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BACKGROUND: 5-Fluorouracil (5-FU) is regarded as the first line treatment for colorectal cancer; however, its effectiveness is limited by drug resistance. The ultimate goal of cancer therapy is induction of cancer cell death to achieve an effective outcome with minimal side effects. The present work aimed to assess the anti-cancer activities of mitocans which can be considered as an effective anticancer drug due to high specificity in targeting cancer cells. METHODS: MTT (3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay was performed to determine the effects of our mitocans on cell viability and cell death. Apoptosis and necrosis, caspase 3 activity, mitochondrial membrane potential and ROS production in HT29 cell lines were analyzed by ApopNexin™ FITC/PI Kit, Caspase- 3 Assay Kit, MitoTracker Green and DCFH-DA, respectively. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) genes in HT29 cell lines. RESULTS: Treatment with mitocans (3Br-P + DCA) inhibited the growth of HT29. Moreover, 3Br-P + DCA significantly induced apoptosis and necrosis, activation of caspase 3 activity, depolarize the mitochondrial membrane potential, and ROS production. At a molecular level, 3Br-P + DCA treatment remarkably down-regulated the expression of Bcl-2, while up-regulated the expression of Bax. CONCLUSION: Mitocans, in particular the combined drug, 3Br-P + DCA, could be regarded and more evaluated as a safe and effective compound for CRC treatment. Targeting hexokinase and pyruvate dehydrogenase kinase enzymes may be an option to overcome 5-FU -mediated chemo-resistant in colorectal cancer.
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Apoptose/efeitos dos fármacos , Ácido Dicloroacético/farmacologia , Glucose/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Piruvatos/farmacologia , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais , Sinergismo Farmacológico , Fluoruracila , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos BiológicosRESUMO
Opioid-induced neuroinflammation plays a role in the development of opioid physical dependence. Moreover, nitric oxide (NO) has been implicated in several oxidative and inflammatory pathologies. Here, we sought to determine whether treatment with venlafaxine during the development of morphine dependence could inhibit naloxone-precipitated withdrawal symptoms. The involvement of neuro-inflammation related cytokines, oxidative stress, and L-arginine (L-arg)-NO pathway in these effects were also investigated. Mice received morphine (50 mg/kg/daily; s.c.), plus venlafaxine (5 and 40 mg/kg, i.p.) once a day for 3 consecutive days. In order to evaluate the possible role of L-arg-NO on the effects caused by venlafaxine, animals received L-arg, L-NAME or aminoguanidine with venlafaxine (40 mg/kg, i.p.) 30 min before each morphine injection for 3 consecutive days. On 4th day of experiment, behavioral signs of morphine-induced physical dependence were evaluated after i.p. naloxone injection. Then, brain levels of tissue necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10), brain-derived neurotrophic factor (BDNF), NO and oxidative stress factors including; total thiol, malondialdehyde (MDA) contents and glutathione peroxidase (GPx) activity were determined. Co-administration of venlafaxine (40 mg/kg) with morphine not only inhibited the naloxone-precipitated withdrawal signs including jumping and weight loss, but also reduced the up-regulation of TNF-α, IL-1ß, IL-6, NO and MDA contents in mice brain tissue. However, repeated administration of venlafaxine inhibited the decrease in the brain levels of BDNF, total thiol and GPx. Pre-administration of L-NAME and aminoguanidine improved, while L-arg antagonized the venlafaxine-induced effects. These results provide evidences that venlafaxine could be used as a candidate drug to inhibit morphine withdrawal through the involvement of inflammatory cytokines and l-arginine-NO in mice.
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Citocinas/antagonistas & inibidores , Morfina/efeitos adversos , Naloxona/toxicidade , Óxido Nítrico/antagonistas & inibidores , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Cloridrato de Venlafaxina/uso terapêutico , Animais , Citocinas/metabolismo , Masculino , Camundongos , Dependência de Morfina/tratamento farmacológico , Dependência de Morfina/metabolismo , Óxido Nítrico/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Síndrome de Abstinência a Substâncias/metabolismo , Cloridrato de Venlafaxina/farmacologiaRESUMO
Bisphenol A (BPA), which is an applied endocrine disrupting chemical in industry for producing epoxy resins and polycarbonate plastics and naringin, is an active flavanone glycoside of grapefruit and many citrus fruits. The present study evaluated the protective effect of naringin against cardiotoxicity induced by BPA. Male Wistar rats were divided into six groups. Control group received oral olive oil; and BPA group orally were administrated 50 mg/kg of BPA for 30 d consecutively to induce toxicity. 40, 80, and 160 mg/kg of naringin were orally administered for 30 consecutive, along with BPA. Naringin group orally received 160 mg/kg of naringin for 30 d consecutively. Animals were sacrificed and their biochemical, histological, and oxidative stress parameters were measured 24 h after the last treatment. Heart injury was induced by BPA as an evidence with a significant increase in levels of aspartate aminotransferase, lactate dehydrogenase, creatine kinase-MB, triglyceride, lipid peroxidation, and a significant decrease in levels of glutathione, superoxide dismutase, catalase, and glutathione peroxidase and triggered myocardial disorganization, myofibrillar loss, congestion of red blood cells, and the inflammation. However, there were not any changes in the total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and alanine aminotransferase. Moreover, our results indicated that administering 80 and 160 mg/kg of naringin significantly altered all examined endpoints that were induced by BPA. Both concentrations of 80 and 160 mg/kg of naringin were more effective than 40 mg/kg. These findings indicated that naringin had a protective effect against cardiotoxicity induced by BPA through lipid-lowering properties, antioxidant activity, and suppressed lipid peroxidation.
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Compostos Benzidrílicos/toxicidade , Cardiotoxicidade/prevenção & controle , Flavanonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Cardiotoxicidade/etiologia , Relação Dose-Resposta a Droga , Disruptores Endócrinos/toxicidade , Flavanonas/administração & dosagem , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer cytokine with minimal toxicity towards normal cells. Nevertheless, most primary cancers are often intrinsically TRAIL-resistant or can acquire resistance after TRAIL therapy. This study aimed to investigate the inhibitory effect of co-treatment of 3-bromopyruvate (3-BP) as a potent anticancer agent with TRAIL on colon cancer cells (HT-29). The results of present study indicated that combined treatment with 3-BP and TRAIL inhibited the proliferation of HT-29 cells to a greater extent (88.4%) compared with 3-BP (54%) or TRAIL (11%) treatment alone. In contrast, the combination of 3-BP and TRAIL had no significant inhibitory effect on the proliferation of normal cells (HEK-293) (8.4%). At a cellular mechanistic level, the present study showed that 3-BP sensitized human colon cancer cells to TRAIL-induced apoptosis via reactive oxygen species generation, upregulation of Bax, downregulation of Bcl-2 and survivin, release of cytochrome c into the cytosol, and activation of caspase-3. In normal cells, 3-BP, TRAIL, or combination of both had no significant effect on the reactive oxygen species levels, release of cytochrome c, and caspase-3 activity. Therefore, the combination of 3-BP and TRAIL can be a promising therapeutic strategy for treatment of colon cancer.
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Apoptose/efeitos dos fármacos , Caspases/metabolismo , Neoplasias do Colo/patologia , Mitocôndrias/efeitos dos fármacos , Piruvatos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Antineoplásicos/farmacologia , Citocromos c/metabolismo , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Survivina/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
Both arsenic (As) and obesity are associated with brain disorders. However, long term studies to evaluate their concomitant adverse effects on the brain functions are lacking. Present study was conducted to evaluate the long term co-exposure of As and high fat diet (HFD) on memory and brain mitochondrial function in mice. Male mice were randomly divided into 7 groups fed with HFD or ordinary diet (OD) and instantaneously exposed to As (25 or 50 ppm) in drinking water for, 4, 8, 12, 16 or 20 weeks. Step-down passive avoidance method was used for memory assessment and post exposure various parameters including mitochondrial damage, level of reactive oxygen species (ROS), malondialdeid (MDA) and glutathione (GSH) were determined. Results indicated that the retention latency decreased in As (25 and 50 ppm) and HFD received mice after 12 and 16 weeks respectively. Same results were observed at significantly shorter duration (8th week) when As was administered along with HFD as compared to control group. In the HFD alone fed mice increased the mitochondrial membrane damage, levels of ROS and MDA were observed while GSH contents decreased significantly. Concomitant administration of HFD and As amplified those mentioned toxic effects (p < 0.001). In conclusion, our findings demonstrated that the simultaneous HFD and As impaired memory at least three times more than exposing each one alone. These toxic effects could be due to the mitochondria originated oxidative stress along with the depleted antioxidant capacity of the brain of mice.
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Intoxicação por Arsênico/metabolismo , Arsenitos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Transtornos da Memória/metabolismo , Memória/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Compostos de Sódio/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs) are broadly applicable across a variety of industrial fields. Despite their usefulness in many different applications, oxidative stress-induced toxicity of SWCNTs and MWCNTs has not been widely investigated. The present study examined the effects of SWCNTs and MWCNTs on rat brain mitochondria using the 3,4 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and indices of reactive oxygen species (ROS), based on measurements of malondialdehyde (MDA), glutathione (GSH), and mitochondrial membrane potential. Based on the MTT assay, exposure to SWCNTs and MWCNTs decreased mitochondrial survival and viability in a dose-dependent manner. Findings also indicated that MWCNTs and SWCNTs could damage mitochondrial membranes and induce the formation of ROS, as indicated by increased levels of MDA and decreased GSH content. The results of this study suggest that SWCNTs and MWCNTs likely damage brain tissue mitochondria by increasing oxidative stress and possibly activating the apoptosis pathway as well as other pathways of cytotoxicity.
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Encéfalo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Sobrevivência Celular , Relação Dose-Resposta a Droga , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
The present study was conducted to evaluate the local antinociceptive actions of fluoxetine, a selective serotonin reuptake inhibitor, and the possible involvement of the l-arginine/NO/cGMP/KATP channel pathway in this effect using the formalin test in rats. To elucidate the underlying mechanisms, animals were pre-treated with l-NAME, aminoguanidine, methylene blue, glibenclamide, l-arginine, sodium nitroprusside, or diazoxide. Local ipsilateral, but not contralateral, administration of fluoxetine (10-300 µg/paw) dose-dependently suppressed flinching number during both early and late phases of the test, and this was comparable with morphine also given peripherally. Pre-treatment with l-NAME, aminoguanidine, methylene blue, or glibenclamide dose-dependently prevented fluoxetine (100 µg/paw)-induced antinociception in the late phase. In contrast, administration of l-arginine, sodium nitroprusside, and diazoxide significantly enhanced the antinociception caused by fluoxetine in the late phase of the test. However, these treatments had no significant effect on the antinociceptive response of fluoxetine in the early phase of the formalin test. Our data demonstrate that local peripheral antinociception of fluoxetine during the late phase of the formalin test could be due to activation of l-arginine/NO/cGMP/KATP channel pathway. The peripheral action of fluoxetine raises the possibility that topical application of this drug (e.g., as a cream, ointment, or jelly) may be a useful method for relieving the inflammatory pain states.
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Arginina/metabolismo , Bioensaio , Fluoxetina/farmacologia , Canais KATP/metabolismo , Óxido Nítrico/metabolismo , Nociceptividade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , GMP Cíclico/metabolismo , Diazóxido/farmacologia , Formaldeído/química , Glibureto/farmacologia , Guanidinas/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Nitroprussiato/farmacologia , Ratos Wistar , Fatores de TempoRESUMO
Arsenic is a common environmental and occupational contaminant worldwide which can influence the development of respiratory diseases. In recent years, alteration in the lifestyle as well as food habits have led to increased consumption of food containing high levels of fat. The present study was designed to evaluate the effects of chronic exposure to a high-fat diet (HFD) on arsenic-induced damages and oxidative stress in the lung tissue of mice. This is the first study to reveal the effect of diet-induced obesity on arsenic-induced lung damages. Seventy-two male Naval Medical Research Institute (NMRI) mice were divided into six groups and fed an HFD or standard diet (SD) while being exposed to 25 or 50 ppm of arsenic through drinking water for 20 weeks. At the end of the experiment, the lung weight to body weight ratio; oxidative stress markers, nitrite level, and hydroxyproline content in the lung tissue; and lung histology were evaluated. The results demonstrated that arsenic exposure leads to a significant decrease in the glutathione level and catalase enzyme activity, and significantly increased reactive oxygen species, malondialdehyde, and nitrite level, but it did not affect the superoxide dismutase activity and hydroxyproline content in the lung tissue. Consequently, all the parameters studied aggravated when HFD was consumed along with arsenic. These findings were confirmed by histological examination. Our study showed that HFD increased arsenic-induced lung damages through oxidative stress in mice. These findings could be important for clinical research to protect against arsenic-induced respiratory toxicity in humans.
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The present study aimed to evaluate the cinnamic acid effect on memory impairment, oxidative stress, and cholinergic dysfunction in streptozotocin (STZ)-induced diabetic model in mice. In this experimental study, 48 male Naval Medical Research Institute (NMRI) mice (30-35 g) were chosen and were randomly divided into six groups: control, cinnamic acid (20 mg/kg day, i.p. ), diabetic, and cinnamic acid-treated diabetic (10, 20 and 40 mg/kg day, i.p. ). Memory was impaired by administering an intraperitoneal STZ injection of 50 mg/kg. Cinnamic acid was injected for 40 days starting from the 21st day after confirming STZ-induced dementia to observe its therapeutic effect. Memory function was assessed using cross-arm maze, morris water maze and passive avoidance test. After the administration, biochemical parameters of oxidative stress and cholinergic function were estimated in the brain. Present data indicated that inducing STZ caused significant memory impairment, whereas administration of cinnamic acid caused significant and dose-dependent memory improvement. Assessment of brain homogenates indicated cholinergic dysfunction, increase in lipid peroxidation and reactive oxygen species (ROS) levels, and decrease in glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the diabetic group compared to the control animals, whereas cinnamic acid administration ameliorated these indices in the diabetic mice. The present study demonstrated that cinnamic acid improves memory by reducing the oxidative stress and cholinergic dysfunction in the brain of diabetic mice.
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This study aimed to determine the potential systemic and local anti-nociceptive effects of simvastatin (SIM) and the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) and nitric oxide (NO) pathways using a formalin assay in rats. After allocation, rats were intraplantarly (i.pl.) treated with formalin solution (2.5%) and the flinching behaviors were recorded for 5 min (phase 1) and 15-60 min (phase 2). SIM was given intraperitoneally (i.p.) and i.pl. 30 and 20 min before test, respectively. Intraperitoneal administration of SIM attenuated the flinching number during both phases of the test. This effect of i.p. SIM was significantly reduced by L -NAME (NO synthase blocker, i.p.), but was augmented by L -arginine (NO precursor, i.p.) during both phases of the formalin assay. Moreover, the antinociception caused by i.p. SIM was blocked by GW-9662 (PPARγ antagonist) at dose 2 mg/kg (i.p.). In another experiment, concurrent ip administration of non-effective dose of simvastatin (5 mg/kg) with pioglitazone (PPARγ agonist; 10, 20 mg/kg) produced antinociception. However, pre-treatment with i.p. GW-9662 inhibited the enhanced antinociceptive effect of pioglitazone on SIM during the phase 2 of formalin assay. Results also showed that i.pl. SIM alone had no anti-nociceptive effects. However, significant anti-nociception was observed when SIM (i.pl.) co-administered with non-effective dose of pioglitazone. Moreover, the enhanced effect was antagonized by pre-treatment with i.pl. GW-9662. Our data suggest that SIM produced antinociception through systemic but not local route of administration in rats. Moreover, the antinociceptive effect of SIM is partly mediated through PPARγ receptors and NO pathway. © 2017 Wiley Periodicals, Inc.
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Nociceptividade/efeitos dos fármacos , PPAR gama/metabolismo , Sinvastatina/farmacologia , Animais , Formaldeído/toxicidade , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Irritantes/toxicidade , Masculino , Óxido Nítrico/metabolismo , Dor/induzido quimicamente , Ratos , Ratos WistarRESUMO
Increasing applications of carbon nanotubes (CNTs) indicate the necessity to examine their toxicity. According to previous studies, CNTs caused oxidative stress that impaired ß-cell functions and reduced insulin secretion. Our previous study indicated that single-walled carbon nanotubes (SWCNTs) could induce oxidative stress in pancreatic islets. However, there is no study on the effects of multi-walled carbon nanotubes (MWCNTs) on islets and ß-cells. Therefore, the present study aims to evaluate effects of MWCNTs on the oxidative stress of islets and the protective effects of caffeic acid (CA) as an antioxidant. The effects of MWCNTs and CA on islets were investigated using MTT assay, reactive oxygen species (ROS), malondialdehyde (MDA), activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), the content of glutathione (GSH) and mitochondrial membrane potential (MMP) and insulin secretion measurements. The lower viability of islet cells was dose-dependent due to the exposure to MWCNTs according to the MTT assay. Further studies revealed that MWCNTs decreased insulin secretion and MMP, induced ROS creation, increased the MDA level, and decreased activities of SOD, GSH-Px, CAT, and content of GSH. Furthermore, the pretreatment of islets with CA returned the changes. These findings indicated that MWCNTs might induce the oxidative stress of pancreatic islets occurring diabetes and protective CA effects that were mediated by the augmentation of the antioxidant defense system of islets. Our research suggested the necessity of conducting further studies on effects of MWCNTs and CA on the diabetes.
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OBJECTIVE: Bisphenol A (BPA) is an organic synthetic compound, often used in manufacturing polycarbonate plastics. Researches have shown the role of BPA as an endocrine disruptor. The present study intended to evaluate the hepatoprotective properties of naringin, an active flavanone glycoside present in many citrus fruit, against hepatotoxicity induced by BPA. MATERIALS AND METHODS: Male Wistar rats were orally treated with 50 mg/kg BPA for 30 consecutive days for induction of toxicity and 40, 80 and 160 mg/kg naringin for the same period along with BPA or alone. RESULTS: This study demonstrated that BPA significantly increased serum levels of triglyceride, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), lipid peroxidation, and aspartate aminotransferase (AST) and significantly reduced catalase, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity, glutathione (GSH) and caused periportal inflammation and microvesicular steatosis in rat tissue. However, BPA did not change serum levels of high-density lipoprotein-cholesterol (HDL-C), total cholesterol, alanine aminotransferase (ALT), or low-density lipoprotein-cholesterol (LDL-C). Furthermore, the results displayed that administration of 80 and 160 mg/kg naringin improved hepatotoxicity and altered lipid peroxidation level, serum values of triglyceride and liver enzymes, and oxidative stress factors that were induced by BPA. The effect of two doses of 80 and 160 mg/kg naringin was more noticeable than that of dose 40 mg/kg. CONCLUSION: The findings suggested the protective effects of naringin against BPA-induced hepatotoxicity via ameliorating liver histopathological alteration, suppressing oxidative stress and lipid-lowering properties.
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Multi-walled carbon nanotubes (MWCNTs) are material with exclusive features that can be applied in different fields including industrial and medicine. It has been determined that the accumulation of MWCNTs in the organs is along with genotoxic and cytotoxic injuries. Previous studies have shown mitochondrial dysfunction in MWCNTs exposure with cell lines, but their exact mechanisms with isolated mitochondria have remained unclear. The present study evaluated toxicity induced by MWCNTs in isolated rat heart mitochondria and protective effect of naringin. Our results showed that MWCNTs toxicity caused the prevention of heart mitochondrial complex II activity. Treatment of isolated heart mitochondria with MWCNTs led to an increase in mitochondrial reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) collapse, and mitochondrial malondialdehyde (MDA) and a decrease in mitochondrial glutathione (GSH) level and mitochondrial catalase (CAT) activity. Pretreatment of isolated heart mitochondria with naringin decreased mitochondrial oxidative damage through decreasing lipid peroxidation, returned mitochondrial complex II changes, decreasing MMP collapse and ROS production, and restoration of GSH level and CAT activity. Our findings indicated that MWCNTs had toxic effects on isolated heart mitochondria by inducing oxidative stress and possibly apoptosis pathway. The protection effects of naringin may be accompanied by mitochondrial conservation by its antioxidant property or due to its free radical scavenging. Our findings indicated that naringin had a possible role in preventing the mitochondria complaints in the heart.
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Mitocôndrias Cardíacas , Nanotubos de Carbono , Animais , Apoptose , Flavanonas , Estresse Oxidativo , Ratos , Espécies Reativas de OxigênioRESUMO
Here, we aimed to investigate the effects of fluoxetine on morphine-induced analgesia, as well as preventive effects of it on morphine induced tolerance and dependence in mice. We also elucidate the involvement of L-type Ca2+ channels in these phenomena. To induce morphine tolerance, mice were treated with morphine (50 mg/kg) for 3 consecutive days. To evaluate the involvement of the calcium channel in the effects of fluoxetine (5, 20 mg/kg), combination ineffective doses of the two L-type calcium channel blockers, nimodipine (5 mg/kg) or diltiazem (20 mg/kg) with flouxetine were used with each morphine dose. Nociceptive behavior was evaluated using hot-plate test, while physical dependence assessed by naloxone-precipitated withdrawal on the fourth day of experiment. The expression of Cav1.2 and Cav1.3 subunits of the L-type calcium channels in cortex and mesolimbic tissues were measured using western immunoassay. Results showed that co-administration of fluoxetine (20 mg/kg) with morphine increased its acute analgesia effect and prevented the induction of morphine antinociceptive tolerance and physical dependence in mice. Moreover, these effects was potentiated by pre-treatment with diltiazem or nimodipine. Results also showed up-regulation of the Cav1.3 and Cav1.2 expression in the cerebral cortex and mesolimbic regions through the development of morphine dependence. Moreover, chronic administration of fluoxetine with morphine reduced the observed up-regulation of Cav1.3 and Cav1.2 expression in cortex and mesolimbic tissues. Our data indicated that co-administering of fluoxetine with morphine could potentiate the antinociceptive effect of morphine, prevent morphine analgesia tolerance and attenuated the morphine withdrawal signs during induction phases. Moreover, we also pointed out for the first time the role of L-type Ca2+ channel channels in the modulatory effects of fluoxetine on the morphine-related effects.
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Canais de Cálcio Tipo L/efeitos dos fármacos , Fluoxetina/farmacologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Analgésicos Opioides/farmacologia , Animais , Diltiazem/farmacologia , Tolerância a Medicamentos/fisiologia , Masculino , Camundongos , Morfina/farmacologia , Dependência de Morfina/metabolismo , Nimodipina/farmacologia , Dor/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/fisiopatologiaRESUMO
Objective: Obesity is associated with reproductive disorders. Arsenic disrupts male reproduction by direct effects on the male gonads or androgens secretion. So, the present study was conducted to evaluate the toxic effects of chronic concomitant administration of high-fat diet (HF) and arsenic on the reproductive system of the male mouse. Materials and methods: In this experimental study, 72 adult male mice were randomly divided into 6 groups: low-fat diet (LF0), LF+arsenic 25 ppm, LF+arsenic 50ppm, HF0, HF+arsenic 25 ppm and, HF+arsenic 50 ppm. 24 hours after the last experimental day, plasma samples, the cauda of epididymis and testis were prepared and removed for hormonal, sperm count and histopathological assessments. Results: Testis weight and volume increased in HF0 than other groups except for LF0. Plasma LH and testosterone levels decreased in LF50, HF0, HF25, and HF50 compared to LF0. A similar effect was observed in plasma FSH levels of HF0, HF25 and HF50 groups compared with LF0. Plasma level of estradiol increased in LF50 versus to other groups. Testosterone to estradiol ratio and sperm count decreased in all groups compared to LF0. Reduced interstitial cells and large numbers of vacuoles were observed in germinal epithelium of HF0 group, that these changes were more intense in both concentrations of arsenic-treated mice. Conclusion: Present study indicated that chronic exposure to HF and arsenic-induced hypogonadotropic hypogonadism concomitant with sperm count reduction and testicular damage.
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OBJECTIVES: Bisphenol A (BPA) as a synthetic compound is applied in many plastic industries. BPA has been reported to have endocrine-disrupting feature with cytotoxic effects. The study aimed to evaluate the efficiency of Naringin against testicular toxicity induced by BPA in adult rats. MATERIALS AND METHODS: The animals were assigned into six groups of control, BPA-treated (50 mg/kg), BPA+Naringin-administrated (40, 80, 160 mg/kg) and Naringin-treated (160 mg/kg) for 30 days. At the end of experiments, testicular weight, total testicular protein, epididymal sperm count, testicular enzymes, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and estradiol, testicular enzymatic and non-enzymatic antioxidants and histopathology of testis tissue were evaluated by their own methods. RESULTS: The results showed a reduction in testicular weight, total testicular protein, epididymal sperm count, testicular enzymes (alkaline phosphatase and lactate dehydrogenase) and decrease in the serum TSH, LH, testosterone and estradiol in BPA-administrated rats. Furthermore, BPA reduced the enzyme activities of glutathione peroxidase, superoxide dismutase, and catalase in testis tissue. Also, BPA caused an induction in lipid peroxidation and increase in reactive oxygen species levels, whereas it decreased the glutathione content of testis tissue. Histological findings exhibited seminiferous tubules vacuoles, atrophy and separation of the germinal epithelium in BPA-administrated rats. Oral administration of Naringin along with BPA normalized the biochemical, morphological and histological changes and reduced the testicular toxic condition. CONCLUSION: These results demonstrated that Naringin significantly managed male reproductive toxicity by antioxidant capabilities, preventing morphological modifications and escalating defense mechanism, thereby reducing oxidative stress from BPA-induced damage.
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Bisphenol A (BPA) is one of the highest volume chemicals produced worldwide, which is used in many plastic industries. The present study aimed to evaluate the effect of BPA on cognitive functions and oxidative stress, and determine whether the naringin (NG) co-administration can modify the effect of this compound on cognitive functions and inhibit any possible oxidative stress in the brain tissue of rats. Adult male Wistar rats were divided into six groups. Group I: control, Group II: BPA-treated rats (50 mg/kg/day), Group III, IV, V: BPA+NG (40, 80, 160 mg/kg/day), Group VI: NG (160 mg/kg/day) alone. Cognitive functions were evaluated using step-down latency (SDL) on a passive avoidance apparatus, and transfer latency (TL) in elevated plus-maze. A significant decrease in SDL, prolongation of TL, noticeable oxidative impairment and increase in acetylcholinesterase activity were observed in the BPA-treated in comparison with the control group. Also, the co-administration of NG (160 mg/kg) antagonized the effect of BPA on SDL and TL, attenuated oxidative damage by lowering malondialdehyde and nitrite concentrations and restored superoxide dismutase, catalase, and glutathione S-transferase activities. On the other hand, acetylcholinesterase activity was reduced in the groups co-administred with NG (80 or 160 mg/kg) and BPA in comparison with the BPA alone-treated group. The present study highlighted the therapeutic potential of NG against BPA-induced cognitive impairment and oxidative damage.
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BACKGROUND: Severe pain reduces quality of life of patients with various diseases, often because chronic morphine therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing adverse effects. Nitric oxide (NO) plays a role in morphine tolerance and dependence. OBJECTIVE: Venlafaxine, an antidepressant, is known to modulate nitric oxide (NO) pathway in nervous tissues. In the present study, the effect of systemic venlafaxine (VLF) on the development of morphine tolerance and dependence, acute morphine-induced antinociception, and the probable involvement of the L-arginine/NO/cGMP pathway in these effects were investigated in mice. METHODS: Animals developed tolerance to the antinociceptive effect of morphine (50 mg/kg, s.c. daily) for 3 consecutive days. NO modulators like L-NAME (NO synthase inhibitor) and L-Arginine (L-Arg, substrate for NO synthase), sildenafil (cGMP-PDE inhibitor) alone or in combination with venlafaxine were used. RESULTS: The results showed that i.p. administration of VLF (5-40 mg/kg) produced antinociceptive effect in a dose-dependent way. Pretreatment with L-Arg (200 mg/kg, i.p.) reversed the antinociception and L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.) potentiated the antinociceptive effect. Moreover, co-administration of VLF in non-effective dose (5 mg/kg) with morphine, potentiated acute morphine-induced analgesia (5 mg/kg, s.c.). This effect was antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.). On the other hand, VLF was prevented the development of morphine antinociceptive tolerance and dependence. These effects were antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.). CONCLUSION: Our data suggest that the combination of VLF with morphine may be a relevant therapeutic implication to manage pain even when tolerance to morphine exists. Moreover, our data demonstrates the involvement of L-Arg/NO/cGMP pathway in the prevention of morphine tolerance and dependence by venlafaxine.
Assuntos
Analgésicos Opioides/toxicidade , Arginina/metabolismo , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , GMP Cíclico/metabolismo , Tolerância a Medicamentos , Dependência de Morfina/prevenção & controle , Morfina/toxicidade , Óxido Nítrico/metabolismo , Dor Nociceptiva/prevenção & controle , Cloridrato de Venlafaxina/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Dependência de Morfina/metabolismo , Dependência de Morfina/fisiopatologia , Dependência de Morfina/psicologia , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Dor Nociceptiva/psicologia , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoRESUMO
The thyroid is one of the major endocrine glands that contribute to body and fat metabolism. The present study evaluated the effects of combined exposure to chronic high-fat diet (HFD) and arsenic on thyroid function and lipid profile. In this experimental study, 72 male Naval Medical Research Institute mice were divided into six groups and fed HFD or low-fat diet (LFD) while being exposed to 25 or 50 ppm of arsenic in drinking water for 20 weeks. After 24 h of the last experimental day, blood samples were collected for hormonal and biochemical measurements. The data indicated that exposure to HFD alone increased the levels of triiodothyronine (T3), thyroid-stimulating hormone (TSH), leptin, lipid profile, reactive oxygen species (ROS), and malondialdehyde (MDA) and decreased the levels of high-density lipoprotein, albumin, adiponectin, and glutathione sulfhydryl reductase (GSH), whereas exposure to arsenic alone decreased the levels of T3 and GSH and increased the levels of TSH, leptin, ROS, MDA, and T4/T3 ratio compared to those in the control LFD group. Furthermore, concomitant administration of HFD and arsenic decreased the lipid profile and levels of T4, albumin, total protein, T3, and GSH and increased the levels of TSH, adiponectin, leptin, ROS, MDA, and T4/T3 ratio compared to those in the control LFD or HFD group. In conclusion, combined exposure to HFD and arsenic induced hypothyroidism via reduction of thyroid hormones and enhancement of plasma TSH and T3 uptake levels concomitant with hypolipidemia, hyperleptinemia, hyperadiponectinemia, induction of oxidative stress, and reduction of GSH levels.
Assuntos
Arsênio/farmacologia , Dieta Hiperlipídica , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Glândula Tireoide/efeitos dos fármacos , Animais , Arsênio/administração & dosagem , Glutationa Redutase/sangue , Glutationa Redutase/metabolismo , Masculino , Malondialdeído/sangue , Camundongos , Espécies Reativas de Oxigênio/sangue , Espécies Reativas de Oxigênio/metabolismo , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiologia , Hormônios Tireóideos/sangue , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
Diet is one of the important risk factors that could potentially affect arsenic-induced cardiotoxicity. The present study was undertaken to investigate the effect of high fat diet on arsenic-induced cardiotoxicity in mice. Mice were divided into six different groups (n = 12), two control groups received either low fat diet (LFD) or high fat diet (HFD) along with deionized drinking water and four test groups given LFD + 25 ppm arsenic, LFD + 50 ppm arsenic, HFD + 25 ppm arsenic, and HFD + 50 ppm arsenic in drinking water for 5 months. The body weight, heart weight to body weight ratio, cardiac biochemical markers, lipid profile, and histological examination of heart were evaluated. The results demonstrated that arsenic exposure led to a significant decrease in heart glutathione level, catalase enzyme activity, and a significant increase in reactive oxygen species (ROS), malondialdehyde levels, and biochemical enzymes. The administration of HFD resulted in above-mentioned changes as well as an alteration in lipid profile; however, arsenic exposure alone or along with HFD caused a reduction in lipid profile factors, except HDL level. Our results revealed that HFD increased arsenic-induced heart injury in the mice. This effect may be because of reduction in antioxidant activities and/or increase in oxidative stress and ROS in mice heart tissues. These findings could be important for clinical intervention to protect against or prevent arsenic-induced cardiotoxicity in humans.