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OBJECTIVE: Neurotoxicity is an adverse effect caused by cisplatin due to inflammation and oxidative stress in the central nervous system. The present study aimed to assess the effects of vitamin E injection on the learning and memory of rats with cisplatin-induced cognitive impairment. METHODS: Male rats were administered with cisplatin (2 mg/kg/7 day; intraperitoneally [i i.p.]) and/or vitamin E (200 mg/kg/7 day; i.p.) for 1 week, and the control group received saline solution. Spatial memory was evaluated using Morris water maze (MWM). In addition, the hippocampal concentrations of malondialdehyde (MDA), thiol, and superoxide dismutase (SOD) were measured using biochemical methods. RESULTS: According to the findings, cisplatin significantly increased the escape latency, while decreasing the time spent and travelled pathway in the target quadrant on the final trial day compared to the control group. Furthermore, pre-treatment with vitamin E significantly reversed all the results in the spatial memory test. The biochemical data indicated that vitamin E could decrease MDA activity and increase thiol and SOD activity compared to the control group. CONCLUSION: According to the results, vitamin E could improve cisplatin-induced memory impairment possibly through affecting the hippocampal oxidative status.
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Cisplatino/efectos adversos , Trastornos de la Memoria/inducido químicamente , Memoria Espacial/efectos de los fármacos , Vitamina E/efectos adversos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Antioxidantes/farmacología , Estudios de Casos y Controles , Cisplatino/administración & dosificación , Disfunción Cognitiva/inducido químicamente , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inflamación/metabolismo , Inyecciones Intraperitoneales , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/química , Modelos Animales , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Superóxido Dismutasa/química , Superóxido Dismutasa/efectos de los fármacos , Vitamina E/administración & dosificación , Vitamina E/farmacologíaRESUMEN
Neuropathic pain (NP) is a chronic condition characterized by persistent pain following nerve injury. It is a challenging clinical problem to manage due to limited treatment options. Mesenchymal stem cells (MSCs)-derived conditioned medium (CM) is a cell-free product that contains the secretome of MSCs and has been shown to have therapeutic potential in various inflammatory and degenerative disorders. Several animal studies have examined the antinociceptive effects of MSCs-CM on established neuropathic pain, but none have investigated the early prevention of neuropathic pain using MSCs-CM. Therefore, in this study, we tested whether preemptive administration of MSCs-CM could attenuate the development of NP in rats. To this end, NP was induced in Wistar rats using a chronic constriction injury (CCI) model (day 0), and then the animals were divided into four groups: Sham, CCI, CCI-Dulbecco's Modified Eagle Medium (DMEM), and CCI-CM. The CCI-CM group received 1 ml intraperitoneal administration of MSCs-CM on days - 1, 1, and 2, while the Sham, CCI, and CCI-DMEM groups received vehicle only (normal saline or DMEM). Mechanical withdrawal threshold and thermal withdrawal latency were assessed to evaluate pain sensitivities. In addition, the expression levels of proinflammatory cytokines (TNF-α and IL-1ß) in the spinal cord tissues were measured using quantitative real-time PCR (qRT-PCR). The results demonstrated that preemptive treatment with MSCs-CM can significantly attenuate the development of NP, as evidenced by improved mechanical withdrawal threshold and thermal withdrawal latency in the CCI-CM group compared to the CCI and CCI-DMEM groups. Furthermore, the relative gene expression of proinflammatory cytokines TNF-α and IL-1ß were significantly decreased in the spinal cord tissues of the CCI-CM group compared to the control groups. These findings suggest that preemptive administration of MSCs-CM can attenuate the development of NP in rats, partly due to the downregulation of proinflammatory cytokines.
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Células Madre Mesenquimatosas , Neuralgia , Ratas , Animales , Citocinas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Medios de Cultivo Condicionados/farmacología , Ratas Sprague-Dawley , Regulación hacia Abajo , Hiperalgesia/tratamiento farmacológico , Ratas Wistar , Neuralgia/tratamiento farmacológico , Células Madre Mesenquimatosas/metabolismoRESUMEN
Objective: Studies have shown the complications of chemotherapy on learning and memory. Empirical evidence suggests that Nigella sativa (NS) has neuroprotective activities. Therefore, the aim of our study was to investigate the effects of NS on cisplatin-induced memory impairment. Materials and Methods: This study was conducted on 40 male rats grouped as: control (saline: 2 ml/kg, intraperitoneally (IP), once weekly/2 weeks), cisplatin (Cis, 2 mg/kg, IP, once weekly/2 weeks), NS (200 mg/kg, IP, once weekly/2 weeks), Cis +NS 200 (2 mg/kg Cis + 200 mg/kg NS, IP, once weekly/2 weeks), and Cis +NS 400 (2 mg/kg Cis + 400 mg/kg NS, IP, once weekly/2 weeks). Morris water maze (MWM) test was used to assess spatial learning and memory. In addition, superoxide dismutase (SOD) activity, and thiol and malondialdehyde (MDA) levels were evaluated in the brain. Results: Cis significantly enhanced the traveled distance and time spent in the target quadrant in the MWM test. Additionally, MDA levels increased in the Cis group, while thiol and SOD decreased in this group. As a result of treatment with NS, behavioral results were reversed in the groups receiving NS compared to the Cis group. Also, NS reduced MDA level but improved SOD and thiol levels in brain tissue samples. Conclusion: NS could improve memory impairment and oxidative stress in animals receiving Cis. Therefore, NS could be used as a potential food supplement to prevent neurotoxicity in patients undergoing chemotherapy.
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Background: The Toll-like receptor 4 (TLR4) gene promotes migration in adenocarcinoma cells. Morphine is an agonist for TLR4 that has a dual role in cancer development. The promoter or inhibitor role of morphine in cancer progression remains controversial. This study aims to evaluate the effects of morphine on the TLR4, myeloid differentiation primary response protein 88-dependent (MyD88), and nuclear factor-kappa B (NF-κB) expressions in the human MDA-MB-231 breast cancer cell line. Materials and Methods: The cells were examined after 24 hours of incubation with morphine using the Boyden chamber system. TLR4, MyD88, and NF-κB mRNA expressions were assessed using quantitative real-time polymerase chain reaction (RT-PCR). The concentration of interleukin-2 beta was also measured using the ELISA assay. Results: According to the findings, three doses of morphine (0.25, 1.25, and 0.025 µM) increased the expression of the TLR4 and NF-κB genes, whereas no significant change was observed in the mRNA expression of MyD88. Furthermore, treatment with morphine and lipopolysaccharide (LPS) significantly decreased the expression of TLR4, MyD88, and NF-κB. However, no significant change was observed in interleukin 2 beta concentration. Conclusions: These findings confirmed the excitatory effects of morphine on TRL4 expression and the MYD88 signaling pathway in vitro.
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BACKGROUND: Despite significant advancements in breast cancer therapy, novel drugs with lower side effects are still being demanded. In this regard, we investigated the anti-cancer features of verbascoside in 4 T1 mouse mammary tumor cell. METHODS: First, MTT assay was performed with various concentrations (ranging between 5 to 200 µM) of verbascoside and IC50 was calculated. Then the expression of Bax, Bcl-2, and caspase-3 was evaluated in treated 4 T1 cells. In addition, we investigated the expression of TLR4, MyD88, and NF-κB to ascertain the underlying mechanism of the anti-proliferative feature of verbascoside. Also, flow cytometry followed by double PI and Annexin V was conducted to confirm the apoptosis-inducing effect of verbascoside. RESULTS: Our results from MTT assay showed verbascoside inhibits proliferation of 4 T1 cancer cells (IC50 117 µM) while is safe for normal HEK293T cells. By qRT-PCR, we observed that verbascoside treatment (100, 117 and, 130 µM) increases the expression of caspase-3 and Bax while reduces the expression of Bcl-2. Also, verbascoside (100, 117 and, 130 µM) increased the expression of TLR4 only at 130 µM dose and the expression of MyD88 whereas reduced the expression of NF-κB at mRNA level. Flow cytometry analysis also confirmed verbascoside induces apoptosis in 4 T1 cells at 117 µM. CONCLUSION: Taken together, our data showed verbascoside is a safe natural compound for normal cells while has apoptosis-inducing feature through TLR4 axis on 4 T1 cells.
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Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Glucósidos/farmacología , Fenoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/genética , Caspasa 3/genética , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Factor 88 de Diferenciación Mieloide/genética , FN-kappa B/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Receptor Toll-Like 4/genéticaRESUMEN
Background Although numerous studies have proven that estrogen (Est) has a protective effect on the development of hypertension, more research needs to be done to show its detailed mechanism in a variety of hypertension. The important role of active oxygen species in blood pressure is well defined. We examined whether or not sex hormones change the growth of reactive oxygen species (ROS) in kidneys after central microinjection of angiotensin II (Ang II). Materials and methods Female Wistar rats, 8 weeks old (200 ± 10 g) were used in this study. The animal groups were (1) Sham, (2) Ovariectomy (OVX), (3) Sham-Hypertension (Sham-Hyper), (4) OVX-Hypertension (OVX-Hyper), (5) Sham-Hyper-Est, (6) OVX-Hyper-Est ; (7) Sham-Hyper-Testosterone (Tst) and (8) OVX-Hyper-Tst. Solutions of 1% NaCl and 0.1 KCl were used and desoxycorticostrone (doca-salt) was injected (45 mg/kg) 3 times a week in Hypertension groups. Estradiol and Tst (2 mg/kg and 5 mg/kg ; daily; subcutaneously) for 4 weeks. Ang II (50 µM, 5 µL) was microinjected by intracerebroventricular ( i.c.v.) infusion and malondialdehyde (MDA) and thiol in the kidneys were measured. Results MDA in the kidneys was increased by Ang II and doca-salt treatments. Both estradiol and Tst decreased the kidney's MDA. The level of thiol was higher in Hyper groups and reversed after treatment with estradiol and Tst. Conclusions Our findings suggest that central effect of Ang II on blood pressure and kidney disease is accompanied with increased levels of oxidative stress in the kidneys. Indeed sex hormones change the ROS level in the kidneys after central microinjection of Ang II. .
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Angiotensina II/farmacología , Desoxicorticosterona/farmacología , Estradiol/farmacología , Riñón/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Testosterona/farmacología , Andrógenos/farmacología , Angiotensina II/administración & dosificación , Animales , Desoxicorticosterona/administración & dosificación , Estrógenos/farmacología , Femenino , Inyecciones Intraventriculares , Riñón/metabolismo , Malondialdehído/metabolismo , Estrés Oxidativo , Ratas , Ratas WistarRESUMEN
BACKGROUND: Overactivity of renin-angiotensin system is involved in the pathophysiology of renal and cardiovascular diseases. It is suggested that endothelial cells can release nitric oxide (NO) and reactive oxygen species in response to angiotensin II (Ang II). Angiotensin type 1 (AT1) receptor of Ang II has been found in the bed nucleus of the stria terminalis (BST). BST is involved in autonomic function. This study was performed to find the role of central Ang II in serum lipid peroxidation product and in releasing NO into circulation. MATERIALS AND METHODS: Twenty-one catheterized rats were placed in stereotaxic instrument. A hole was drilled above BST. In the control group, saline 0.9% (100 nl) was microinjected into the BST. In the second group, Ang II (100 µM, 100-150 nl) was microinjected into the BST. In the third group losartan (an AT1 antagonist) was microinjected (100 µM, 200 nl) before Ang II into the BST. Systolic blood pressure was recorded. The NO metabolite (nitrite) and malondialdehyde (MDA) were measured in the rat's serum. RESULTS: The data indicated that microinjection of Ang II into the BST produced a pressor response (P < 0.0001). It also increased MDA and nitrite levels of the serum significantly (P < 0.001, P < 0.0001). Pretreatment with losartan before Ang II microinjection attenuated serum's levels of MDA and nitrite (P < 0.001, P < 0.0001). CONCLUSION: Our findings suggest that central effect of Ang II on blood pressure is accompanied with increased levels of MDA and nitrite in the circulation.
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The bed nucleus of the stria terminalis (BST) is involved in cardiovascular regulation. The angiotensin II (Ang II) receptor (AT1), and angiotensinogen were found in the BST. In our previous study we found that microinjection of Ang II into the BST produced a pressor response. This study was performed to find the mechanisms mediating this response in anesthetized rats. Ang II was microinjected into the BST and the cardiovascular responses were re-tested after systemic injection of a blocker of autonomic or vasopressin V1 receptor. The ganglionic nicotinic receptor blocker, hexamethonium dichloride, attenuated the pressor response to Ang II, indicating that the cardiovascular sympathetic system is involved in the pressor effect of Ang II. A selective vasopressin V1 receptor antagonist greatly attenuated the pressor effect of Ang II, indicating that the Ang II increases the arterial pressure via stimulation of vasopressin release as well. In conclusion, in the BST, Ang II as a neurotransmitter increases blood pressure by exciting cardiovascular sympathetic system and directly or indirectly causing vasopressin to release into bloodstream by VPN. This is an interesting new finding that not only circulating Ang II but also brain Ang II makes vasopressin release.
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Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Núcleos Septales/efectos de los fármacos , Vasopresinas/farmacología , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Ganglios Autónomos/metabolismo , Masculino , Microinyecciones , Sistema Nervioso Parasimpático/metabolismo , Ratas Wistar , Receptores de Vasopresinas/metabolismo , Núcleos Septales/fisiologíaRESUMEN
The bed nucleus of the stria terminalis (BST) is part of the limbic system located in the rostral forebrain. BST is involved in behavioral, neuroendocrine and autonomic functions, including cardiovascular regulation. The amygdala, plays an important role in mediating the behavioral and physiological responses associated with fear and anxiety, including cardiovascular responses. In a previous study, we showed that microinjection of AngII into the BST produced a pressor and two types of single-unit responses in the BST, short excitatory and long inhibitory. This study was performed to find possible involvement of amygdala in cardiovascular responses elicited by microinjection of AngII into the BST, using blockade of the central nucleus of amygdala (CeA) and single unit recording from the CeA, while injecting AngII into the BST in anesthetized rat. Blockade of CeA attenuated the pressor response to microinjection of AngII into the BST. Eighty-six AngII microinjections were given into the BST and 198 single unit responses were recorded from CeA simultaneously, from which 89 showed a short duration excitatory response and 109 showed no responses. In conclusion, microinjection of AngII into the BST produces a short excitatory single unit response in the CeA, resulting in contribution of amygdala to the resulted pressor response. Taken together, our study and previous studies suggest a plausible hypothesis that these two nuclei perform their cardiovascular functions in cooperation with each other.
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Angiotensina II/administración & dosificación , Núcleo Amigdalino Central/fisiología , Núcleos Septales/efectos de los fármacos , Núcleos Septales/fisiología , Vasoconstrictores/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Núcleo Amigdalino Central/citología , Núcleo Amigdalino Central/efectos de los fármacos , Masculino , Microinyecciones , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas Wistar , Núcleos Septales/citologíaRESUMEN
BACKGROUND: There is a probable interaction of central angiotensin II (Ang II) and estrogen (Est) on blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Therefore, in the present study, the interaction between Ang II and Est in ovariectomized (Ovx) and Sham rats that were treated with DOCA- salt was evaluated. MATERIALS AND METHODS: The female rats were divided into 10 groups as follows: Sham, Ovx, Sham-DOCA, Ovx-DOCA, Sham-DOCA-estrogen (E), Ovx DOCA-E, Sham-DOCA-losartan (L), Ovx-DOCA-L, Sham-DOCA-L-E, and Ovx-DOCA-L-E. The Est groups received estradiol valerate (2 mg/kg; daily; subcutaneously (s.c)) for four weeks. Following that, several doses of Ang II (0.5, 5, 50, 500, 5000 ng/5 µl) were injected via the intracerebroventricular (i.c.v) route and the changes in systolic blood pressure (SBP) were evaluated. In the losartan groups, 200 µg losartan was injected (i.c.v) 15 minutes after the Ang II injection and the blood pressure was recorded. Treatment by DOCA was performed by removal of one kidney, injection of DOCA (45 mg/kg i.p), and adding of sodium chloride (NaCl) (1%) and potassium chloride (KCl) (0.1%) in the drinking water. RESULTS: The SBP was increased by Ang II and this effect in DOCA-salt treated rat was higher than in the untreated groups. The effect of Ang II on SBP in groups that were treated with Est and L was lower than that in the DOCA-salt groups. Increase in SBP was strongly attenuated by Ang II in groups that were co-treated with both Est and L compared to the DOCA-treated rats. These results showed that Est significantly attenuated the effect of central Ang II on SBP in the DOCA-salt treated rats. CONCLUSION: We suggest that there are interactions between E and Ang II in the control of blood pressure in DOCA-salt treated rats.