RESUMEN
Diabetes mellitus is a common metabolic disorder affecting different body organs; one of its serious complications is diabetic cardiomyopathy (DCM). Thus, finding more cardiopreserving agents to protect the heart against such illness is a critical task. For the first time, we planned to study the suspected role of diacerein (DIA) in ameliorating DCM in juvenile rats and explore different mechanisms mediating its effect including inflammasome/caspase1/interleukin1ß pathway. Four-week-aged juvenile rats were randomly divided into groups; the control group, diacerein group, diabetic group, and diabetic-treated group. Streptozotocin (45 mg/kg) single intraperitoneal (i.p.) dose was administered for induction of type 1 diabetes on the 1st day which was confirmed by detecting blood glucose level. DIA was given in a dose of 50 mg/kg/day for 6 weeks to diabetic and non-diabetic rats, then we evaluated different inflammatory, apoptotic, and oxidative stress parameters. Induction of DCM succeeded as there were significant increases in cardiac enzymes, heart weights, fasting blood glucose level (FBG), and glycosylated hemoglobin (HbA1c) associated with elevated blood pressure (BP), histopathological changes, and increased caspase 3 immunoexpression. Furthermore, there was an increase of malondialdehyde (MDA), inflammasome, caspase1, angiotensin II, nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNFα), and interleukin 1ß (IL1ß). However, antioxidant parameters such as reduced glutathione (GSH) and total antioxidant capacity (TAC) significantly declined. Fortunately, DIA reversed the diabetic cardiomyopathy changes mostly due to the observed anti-inflammatory, antioxidant, and anti-apoptotic properties with regulation of blood glucose level.DIA has an ability to regulate DCM-associated biochemical and histopathological disturbances.
Asunto(s)
Antraquinonas , Caspasa 1 , Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Inflamasomas , Interleucina-1beta , Animales , Cardiomiopatías Diabéticas/prevención & control , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Inflamasomas/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Caspasa 1/metabolismo , Interleucina-1beta/metabolismo , Masculino , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Ratas , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Estreptozocina , Antiinflamatorios/farmacologíaRESUMEN
BACKGROUND: Resistance to antibiotics has increased steadily over time, thus there is a pressing need for safer alternatives to antibiotics. Current study aims to evaluate the influence of vitamin C as an antibacterial and anti-biofilm agent against uropathogenic E. coli (UPEC) strains. The expression of beta-lactamases and biofilm encoding genes among E. coli isolates before and after treating the isolates with sub MIC of vitamin C was analyzed by Real-time PCR. The in vivo assessment of the antibacterial and anti-biofilm effects of vitamin C against uropathogenic E. coli strains was done using a urinary tract infection (UTI) rat model. RESULTS: The effective concentration of vitamin C that could inhibit the growth of most study isolates (70%) was 1.25 mg/ml. Vitamin C showed a synergistic effect with most of the studied antibiotics; no antagonistic effect was detected at all. Vitamin C showed an excellent anti-biofilm effect against studied isolates, where 43 biofilm-producing isolates were converted to non-biofilm at a concentration of 0.312 mg/ml. The expression levels of most studied genes were down-regulated after treatment of E. coli isolates with vitamin C. In vivo assessment of vitamin C in treating UTIs showed that vitamin C has a rapid curative effect as the comparable antibiotic. Administration of both vitamin C and nitrofurantoin at a lower dose for treatment of UTI in rats had a better effect. CONCLUSION: Vitamin C as an antibacterial and anti-biofilm agent either alone or in combination with antibiotics could markedly improve UTI in experimental rats.
Asunto(s)
Infecciones por Escherichia coli , Infecciones Urinarias , Escherichia coli Uropatógena , Animales , Ratas , Ácido Ascórbico/farmacología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Nitrofurantoína/farmacología , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/microbiología , Vitaminas/farmacologíaRESUMEN
BACKGROUND: Methotrexate (MTX) is a commonly used chemotherapeutic agent; however, its clinical use is challenged by various types of injuries, including hepatotoxic side effects. Therefore, finding new protective drugs against MTX-induced toxicities is a critical need. Moreover, the different mechanisms mediating such effects are still not clear. The current study aimed to evaluate the possible ameliorative action of nicorandil (NIC) in MTX-induced hepatotoxicity and examine the roles of the ATP-sensitive potassium channel (KATP), endothelial nitric oxide synthase (eNOS), and P-glycoprotein (P-gp). MATERIALS AND METHODS: Thirty-six male Wistar albino rats were used. NIC (3 mg/kg/day) was given orally for 2 weeks, and hepatotoxicity was induced by a single intraperitoneal injection of MTX (20 mg/kg) on the 11th day of the experiment. We confirmed the role of KATP by co-administering glimepiride (GP) (10 mg/kg/day) 30 min before NIC. The measured serum biomarkers were [alanine transaminase (ALT) and aspartate transaminase (AST)], total antioxidant capacity (TAC), malondialdehyde (MDA), nitric oxide (NOx), tumor necrosis factor-alpha (TNFα), superoxide dismutase (SOD), and P-gp. Histopathology, eNOS, and caspase-3 immunoexpression were evaluated. RESULTS: The MTX group displayed hepatotoxicity in the form of elevations of ALT, AST, MDA, NOx, and caspase-3 immunoexpression. Furthermore, the histopathological examination showed marked liver injury. TAC, SOD, P-gp, and eNOS immunoexpression showed significant inhibition. In the protective group, all parameters improved (P value < 0.05). CONCLUSION: NIC has an ameliorative action against MTX-induced hepatotoxicity, most probably via its antioxidant, anti-inflammatory, and anti-apoptotic functions together with the modulation of the KATP channel, eNOS, and P-glycoprotein.
Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Ratas , Masculino , Animales , Antioxidantes/farmacología , Metotrexato/toxicidad , Ratas Wistar , Nicorandil/farmacología , Caspasa 3/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/farmacología , Estrés Oxidativo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Canales KATP/metabolismo , Canales KATP/farmacología , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/patología , Hígado , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/farmacología , Superóxido Dismutasa/metabolismo , Adenosina Trifosfato , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismoRESUMEN
Cadmium (Cd) is a common environmental pollutant that leads to severe cardiotoxic hazards. Several studies were carried out to protect the myocardium against Cd-induced cardiotoxicity. Up till now, no researches evaluated the protective effect of dapagliflozin (DAP) against Cd induced cardiotoxicity. Thus, we aimed to explore the role of DAP in such model with deep studying of the involved mechanisms. 40 male Wistar albino rats were included in current study. Cd (5 mg/kg/day) was administered orally for 7 days to induce cardiotoxicity with or without co-administration of DAP in three different doses (2.5, 5, 10 mg/kg/day) orally for 7 days. Our data revealed that Cd could induce cardiotoxicity with significant increase in serum cardiac enzymes, heart weight, tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), nuclear factor kappa B (NFκB), toll like receptor2 (TLR2), interleukin 6 (IL6) and caspase3 immunoexpression with abnormal histopathological changes. In addition, Cd significantly decreased the level of heme oxygenase1 (HO1), nuclear factor erythroid 2-related factor 2 (Nrf2), signal transducer and activator of transcription (STAT3), reduced glutathione (GSH), glutathione peroxidase (GPx), and total antioxidant capacity (TAC). Co-administration of DAP could ameliorate Cd cardiotoxicity with significant improvement of the biochemical and histopathological changes. We found that DAP had protective properties against Cd induced cardiotoxicity and this may be due to its anti-oxidant, anti-inflammatory, anti-apoptotic properties and modulation of IL6/STAT3 and TLR2/TNFα-signaling pathways.
Asunto(s)
Cadmio , Contaminantes Ambientales , Masculino , Ratas , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Cadmio/toxicidad , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/metabolismo , Cardiotoxicidad/patología , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Hemo/metabolismo , Hemo/farmacología , Hemo/uso terapéutico , Interleucina-6/metabolismo , Malondialdehído/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Transducción de Señal , Receptor Toll-Like 2/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , AnimalesRESUMEN
METHODS: 50 male Wistar albino rats were subjected to DOX toxicity via administration of single i.p. Dose (15 mg/kg) on the 4th day with or without co-administration of VIN (10, 20, 30 mg/kg/day) orally for 5 days. RESULTS: Our data revealed that VIN succeeded in protecting the heart against DOX induced damage as manifested by significant decrease of cardiac enzymes, hypoxia inducible factor alpha (HIF-1α), vascular endothelial growth factor-A (VEGF-A), tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and caspase3 levels. Furthermore, VIN given group showed marked improvement of the histopathological changes of cardiac injury, total antioxidant capacity (TAC), elevation of reduced glutathione (GSH), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP) and sirtuin-1 (SIRT-1). CONCLUSION: We concluded that VIN could ameliorate DOX induced cardiac damage and this effect may be attributed to modulation of HIF/VEGF signaling pathway, up-regulation of cGMP/cAMP/SIRT pathway, inhibition of phosphodiesterase enzyme, besides its anti-apoptotic, anti-inflammatory, and anti-oxidant properties.
Asunto(s)
Cardiotoxicidad , Sirtuinas , Animales , Ratas , Masculino , Cardiotoxicidad/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Guanosina Monofosfato , Estrés Oxidativo , Doxorrubicina/toxicidad , Malondialdehído/metabolismo , Transducción de Señal , Ratas Wistar , Glutatión/metabolismo , Sirtuinas/metabolismo , Hidrolasas Diéster Fosfóricas , Adenosina Monofosfato/metabolismo , Adenosina Monofosfato/farmacologíaRESUMEN
There is a persistent need to look for alternative therapeutic modalities to help control the pandemic of antimicrobial resistance. Assessment of antibacterial and anti-biofilm effects of vitamin C (ascorbic acid) was the aim of the current study. The micro-dilution method determined the minimal inhibitory concentration (MIC) of ascorbic acid or antibiotics alone and in combinations against Pseudomonas aeruginosa (P. aeruginosa) clinical isolates. The micro-titer plate method monitored the effect of ascorbic acid on the biofilm-producing isolates of P. aeruginosa. The effect of ascorbic acid on the differential expression of different antibiotic-resistant genes and biofilm encoding genes of P. aeruginosa isolates were also tested using real-time polymerase chain reaction (PCR). For in vivo assessment of the antibacterial effects of ascorbic acid alone or combined with an antibiotic, rats were infected with P. aeruginosa clinical isolate followed by different treatment regimens. MICs of ascorbic acid among P. aeruginosa isolates were in the range of 156.2-1,250 µg/ml, while MIC50 and MIC90 were 312.5 and 625 µg/ml, respectively. At sub-inhibitory concentrations (19.5-312.5 µg/ml), ascorbic acid had 100% biofilm inhibitory effect. Furthermore, ascorbic acid-treated bacteria showed downregulation of genes underpinning biofilm formation and antibiotic resistance. In vivo assessment of vitamin C and ceftazidime in rats showed that administration of both at a lower dose for treatment of pseudomonas infection in rats had a synergistic and more powerful effect. Vitamin C shows excellent in vitro results as an antibacterial and anti-biofilm agent. Vitamin C should be routinely prescribed with antibiotics to treat bacterial infections in the clinical setting.
RESUMEN
BACKGROUND: One of the most dangerous gynecological emergencies is ovarian ischemia that commonly occurs during surgical manipulation or presence of ovarian masses. OBJECTIVES: finding new therapies to prevent the associated harmful effects of ischemia/reperfusion-induced damage is still a critical need. For the first time, we aimed to evaluate the possible role of phosphodiesterase (PDE) 3 A inhibitor (PDEI), cilostazol (CLZ) in the treatment of ovarian ischemia reperfusion induced damage (OIR). METHODS: Rats were divided into five groups; sham, OIR group; CLZ (5, 10, 20 mg/kg) was given orally with induced OIR. Different biochemical parameters were detected such as total anti-oxidant capacity (TAC), reduced glutathione (GSH), malondialdehyde (MDA), cyclic adenosine monophosphate (cAMP), sirtuin1 (SIRT1), toll like receptor 4 (TLR4), nuclear factor kappa b (NF-κB) and tumor necrosis factor alpha (TNFα). In addition, histopathological features, ovarian weight changes and casapse3 immunoexpression were detected. RESULTS: Data revealed significant increase in ovarian weight changes, MDA, TLR4, TNFα, NF-κB and caspase 3 expressions in OIR induced group. Moreover, OIR group had histopathological features of ovarian damage with depletion of cAMP, SIRT1, TAC and GSH. CONCLUSION: CLZ could ameliorate OIR-induced damage due to PDE inhibition, anti-oxidant, anti-inflammatory and anti-apoptotic properties with modulation of TLR4/NF-κB/TNFα and cAMP/SIRT1 signaling pathways.
Asunto(s)
FN-kappa B , Daño por Reperfusión , Animales , Antioxidantes/farmacología , Cilostazol/farmacología , FN-kappa B/metabolismo , Ratas , Reperfusión , Daño por Reperfusión/tratamiento farmacológico , Sirtuina 1 , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfaRESUMEN
Polycystic ovary syndrome (PCOS) is a very common gynecological disease during childbearing period and markedly affects female fertility. Until now, there are no studies evaluating the possible curative effect of diacerein (DIA) in induced PCOS. For the first time, we aimed in current model to study the effect of DIA (50 mg/kg/day) orally for 3 weeks on experimentally induced PCOS by letrozole (1 mg/kg/day) for 3 weeks. We measured rats' body weight changes, levels of serum insulin, anti-Müllerian hormone (AMH), testosterone, inflammasome, caspase1, and total anti-oxidant capacity (TAC). Moreover, we measured ovarian tissue parameters as malondialdehyde (MDA), interleukin 1ß (IL1ß), real-time polymerase chain reaction (rt-PCR) of Bcl2-associated X protein (Bax), and interleukin 10 (IL10) gene expression changes. Furthermore, histopathological features and anti-apoptotic marker B cell lymphoma 2 (Bcl2) immunoexpression changes were evaluated. Our results showed that letrozole markedly induced PCOS as manifested by significant increase in serum testosterone, insulin, AMH, rats' body weights, ovarian tissue MDA, IL1ß, inflammasome, and caspase1 but decrease of serum TAC. In addition, gene expression of Bax increased but IL10 gene expression decreased. Ovaries showed the typical histopathological changes of PCOS with no immunoexpression of Bcl2. DIA was greatly able to ameliorate letrozole-induced PCOS changes in rats mainly via prevention of IL1ß, and improving metabolic disturbances, and its anti-apoptotic, anti-oxidant, and anti-inflammatory effects with further regulation of inflammasome/caspase1/IL1ß and Bax/Bcl2 pathways.
Asunto(s)
Antraquinonas/farmacología , Antiinflamatorios/farmacología , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Femenino , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Letrozol , Síndrome del Ovario Poliquístico/fisiopatología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Wistar , Proteínas y Péptidos Salivales/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
5-fluorouracil (5-FU) is a widely used chemotherapeutic agent but cardiotoxicity challenges its clinical usefulness. Thus, searching for more cardioprotective drugs is highly required to prevent the accompanied cardiac hazards. Up to date, the different mechanisms involved in 5-FU cardiotoxicity are still unclear and there is no evaluation of bosentan's role in controlling these cardiac complications. This forced us to deeply study and evaluate the possible cardiopreserving properties of bosentan and different mechanisms involved in mediating it. 32 Wistar albino rats were included in our experiment and induction of cardiotoxicity was performed via administration of 5-FU (150 mg/kg) on 5th day of the experiment by intraperitoneal (i.p.) injection with or without co-administration of bosentan (50 mg/kg/day) orally for 7days. Our data revealed that 5-FU could induce cardiotoxicity which was detected as significant increases of troponin I, lactate dehydrogenase (LDH), creatine kinase- MB (CK-MB), endothelin receptors, malondialdehyde (MDA), toll like receptor4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa B (NFκB), and caspase 3 levels. However, there is marked decrease in endothelial nitric oxide synthase (eNOS), reduced glutathione (GSH) and total antioxidant capacity (TAC). In addition, the histopathological examination showed severe toxic features of cardiac injury. Interestingly, co-administration of bosentan could ameliorate 5-FU-induced cardiotoxicity via improving the detected biochemical and histopathological changes besides modulation of TLR4/MyD88/NFκB signaling pathway, eNOS, and endothelin receptors. Bosentan had a significant cardioprotective effect against 5-FU induced cardiac damage. This effect may be attributed to its ability to inhibit endothelin receptors, stimulates eNOS, anti-oxidant, anti-inflammatory, anti-apoptotic properties with modulation of TLR4/MyD88/NFκB signaling pathway.
Asunto(s)
Antimetabolitos Antineoplásicos/toxicidad , Bosentán/farmacología , Antagonistas de los Receptores de Endotelina/farmacología , Fluorouracilo/toxicidad , Cardiopatías/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Receptores de Endotelina/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Cardiotoxicidad , Cardiopatías/inducido químicamente , Cardiopatías/metabolismo , Cardiopatías/patología , Factor 88 de Diferenciación Mieloide/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Receptores de Endotelina/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
PURPOSE: The cardiotoxicity of anticancer drugs such as 5-fluorouracil (5FU) is a major complication that challenges their clinical usefulness. Thus there is a critical need to find new protective drugs to defend against these harmful side effects. Up to now, there have been no studies evaluating the possible cardioprotective effects of fenofibrate (FEN) in 5FU-induced cardiotoxicity. Therefore, we aimed in the current model to evaluate such an effect of FEN and to explore different mechanisms mediating it. METHODS: We used FEN (25, 50, 100 mg/kg/day) administered orally for 7 days with induction of cardiotoxicity by intraperitoneal (i.p.) injection of 5FU (150 mg/kg) on the fifth day. RESULTS: The current study showed that 5FU succeeded in inducing cardiotoxicity, manifested by significantly elevated levels of cardiac enzymes, tissue malondialdehyde (MDA), interleukin 6 (IL-6), signal transducer and activator of transcription 4 (STAT4), and caspase-3. Furthermore, the 5FU group showed toxic histopathological changes including marked cardiac damage and a significant decrease in reduced glutathione (GSH), total antioxidant capacity (TAC), and peroxisome proliferator-activated receptor alpha (PPARα) expression. FEN reversed 5FU-induced cardiotoxicity by various mechanisms including upregulation of PPARα, inhibition of the IL-6/STAT signaling pathway, and anti-inflammatory, antiapoptotic, and antioxidant properties. CONCLUSION: FEN demonstrated a significant cardioprotective effect against 5FU-induced cardiac damage.
Asunto(s)
Fenofibrato , PPAR alfa , Antioxidantes/farmacología , Cardiotoxicidad , Caspasa 3/metabolismo , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Fluorouracilo/toxicidad , Glutatión/metabolismo , Glutatión/farmacología , Glutatión/uso terapéutico , Humanos , Interleucina-6/metabolismo , Malondialdehído/metabolismo , Malondialdehído/farmacología , Estrés Oxidativo , Factor de Transcripción STAT4/metabolismo , Transducción de SeñalRESUMEN
Twisting of the spermatic cord is a common dangerous health problem that may be accompanied with testicular necrosis and infertility. Cilostazol (CLZ) is a selective phosphodiesterase (PDE) 3A inhibitor used for treatment of intermittent claudication. It has a great role in myocardial, spinal cord and hepatic ischaemia/reperfusion. However, till now, there are no researches evaluating its role in testicular ischaemia/reperfusion (TIR). The current work studies its capability to improve TIR induced injury with more concentration on the mechanisms involved in such effect. Four groups of animals were included: sham, TIR induced group, TIR plus CLZ low dose (10â¯mg/kg), TIR plus CLZ high dose (30â¯mg/kg). Our results proved that TIR had significant decrease of the serum ELISA of testosterone, marked disturbances in oxidative stress evaluated parameters as malondialdehyde (MDA), reduced glutathione (GSH), total antioxidant capacity (TAC), ELISA measurement of tumor necrosis factor alpha (TNFα) and interleukin 1 beta (IL1ß) inflammatory mediators, apoptotic marker (caspase3) using western blotting, immunohistochemistry of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). TIR reduced the protective agents as cyclic adenosine monophosphate (cAMP) and sirtuin-1 (SIRT1) by ELISA method with marked germinal cell apoptosis. The biochemical results were confirmed by the histopathological findings that showed marked decrease in both Johnsen's score and Cosentino's score. However, treatment with CLZ significantly reversed the profound TIR damaging effects, on the basis of its anti-inflammatory, anti-oxidant, and anti-apoptotic activities with recuperation of the testicular vascularity. Modulation of HIF/VEGF and cAMP/SIRT1 pathways showed a great role in mediating such effect.
Asunto(s)
Cilostazol/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Enfermedades Testiculares/tratamiento farmacológico , Animales , Western Blotting , Cilostazol/administración & dosificación , AMP Cíclico/análisis , Relación Dosis-Respuesta a Droga , Interleucina-1beta/análisis , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Sirtuina 1/análisis , Torsión del Cordón Espermático/complicaciones , Enfermedades Testiculares/etiología , Testículo/química , Testículo/patología , Testosterona/análisis , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Doxorubicin (DOX) is one of the most widely used chemotherapeutic drugs, but its cardiotoxicity has been shown to be a dose-restricting factor during therapy. Finding new agents for reducing these complications is still in critical need. The current study aimed to evaluate the possible cardioprotective effect of hemin (HEM) in DOX-induced cardiotoxicity and exploring the role of toll like receptor-5/nuclear factor kappa-B/tumor necrosis factor-alpha (TLR-5/NF-κB/TNF-α) and nuclear factor erythroid 2-related factor-2/hemeoxygenase-1 (Nrf-2/HO-1) signaling pathways in mediating such effect. Wistar albino rats were randomly divided into five groups. They were administered DOX by interaperitoneal (i.p.) injection (15 mg/kg) on the 5th day of the experiment with or without HEM in different doses (2.5, 5, 10 mg/kg/day) i.p. for 7 days. Results showed that the DOX group had cardiotoxicity as manifested by a significant increase in cardiac enzymes, malondialdehyde (MDA), TLR-5, NF-κB, TNF-α, and cleaved caspase-3 levels with toxic histopathological changes. Based on these findings, HEM succeeded in reducing DOX-induced cardiotoxicity in a dose-dependent effect by stimulation of Nrf-2/HO-1 and inhibition of TLR-5/NF-κB/TNF-α pathways with subsequent antioxidant, anti-inflammatory, and anti-apoptotic effects.
Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Cardiopatías/prevención & control , Hemo Oxigenasa (Desciclizante)/metabolismo , Hemina/farmacología , Miocitos Cardíacos/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Receptor Toll-Like 5/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Cardiotoxicidad , Modelos Animales de Enfermedad , Doxorrubicina , Cardiopatías/inducido químicamente , Cardiopatías/enzimología , Cardiopatías/patología , Masculino , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Transducción de SeñalRESUMEN
Endometrial hyperplasia (EH) is a common gynecological problem and may progress to carcinoma. Early detection and management of EH are mandatory for the prevention of endometrial cancer. Activation of the renin-angiotensin system and angiotensin II signaling are involved in the progression of precancerous and cancerous lesions. However, no studies have evaluated the role of this system in estradiol benzoate (EB)-induced EH and atypia. Irbesartan (IRB), an angiotensin II receptor blocker with peroxisome proliferator-activated receptor gamma (PPARγ) agonistic activity was administered (30 mg/kg/d) in EB-treated (60 µg/100 g bodyweight, intramuscularly, three times per week) or untreated rats for 4 weeks. Uterine weight changes, malondialdehyde, superoxide dismutase (SOD), tumor necrosis factor-alpha (TNFα), survivin, cleaved caspase 3, interleukin-10 (IL10), and PPARγ were measured in addition to undergoing histopathological examination. Results showed that EB-induced EH and atypia significantly increased the uterine body weight, malondialdehyde, TNFα, and survivin, accompanied with significantly decreased SOD, cleaved caspase 3, IL10, and PPARγ, with typical histopathological changes of EH and atypia. Coadministration of IRB significantly prevented EB-induced biochemical and histopathological changes. The protective effects of IRB may be attributed to its anti-inflammatory and antioxidant properties, reduction of survivin, and increased levels of cleaved caspase 3.
RESUMEN
New hydrazinecarbothioamides with a phenylsulfonyl group were synthesized and their structures were identified by different spectroscopic data (1 H NMR, 13 C NMR, two-dimensional NMR, mass spectrometry, elemental analysis, and single-crystal X-ray analysis). The mechanism describing the formation of the products was also discussed. The antidiabetic activity of the isolated products was investigated histochemically. The synthesized sulfonylalkylthiosemicarbazide exhibited antihyperglycemic activity in streptozotocin-induced diabetic mice. Compounds 5a and 5c significantly lowered the blood glucose level to 103.3 ± 1.8 and 102 ± 3.9 mg/dl, respectively. Also, they caused a significant decrease in malondialdehyde levels and normalized the glutathione levels in streptozotocin-induced diabetic mice, compared with the diabetic group. The results suggest that the synthesized hydrazinocarbothioamides may effectively inhibit the development of oxidative stress in diabetes.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diseño de Fármacos , Hidrazinas/farmacología , Hipoglucemiantes/farmacología , Tioamidas/farmacología , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Hidrazinas/síntesis química , Hidrazinas/química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Masculino , Ratones , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Estreptozocina , Relación Estructura-Actividad , Tioamidas/síntesis química , Tioamidas/químicaRESUMEN
Ischemic heart disease is a common cardiac health problem. Despite the significant advances in prevention and treatment of this disorder, its incidences and complications are very serious. So, the search for more antioxidants and anti-inflammatory agents with cardioprotective effects is an urgent task. We aimed to evaluate the effects of a heme oxygenase 1 (HO1) inducer, hemin (HEM), on isoprenaline (ISO)-induced myocardial damage. Forty-five Wistar albino rats were used. Animals were treated with HEM (25 mg/kg/day) i.p. for 5 days and injected with ISO (150 mg/kg/day) i.p. on 4th and 5th day of the experiment. Detection of the role of ATP-sensitive potassium channel (KATP ) was performed by administration of glibenclamide (GP) (5 mg/kg/day) orally 2 h before HEM. Moreover, the role of endothelial nitric oxide synthase (eNOS) was detected by coadministration of Nitro- ω-L-arginine (L-NNA) (25 mg/kg/day) for 5 days. The ISO group showed increase in heart weight, cardiac enzymes, tumor necrosis factor alpha (TNFα), and malondialdehyde (MDA) with decrease in reduced glutathione (GSH), HO1, and total antioxidant capacity (TAC). In addition, there were increases in Bcl-2 associated X protein (Bax) and cleaved caspase-3, but decreases in B-cell lymphoma-2 (Bcl-2) and eNOS. Moreover, the histopathological examination of the ISO group showed degeneration of the cardiac muscle fibers and marked infiltration of the inflammatory cells. The biochemical and histopathological changes induced by ISO were markedly ameliorated in the HEM plus ISO group. This protective effect was diminished with coadministration of GP or L-NNA; thus, KATP and eNOS might mediate HEM cardioprotection.
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Cardiotónicos/farmacología , Hemina/farmacología , Canales KATP/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Animales , Antioxidantes/metabolismo , Caspasa 3/metabolismo , Hemo-Oxigenasa 1/metabolismo , Isoproterenol/farmacología , Masculino , Malondialdehído/metabolismo , Infarto del Miocardio/inducido químicamente , Miocardio/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Cyclophosphamide (CP) is a widely used chemotherapeutic agent but its clinical usefulness is challenged with different forms of toxicities. No studies have evaluated the possible protective effect of nicorandil (NIC) in CP-induced cardiotoxicity. Our study aimed to investigate this effect by using NIC (3 mg/kg/day) orally for 5 days, in the presence or absence of cardiotoxicity induced by intraperitoneal (i.p.) injection of CP (150 mg/kg) on 4th and 5th days. We confirmed the role of ATP-sensitive potassium channel (KATP) by coadministration of glibenclamide (GP) (5 mg/kg/day) 2 h before NIC (3 mg/kg/day) for 5 days. Moreover, the role of endothelial nitric oxide synthase (eNOS) was confirmed by coadministration of nitro-ω-L-arginine (L-NNA) (25 mg/kg/day) for 5 days. Results showed that CP succeeded in induction of cardiotoxicity which manifested by a significant increase in heart weights, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin I, cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1ß (IL1 ß), and caspase-3 levels. Furthermore, CP group showed toxic histopathological changes of marked cardiac damage in addition to a significant decrease in total antioxidant capacity (TAC), superoxide dismutase (SOD), eNOS gene expression, and B cell lymphoma 2 (Bcl2) immunoexpression. NIC succeeded in reversing CP-induced cardiotoxicity by its potassium channel opening effect, stimulating eNOS gene expression, anti-inflammatory, antiapoptotic, and antioxidant properties. Coadministration of GP or L-NNA could diminish the protective effect of NIC. This proves the important role of KATP and eNOS in mediating such protection.
Asunto(s)
Ciclofosfamida , Cardiopatías/prevención & control , Canales KATP/agonistas , Miocitos Cardíacos/efectos de los fármacos , Nicorandil/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Sustancias Protectoras/farmacología , Animales , Apoptosis/efectos de los fármacos , Cardiotoxicidad , Modelos Animales de Enfermedad , Cardiopatías/inducido químicamente , Cardiopatías/enzimología , Cardiopatías/patología , Mediadores de Inflamación/metabolismo , Canales KATP/metabolismo , Masculino , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Óxido Nítrico Sintasa de Tipo III/genética , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Transducción de Señal , Regulación hacia ArribaRESUMEN
Cadmium (Cd) is a highly toxic heavy metal with several harmful effects including cardiotoxicity. For the first time, we aimed to evaluate the possible cardioprotective effect of carvedilol (CAR) in Cd induced cardiotoxicity and study the mechanisms involved in such protection including endothelial nitric oxide synthase (eNOS) and HO1/Nrf2 pathway. CAR (1,10â¯mg/kg/d) was administered orally for 4 weeks with Cd induced cardiac injury (3â¯mg/kg/d) orally for 4 weeks. We measured cardiac enzymes, mean arterial pressure changes, heme oxygenase-1 (HO1) and total antioxidant capacity (TAC). Moreover; cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), western blotting of caspase3 and eNOS levels and histopathology were evaluated. Immunoexpression of eNOS in cardiac tissue, gene expression changes of HO1, and nuclear factor erythroid 2-related factor 2 (Nrf2) using real time polymerase chain reactions (rtPCR) were detected. Our results showed that CAR could significantly decrease Cd induced cardiotoxicity.
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Cadmio/toxicidad , Cardiotónicos/farmacología , Cardiotoxicidad/metabolismo , Carvedilol/farmacología , Animales , Cardiotónicos/uso terapéutico , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/genética , Carvedilol/uso terapéutico , Hemo Oxigenasa (Desciclizante)/genética , Masculino , Malondialdehído/metabolismo , Miocardio/metabolismo , Miocardio/patología , Factor 2 Relacionado con NF-E2/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
Cisplatin (CP) and doxorubicin (DX) can cause testicular injury by inducing oxidative/nitrosative stress, inflammation, and apoptosis, Naringenin (NG) has antioxidant, antinitrative, anti-inflammatory, and anti-apoptotic effects. This study investigated the potential ability of NG to block gonadotoxicity induced CP and DX in male rats. The rats received one injection of either CP (10 mg/kg, i.p.) or DX (15 mg/kg, i.p.), and treated with NG (50 mg/kg/day, p.o.) for 10 days beginning 6 days prior to CP and DX administration. NG significantly prevented the decreases of serum testosterone and inhibin B in rats received CP and DX. Additionally, NG significantly decreased the elevated testicular malondialdehyde, tumor necrosis factor-α/interleukin-10 ratio, and caspase-3 in CP- and DX-treated rats. NG also significantly raised the decreased testicular Bcl-2/Bax ratio, and total antioxidant status in CP- and DX-challenged rats. In addition, NG significantly increased P-glycoprotein level in testes of rats received CP and DX. Moreover, NG significantly decreased the testicular histopathological injury, and immunohistochemical expression of inducible nitric oxide synthase induced by CP and DX in rat testes. It was concluded that NG impeded gonadotoxicity of CP and DX in male rats by mitigating oxidative stress, nitrosative stress, inflammation, and apoptosis.
Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Doxorrubicina/toxicidad , Flavanonas/farmacología , Sustancias Protectoras/farmacología , Testículo/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Biomarcadores/sangre , Inhibinas/sangre , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Testículo/metabolismo , Testículo/patología , Testosterona/sangreRESUMEN
AIMS: Torsion of the spermatic cord is a common urologic emergency and can lead to testicular necrosis and infertility. Diacerein (DIA) is interleukin-1b (IL-1b) blocker which has a protective role against myocardial ischemia-reperfusion, however, to-date this role has not been investigated in testicular ischemia- reperfusion (TIR). We aimed to investigate the role and mechanism of action of DIA in induced TIR. MAIN METHODS: DIA (50â¯mg/kg) was administered i.m (intramuscular) to rats in the presence or absence of TIR. Testicular weight changes and serum testosterone and total cholesterol levels were evaluated. In addition; the level of testicular tissue reduced glutathione (GSH), malondialdehyde (MDA), total nitrites (NOx) and the activity of superoxide dismutase (SOD) were measured. Histopathology and interleukin1b (IL-1b) immunoexpression were evaluated. KEY FINDINGS: TIR manifested by significant decrease in testicular weight, serum testosterone and testicular tissue GSH levels and SOD activity as well as increase in serum total cholesterol, testicular MDA and NOx levels. TIR showed the histopathological changes of marked testicular damage with increase in IL-1b immunoexpression. DIA was able to normalize both testicular weight, serum testosterone and cholesterol levels with attenuation of oxidative stress parameters along with amelioration of histopathological changes and IL-1 b immunostaining induced by TIR. SIGNIFICANCE: DIA has a protective effect against TIR induced injury in rats mediated by its anti-inflammatory and anti-oxidant activities.