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AIMS: Apoptosis may contribute to a considerable proportion of neuron death after acute cerebral ischemia, although the underlying mechanisms remain unknown. The purpose of this research is to investigate the effect of cerebral ischemia-reperfusion on miR-27a/smurf1 axis in rat cerebral cortex alone and in combination with chlorogenic acid. METHODS: To create a model of ischemic brain injury, nylon monofilament occlusion of the common carotid artery (CCAO) was used for 20 min. Chlorogenic acid (30 mg/kg) was given intraperitoneally (ip) 10 min before ischemia and 10 min before reperfusion. RESULTS: TUNEL staining of cerebral cortex neurons revealed an increase in the number of apoptotic neurons 24 h after reperfusion. At the molecular level, IR damage lowered bcl2 protein expression while simultaneously increasing bax levels and the bax/bcl2 ratio. Also, we observed higher miR-27a gene expression and higher TNF-α protein level as well as lower smurf1 protein expression after 24 h following CCAO. Treatment with chlorogenic acid significantly reduced the apoptotic damage and reversed molecular alterations in cerebral cortex neurons after IR. CONCLUSION: Our findings indicate that miR-27a/smurf1/TNF-α axis may play a regulatory function in cerebral cortex cell death, providing a new target for novel therapeutic approaches during transit ischemic stroke. It was also shown that chlorogenic acid could restore these molecular changes, demonstrating that it is an effective agent against cerebral cortex apoptotic damage after acute IR injury.
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Isquemia Encefálica , MicroRNAs , Traumatismo por Reperfusão , Ratos , Animais , Fator de Necrose Tumoral alfa , Ácido Clorogênico/farmacologia , Ácido Clorogênico/uso terapêutico , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo , Apoptose , Isquemia Encefálica/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , MicroRNAs/metabolismoRESUMO
BACKGROUND: Cyclosporine A (CsA)-induced cardiac interstitial fibrosis and cardiac hypertrophy are highly known phenomena; however, the basic mechanisms of CsA cardiotoxicity are unclear. The present study evaluated the role of the Transforming growth factor-beta (TGF-ß)/Smad3/miR-29b signaling pathway and CaMKIIδ isoforms gene expression in cardiac remodeling under CsA exposure alone or combined with moderate exercise. METHODS: A total of 24 male Wistar rats were divided into control, cyclosporine (30 mg/kg BW), and cyclosporine-exercise groups. RESULTS: After 42 days of treatment, the findings revealed a significant decline in miR-29 and miR-30b-5p gene expression and an increase in gene expression of Smad3, calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ) isoforms, Matrix Metalloproteinases (MMPs), protein expression of TGF-ß, heart tissue protein carbonyl and oxidized LDL (Ox-LDL), and plasma LDL and cholesterol levels in the CsA-treated group compared to the control group. The CsA group presented greater histological heart changes such as fibrosis, necrosis, hemorrhage, infiltrated leukocyte, and left ventricular weight/heart weight than the control group. Moreover, combined moderate exercise and CsA relatively improved gene expression changes and histological alternations compared to the CsA group. CONCLUSION: TGF-ß-Smad3-miR-29 and CaMKIIδ isoforms may mainly contribute to the progression of heart fibrosis and hypertrophy due to CsA exposure, providing new insight into the pathogenesis and treatment of CsA-induced side effects on the heart tissue.
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Ciclosporina , MicroRNAs , Ratos , Animais , Masculino , Ciclosporina/farmacologia , Remodelação Ventricular , Ratos Wistar , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fibrose , MicroRNAs/metabolismo , Isoformas de Proteínas/genética , Transdução de Sinais , Expressão GênicaRESUMO
Background and purpose: The present study investigated the role of the prostaglandin I2/peroxisome proliferator activator receptor (PGI2/PPAR) signaling pathway in cardiac cell proliferation, apoptosis, and systemic hemodynamic variables under cyclosporine A (CsA) exposure alone or combined with moderate exercises. Experimental approach: Twenty-four male Wistar rats were classified into three groups, namely, control, CsA, and CsA + exercise. Findings/Results: After 42 days of treatment, the findings showed a significant enhancement in the expression of the ß-MHC gene, enhancement in protein expression of Bax and caspase-3, and a significant decline in the protein expression of Bcl-2 expression, as well as increased proliferation intensity in the heart tissue of the CsA group compared to the control group. Systolic pressure, pulse pressure, mean arterial pressure (MAP), QT and QRS duration, and T wave amplitude, as well as QTc amount in the CsA group, showed a significant increase compared to the control group. PPAR-γ and PGI2 showed no significant changes compared to the control group. Moderate exercise along with CsA significantly enhanced the protein expression of PPAR-γ and PGI2 and declined protein expression of Bax, and caspase-3 compared to those in the CsA group. In the CsA + exercise group, systolic pressure, MAP, and Twave showed a significant decrease compared to the CsA group. Moderate exercises along CsA improved heart cell proliferation intensity and significantly reduced ß- MHC gene expression compared to the CsA group. Conclusions and implications: The results showed moderate exercise alleviated CsA-induced heart tissue apoptosis and proliferation with the corresponding activation of the PGI2/PPAR-γ pathway.
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Background: Alcohol consumption in pregnancy is associated with an increased risk of cardiovascular abnormalities, but the mechanisms are unknown. This study evaluated the impact of ethanol exposure on the offspring's aorta structural, functional, and molecular alterations on postnatal (PN) both on days 21 and 90. Methods: This experimental study was conducted at Urmia University of Medical Sciences (Urmia, Iran) in 2019. Twenty Pregnant Wistar rats on the seventh day of Gestation Day (GD) were randomly divided into two groups: control and ethanol-treated groups (n=10 per group). From the seventh day of GD throughout lactation, rats in the ethanol group were fed binge alcohol (4.5 g/Kg body weight) once daily. Systemic hemodynamic variables in the offspring were analyzed using waveform contour analysis 90 days after birth. On postnatal days (PN) 21 and 90, aorta wall histological alterations and the level of inflammatory factors were assessed in the aorta of male offspring. The statistical differences were examined via an independent samples t test. P<0.05 was considered to be statistically significant. Results: The results revealed that offspring in the ethanol group had higher systolic, diastolic, mean arterial pressure, and dicrotic pressure than the control group (P<0.001). The level of aorta tissue tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, nuclear factor (NF)-κ, and endothelin-1 were significantly higher in the ethanol offspring group than in the control group (P<0.001). Histopathological changes such as total aorta thickness, tunica media, tunica adventitia, elastin fiber thickness, fiber interval, and elastin/media ratio significantly increased in the aorta of the offspring of the ethanol group compared to the control group 21 and 90 days after birth. Conclusion: Our findings suggest that prenatal and early postnatal ethanol exposure-induced cardiovascular abnormalities are, in part, due to predisposing the aorta to atherosclerosis, which was mediated through the aorta wall remodeling and inflammation process.
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Elastina , Endotelina-1 , Animais , Aorta , Moléculas de Adesão Celular , Etanol/efeitos adversos , Feminino , Seguimentos , Hemodinâmica , Masculino , Gravidez , Ratos , Ratos Wistar , Fatores de Necrose TumoralRESUMO
Ethanol exposure during pregnancy induces cardiac fibrosis in the fetal heart. However, the mechanisms by which consumption of ethanol induces fibrotic changes are not known. Pregnant rats were received ethanol 4.5 g/kg BW once per day from the 7th day of pregnancy (GD7) throughout lactation. Our findings demonstrated that, area of fibrosis increased in cardiac tissue in the pups on both postnatal day twenty one (PN21) and postnatal day ninety (PN90) after prenatal and early postnatal period ethanol treatment compared with the controls. It was accompanied by a decline in the expression of SIRT1 protein along with the elevation of FOXO3a and TGF-ß protein expressions which were determined by western blot. Overall, our data reveal that prenatal alcohol usage increase in fibrotic regions in the pup hearts possibly by regulating TGF-ß, FOXO3a and SIRT1 protein levels. These are potential therapeutic molecular targets that can be modulated to protect heart against maternal ethanol exposure.
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Efeitos Tardios da Exposição Pré-Natal , Sirtuína 1 , Animais , Animais Recém-Nascidos , Etanol/toxicidade , Feminino , Fibrose , Seguimentos , Humanos , Masculino , Gravidez , Ratos , Fator de Crescimento Transformador betaRESUMO
BACKGROUND: Cardiac syndrome X (CSX) has been associated with endothelial dysfunction and inflammation. We conducted a case-control study to evaluate the association between plateletý and endothelial-derived microparticles (PMPs and EMPs), as specific quantitative plasma markers of endothelial dysfunction, and the presence of CSX. METHODS: The present study was conducted on 40 CSX patients and 19 healthy individuals. C-reactive protein (CRP), and hematological and biochemical parameters were evaluated. The MP concentration in platelet-poor plasma (PPP) was quantitatively determined through flow cytometry using specific anti-human CD31, CD41a, CD62E, and CD144 antibodies. RESULTS: The mean platelet volume (MPV) and positive CRP rate (≥ 3.8 mg/l) were higher in patients compared to controls (P = 0.020 and P = 0.010, respectively). The CD62E+, CD144+, and CD31+41- EMPs, as well as CD41+ and CD31+CD41+ PMPs showed significant increase in CSX patients compared to controls (P < 0.050). There were direct correlations between the mean percentage of detected EMPs and PMPs as well as between their expression intensity; however, a reverse correlation was seen between the percentage of MPs and CD144 and CD41. Moreover, the MP level was reversely associated with prothrombin time (PT) and partial thromboplastin time (PTT) values. Only CD31+CD41+ PMP was correlated with CRP. CONCLUSION: It seems that EMPs and PMPs increase in CSX, which may contribute to various processes involved in the development of this syndrome.
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BACKGROUND AND PURPOSE: The specific molecular mediators involved in dyslipidemia in older people are not yet clearly understood. The current study was, thus, an attempt to investigate whether moderate aerobic exercises and curcumin administration alleviates the abnormalities caused by aging in the rats' liver. EXPERIMENTAL APPROACH: Thirty-two eight-year-old young rats were classified into five groups, namely, young control, aged control, aged-curcumin, aged-exercise, and aged-curcumin-exercise co-treatment. The rats in the exercise groups were trained on an animal treadmill for 60 min/day five times per week for eight weeks. FINDINGS/RESULTS: The results revealed a significant increase in FAT/CD36, PTP1B, significantly decreased HNF4α genes expression, increase in LDL and cholesterol in the aged group compared to the young control. Compared to those in the young control group, no significant changes in HDL and TG amounts in the aged control were observed. Moreover, compared to the young control, the aged group showed liver histological changes such as fibrosis and mild or grade 1 steatohepatitis. Moderate aerobic exercise and curcumin alone or in combination completely masked this effect. CONCLUSION AND IMPLICATIONS: The findings revealed dyslipidemia and liver steatosis related to aging might be partly associated with changes in hepatic transcriptional factors which can be mitigated via moderate aerobic exercise and curcumin.
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BACKGROUND: This research aimed at investigating the cyclosporine A intake impact with/without curcumin on podocyte protein gene expressions and matrix metalloproteins (MMPs) changes in rat kidney. METHODS: Thirty-two Wistar male rats were assigned to the control, sham, cyclosporine A, and cyclosporine A with curcumin groups. RESULTS: A significant increase was observed in CD2AP, ACTN4, podocin and also MMP9 and 2, cystatin C levels in the cyclosporine A group following treatment for four weeks, whereas a decrease was found in nephrin gene expression than the control group. In addition, a significant reduction was observed in the cyclosporine A group in glomerular filtration rate (GFR), urine creatinine, and increased plasma creatinine levels than the control group. Using curcumin plus cyclosporine A ameliorated gene expression alterations and increased the reduced amount of GFR, urine urea, and creatinine while reducing the increased plasma cystatine C, urea, and creatinine levels compared with the cyclosporine A group. CONCLUSION: Accordingly, cyclosporine A-induced kidney abnormalities are possibly associated with changes in podocyte intra- and extra-cellular protein gene expression that influence the quality of filtrated fluid via altering the foot process shape and slit diaphragm size. Finally, such impacts are reduced via curcumin as an antioxidant and anti-inflammatory compound.
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Curcumina/farmacologia , Ciclosporina/toxicidade , Nefropatias/induzido quimicamente , Metaloproteínas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Taxa de Filtração Glomerular , Imunossupressores/toxicidade , Nefropatias/prevenção & controle , Masculino , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: Diabetes mellitus (DM) is one of the most common diseases in the worldwide. Type 1 diabetes mellitus (T1DM) is characterized by insulin deficiency and beta cells apoptosis. Tropisetron as a 5-HT3 receptor antagonist has positive effects on the inflammation, apoptosis and glucose lowering. The aim of this study was to investigate the effect of tropisetron on ß-cells apoptosis and its possible pathways. METHODS: Animals were divided into five equal groups: the control, tropisetron, diabetes, tropisetron-DM and glibenclamide-DM (seven in each group). Tropisetron and glibenclamide were administrated for 2 weeks after type 1 diabetes induction. Real-time PCR, western blot analysis and TUNEL assay were performed. RESULTS: We found that tropisetron decreased blood glucose and increased insulin secretion. Protein expression of NF-κB was downregulated, while protein expression of SIRT1 upregulated after tropisetron treatment. Moreover, Bax/Bcl2 ratio decreased in tropisetron-DM group and finally, apoptosis improved in pancreas tissue. CONCLUSIONS: It seems that tropisetron administration improves STZ-induced apoptosis and diabetes in the animals. This effect might be resulted from involvement in NF-κB/ SIRT1 pathway.
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Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Tropizetrona/farmacologia , Animais , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Masculino , NF-kappa B/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , EstreptozocinaRESUMO
Testicular damage contributes to cyclosporine A (CsA) induced male infertility. However, the exact underlying molecular mediators involved in CsA-induced testis disorder remains unclear. The present study aimed to characterize the role of mir-34a/sirt-1 in CsA induced testicular injury alone or in combination with curcumin. A total of twenty-eight male Wistar rats were subdivided into four groups: control (Con), sham, cyclosporine A (CsA), cyclosporineA + curcumin (CsA + cur). The animals received cyclosporine A (30 mg/kg) and curcumin (40 mg/kg) for 28 days by oral gavage. At the end of the experiment, CsA administration signiï¬cantly resulted in a decrease in testis weight and testis coefficient. The molecular analysis demonstrated that CsA exposure increased 8-OHdg and Nox4 protein contents in the testis tissue. TUNEL staining indicated that CsA caused the number of apoptotic cells to increase in the testes of male rats. In addition, exposure to CsA resulted in an increased expression of Bax, and a decreased expresion in that of Bcl-2, with a concomitant up-regulation of the Bax/Bcl-2, c-Caspase-3/p-Caspase-3 ratio and cytochrome c level. Meanwhile, exposure to CsA increased the expression of mir-34a and decreased sirt-1 protein level in the testis tissue samples compared to the control group. Taken together, our ï¬ndings suggested that CsA can cause damage to testicular germ cells via oxidative stress and mitochondrial apoptotic pathway, and probably mir-34a/sirt-1 play a crucial role in this process. It also demonstrates that these negative effects of CsA can be reduced by using curcumin as an antioxidant and anti-inï¬ammatory agent.
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Apoptose/efeitos dos fármacos , Curcumina/uso terapêutico , Ciclosporina/toxicidade , MicroRNAs/metabolismo , Sirtuína 1/metabolismo , Doenças Testiculares/tratamento farmacológico , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Citocromos c/metabolismo , Expressão Gênica/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo , Ratos Wistar , Doenças Testiculares/induzido quimicamente , Testículo/efeitos dos fármacos , Testículo/patologiaRESUMO
OBJECTIVES: Diabetes mellitus is one of the most common metabolic diseases. Tropisetron, as a 5-HT3 receptor antagonist, has a considerable role in the inflammation and oxidative stress lowering. This study aimed to investigate the effect of this 5-HT3 receptor antagonist on insulin secretion in male diabetic rats and the possible mechanisms. METHODS: Animals were divided into five equal groups; the control, tropisetron, diabetes, tropisetron-diabetes and glibenclamide-diabetes (7 in each group). Tropisetron and glibenclamide were administrated for 2 weeks after inducing type 1 diabetes. KEY FINDINGS: We demonstrated that insulin secretion improved robustly in diabetes-tropisetron compared with the diabetic group. Oxidative stress biomarkers were lower in a diabetes-tropisetron group than in diabetic rats. Simultaneously, tropisetron administration promoted the expression of ZnT8 and GLUT2 and also beta-cell mass in pancreatic tissue, while the expression of uncoupling protein 2 (UCP2) was restrained. The histological evaluation confirmed our results. These effects were equipotent with glibenclamide, indicating that tropisetron can protect islets from the abnormal insulin secretion and morphological changes induced by type 1 diabetes. CONCLUSIONS: This effect might be partly related to the modulated UCP2/ZnT8 signal pathway and improved oxidative stress-induced damage.
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Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/farmacologia , Insulina/biossíntese , Pâncreas/efeitos dos fármacos , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Tropizetrona/farmacologia , Proteína Desacopladora 2/metabolismo , Transportador 8 de Zinco/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Ratos Wistar , Via Secretória , EstreptozocinaRESUMO
Previous studies proved the pro-angiogenic effect of Crocetin, a natural carotenoid dicarboxylic acid, in both in vivo and in vitro models. However, the exact mechanism of Crocetin action has not completely been elucidated yet. The current experiment was designed to find the activity of PI3K-Akt-eNOS axis after the treatment of endothelial cells with Crocetin in vitro. Human Umbilical Vein Endothelial Cells (HUVECs) were incubated with various concentrations of Crocetin (1, 5, 25, 50, and 100 µM) over a period of 72 h. Crocetin significantly increased HUVECs viability after 72 h as compared with the control group. We also found that Crocetin promoted the formation of the capillary-like structure compared to the control (p<0.05). Moreover, an improved migration rate and increased MMP-9 activity were observed in HUVECs that received 50 µM Crocetin (p<0.05). Crocetin enhanced the uptake of Ac-LDL which is correlated with increased lipid metabolism. Based on the data from the current experiment, protein level of VEGFR-1, -2 and p-Akt/Akt, p-eNOS/eNOS ratios were increased 72 h after the treatment of HUVECs with Crocetin (p<0.05). In contrast, the transcription level of VEGF was reduced in Crocetin-treated cells. These data demonstrated that Crocetin promotes HUVECs angiogenesis potential by the modulation of VEGF signaling pathway and increased cell viability. The PI3K/Akt/eNOS axis is required for a Crocetin-associated activity in endothelial cells.
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Alcohol exposure during pregnancy induces a wide range of structural and functional abnormalities in the fetal heart. However, the underlying mechanism of this phenomenon is not well known. This study was undertaken to elucidate probable mechanisms of myocardial damage induced by prenatal and early postnatal ethanol treatment. Pregnant Wistar rats received ethanol 4.5 g/kg BW once per day from the seventh day of gestation (GD7) throughout lactation. The oxidative stress injury of the myocardium in pups was evaluated by measuring levels of oxidative stress biomarkers. Histopathological examinations and Western blot were performed to evaluate histological features, apoptosis, and molecular alterations in the myocardial tissue of male pups on the postnatal day 21 (PN-21) and postnatal day 90 (PN-90). The results showed that maternal ethanol consumption caused oxidative stress (impaired total antioxidant capacity and malondialdehyde), histological changes, and apoptosis of the myocardium in the pups on PN-21 and PN-90. At the molecular levels, Western blot analysis revealed that ethanol modulated the protein expression of p-ERK1/2, p-JNK, and Hsp70 in the myocardial tissue of the pups after 21 and 90 days of birth compared with the controls. These findings revealed that maternal ethanol intake induced cardiac toxicity in part, mediated by oxidative stress and apoptosis in the pups. A further mechanism study revealed that ethanol enhanced ERK1/2 and JNK phosphorylation and Hsp70 protein expression.
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Apoptose/efeitos dos fármacos , Etanol/toxicidade , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Gravidez , Ratos , Ratos WistarRESUMO
Chronic alcohol ingestion causes sexual dysfunction, impairs sperm motility and fertility, and changes semen quality. Considering the key role of epididymis in sperm development, the aim of the present study was to evaluate the effects of long-term ethanol consumption on epididymis changes, including alterations in ß-defensin isoform gene expression, oxidative stress, and pathological changes, such as cell proliferation and fibrosis in the epididymis of rats. In this study, male Wistar rats were equally divided into control and ethanol (4.5 g/kg BW) groups. After six weeks of treatment, the results revealed the proliferation of epididymis cells, fibrosis in the epididymis tissue, and a significant rise in the level of 8-OHdG and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the ethanol group, compared with the control group. Moreover, the ethanol group showed an increase in the gene expression of epididymal ß-defensin isoforms 15 and 21 and a reduction in the gene expression of ß-defensin isoforms 27 and 30, compared with the controls. These findings indicate that ethanol-induced epididymal damage and sperm abnormalities might be partly associated with changes in ß-defensin isoforms and epididymal structure, mediated by the increased activities of 8-OHdG and NADPH oxidase.
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Consumo de Bebidas Alcoólicas/metabolismo , Dano ao DNA , Regulação da Expressão Gênica , beta-Defensinas/biossíntese , Consumo de Bebidas Alcoólicas/patologia , Animais , Epididimo/metabolismo , Epididimo/patologia , Masculino , Oxirredução , Isoformas de Proteínas/biossíntese , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Misuse of anabolic androgenic steroids (AAS) increases prevalence of cardiovascular abnormalities in athletes, and the underlying molecular mechanism involved in those abnormalities continues to be investigated. The aim of this study was to investigate the effect of chronic nandrolone exposure on alpha and beta-myosin heavy chain (MHC) isoforms gene expression transition, blood pressure related parameters, calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ), and monoamine oxidase (MAO) activities in rats' hearts. It was also planned to evaluate the effect of strenuous exercise on cardiac abnormalities induced by nandrolone. Thirty-two male wistar rats were assigned into four groups, namely control, nandrolone, nandrolone with strenuous exercise, and strenuous exercise groups. Nandrolone consumption significantly increased systolic, diastolic, pulse and dicrotic pressure, mean arterial pressure, as well as the amplitude of first peak (H1). Moreover, exercise combined with nandrolone completely masked this effect. The mRNA expression of ß-MHC and the ratio of ß -MHC/α -MHC showed a significant increase in the nandrolone and nandrolone with strenuous exercise groups compared to those in the control group. The values of heart tissue calcium/calmoldulin-dependent protein kinase IIδ (CaMKIIδ), and monoamine oxidase (MAO) in the nandrolone, nandrolone with strenuous exercise and exercise groups were significantly higher than those values in the control group. These findings indicate that nandrolone-induced heart and hemodynamic abnormalities may in part be associated with MHC isoform changes and Ca2+ homeostasis changes mediated by increased CaMKIIδ and MAO activities and that these effects can be provoked via strenuous exercise.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Monoaminoxidase/efeitos dos fármacos , Nandrolona/farmacologia , Animais , Pressão Arterial , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Calmodulina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Frequência Cardíaca , Hipertensão/tratamento farmacológico , Masculino , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Miocárdio/metabolismo , Cadeias Pesadas de Miosina/efeitos dos fármacos , Nandrolona/administração & dosagem , Condicionamento Físico Animal/fisiologia , Isoformas de Proteínas , Ratos , Ratos WistarRESUMO
Background: Due to the possible biomedical potential of nanoparticles, titanium dioxide nanoparticles (TiO2 NPs) have received great attention in cancer research. Although selectivity of cytotoxicity with TiO2 NPs in various cells is clinically significant comparisons of cancer and non-cancer cells have been limited. Therefore, we here studied exposure to TiO2 NPs in colorectal cancer cells (CRCs) and human umbilical vein endothelial cells (HUVECs). Methods: After characterization of TiO2 NPs, culture and treatment of cells (HCT116, HT29 and HUVEC), viability was assessed by MTT assay and in terms of morphological features. Acridine orange (AO) and propidium iodide (PI) assays were carried out to estimate the incidence of apoptosis. The RT-PCR method was also employed to evaluate the expression of P53, Bax, Bcl-2 and Caspase 3. Results: Exposure to increasing concentrations of TiO2 NPs enhanced overall cell survival of HCT116 cells and reduced the Bcl-2 and Caspase 3 expression while the ratio of Bax/Bcl-2 was down-regulated. TiO2 NPs at 400 and 50 µg/ml concentrations suppressed cell proliferation and induced apoptosis of HT29 cells and also up-regulated P53 and Bax at the mRNA level, enhanced the Bax/Bcl-2 ratio and eventually up-regulated Caspase 3 mRNA. Although, inhibition of cell proliferation in HUVECs was seen at 200 and 400 µg/ml TiO2 NPs, it was not marked. Conclusion: TiO2 NPs have selective bio-effects on exposed cells with dose- and cell-dependent influence on viability. Cell proliferation in HCT116 as a metastatic colorectal cancer cell line appeared to be stimulated via multiple signaling pathways, with promotion of apoptosis in less metastatic cells at 50 and 400 µg/ml concentrations. This was associated with elevated P53, Bax and Caspase 3 mRNA and reduced Bcl-2 expression. However, TiO2 NPs did not exert any apparent significant effects on HUVECs as hyperproliferative angiogenic cells.
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Neoplasias Colorretais/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Titânio/farmacologia , Veias Umbilicais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Células Endoteliais/metabolismo , Células HCT116 , Células HT29 , Células Endoteliais da Veia Umbilical Humana , Humanos , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Veias Umbilicais/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
The association between chronic alcohol consumption and the development of alcpholic liver disease is a very well known phenomenon, but the precise underlying molecular mediators involved in ethanol-induced liver disease remain elusive. This study aimed to characterize the lipid metabolism alterations and the molecular mediators which are related to lipid metabolism in liver under the heavy ethanol exposure alone or combined with ginger extract. Twenty-four male wistar rats were assigned into three groups, namely control, ethanol, and ginger extract treated ethanol (GETE) groups. Six weeks after the treatment, the ethanol group showed a significant increase in fatty acid translocase (FAT)/CD36, protein tyrosine phosphatase 1B (PTP1B) and decrease hepatocyte nuclear factor 4 Alpha (HNF4A) genes expressions compared to the control group. The ethanol administration also significantly increased plasma LDL, cholesterol, triglyceride, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared to the control group. Moreover, compared to the control group, the ethanol group showed liver histhological changes, such as fibrosis, focal microvesicular steatosis, some apoptotic hepatocytes, spotty necrosis, portal lymphocytic inflammation, mallory-denk bodies, giant mitochondria, piecemeal necrosis. Consumption of ginger extract along with ethanol, partially ameliorated gene expression alteration and histological changes, improved undesirable lipid profile and liver enzymes changes compare to those in the ethanol group. These findings indicate that ethanol-induced liver abnormalities may in part be associated with lipid homeostasis changes mediated by overexpression of FAT/CD36, PTP1B and downexpressionof HNF4A genes. It also show that these effects can be reduced by using ginger extract as an antioxidant and anti-inflammatory agent.
Assuntos
Antígenos CD36/metabolismo , Dislipidemias/tratamento farmacológico , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Zingiber officinale/química , Animais , Antígenos CD36/genética , Dislipidemias/complicações , Dislipidemias/metabolismo , Expressão Gênica/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/metabolismo , Testes de Função Hepática , Masculino , Extratos Vegetais/isolamento & purificação , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Ratos WistarRESUMO
OBJECTIVE: Association between chronic alcohol intake and cardiac abnormality is well known; however, the precise underlying molecular mediators involved in ethanol-induced heart abnormalities remain elusive. This study investigated the effect of chronic ethanol exposure on calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) gene expression and monoamine oxidase (MAO) levels and histological changes in rat heart. It was also planned to find out whether Zingiber officinale (ginger) extract mitigated the abnormalities induced by ethanol in rat heart. METHODS: Male wistar rats were divided into three groups of eight animals each: control, ethanol, and ginger extract treated-ethanol (GETE) groups. RESULTS: After 6 weeks of treatment, the results revealed a significant increase in CaMKIIδtotal and isoforms δ2 and δ3 of CaMKIIδ gene expression as well as a significant decrease in the MAO levels in the ethanol group compared to that in the control group. Moreover, compared to the control group, the ethanol group showed histological changes, such as fibrosis, heart muscle cells proliferation, myocyte hypertrophy, vacuolization, and focal lymphocytic infiltration. Consumption of ginger extract along with ethanol ameliorated CaMKIIδtotal. In addition, compared to the ethanol group, isoforms gene expression changed and increased the reduced MAO levels and mitigated heart structural changes. CONCLUSION: These findings indicate that ethanol-induced heart abnormalities may, in part, be associated with Ca2+ homeostasis changes mediated by overexpression of CaMKIIδ gene and the decrease of MAO levels and that these effects can be alleviated by using ginger extract as an antioxidant and anti-inflammatory agent.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Cardiotônicos/farmacologia , Cardiopatias/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Zingiber officinale , Animais , Cálcio/metabolismo , Calmodulina/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Cardiopatias/etiologia , Cardiopatias/metabolismo , Masculino , Monoaminoxidase/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: The interaction of ethanol consumption and sexual behavior has been evaluated over the past three decades; however, some studies have assessed how ethanol consumption affects the general behavioral aspects of the copulatory cycle patterns in male rats. The aim of this study was to investigate the effect of chronic ethanol consumption on adult male Wistar rats' sexual motivation and behavior alteration in pre-copulatory, copulatory, and executive phases of the copulatory cycle. METHODS: Male Wistar rats were randomly allocated to two groups (control and ethanol treated groups). After 42 days of treatment, male rats were given access to adult female rats for 2 hours and their sexual behavior were recorded in a fully dark room using an infrared camera. FINDINGS: Chronic ethanol consumption caused a significant increase in anogenital sniffing and mounting, intermission, and ejaculation latencies periods, as well as a significant decrease in the sexual activity index (SAI) and copulatory efficiency (CE) compared to the control group. CONCLUSION: It is suggested that chronic ethanol consumption suppresses sexual behavior and reduces male rats' tendency toward sexual interaction with female rats as manifested by the enhanced latency periods in the copulatory phases and reduced SAI of ethanol treated animals.
RESUMO
BACKGROUND: Chronic alcohol ingestion-induced kidney structure and function alterations are very well known, but the precise underlying molecular mediators involved in ethanol-induced kidney abnormalities remain elusive. The aim of this study was to investigate the effect of chronic ethanol exposure on matrix metalloproteinase 2, 9 (MMP), glomerular filtration barrier proteins (nephrin and podocin), as well as vascular endothelial growth factor receptor 1, 2 (VEGFRs) isoforms gene expression in the kidney of rats. METHODS: Sixteen male Wistar rats with an initial body weight of 220 ± 10 g were divided into the following two groups: (1) control and (2) ethanol (4.5 g/kg BW). RESULTS: After 6 weeks of treatment, the results revealed a significant increase in isoforms VEGFR1 and VEGFR2 of VEGFR gene expression, significant increases of MMP2 and MMP9 activities, as well as significant decrease of nephrin and podocin gene expressions in the ethanol group, compared with that in the control group. CONCLUSION: These findings indicate that ethanol-induced kidney abnormalities may be in part associated with alteration in expressions of VEGFRs, nephrin, and podocin and in increasing activities of MMP2 and MMP9 as key molecular mediators in the kidney function.