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Diabetic nephropathy (DN), a severe diabetes complication, causes kidney morphological and structural changes due to extracellular matrix accumulation. This accumulation is caused mainly by oxidative stress. Semi-essential amino acid derivative taurine has powerful antioxidant and antifibrotic effects. The aim of this study was to investigate the renoprotective effects of taurine through its possible roles in oxidative stress, extracellular matrix proteins, and the signaling pathways associated with the accumulation of extracellular matrix proteins in DN rats. 29 Wistar albino rats were randomly separated into control, taurine, diabetes, and diabetes + taurine groups. Diabetes animals were injected 45 mg/kg streptozosine. Taurine is given by adding to drinking water as 1% (w/v). Urine, serum, and kidney tissue were collected from rats for biochemical and histological analysis after 12 weeks. According to the studies, taurine significantly reduces the levels of malondialdehyde (MDA), total oxidant status (TOS), and protein expression of NADPH oxidase 4 (NOX4) that increase in diabetic kidney tissue. Also, decreased superoxide dismutase (SOD) activity levels significantly increased with taurine in diabetic rats. Moreover, increased mRNA and protein levels of fibronectin decreased with taurine. The matrix metalloproteinase (MMP)-2 and MMP-9 activities and their mRNA levels increased significantly, and this increase was significantly summed with taurine. There was a decrease in mRNA expression of Extracellular matrix metalloproteinase inducer (EMMPRIN). Taurine significantly increased this decrease. Diabetes increased mRNA expressions of transforming growth factor (TGF)-ß and Smad2/3. Taurine significantly reduced this induction. TGF-ß protein expression, p38, and Smad2/3 activations were also inhibited, but taurine was suppressed significantly. All these findings indicate that taurine may be an effective practical strategy to prevent renal diabetic injury.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Ratos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/metabolismo , Ratos Wistar , Diabetes Mellitus Experimental/patologia , Taurina/farmacologia , Taurina/uso terapêutico , Taurina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Rim/metabolismo , Transdução de Sinais , Estresse Oxidativo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , RNA Mensageiro/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/farmacologiaRESUMO
Background/aim: To investigate the effect of intravitreal golimumab on rabbit retina histopathology. Materials and methods: Sixteen albino New Zealand rabbits were divided into three groups. The right eye of each rabbit in groups I, II, and III received a single intravitreal injection of 5 mg/0.05 mL (6 eyes), 10 mg/0.1 mL (6 eyes), or 20 mg/0.2 mL (4 eyes) golimumab, while left eyes served as controls with the same volume of a balanced salt solution injection. All animals were examined using slit-lamp biomicroscopy and indirect ophthalmoscopy before and after intravitreal injection and at days 1 and 7. Animals were euthanized on day 7 and the eyes were enucleated for immunohistochemistry evaluation and electron microscopic examination of the retinas. Results: For groups I, II, and III, the number of cells in the outer nuclear layer and the inner nuclear layer was decreased compared to those in the control groups. In group I, the percentage of caspase-3 staining of the outer nuclear layer was significantly higher than that in the control. For groups II and III, TUNEL and caspase-3 staining percentages in the outer and inner nuclear layers were found to be significantly higher than those for the control groups. In the ganglion cell layer, for groups I, II, and III, neither TUNEL nor caspase-3 staining percentages showed any significant difference between two groups. No significant dose-dependent relationship was found for increasing doses of golimumab in all layers. Myelin figures and karyorrhexis in the photoreceptor cells were prominent in electron microscopy of the golimumab-injected eyes. Conclusion: Golimumab caused apoptosis in both photoreceptors and bipolar cells of the rabbit retina. Potential retinal toxicity of intravitreal golimumab should be considered if an intravitreal administration is planned.
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Anticorpos Monoclonais/toxicidade , Neuropatia Óptica Tóxica/etiologia , Animais , Anticorpos Monoclonais/administração & dosagem , Apoptose , Modelos Animais de Doenças , Injeções Intravítreas , Oftalmoscopia , Coelhos , Lâmpada de FendaRESUMO
OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease.
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Nefropatias/etiologia , Lipodistrofia/complicações , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Lactente , Resistência à Insulina/fisiologia , Rim/patologia , Nefropatias/fisiopatologia , Lipodistrofia/fisiopatologia , Lipodistrofia Parcial Familiar/complicações , Lipodistrofia Parcial Familiar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
In this study, experimental diabetes and nephrectomy have been applied separately and together in order to investigate the possible therapeutic effects of lipoic acid (LA) on hypertensive and diabetic rat kidneys. Wistar rats were divided into eight groups: control, diabetes mellitus (DM), 5/6 nephrectomy, DM + 5/6 nephrectomy, LA administration, DM + LA treated, 5/6 nephrectomy + LA treated, and DM + 5/6 nephrectomy + LA-treated groups, respectively. Renal damage was evaluated histomorphometrically, ultrastructurally, and biochemically. Our findings supported that diabetes and hypertension together increased the rate of renal injury, and LA had therapeutic effects on hypertensive and diabetic rat kidneys.
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Diabetes Mellitus Experimental/tratamento farmacológico , Hipertensão/tratamento farmacológico , Ácido Tióctico/uso terapêutico , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/prevenção & controle , Modelos Animais de Doenças , Hipertensão/etiologia , Masculino , Nefrectomia/efeitos adversos , Ratos , Ratos Wistar , Estreptozocina/efeitos adversosRESUMO
Exposure to electromagnetic fields (EMFs) causes increased adverse effects on biological systems. The aim of this study was to investigate the effects of EMF on heart tissue by biochemical and histomorphological evaluations in EMF-exposed adult rats. In this study, 28 male Wistar rats weighing 200-250 g were used. The rats were divided into two groups: sham group (n = 14) and EMF group (n = 14). Rats in sham group were exposed to same conditions as the EMF group except the exposure to EMF. Rats in EMF group were exposed to a 50-Hz EMF of 3 mT for 4 h/day and 7 days/week for 2 months. After 2 months of exposure, rats were killed; the hearts were excised and evaluated. Determination of oxidative stress parameters was performed spectrophotometrically. To detect apoptotic cells, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and caspase-3 immunohistochemistry were performed. In EMF-exposed group, levels of lipid peroxidation significantly increased and activities of superoxide dismutase and glutathione peroxidase decreased compared with sham group. The number of TUNEL-positive cells and caspase-3 immunoreactivity increased in EMF-exposed rats compared with sham. Under electron microscopy, there were mitochondrial degeneration, reduction in myofibrils, dilated sarcoplasmic reticulum and perinuclear vacuolization in EMF-exposed rats. In conclusion, the results show that the exposure to EMF causes oxidative stress, apoptosis and morphologic damage in myocardium of adult rats. The results of our study indicate that EMF-related changes in rat myocardium could be the result of increased oxidative stress. Further studies are needed to demonstrate whether the exposure to EMF can induce adverse effects on myocardium.
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Campos Eletromagnéticos/efeitos adversos , Coração/efeitos da radiação , Animais , Apoptose/efeitos da radiação , Glutationa Peroxidase/metabolismo , Imuno-Histoquímica , Masculino , Malondialdeído/metabolismo , Miocárdio/enzimologia , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos da radiação , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Superóxido Dismutase/metabolismoRESUMO
In the present study, the effects of dexmedetomidine on secondary lung and kidney injuries were studied in the rat model of intra-abdominal sepsis by immunohistological and biochemical examinations. We measured serum creatinine, kidney tissue malondialdehide and plasma neutrophil gelatinase-associated lipocalin levels. In order to evaluate tissue injury we determined kidney tissue mononuclear cell infiltration score, alveolar macrophage count, histological kidney and lung injury scores and kidney and lung tissue immunoreactivity scores. We demonstrated that dexmedetomidine attenuates sepsis-induced lung and kidney injuries and apoptosis in the rat model of sepsis. There is still need for comparative studies in order to determine the effects of dexmedetomidine on organ functions in early human sepsis.
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Injúria Renal Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Ceco/lesões , Dexmedetomidina/farmacologia , Sepse/patologia , Injúria Renal Aguda/patologia , Lesão Pulmonar Aguda/patologia , Proteínas de Fase Aguda , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Contagem de Células , Creatinina/sangue , Fragmentação do DNA , Modelos Animais de Doenças , Rim/efeitos dos fármacos , Rim/patologia , Lipocalina-2 , Lipocalinas/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos Alveolares/metabolismo , Masculino , Malondialdeído/metabolismo , Proteínas Proto-Oncogênicas/sangue , Ratos , Ratos WistarRESUMO
Citalopram is a selective serotonin re-uptake inhibitor (SSRI) antidepressant; it exhibits the greatest cardiotoxic effect among SSRIs. Citalopram can cause drug-induced long QT syndrome (LQTS) and ventricular arrhythmias. We investigated the protective effect of nicorandil, a selective mitochondrial KATP (mito-KATP) channel opener, on LQTS and myocardial damage caused by citalopram in male rats. In a preliminary study, we determined that the minimum citalopram dose that prolonged the QT interval was 102 mg/kg injected intraperitoneally. For the main study, rats were divided randomly into five experimental groups: untreated control, normal saline + citalopram, nicorandil + citalopram, 5-hydroxydecanoate (5-HD) + citalopram, 5-HD + nicorandil + citalopram. Biochemical and histologic data from blood and heart tissue samples from six untreated control rats were evaluated. Electrocardiographic parameters including QRS duration, QT interval, corrected QT interval (QTc) and heart rate (HR) were assessed, and biochemical parameters including malondialdehyde, reduced glutathione, glutathione peroxidase, superoxide dismutase were measured. We also performed histomorphologic and immunohistochemical examination of heart tissue. Citalopram prolonged QT-QTc intervals significantly and increased significantly the histomorphologic score and proportion of apoptotic cells, but produced no differences in the oxidant and antioxidant parameters. Nicorandil did not prevent citalopram induced QT-QTc interval prolongation and produced no significant changes in oxidant and antioxidant parameters; however, it did reduce histologic damage and apoptosis caused by citalopram.
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Síndrome do QT Longo , Nicorandil , Masculino , Ratos , Animais , Nicorandil/efeitos adversos , Citalopram/efeitos adversos , Antioxidantes/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/tratamento farmacológico , Oxidantes , Trifosfato de Adenosina/efeitos adversosRESUMO
Deep frying is one of the strongest emission sources into indoor air. A vegetable margarine has recently been used in commercial kitchens. This study investigated the respiratory effects of exposure to its fumes in an experimental model. A setup with glass chambers was constructed. A chamber housed a fryer. The fumes were transported to the other chamber where 24 Wistar albino rats were placed in four randomized groups: acute, subacute, chronic, and control for the exposure durations. PM10 concentration in the exposure chamber was monitored to ensure occupational levels were obtained. Sacrification was performed 24 h after exposure. Lung, trachea, and nasal concha specimens were evaluated by two blinded histologists under a light microscope with hematoxylin-eosin. Mild mononuclear cell infiltration, alveolar capillary membrane thickening, alveolar edema, and diffuse alveolar damage, along with diffuse hemorrhage, edema, and vascular congestion in the interstitium were observed in the acute and subacute groups, and were overexpressed in the chronic group, whereas normal lung histology was observed in the control group. The results indicate that exposure to fumes of vegetable margarine for frying in commercial kitchens may cause pulmonary inflammation that becomes severe as the duration of the exposure increases.
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OBJECTIVES: The aim of this study is to evaluate the protective effect of nicorandil, a selective mitochondrial KATP channel opener, on QT prolongation and myocardial damage induced by amitriptyline. METHODS: The dose of amitriptyline (intraperitoneal, i.p.) that prolong the QT interval was found 75 mg/kg. Rats were randomized into five groups the control group, amitriptyline group, nicorandil (selective mitochondrial KATP channel opener, 3 mg/kg i.p.) + amitriptyline group, 5-hdyroxydecanoate (5-HD, selective mitochondrial KATP channel blocker, 10 mg/kg i.p.) + amitriptyline group and 5-HD + nicorandil + amitriptyline group. Cardiac parameters, biochemical and histomorphological/immunohistochemical examinations were evaluated. p < 0.05 was accepted as statistically significant. KEY FINDINGS: Amitriptyline caused statistically significant prolongation of QRS duration, QT interval and QTc interval (p < 0.05). It also caused changes in tissue oxidant (increase in malondialdehyde)/anti-oxidant (decrease in glutathione peroxidase) parameters (p < 0.05), myocardial damage and apoptosis (p < 0.01 and p < 0.001). While nicorandil administration prevented amitriptyline-induced QRS, QT, QTc prolongation (p < 0.05), myocardial damage and apoptosis (p < 0.05), it did not affect the changes in oxidative parameters (p > 0.05). CONCLUSIONS: Our results suggest that nicorandil, a selective mitochondrial KATP channel opener, plays a protective role in amitriptyline-induced QT prolongation and myocardial damage. Mitochondrial KATP channel opening and anti-apoptotic effects may play a role in the cardioprotective effect of nicorandil.
Assuntos
Síndrome do QT Longo , Nicorandil , Ratos , Animais , Nicorandil/farmacologia , Amitriptilina , Miocárdio , Canais KATPRESUMO
BACKGROUND: Microfracture is the most common treatment for cartilage defects of the knee. In microfracture surgery, holes are randomly drilled into the subchondral bone. The effect of the hole's location on its interaction with the cartilage defect site and its influence on the healing process is currently uncertain. PURPOSE: To investigate the effects of different microfracture locations on healing in a rabbit knee osteochondral defect model. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 29 adult New Zealand White rabbits were divided into 5 groups. In the healthy cartilage control group (n = 5), no surgical procedure was performed. Cylindrical full-thickness cartilage defects (5 × 3 mm) were created in the patellar groove of the remaining 24 rabbits. In the defect control group (n = 6), only the defect was created. A microfracture was performed at the 12-o'clock position (group peripheral single; n = 6), centrally (group central; n = 6), and at the 12- and 6-o'clock positions (group peripheral double; n = 6) of the defect. The animals were sacrificed after 8 weeks. Cartilage healing was evaluated by International Cartilage Regeneration & Joint Preservation Society (ICRS) score, modified O'Driscoll score, immunohistochemical analysis (type 1 collagen, type 2 collagen, and aggrecan), and scanning electron microscopy analysis. RESULTS: In group peripheral double, better cartilage healing was observed in all parameters compared with the other groups (P < .05). Group peripheral double had the greatest amount of filling, with 79% of the defect area filled with fibrocartilage repair tissue. Group peripheral single demonstrated filling of 73% of the defect area, group central 56%, and the defect control group 45%. The ICRS score was significantly higher in group peripheral single compared with group central and the defect control group. Type 2 collagen and aggrecan immunoreactivity were significantly stronger in group central than group peripheral single and the defect control group (P < .05). CONCLUSION: Microfracture performed at the peripheral margin of the defect had better filling characteristics in a rabbit model. This study suggests that interaction of pluripotent cells released from the microfracture site with the intact cartilage may enhance the quality of the repair tissue. CLINICAL RELEVANCE: The location of microfracture holes in relation to the peripheral border of the osteochondral defect (to the intact cartilage) is important in both the quality and the quantity of the newly formed repair tissue.
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Fraturas de Estresse , Fraturas Intra-Articulares , Coelhos , Animais , Agrecanas , Fibrocartilagem , Colágeno Tipo I , Colágeno Tipo IIRESUMO
Testicular torsion is one of the urologic emergencies occurring frequently in neonatal and adolescent period. Testis is sensitive to ischemia-reperfusion injury, and, therefore, ischemia and consecutive reperfusion cause an enhanced formation of reactive oxygen species that result in testicular cell damage and apoptosis. α-lipoic acid is a free radical scavenger and a biological antioxidant. It is widely used in the prevention of oxidative stress and cellular damage. We aimed to investigate the protective effect of α-lipoic acid on testicular damage in rats subjected to testicular ischemia-reperfusion injury. 35 rats were randomly divided into 5 groups: control, sham operated, ischemia, ischemia-reperfusion, and ischemia-reperfusion +lipoic acid groups, 2 h torsion and 2 h detorsion of the testis were performed. Testicular cell damage was examined by H-E staining. TUNEL and active caspase-3 immunostaining were used to detect germ cell apoptosis. GPx , SOD activity, and MDA levels were evaluated. Histological evaluation showed that α-lipoic acid pretreatment reduced testicular cell damage and decreased TUNEL and caspase-3-positive cells. Additionally, α-lipoic acid administration decreased the GPx and SOD activity and increased the MDA levels. The present results suggest that LA is a potentially beneficial agent in protecting testicular I/R in rats.
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Traumatismo por Reperfusão/tratamento farmacológico , Ácido Tióctico/uso terapêutico , Animais , Antioxidantes/metabolismo , Caspase 3/metabolismo , Marcação In Situ das Extremidades Cortadas , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Traumatismo por Reperfusão/metabolismo , Torção do Cordão Espermático/tratamento farmacológico , Torção do Cordão Espermático/metabolismo , Doenças Testiculares/tratamento farmacológico , Doenças Testiculares/metabolismoRESUMO
BACKGROUND: Levosimendan has been reported to have a positive effect on ischemia-reperfusion injury. Herein, we aimed to evaluate the effects of levosimendan applied after reperfusion in an experimental intestinal injury-reperfusion (IR) model. METHODS: Twenty-one Wistar-albino male rats were separated into three groups: Sham group (n = 7): solely superior mesenteric artery (SMA) was dissected after laparotomy; intestinal ischemia-reperfusion group (IIR, n = 7): SMA was clamped for 60 min and unclamped for 120 min to cause ischemia-reperfusion; IIR + levosimendan group (IIR + L, n = 7): levosimendan was administered in ischemia-reperfusion model. The mean arterial pressures (MAP) were measured in all groups. MAP measurements were performed at the end of stabilization, at the 15th, 30th, and 60th minute of ischemia; at the 15th, 30th, 60th, and 120th minute of reperfusion; and at the end of levosimendan bolus application and when levosimendan infusion concluded. Reperfusion injury was evaluated with tissue malondialdehyde (MDA) and by Chiu score. RESULTS: MAP at 15 min, 30 min, and 60 min of reperfusion was lower in IIR and IIR + L groups compared with basal inter-group measurements. Decline in MAP at 30 min after reperfusion was statistically significant in IIR and IIR + L groups when compared with the sham group. There was no significant difference between MDA levels in the groups. Chiu score was significantly lower in the sham group when compared to IIR and IIR + L groups and higher in IIR when compared to the IIR + L group. CONCLUSION: Levosimendan leads to a decrease in intestinal damage although it did not affect lipid peroxidation and MAP when administered after reperfusion in an experimental intestinal IR model.
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The main goal of the study was to produce chitosan-collagen hydrogel composite scaffolds consisting of 3D printed poly(lactic acid) (PLA) strut and nanofibrous cellulose for meniscus cartilage tissue engineering. For this purpose, first PLA strut containing microchannels was incorporated into cellulose nanofibers and then they were embedded into chitosan-collagen matrix to obtain micro- and nano-sized topographical features for better cellular activities as well as mechanical properties. All the hydrogel composite scaffolds produced by using three different concentrations of genipin (0.1, 0.3, and 0.5%) had an interconnected microporous structure with a swelling ratio of about 400% and water content values between 77 and 83% which is similar to native cartilage extracellular matrix. The compressive strength of all the hydrogel composite scaffolds was found to be similar (â¼32 kPa) and suitable for cartilage tissue engineering applications. Besides, the hydrogel composite scaffold comprising 0.3% (w/v) genipin had the highest tan δ value (0.044) at a frequency of 1 Hz which is around the walking frequency of a person. According to the in vitro analysis, this hydrogel composite scaffold did not show any cytotoxic effect on the rabbit mesenchymal stem cells and enabled cells to attach, proliferate and also migrate through the inner area of the scaffold. In conclusion, the produced hydrogel composite scaffold holds great promise for meniscus tissue engineering.
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Quitosana , Menisco , Animais , Coelhos , Celulose , Quitosana/química , Colágeno , Hidrogéis/química , Iridoides , Poliésteres/química , Impressão Tridimensional , Engenharia Tecidual , Alicerces Teciduais/química , ÁguaRESUMO
INTRODUCTION: Olmesartan Medoxomil (OM) is an angiotensin receptor blocker and has the adverse effect of celiac like enteropathy which was accepted by the FDA in 2013. This disease is characterized by severe diarrhea, weight loss and enteropathy. Although there are many case reports associated with olmesartan-related enteropathy in humans, it has not been described in a long-term animal model study so far. AIM: We developed a self-microemulsifying drug delivery system (OM-SMEDDS) in our previous study to reduce this side effect of the drug and to enhance bioavailability. METHODS: In this study, an artificial hypertension model was established with a dose of 185 µmol /kg L-NAME (N ω-nitro-L-arginine methyl ester) twice in a day intraperitoneally in Wistar albino rats. To determine and compare side effects, the OM-Suspension and OM-SMEDDS were administered at 1.3 mg/kg therapeutic dose during one-month period to the rats. RESULTS: Tension of rats was recorded by measuring from their tails with non invasive blood pressure system. We observed celiac like enteropathy findings like villous atrophy and intraepithelial lymphocytosis and clinical changes like weight loss and severe diarrhea after the treatment with OM-Suspension during one-month experiment. It was also observed that the antihypertensive efficacy of the OM-SMEDDS formulation was higher than the suspension during the experiment, which did not cause enteropathy, diarrhea and weight loss by reducing intestinal exposure. CONCLUSION: Hereby, we evaluated the side effects of two different pharmaceutical forms by designing a sustainable and reproducible celiac rat model that can be induced with olmesartan medoxomil.
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Imidazóis , Tetrazóis , Animais , Anti-Hipertensivos , Olmesartana Medoxomila , Ratos , Ratos WistarRESUMO
Iron has been implicated in oxidative tissue injury owing to its ability to generate reactive oxygen species (ROS). We investigated the reno-protective effects of alpha lipoic acid (ALA) by investigating its effects on the kidney isoform of NADPH oxidase (Nox4) and the specific signaling pathways, p38 MAPK and PI3K/Akt, which participate in apoptosis and survival, respectively. We established four groups of seven rats: control, 100 mg/kg ALA, 80 mg/kg iron sucrose (IS) and IS + ALA. IS and ALA were injected intravenously and rats were sacrificied after 6 h. The mRNA expression of the subunits of NADPH oxidase, Nox4 and p22phox; tumor necrosis factor-alpha (TNF-α); and kidney injury molecule-1 (KIM-1) were measured using quantitative real time polymerase chain reaction (qRT-PCR). Active caspase-3 protein expression was evaluated by immunostaining. Also, p38 MAPK and PI3K/Akt signaling pathways were analyzed using western blot. ALA suppressed the mRNA expression of Nox4, p22phox, TNF-α and KIM-1. Active caspase-3 protein expression induced by IS was decreased by ALA. ALA also suppressed p38 MAPK and activated the PI3K/Akt signaling pathway following IS administration. We found that ALA may be an effective strategy for preventing oxidative acute kidney injury caused by IS.
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Injúria Renal Aguda , Ácido Tióctico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Animais , Ferro , Estresse Oxidativo , Fosfatidilinositol 3-Quinases , Ratos , Espécies Reativas de Oxigênio , Ácido Tióctico/farmacologiaRESUMO
The aim of this study was to evaluate the effects of different doses of an adenosine A(1) selective agonist, phenylisopropyl adenosine (PIA), on metamidophos-induced cholinergic symptoms, mortality, diaphragm muscle necrosis, and brain oxidative stress. A LD(50) dose of metamidophos (20 mg/kg body weight, p.o.) was followed by 1 mL/kg body weight of 0.9% NaCl or 1 mg/kg, 2 mg/kg, 3 mg/kg, or 5 mg/kg body weight PIA ip. Incidence of clinical signs including chewing, salivation, convulsion, and respiratory distress did not show any significant difference among all treatment groups (p > 0.05). PIA was found to be effective to reverse the necrotic changes in diaphragm muscle induced by metamidophos significantly in all groups. Brain Thiobarbituric Acid Reactive Substance (TBARS) levels were significantly increased after the metamidophos poisoning. Administration of 2 to 5 mg/kg body weight PIA decreased brain TBARS levels compared to 0.9% NaCl treated rats. The results indicate that, although different doses of PIA reduced the OP-induced oxidative stress and diaphragm necrosis, a single dose of PIA was not able to recover cholinergic signs and symptoms of metamidophos poisoning.
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Agonistas do Receptor A1 de Adenosina , Adenosina/análogos & derivados , Encéfalo , Inseticidas/toxicidade , Compostos Organotiofosforados/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Diafragma/efeitos dos fármacos , Diafragma/patologia , Relação Dose-Resposta a Droga , Humanos , Dose Letal Mediana , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Taxa de Sobrevida , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
α-Lipoic acid (ALA) is a safe natural molecule involved in the immunomodulation of many physiological processes. Orally administered ALA has been reported to treat several inflammatory pathologies and support pregnancy. Our study aimed at testing ALA vaginal administration in female Wistar rats evaluating its tissue distribution (experiment I), impact on implantation process (experiment II), and effectiveness in contrasting induced preterm birth (experiment III). In experiment I, rats were intravaginally treated with 50 mg/kg or 500 mg/kg ALA, or with a physiologic solution, for 4 days. α-Lipoic acid distribution in uterus and cervical tissues was evaluated by immunohistochemical analyses. In experiment II, rats received intravaginally the above treatments for 5 days, then they were mated and, if pregnant, included in the experiment to evaluate both implantation rate and the content of implantation mediators in uterus tissues. In experiment III, pregnant rats were pretreated with placebo or with vaginal ALA for 4 days and then induced to delivery with mifepristone plus PGE2 on the 19th day of pregnancy. The delivery time was recorded, and the messenger RNA (mRNA) levels of pro-inflammatory cytokines were detected in the uterine tissues by real-time polymerase chain reaction. Immunohistochemistry was also performed. Results showed that vaginal ALA was well absorbed and distributed. The treatment did not affect the implantation process and was able to significantly revert mifepristone plus prostaglandin E2 effects, delaying the timing of delivery and significantly decreasing mRNA synthesis and release of pro-inflammatory cytokines. We provide for the first time new information on vaginal ALA use, even during pregnancy, opening a perspective for further studies.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Implantação do Embrião/efeitos dos fármacos , Inflamação/tratamento farmacológico , Nascimento Prematuro/tratamento farmacológico , Ácido Tióctico/administração & dosagem , Administração Intravaginal , Animais , Colo do Útero/efeitos dos fármacos , Feminino , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Gravidez , Ratos Wistar , Distribuição Tecidual , Útero/efeitos dos fármacosRESUMO
Osteochondral tissue is hard to regenerate after injuries or degenerative diseases. Traditional treatments still have disadvantages, such as donor tissue availability, donor site morbidity, implant loss, and limited durability of prosthetics. Thus, recent studies have focused on tissue engineering strategies to regenerate osteochondral defects with different scaffold designs. Scaffolds have been developed from monolayer structures to bilayer scaffolds to repair the cartilage-bone interface and to support each tissue separately. In this study, Si-substituted nanohydroxyapatite particles (Si-nHap) and silica-based POSS nanocages were used as reinforcements in different polymer layers to mimic a cartilage-bone tissue interface. Chitosan and zein, which are widely used biopolymers, are used as polymer layers to mimic the structure. This study reports the development of a bilayer scaffold produced via fabrication of two different nanocomposite layers with different polymer-inorganic composites in order to satisfy the complex and diverse regenerative requirements of osteochondral tissue. The chitosan/Si-nHap microporous layer and the zein/POSS nanofiber layer were designed to mimic a bone-cartilage tissue interface. Bilayer scaffolds were characterized with SEM, compression, swelling, and biodegradation tests to determine morphological, physical, and mechanical properties. The results showed that the bilayer scaffold had a structure composed of microporous and nanofiber layers joined at a continuous interface with appropriate mechanical properties. Furthermore, in vitro cell culture studies have been performed with LDH, proliferation, fluorescence imaging, and ALP activity assays using osteosarcoma and chondrosarcoma cell lines. ALP expression levels provide a good illustration of the improved osteogenic potential of a porous chitosan/Si-nHap layer due to the Si-doped nHap incorporation. Histological data showed that both fiber and porous layers that mimic the cartilage and bone sections exhibit homogeneous cell distribution and matrix formation. Histochemical staining was used to determine the cell proliferation and ECM formation on each layer. In vitro studies indicated that zein-POSS/chitosan/Si-nHap nanocomposite bilayer scaffolds showed promising results for osteochondral regeneration.
RESUMO
Objective: Maternal folic acid supplementation has been recommended prior to and during the first trimester of pregnancy to reduce the risk of infant neural tube defects. However, an uncertain relationship between folic acid supplementation during pregnancy and development of childhood asthma exists. Recent data show a methyl donor-rich diet could increase the risk of developing allergic airway disease through DNA methylation and aberrant gene transcription. This study evaluated the effect of folic acid supplementation during pregnancy on airway remodeling and allergic airway disease vulnerability in a mouse asthma model. Methods: BALB/c mice were divided into four groups according to gestational folic acid supplementation and postnatal ovalbumin (OVA) exposure: Group 1 (whole pregnancy folic acid supplementation + OVA-exposed group), Group 2 (first gestational week folic acid supplementation + OVA-exposed group), Group 3 (no folic acid supplementation + OVA-exposed group), and Group 4 (control group). Offspring were sacrificed on day 45 for immunohistological and ultrastructural tests. Results: In OVA challenged groups, folic acid supplementation led to a thicker epithelial and subepithelial smooth muscle layer than in the unsupplemented group. Moreover, folic acid supplementation during whole pregnancy (Group 1) was associated with a thicker epithelial and subepithelial smooth muscle layer than folic acid supplementation during the first week of pregnancy (Group 2), suggesting a duration-response relationship. Electron microscopic imaging revealed that structural changes including the loss of epithelial integrity, thickening of basement membrane, and subepithelial fibrosis were more prominent in the folic acid supplementation groups. Conclusions: This study suggested that maternal folic acid supplementation during pregnancy affects airway remodeling and increases the allergic responses induced by ovalbumin challenge in offspring. In addition, the effect size increased as the duration and cumulative dose increased.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Complexo Vitamínico B/administração & dosagem , Animais , Asma/etiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Ácido Fólico/efeitos adversos , Humanos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Gravidez , Distribuição Aleatória , Complexo Vitamínico B/efeitos adversosRESUMO
Cerebral ischemia leads to neuronal damage in the hippocampus and cognitive decline. Reactive oxygen species play an important role in the neuronal loss after cerebral ischemia and reperfusion injury. Deprenyl, an irreversible monoamine-oxidase B inhibitor, has antioxidant and neuroprotective effects against reactive oxygen species. In the present study, the effect of deprenyl on spatial memory impairment, oxidative stress and apoptotic neuronal cell death following transient cerebral ischemia in rats was investigated. Transient ischemia was induced by occlusion of left common carotid artery of rats for 30 min and reperfusion for 24 h or 1 week. Rats received intraperitoneal injection of 1 mg/kg deprenyl (n = 24) or equal volume of saline (n = 24) for 14 days before the experiment. Deprenyl treatment attenuated spatial memory deficits following ischemia-reperfusion as measured by the Morris water maze task. Deprenyl treatment elicited a significant decrease in lipid peroxidation and increase in superoxide dismutase activities in ischemic rat brains. The number of TUNEL-positive cells decreased significantly in deprenyl-treated group when compared with the control group. The results show that deprenyl reduces the ischemia-induced oxidative stress and thus prevents spatial memory deficits and apoptotic neuronal cell death when it is administered before ischemia-reperfusion.