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INTRODUCTION: Experimental hepatopulmonary syndrome (HPS) is best reproduced in the rat common bile duct ligation (CBDL) model. Vildagliptin (Vild) is an anti-hyperglycemic drug that exerts beneficial anti-inflammatory, anti-oxidant and anti-fibrotic effects. Therefore, the present search aimed to explore the possible effectiveness of Vild in CBDL-induced HPS model. METHODS: Four groups of male Wistar rats which weigh 220-270 g were used, including the normal control group, the sham control group, the CBDL group and CBDL+Vild group. The first three groups received i.p. saline, while the last group was treated with i.p. Vild (10 mg/kg/day) from the 15th to 28th day of the experiment. RESULTS: CBDL decreased the survivability and body weight of rats, increased diameter of the pulmonary vessels, and altered the arterial blood gases and the liver function parameters. Additionally, it increased the pulmonary expressions of endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) mRNA as well as endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) proteins. The CBDL rats also exhibited elevation of the pulmonary interleukin-6 (IL-6), dipeptidyl peptidase-4 (DPP-4) and nitric oxide (NO) levels along with reduction of the pulmonary total anti-oxidant capacity and glucagon-like peptide-1 (GLP-1) levels. Vild mitigated these alterations and improved the histopathological abnormalities caused by CBDL. CONCLUSION: Vild effectively attenuated CBDL-induced HPS through its anti-oxidant and anti-inflammatory effects along with its modulatory effects on ET-1/NOS/NO and TNF-α/IL-6/VEGF-A signaling implicated in the regulation of intrapulmonary vasodilatation and angiogenesis, respectively.
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Ducto Colédoco , Síndrome Hepatopulmonar , Ratos Wistar , Vasodilatação , Vildagliptina , Animais , Síndrome Hepatopulmonar/tratamento farmacológico , Vildagliptina/farmacologia , Masculino , Ligadura , Ducto Colédoco/cirurgia , Ratos , Vasodilatação/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Adamantano/análogos & derivados , Adamantano/farmacologia , Adamantano/uso terapêutico , AngiogêneseRESUMO
Acute kidney injury and other renal disorders are thought to be primarily caused by renal ischemia-reperfusion (RIR). Cyclic adenosine monophosphate (cAMP) has plenty of physiological pleiotropic effects and preserves tissue integrity and functions. This research aimed to examine the potential protective effects of the ß3-adrenergic receptors agonist mirabegron in a rat model of RIR and its underlying mechanisms. Male rats enrolled in this work were given an oral dose of 30 mg/kg mirabegron for two days before surgical induction of RIR. Renal levels of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), Interleukin-10 (IL-10), cAMP, cAMP-responsive element binding protein (pCREB), and glycogen synthase kinase-3 beta (GSK-3ß) were assessed along with blood urea nitrogen and serum creatinine. Additionally, caspase-3 and nuclear factor-kappa B (NF-κB) p65 were explored by immunohistochemical analysis. Renal specimens were inspected for histopathological changes. RIR led to renal tissue damage with elevated blood urea nitrogen and serum creatinine levels. The renal KIM-1, MCP-1, TNF-α, and GSK-3ß were significantly increased, while IL-10, cAMP, and pCREB levels were reduced. Moreover, upregulation of caspase-3 and NF-κB p65 protein expression was seen in RIR rats. Mirabegron significantly reduced kidney dysfunction, histological abnormalities, inflammation, and apoptosis in the rat renal tissues. Mechanistically, mirabegron mediated these effects via modulation of cAMP/pCREB and GSK-3ß/NF-κB p65 signaling pathways. Mirabegron administration could protect renal tissue and maintain renal function against RIR.
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Acetanilidas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , AMP Cíclico , Glicogênio Sintase Quinase 3 beta , Rim , Traumatismo por Reperfusão , Transdução de Sinais , Tiazóis , Fator de Transcrição RelA , Animais , Masculino , Ratos , Acetanilidas/farmacologia , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Fator de Transcrição RelA/metabolismoRESUMO
Quantitation of protein-nanoparticle interactions is essential for the investigation of the protein corona around NPs in vivo and when using synthetic polymer nanoparticles as affinity reagents for selective protein recognition in vitro. Here, a method based on steady-state fluorescence anisotropy measurement is presented as a novel, separation-free tool for the assessment of protein-nanoparticle interactions. For this purpose, a long-lifetime luminescent Ru-complex is used for protein labelling, which exhibits low anisotropy when conjugated to the protein but displays high anisotropy when the proteins are bound to the much larger polymer nanoparticles. As a proof of concept, the interaction of lysozyme with poly(N-isopropylacrylamide-co-N-tert-butylacrylamide-co-acrylic acid) nanoparticles is studied, and fluorescence anisotropy measurements are used to establish the binding kinetics, binding isotherm and a competitive binding assay.
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Nanopartículas , Polímeros , Ligação Proteica , Corantes Fluorescentes , Proteínas , Polarização de FluorescênciaRESUMO
Highly selective multifunctional magnetic nanoparticles containing a thermoresponsive polymer shell were developed and used in the sample pretreatment of urine for the assessment of lysozymuria in leukemia patients. Crosslinked poly(N-isopropylacrylamide-co-acrylic acid-co-N-tert-butylacrylamide) was grown onto silica-coated magnetic nanoparticles by reversible addition fragmentation chain transfer (RAFT) polymerization. The lysozyme binding property of the nanoparticles was investigated as a function of time, protein concentration, pH, ionic strength and temperature and their selectivity was assessed against other proteins. High-abundant proteins, like human serum albumin and γ-globulins did not interfere with the binding of lysozyme even at elevated concentrations characteristic of proteinuria. A sample cleanup procedure for urine samples has been developed utilizing the thermocontrollable protein binding ability of the nanoparticles. Method validation was carried out according to current bioanalytical method validation guidelines. The method was highly selective, and the calibration was linear in the 25 to 1000 µg/mL concentration range, relevant in the diagnosis of monocytic and myelomonocytic leukemia. Intra- and inter-day precision values ranged from 2.24 to 8.20% and 1.08 to 5.04%, respectively. Intra-day accuracies were between 89.9 and 117.6%, while inter-day accuracies were in the 88.8 to 111.0% range. The average recovery was 94.1 ± 8.1%. Analysis of unknown urine samples in comparison with a well-established reference method revealed very good correlation between the results, indicating that the new nanoparticle-based method has high potential in the diagnosis of lysozymuria.
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Hemorrhagic cystitis is a potentially deadly complication associated with radiation therapy and chemotherapy. This study explored the protective effect of edaravone (ED) on cyclophosphamide (CP)-induced hemorrhagic cystitis, oxidative stress, and inflammation in rats. The animals received 20 mg/kg ED for 10 days and a single injection of 200 mg/kg CP on day 7. CP induced tissue injury manifested by the diffuse necrotic changes, disorganization of lining mucosa, focal hemorrhagic patches, mucosal/submucosal inflammatory cells infiltrates, and edema. CP increased malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha, and interleukin 6 (IL-6), decreased IL-10, and upregulated toll-like receptor 4 (TLR-4), nuclear factor-kappa B (NF-κB) p65, Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) in the urinary bladder of rats. ED effectively prevented the histopathological alterations, decreased MDA, NO, and inflammatory mediators, and downregulated TLR-4, NF-κB, JAK1, and STAT3 in CP-induced rats. Treatment with ED upregulated ikß kinase ß, IL-10, nuclear factor-erythroid 2 related factor 2 (Nrf2), and cytoglobin, and boosted glutathione, superoxide dismutase, and glutathione S-transferase. Molecular docking simulations revealed the ability of ED to bind TLR-4, NF-κB, JAK1, and STAT3. In vitro, ED increased the cytotoxic activity of CP against HeLa, Caco-2, and K562 cell lines. In conclusion, ED prevented CP-induced hemorrhagic cystitis in rats by attenuating oxidative stress, suppressing TLR-4/NF-κB, and JAK1/STAT3 signaling and boosted Nrf2, cytoglobin, and antioxidants.
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Antineoplásicos Alquilantes/toxicidade , Ciclofosfamida/toxicidade , Cistite/prevenção & controle , Edaravone/toxicidade , Hemorragia/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Cistite/complicações , Hemorragia/complicações , Janus Quinase 1/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismoRESUMO
AIMS: Cigarette smoking (CS) is the main cause of chronic obstructive pulmonary disease (COPD). Endothelial dysfunction is related to the severity of pulmonary disease in COPD. This study aimed to evaluate the effectiveness of single and combined administration of pioglitazone (Pio) and irbesartan (Irb) against COPD-induced endothelial dysfunction in mice and the involvement of NO and H2S in their effects. MATERIALS AND METHODS: Adult male Swiss mice (n = 40, weighing 25-30 g) were assigned into 5 groups. The normal control group received 1% carboxy methyl cellulose (CMC). The CS group was exposed to CS and administered 1% CMC for 3 months. The CS + Pio, CS + Irb, and CS + Pio/Irb groups were subjected to CS and received Pio (60 mg/kg), Irb (50 mg/kg), and their combination respectively, daily orally for 3 months. Body weight gain, mean blood pressure, urinary albumin, serum NO and ET-1 levels with TNF-α and IL-2 levels in lung tissue and bronchoalveolar lavage were measured. Lung H2S and ET-1 levels, protein expression of PPARγ in lung and VEGF in lung and aortic tissues with histological changes were assessed. KEY FINDINGS: Our results illustrated that CS induced a model of COPD with endothelial dysfunction in mice. Pio/Irb singly and in combination elicited protective effects against the pathophysiology of the disease with more improvement in the combined group. There is a strong correlation between NO and H2S as well as the other measured parameters. SIGNIFICANCE: Collectively, both drugs performed these effects via their anti-inflammatory potential and increasing H2S and NO levels.
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Anti-Hipertensivos/uso terapêutico , Fumar Cigarros/efeitos adversos , Hipoglicemiantes/uso terapêutico , Irbesartana/uso terapêutico , Pioglitazona/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Endotélio/efeitos dos fármacos , Endotélio/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fumaça/efeitos adversosRESUMO
INTRODUCTION: Cyclophosphamide (CP) causes redox imbalance and its use is associated with marked cardiotoxicity that limits its clinical applications. The present study investigated the protective effects of acetovanillone (AV) and edaravone (ED) against CP-induced oxidative stress and cardiac damage, emphasizing the role of PI3K/Akt/mTOR and Nrf2 signaling. MATERIALS AND METHODS: Rats received either AV (100 mg/kg) or ED (20 mg/kg) orally for 10 days and CP (200 mg/kg) on day 7. At day 11, the rats were sacrificed, and samples were collected for analysis. RESULTS: AV and ED ameliorated serum troponin I, CK-MB, LDH, AST and ALP, and prevented cardiac histological alterations in CP-intoxicated rats. Both treatments decreased cardiac lipid peroxidation and enhanced GSH, SOD and cytoglobin in CP-induced rats. AV and ED downregulated Keap1, whereas increased the expression of PI3K, Akt, mTOR and Nrf2 in the heart of rats received CP. Additionally, the binding modes of AV and ED to Keap1 were pinpointed in silico using molecular docking simulations. CONCLUSION: AV and ED prevent CP cardiotoxicity by attenuating oxidative stress and tissue injury, and modulating cytoglobin, and PI3K/Akt/mTOR and Keap1/Nrf2 signaling. Therefore, AV and ED may represent promising agents that can prevent cardiac injury in patients receiving CP.
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Acetofenonas/farmacologia , Antioxidantes/farmacologia , Edaravone/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Regulação para Cima/efeitos dos fármacos , Acetofenonas/administração & dosagem , Administração Oral , Animais , Antioxidantes/administração & dosagem , Ciclofosfamida , Edaravone/administração & dosagem , Masculino , Simulação de Acoplamento Molecular , Traumatismo por Reperfusão Miocárdica/induzido quimicamente , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
Mange has been considered one of the most common parasitic infestations among camels. It adversely impacts animal productivity and poses a risk to human health. Given the scarcity of available data about mange in camels, the current study focused on the prevalence of camel mange and its associated risk factors in Aswan Governorate, Egypt. Towards this end, a general visual inspection was conducted on camels (N = 210) in different markets and slaughterhouses in Aswan Governorate. Skin scrapings from suspect infected camels were also examined microscopically. Importantly, these findings were further checked and confirmed by histopathology on samples from suspected cases collected post-slaughter in abattoirs. The possible risk-associated factors, which include the camel's age, sex and sampling season, were recorded and statistically analyzed. Interestingly, the data showed that a total of 100 camels (47.6%) were found exclusively infested by sarcoptic mange. Furthermore, the predominant histopathological changes included burrowing tunnel of mites in the skin, hyperkeratosis and acanthosisconsis of the epidermis, while the dermis showed hemorrhage, mononuclear inflammatory cell infiltration around the blood vessels and perifolliculitis. These major histopathological findings are consistent with sarcoptic mange. Furthermore, the statistical analysis of the possible associated risk factors, camel's age (p = 0.006), gender (p = 0.032) and sampling season (p = 0.004), were all found to be significantly affected and related to the disease. In this regard, camels ≥2 years old were found at higher risk of infection (odds ratio (OR) = 2.75; 95% confidence interval (CI), 1.345 to 5.604) versus younger animals (OR = 0.36; 95 CI, 0.1784 to 0.743). Females had higher odds of exposure (OR = 2.02; 95% CI, 1.096 to 3.708) compared to males (OR = 0.50; 95% CI, 0.269 to 0.912). Moreover, the exposure to infection was reported higher in winter (OR = 2.30; 95% CI, 1.297 to 4.098) than in summer (OR = 0.43; 95% CI, 0.244 to 0.771). Collectively, our data provide novel epidemiological and histopathological support for sarcoptic mange being widespread among camels in the studied area. Sarcoptic mange is extremely contagious and zoonotic. Therefore, our baseline investigation indicates an urgent need for additional multicenter-studies to investigate the occurrence of this disease in camels and humans combined with the appropriate control measures of camel importation for combating this disease.
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Cognitive dysfunction was observed in pentylenetetrazole (PTZ)-kindled mice. The potential effectiveness of simvastatin (SIM) on PTZ-induced kindling and cognitive impairments in mice was evaluated. The influence of SIM on hydrogen sulphide (H2 S), nitric oxide (NO), reactive aldehydes and brain-derived neurotrophic factor/tyrosine receptor kinase B (BDNF-TrkB) signalling was also investigated. Kindling and cognitive impairments in mice were induced by 12 ip injections of PTZ (35 mg/kg) once every alternate day. The levels of reactive aldehydes and nitrite were increased while H2 S was decreased in PTZ-treated mice. These results were accompanied by a reduction in the gene expression of aldehyde dehydrogenase 2, cystathionine ß-synthase, BDNF and TrkB. In PTZ-kindled mice, a rise in brain inducible nitric oxide synthase protein expression associated with histopathological changes was observed. SIM administration (1, 5 and 10 mg/kg, daily orally) along with alternate day of PTZ (35 mg/kg) resulted in a decrease in PTZ-induced kindling with a dose-dependent improvement in cognitive function. SIM (10 mg/kg) prevented, to variable extent, the disturbances associated with PTZ-kindled mice with cortical, cerebellar and hippocampal structural improvement. These results suggested that SIM triggers multiple mechanisms that improve cognitive function in PTZ-kindled mice through modulation of oxidative stress, H2 S, NO and BDNF-TrkB signalling pathway.
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Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Sulfeto de Hidrogênio/metabolismo , Excitação Neurológica/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Óxido Nítrico/metabolismo , Proteínas Tirosina Quinases/metabolismo , Sinvastatina/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Masculino , Camundongos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Pentilenotetrazol , Transdução de SinaisRESUMO
This study was designed to evaluate the protective effects of hydrogen sulphide (H2 S) against NG-Nitro l-Arginine Methyl Ester (l-NAME)-induced hypertension and its possible effects on the inflammatory process, oxidative stress, and vascular remodelling in rats. Forty male Wistar Albino rats were assigned to four equal groups: the control group, the H2 S control group, the hypertensive group, and the treated group, which received concomitant treatment with sodium hydrosulphide (NaHS) and l-NAME. Systolic blood pressure (SBP) was measured weekly. Serum levels of nitric oxide (NO), total peroxide, and total antioxidant capacity (TAC) were measured and the oxidative stress index (OSI) was calculated. Aortic weight and length were measured and the aortic weight/length ratio determined. Aortic fold expression of interferon-γ (IFN-γ) and vascular cell adhesion molecule-1 (VCAM-1) mRNA was measured using qPCR. Aortic media thickness and elastin content were measured morphometrically. l-NAME administration increased SBP, serum levels of total peroxide and OSI, but reduced serum levels of NO and TAC. Aortic fold expression of IFN-γ and VCAM-1 mRNA, aortic weight, aortic weight/length ratio, aortic media thickness, and elastin area percentage were increased in the hypertensive group. Concurrent administration of l-NAME and H2 S attenuated these changes. Thus, H2 S could attenuate the increase in ABP through restoration of the NO level, reduction in the oxidative state, and attenuation of the inflammatory process, thereby reduced vascular remodelling.
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Citocinas/metabolismo , Sulfeto de Hidrogênio/farmacologia , Hipertensão/metabolismo , Hipertensão/patologia , NG-Nitroarginina Metil Éster/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Hipertensão/sangue , Hipertensão/induzido quimicamente , Inflamação/metabolismo , Masculino , Óxido Nítrico/sangue , Ratos , Ratos WistarRESUMO
Hepatic ischemia reperfusion (IR) is an inevitable clinical problem for surgical procedures such as liver transplantation and liver resection. This study was designed to evaluate the protective effect of perindopril (PER) against hepatic IR injury. Thirty-two rats were used and randomly allocated into four groups. Sham control group was subjected to sham operation and received saline only, IR group was subjected to IR and received vehicle, PER group was pretreated with PER (one milligram per kilogram per day i.p. for 10 consecutive days), and IR+PER group was pretreated with PER then subjected to IR. Liver function biomarkers (aspartate aminotransferase and alanine aminotransferase), oxidative stress (glutathione, malondialdehyde, myeloperoxidase, and superoxide dismutase) and inflammation markers (tumor necrosis factor-alpha, interferon-gamma, and inteleukin-10 [IL-10]), mRNA expression of NF-κB-p65 and TLR-4, as well as protein expression of JAK1, STAT-3, PI3K, mTOR, Akt, and Nrf-2 were investigated concomitantly with histopathological examination. The results indicated that, hepatic IR induced a significant alteration in liver function biomarkers and structure, oxidative stress, and inflammation. At the molecular level, up-regulation of NF-κB-p65, TLR-4, JAK1, and STAT-3 concomitantly with down-regulation of Nrf-2, IL-10, PI3K, Akt, and mTOR were observed. These disturbances were alleviated by pretreatment of IR rats with PER in concomitant with hepatic structural improvement. Conclusively, the protective effect of PER presumably may be relevant to its ability to reduce oxidative stress, ameliorate the inflammatory processes, and modify the related signaling pathways. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1935-1949, 2020. © 2019 American Association for Anatomy.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fígado/irrigação sanguínea , Perindopril/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Biomarcadores/sangue , Janus Quinase 1/metabolismo , Fígado/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Perindopril/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
AIMS: Few studies have compared the interaction of single and repeated administration of amitriptyline (amit) with the nitrergic system and glutamatergic system in the experimental model of neuropathic pain. We aimed to evaluate the antinociceptive effect of single and repeated administration of amit and to assess whether glutamate preceded inducible nitric oxide synthase (iNOS) inhibition as a mechanism of the analgesic effect of amit in the neuropathic model of pain. MATERIALS AND METHODS: Male Wistar rats were subjected to left sciatic nerve ligation. The effect of single (25â¯mgâ¯kg-1) and repeated (10â¯mgâ¯kg-1 daily for 3â¯weeks) administration of amit intraperitoneally (i.p.) alone or in combination with aminoguanidine (AG i.p., 100â¯mgâ¯kg-1 for 3â¯days, a selective iNOS inhibitor) and MK-801 (0.05â¯mgâ¯kg-1â¯i.p., NMDA antagonist) on resting paw posture and mechanical hyperalgesia were studied. Glutamate level and iNOS protein expression in hippocampus were detected. KEY FINDINGS: Single and repeated administration of amit alone or in combination with AG or MK-801 demonstrated a significant decrease in resting pain score and increase in the pain threshold. Both glutamate and nitrite levels decreased in the hippocampi of single and repeated amitâ¯+â¯MK-801 groups. Immunohistochemistry showed a marked decrease in iNOS immunoreactivity in rats treated with single and repeated amitâ¯+â¯MK-801. SIGNIFICANCE: Our results suggest that glutamate-dependent mechanisms are involved in the analgesic responses to amit administration. Importantly, glutamatergic system and its upstream nitrergic system play an important role in the antinociceptive action of amit.
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Amitriptilina/farmacologia , Analgésicos não Narcóticos/farmacologia , Ácido Glutâmico/metabolismo , Neuralgia/tratamento farmacológico , Nitrogênio/metabolismo , Amitriptilina/administração & dosagem , Analgésicos não Narcóticos/administração & dosagem , Animais , Modelos Animais de Doenças , Masculino , Neuralgia/metabolismo , Neuralgia/patologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Limiar da Dor , Ratos , Ratos WistarRESUMO
Statins are the most widely prescribed cholesterol-lowering drugs to reduce the risk of cardiovascular diseases. Statin-induced myopathy is the major side effect of this class of drugs. Here, we studied whether standardized leaf extracts of ginkgo biloba (EGb761) would improve simvastatin (SIM)-induced muscle changes. Sixty Wistar rats were allotted into six groups: control group, vehicle group receiving 0.5% carboxymethyl cellulose (CMC) for 30 days, SIM group receiving 80 mg/kg/day SIM in 0.5% CMC orally for 30 days, SIM withdrawal group treated with SIM for 16 days and sacrificed 14 days later, and EGb761-100 and EGb761-200 groups posttreated with either 100 or 200 mg/kg/day EGb761 orally. Muscle performance on the rotarod, serum creatine kinase (CK), coenzyme Q10 (CoQ10), serum and muscle nitrite, muscle malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) activities were estimated. Additionally, muscle samples were processed for histopathological evaluation. We found that SIM decreased muscle performance on the rotarod, serum CoQ10, as well as muscle SOD and CAT activities while it increased serum CK, serum and muscle nitrite, as well as muscle MDA levels. SIM also induced sarcoplasmic vacuolation, splitting of myofibers, disorganization of sarcomeres, and disintegration of myofilaments. In contrast, posttreatment with EGb761 increased muscle performance, serum CoQ10, as well as muscle SOD and CAT activities while it reduced serum CK as well as serum and muscle nitrite levels in a dose-dependent manner. Additionally, EGb761 reversed SIM-induced histopathological changes with better results obtained by its higher dose. Interestingly, SIM withdrawal increased muscle performance on the rotarod, reduce serum CK and CoQ10, and reduced serum and muscle nitrite while it reversed SIM-induced histopathological changes. However, SIM withdrawal was not effective enough to restore their normal values. Additionally, SIM withdrawal did not improve SIM-induce muscle MDA, SOD, or CAT activities during the period studied. Our results suggest that EGb761 posttreatment reversed SIM-induces muscle changes possibly through its antioxidant effects, elevation of CoQ10 levels, and antagonizing mitochondrial damage.
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Nicotine administration has been shown to increase the risk for cardiovascular diseases and death. The present study was designed to investigate the impact of nicotine administration on serum level tumor necrosis factor and cycloxygenase -2 (COX-2) expression mediated cardiac injury in rat off springs, and the possible protective effect of folic acid. Eighteen pregnant female rats were randomly divided into three groups, six animals each. Control group received the vehicle, nicotine group received a dose of nicotine 0.1â¯mg/kg body weight, daily with subcutaneous injection from day 3 of gestation until weaning on postnatal day 21. Nicotine treated group received daily oral supplementation with folic acid 200â¯mg/kg body weight by intragastric tube prior to injection of nicotine. In serum of the pups, levels of tumor necrosis factor (TNF), nitric oxide (NO), total antioxidant capacity (TAC) and malondialdehyde (MDA) were measured. Histopathological studies of cardiac tissues using hematoxylin-eosin (H&E) were carried out. The expression of COX-2 was evaluated using immunohistochemistry. Serum TNF and MDA were significantly increased, while serum NO and TAC were significantly decreased in nicotine group. Moreover, nicotine-exposed rats showed complete lysis of cardiac myocytes, marked cytoplasmic vacuolation of myocytes, muscle fibers show loss of striation and increased COX-2 expression. Concomitant folic acid administration resulted in a significant alleviation of biochemical and structural alteration-induced by nicotine. In conclusion, folic acid has a protective role against nicotine induced cardiac injury by reduction of COX-2 expression, decreasing TNF production and lipid peroxidation mediated cell injury.
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Plantar fascial disorder is comprised of plantar fasciitis and plantar fibromatosis. Plantar fasciitis is the most common cause of heel pain, especially for athletes involved in running and jumping sports. Plantar fibromatosis is a rare fibrous hyperproliferation of the deep connective tissue of the foot. To identify genetic loci associated with plantar fascial disorders, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 21,624 cases of plantar fascial disorders and 80,879 controls. One indel (chr5:118704153:D) and one SNP (rs62051384) showed an association with plantar fascial disorders at genome-wide significance (p<5×10-8) with small effects (odds ratios=0.93 and 1.07 per allele, respectively). The indel chr5:118704153:D is located within TNFAIP8 (encodes a protein induced by TNF alpha) and rs62051384 is located within WWP2 (which is involved in proteasomal degradation). These DNA variants may be informative in explaining why some individuals are at higher risk for plantar fascial disorders than others.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Fasciíte Plantar/genética , Fibromatose Plantar/genética , Ubiquitina-Proteína Ligases/genética , Traumatismos em Atletas/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Rotator cuff tears are common, especially in the fifth and sixth decades of life, but can also occur in the competitive athlete. Genetic differences may contribute to overall injury risk. Identifying genetic loci associated with rotator cuff injury could shed light on the etiology of this injury. We performed a genome-wide association screen using publically available data from the Research Program in Genes, Environment and Health including 8,357 cases of rotator cuff injury and 94,622 controls. We found rs71404070 to show a genome-wide significant association with rotator cuff injury with p = 2.31x10-8 and an odds ratio of 1.25 per allele. This SNP is located next to cadherin8, which encodes a protein involved in cell adhesion. We also attempted to validate previous gene association studies that had reported a total of 18 SNPs showing a significant association with rotator cuff injury. However, none of the 18 SNPs were validated in our dataset. rs71404070 may be informative in explaining why some individuals are more susceptible to rotator cuff injury than others.
Assuntos
Estudo de Associação Genômica Ampla , Lesões do Manguito Rotador/genética , Mapeamento Cromossômico , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
De Quervain's tenosynovitis is a repetitive strain injury involving synovial inflammation of the tendons of the first extensor compartment of the wrist. It is relatively common in the general population, and is the most common radial-sided tendinopathy seen in athletes. Identifying a genetic marker associated with de Quervain's tenosynovitis could provide a useful tool to help identify those individuals with an increased risk for injury. A genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health (RPGEH) including 4,129 cases and 98,374 controls. rs35360670 on chromosome 8 showed an association with de Quervain's tenosynovitis at genome-wide significance (p=1.9×10-8; OR=1.46; 95% CI=1.38-1.59). This study is the first genome-wide screen for de Quervain's tenosynovitis and provides insights regarding its genetic etiology as well as a DNA marker with the potential to inform athletes and other high-risk individuals about their relative risk for injury.
Assuntos
Cromossomos Humanos Par 8/genética , Doença de De Quervain/genética , Marcadores Genéticos , Polimorfismo de Nucleotídeo Único , Idoso , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Ankle injuries, including sprains, strains and other joint derangements and instability, are common, especially for athletes involved in indoor court or jumping sports. Identifying genetic loci associated with these ankle injuries could shed light on their etiologies. A genome-wide association screen was performed using publicly available data from the Research Program in Genes, Environment and Health (RPGEH) including 1,694 cases of ankle injury and 97,646 controls. An indel (chr21:47156779:D) that lies close to a collagen gene, COL18A1, showed an association with ankle injury at genome-wide significance (p = 3.8x10-8; OR = 1.99; 95% CI = 1.75-2.23). A second DNA variant (rs13286037 on chromosome 9) that lies within an intron of the transcription factor gene NFIB showed an association that was nearly genome-wide significant (p = 5.1x10-8; OR = 1.63; 95% CI = 1.46-1.80). The ACTN3 R577X mutation was previously reported to show an association with acute ankle sprains, but did not show an association in this cohort. This study is the first genome-wide screen for ankle injury that yields insights regarding the genetic etiology of ankle injuries and provides DNA markers with the potential to inform athletes about their genetic risk for ankle injury.
Assuntos
Traumatismos do Tornozelo/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Actinina/genética , Demografia , Feminino , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Entorses e Distensões/genéticaRESUMO
Shoulder dislocations are common shoulder injuries associated with athletic activity in contact sports, such as football, rugby, wrestling, and hockey. Identifying genetic loci associated with shoulder dislocation could shed light on underlying mechanisms for injury and identify predictive genetic markers. To identify DNA polymorphisms associated with shoulder dislocation, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 662 cases of shoulder dislocation and 82 602 controls from the European ancestry group. rs12913965 showed an association with shoulder dislocation at genome-wide significance (p=9.7×10-9; odds ratio=1.6) from the European ancestry group. Individuals carrying one copy of the risk allele (T) at rs12913965 showed a 69% increased risk for shoulder dislocation in our cohort. rs12913965 is located within an intron of the TICRR gene, which encodes TOPBP1 interacting checkpoint and replication regulator involved in the cell cycle. rs12913965 is also associated with changes in expression of the ISG20 gene, which encodes an antiviral nuclease induced by interferons. This genetic marker may one day be used to identify athletes with a higher genetic risk for shoulder dislocation. It will be important to replicate this finding in future studies.