effects of exercise against gastric ulcers has not yet been evaluated. This study was designed to investigate the impact of regular swimming exercise on oxidative gastric injury, and the role of oxytocin receptor activity in the anxiolytic and anti-inflammatory actions of exercise. Adult Wistar albino rats of both sexes performed swimming exercise (30 min/day, 5 days) or stayed sedentary. At the end of the 6-week exercise/sedentary protocol, rats were injected intraperitoneally with atosiban (0.1 mg/kg/day) or saline for 4 days. On the 5th day, under anaesthesia, acetic acid (ulcer) or saline (sham) was applied onto the gastric serosa and the treatments were continued. On the 9th day, anxiety levels were determined; gastric blood flow was measured, and blood, gastric and brain tissues were obtained. Induction of ulcers in sedentary rats increased anxiety and serum corticosterone levels; but reduced gastric blood flow and resulted in apoptosis and oxidative gastric damage with increased cytokine expressions. However, when ulcers were induced in pre-exercised rats, behavioural and biochemical alterations due to gastric damage were reversed. The inhibition of oxytocin receptors by atosiban exaggerated pro-inflammatory cytokine expressions and gastric lipid peroxidation in the stomachs of exercised rats with ulcers. When rats had regularly exercised prior to ulcer induction, reductions in the immunolabelling of hypothalamic oxytocin and myenteric oxytocin receptors were abolished, suggesting that exercise-induced alleviation of gastric injury may involve the reversal of down-regulated oxytocinergic activity.
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Receptores de Oxitocina , Úlcera Gástrica , Animales , Femenino , Mucosa Gástrica , Masculino , Estrés Oxidativo , Ratas , Ratas Wistar , Receptores de Oxitocina/metabolismo , Úlcera Gástrica/metabolismo , Úlcera Gástrica/prevención & controlRESUMEN
NEW FINDINGS: What is the central question of this study? Could different hormonally active substances, including oestrogen receptor (ER) agonists, protect against oxidative brain damage and memory impairment induced by a single epileptic seizure in rats? If so, which signalling mechanisms are involved in their anti-inflammatory effects? What is the main finding and its importance? Chronic administration of oestrogen, progesterone, ER modulators/agonists or blockade of testosterone exhibited anti-inflammatory and antioxidant actions on single seizure-induced neuronal injury, while ER agonists additionally improved memory function and up-regulated CREB signalling and hippocampal GABA(A)α1 receptor density, suggesting that ERα or ERß receptor activation may be beneficial in protecting against seizure-related oxidative brain injury and cognitive dysfunction. ABSTRACT: The susceptibility to epileptic seizures is dependent on sex as well as fluctuations in oestrogen levels, while exogenous oestrogen was shown to have no effect or to facilitate or to inhibit seizure activity. Oestrogen receptors (ERs) mediate antioxidant and anti-inflammatory actions in several inflammatory models, but the involvement of ERs in seizure-induced neuronal injury has not been evaluated previously. In order to assess the effects of resveratrol, progesterone, oestradiol (E2), an anti-testosterone (cyproterone acetate; CPA), a selective ER modulator (tamoxifen; TMX) and ERα/ERß agonists (propyl pyrazole triol (PPT), diarylpropionitrile (DPN)) on oxidative brain damage and memory impairment due to epileptic seizure, male Wistar rats (n = 120) received one of the treatment choices either in drinking water or intraperitoneally for 31 days, and epileptic seizure was induced on the 28th day by injection of a single-dose of pentylenetetrazole (45 mg kg-1 ). The results demonstrate that chronic pretreatment with resveratrol, progesterone, E2, CPA or TMX suppressed most of the inflammatory parameters indicative of oxidative neuronal injury, while treatment with the ER agonists DPN or PPT were found to be even more effective in limiting the oxidative damage. Treatment with DPN resulted in the up-regulation of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) expression, while PPT up-regulated expression of CREB without affecting BDNF levels. Moreover, both ER agonists provided protection against seizure-induced memory loss with a concomitant increase in hippocampal GABA(A)α1-positive cells. In conclusion, ER agonists, and more specifically ERß agonist, appear to provide maximum protection against seizure-induced oxidative brain injury and associated memory dysfunction by up-regulating the expression of CREB, BDNF and GABA(A)α1 receptors.
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Lesiones Encefálicas/tratamiento farmacológico , Receptor alfa de Estrógeno/agonistas , Receptor beta de Estrógeno/agonistas , Trastornos de la Memoria/tratamiento farmacológico , Estrés Oxidativo/fisiología , Convulsiones/tratamiento farmacológico , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Lesiones Encefálicas/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Nitrilos/farmacología , Nitrilos/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Pentilenotetrazol/toxicidad , Propionatos/farmacología , Propionatos/uso terapéutico , Ratas , Ratas Wistar , Convulsiones/metabolismoRESUMEN
BACKGROUND: Free jejunal flaps are among the most commonly used flaps for esophageal reconstruction. However, ischemia-reperfusion injury caused by warm ischemia seen during transfer limits their use. Iloprost, a prostacyclin analogue, has been shown to reduce ischemia-reperfusion injury in various organs. The authors investigated tissue damage in jejunal flaps with iloprost and ischemic preconditioning and compared the effectiveness of these two modalities. METHODS: Thirty-four Sprague-Dawley rats were randomized into five groups: sham, ischemia-reperfusion (control), ischemic preconditioning, iloprost, and ischemic preconditioning plus iloprost. All flaps, except those in the sham group, underwent ischemia for 60 minutes and reperfusion for 2 hours. Flap perfusion was assessed by laser Doppler perfusion monitoring. Histologic sections were scored using the Chiu scoring system. Superoxide dismutase and myeloperoxidase levels were measured spectrophotometrically. RESULTS: Animals that were administered iloprost and/or underwent ischemic preconditioning had better postischemic recovery of mesenteric perfusion (ischemic preconditioning, 78 percent; iloprost, 83 percent; ischemic preconditioning plus iloprost, 90 percent; versus ischemia-reperfusion, 50 percent; p < 0.05). All intervention groups showed improved histology of jejunal flaps following ischemia-reperfusion injury (ischemic preconditioning, 3; iloprost, 2.3; ischemic preconditioning plus iloprost, 3.2; versus ischemia-reperfusion, 4.7; p < 0.01, p < 0.001, and p < 0.05, respectively). Superoxide dismutase levels were higher in ischemic preconditioning, iloprost plus ischemic preconditioning, and iloprost groups (ischemic preconditioning, 2.7 ± 0.2; ischemic preconditioning plus iloprost, 2.5 ± 0.3; versus ischemia-reperfusion, 1.2 ± 0.1; p < 0.01; iloprost, 2.4 ± 1.1; versus ischemia-reperfusion, 1.2 ± 0.1; p < 0.05). Myeloperoxidase, a marker for neutrophil infiltration, was lower in the iloprost group (iloprost, 222 ± 5; versus ischemia-reperfusion, 291 ± 25; p < 0.05). CONCLUSIONS: This study showed that both iloprost and ischemic preconditioning reduced reperfusion injury in jejunal flaps. Based on histologic results, iloprost may be a novel treatment alternative to ischemic preconditioning.
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Colgajos Tisulares Libres , Iloprost/farmacología , Precondicionamiento Isquémico/métodos , Yeyuno/trasplante , Inhibidores de Agregación Plaquetaria/farmacología , Daño por Reperfusión/prevención & control , Animales , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Esófago/cirugía , Flujometría por Láser-Doppler/métodos , Masculino , Infiltración Neutrófila/efectos de los fármacos , Peroxidasa/metabolismo , Distribución Aleatoria , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismoRESUMEN
High-fat diet (HFD) consumption leads to metabolic disorders, gastrointestinal dysfunction and intestinal dysbiosis. Antibiotics also disrupt the composition of intestinal microbiota. The aim of the present study was to investigate the impact of a short-term feeding with HFD on oxidative status, enteric microbiota, intestinal motility and the effects of antibiotics and/or melatonin treatments on diet-induced hepato-intestinal dysfunction and inflammation. Male Sprague-Dawley rats were pair-fed with either standard chow or HFD (45 % fat) and were given tap water or melatonin (4 mg/kg per d) or melatonin plus antibiotics (ABX; neomycin, ampicillin, metronidazole; each 1 g/l) in drinking water for 2 weeks. On the 14th day, colonic motility was measured and the next day intestinal transit was assessed using charcoal propagation. Trunk blood, liver and intestine samples were removed for biochemical and histopathological evaluations, and faeces were collected for microbiota analysis. A 2-week HFD feeding increased blood glucose level and perirenal fat weight, induced low-level hepatic and intestinal inflammation, delayed intestinal transit, led to deterioration of epithelial tight junctions and overgrowth of colonic bacteria. Melatonin intake in HFD-fed rats reduced ileal inflammation, colonic motility and perirenal fat accumulation. ABX abolished increases in fat accumulation and blood glucose, reduced ileal oxidative damage, suppressed HFD-induced overgrowth in colonic bacteria, and reversed HFD-induced delay in intestinal transit; however, hepatic neutrophil accumulation, hepatic injury and dysfunction were further enhanced. In conclusion, the results demonstrate that even a short-term HFD ingestion results in hepato-intestinal inflammatory state and alterations in bacterial populations, which may be worsened with antibiotic intake, but alleviated by melatonin.
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Antibacterianos/farmacología , Antioxidantes/farmacología , Disbiosis/tratamiento farmacológico , Enfermedades Intestinales/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Melatonina/farmacología , Animales , Colon/efectos de los fármacos , Colon/microbiología , Colon/patología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Disbiosis/etiología , Disbiosis/patología , Microbioma Gastrointestinal/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Íleon/efectos de los fármacos , Íleon/microbiología , Íleon/patología , Inflamación , Enfermedades Intestinales/etiología , Enfermedades Intestinales/patología , Intestinos/efectos de los fármacos , Intestinos/microbiología , Intestinos/patología , Hígado/efectos de los fármacos , Hígado/patología , Hepatopatías/etiología , Hepatopatías/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: The purpose of the present study was to investigate the potential antioxidant, anti-apoptotic and sperm function-preserving effects of estrogen, estrogen receptor (ER)α and ERß agonists in a rat model of testis torsion-detorsion (T/D). MAIN METHODS: Under anesthesia, 6-8-week-old male Sprague-Dawley rats underwent sham-operation or testicular torsion by fixing left testis rotated at 720° for 2â¯h. After detorsion, rats were treated with ERα agonist (1â¯mg/kg/day, subcutaneously, sc) or ERß agonist (1â¯mg/kg/day, sc) or estradiol (E2, 1â¯mg/kg/day, in drinking water) or vehicle on the following two days. On the third day, testicular blood-flow was recorded and then left testes were extracted for molecular and histochemical analysis. KEY FINDINGS: The findings showed that reduced testicular blood-flow following torsion was partially restored on the 3rd day of detorsion, while treatments with either of the ER agonists or E2 returned blood flow fully back to the control levels. When the testis-torsioned rats were given ERß agonist during the detorsion period, tubular injury was lessened, sperm count and motility were increased, while the production of reactive oxygen metabolites and apoptosis in the testis tissues were totally suppressed. Although a down-regulated expression of androgen receptor (AR) along with a reduction in serum testosterone level was observed in the vehicle-treated T/D group, all three treatments up-regulated the expressions of AR and its mRNA, while ERα agonist and E2 suppressed the testosterone level. SIGNIFICANCE: ERß receptor activation during the post-ischemic period may be beneficial in protection against torsion-related oxidant testicular injury and infertility.
Asunto(s)
Receptor beta de Estrógeno/agonistas , Estrógenos/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Torsión del Cordón Espermático/tratamiento farmacológico , Testículo/irrigación sanguínea , Testículo/efectos de los fármacos , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Velocidad del Flujo Sanguíneo/fisiología , Estrógenos/farmacología , Masculino , Estrés Oxidativo/fisiología , Ratas , Ratas Sprague-Dawley , Torsión del Cordón Espermático/patología , Testículo/patología , Resultado del TratamientoRESUMEN
Testicular torsion causes ischemia-reperfusion injury and an increased risk of infertility. Nesfatin-1 is a novel peptide with antioxidant, anti-inflammatory and anti-apoptotic properties. In the present study, we aimed to investigate the putative beneficial effects of nesfatin-1 on oxidative injury and impaired testicular function induced by testis torsion. Under anesthesia, male Sprague-Dawley rats (180-230â¯g; nâ¯=â¯24) had sham-operation or they underwent testicular torsion by rotating the left testis 720° and fixing it for 2â¯h, followed by a 2-h detorsion. Rats in each group were treated intraperitoneally with either nesfatin-1 (0.3⯵g/kg) or saline prior to the torsion or sham-torsion. At the end of the 4-h experimental period, tissue samples were removed for evaluation of spermatozoa, molecular and histochemical analyses. In saline-treated torsion/detorsion group, a high percentage of abnormal spermatozoa with head defects was observed, which was abolished in nesfatin-1-treated torsion/detorsion group. The levels of 8-OHdG, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, caspase-3 were increased in the saline-treated torsion/detorsion group as compared to sham-operated group, while nesfatin-1 pre-treatment significantly decreased the expressions of the pro-inflammatory cytokines, depressed apoptosis, and also reduced the tubular degeneration. In addition, nesfatin-1 in torsion/detorsion group elevated expressions of transforming growth factor (TGF)-beta and reduced expressions of protein kinase B (AKT) and cAMP response element binding protein (CREB) in the testis tissue. The present findings show that nesfatin-1, by regulating AKT and CREB signaling pathways and pro-inflammatory/anti-inflammatory cytokine balance, preserves the spermatogenic cells and ameliorates torsion-detorsion-induced tubular degeneration.