RESUMEN
Antioxidants given concurrently with chemotherapy offer an effective strategy for reducing the negative effects of the drug. One remaining obstacle to the use of doxorubicin (DOX) in chemotherapy is cardiotoxicity. Using vitamin E (Vit. E) as a reference standard, our study focuses on the potential preventive benefits of oxyresveratrol (ORES) and/or dapagliflozin (DAPA) against DOX-induced cardiac injury. Acute cardiotoxicity was noticed after a single intravenous injection of a male rat's tail vein with 10 mg/kg of DOX. Oral doses of ORES (80 mg/kg), DAPA (10 mg/kg), and Vit. E (1 g/kg) were given, respectively. Pretreatment of animals with Vit. E, ORES and/or DAPA revealed a considerable alleviation of heart damage, as evidenced by histopathological change mitigation and a notable drop in serum AST, LDH, CK, CK-MB, and cardiac contents of MDA and NO2-. Also, serum TAC, tissue GSH, and SOD showed substantial increases. Additionally, tissue caspase-3, serum IL-6, and TNF-α were considerably reduced. Moreover, a downregulation in cardiac gene expression of ATG-5, Keap-1, and NF-κB in addition to an upregulation of Bcl-2 gene expression and HO-1, Nrf-2, and PPAR-γ protein expression clearly appeared. Ultimately, ORES and/or DAPA have an optimistic preventive action against severe heart deterioration caused by DOX.
RESUMEN
Hepatic ischemia/reperfusion injury (IRI) is a clinical problem commonly during liver transplantation and other liver surgery. This study aimed to evaluate the protective effect of zafirlukast (ZFK) on IR-induced hepatic injury and investigate its relevant protective mechanism. Thirty-two male Wistar albino rats were randomly allocated to four groups: sham, IRI, ZFK, and ZFK + IR groups. ZFK was administered orally in a dose of 80 mg/kg/day for 10 consecutive days. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL) levels, and gamma glutamyl transferase (GGT) activity were estimated. Liver tissues were used to assess oxidative stress biomarkers including malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NOx), and reduced glutathione (GSH) contents. Inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-33 (IL-33), in addition to apoptosis biomarkers, BCL2 associated X protein (Bax), B-cell lymphoma 2 (Bcl2) and galactine-9 (GAL9) proteins were also assessed. Western blot analysis was performed for vascular endothelial growth factor (VEGF) and fibrinogen expressions. Immunohistochemical analysis for hepatic nuclear factor-kappa B (NF-κB) and SMAD-4 was done in addition to histopathological examination. Our study revealed that ZFK pre-treatment resulted in liver function restoration and oxidative stress correction. Moreover, inflammatory cytokines were significantly reduced and a remarkable reduction of apoptosis, angiogenesis, and clotting formation has been indicated. Additionally, a significant reduction in SMAD-4 and NF-kB protein expressions was observed. These results were supported by hepatic architecture improvement. Our findings revealed that ZFK possesses a potential protective effect against liver IR possibly through its antioxidant, anti-inflammatory and anti-apoptotic properties.
Asunto(s)
FN-kappa B , Daño por Reperfusión , Ratas , Masculino , Animales , FN-kappa B/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratas Wistar , Hígado/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Citocinas/metabolismo , Estrés Oxidativo , Factor de Necrosis Tumoral alfa/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , BiomarcadoresRESUMEN
AIM: Cyclophosphamide (CP) is used to treat a variety of cancers and autoimmune illnesses. CP has been found to frequently cause premature ovarian failure (POF). The study's objective was to assess LCZ696's potential for protection against CP-induced POF in a rat model. MAIN METHODS: Rats were randomly assigned into seven groups as follows: control, valsartan (VAL), LCZ696, CP, CP + VAL, CP + LCZ696, and CP + triptorelin (TRI). Ovarian malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-18 (IL-18), IL-1ß, and tumor necrosis factor-alpha (TNF-α) were assessed using ELISA. Serum anti-mullerian hormone (AMH), estrogen, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also measured using ELISA. The expression of NLRP3/Caspase-1/GSDMD C-NT and TLR4/MYD88/NF-B P65 proteins was estimated using western blot assay. The histopathology of the ovaries was also investigated. The estrous cycle, body, and ovarian weights were also monitored. KEY FINDINGS: CP treatment significantly elevated levels of MDA, IL-18, IL-1ß, TNF-α, FSH, LH, and up-regulated TLR4/NF-κB/NLRP3/Caspase-1 proteins, as compared to the control group, however, ovarian follicles count, and levels of GSH, SOD, AMH, and estrogen were reduced with CP administration. All the aforementioned biochemical and histological abnormalities were considerably alleviated by the LCZ696 therapy compared to valsartan alone. SIGNIFICANCE: LCZ696 effectively mitigated CP-induced POF, offering promising protection that could be related to its suppression power on NLRP3-induced pyroptosis and TLR4/NF-B P65 pathway.
Asunto(s)
Insuficiencia Ovárica Primaria , Animales , Femenino , Ratas , Caspasa 1/metabolismo , Ciclofosfamida/toxicidad , Estrógenos , Hormona Folículo Estimulante , Interleucina-18 , Hormona Luteinizante , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Insuficiencia Ovárica Primaria/prevención & control , Transducción de Señal , Superóxido Dismutasa/metabolismo , Receptor Toll-Like 4 , Factor de Necrosis Tumoral alfa , ValsartánRESUMEN
BACKGROUND: Methotrexate (MTX) is used potently for a wide range of diseases. However, hepatic intoxication by MTX hinders its clinical use. OBJECTIVES: The present study was conducted to investigate the diallyl disulfide (DADS) ability to ameliorate MTX-induced hepatotoxicity. METHODS: Thirty-two rats were randomly divided into four groups: normal control, DADS (50 mg/kg/day, orally), MTX (single i.p. injection of 20 mg/kg) and DADS+MTX. Liver function biomarkers, histopathological examinations, oxidative stress, inflammation, and apoptosis biomarkers were investigated. Besides, an in vitro cytotoxic activity study was conducted to explore the modulatory effects of DADS on MTX cytotoxic activity using Caco-2, MCF-7, and HepG2 cells. RESULTS: DADS significantly reduced the increased serum activities of ALT, AST, ALP, and LDH. These results were confirmed by the alleviation of liver histopathological changes. It restored the decreased GSH content and SOD activity, while significantly decreased MTX-induced elevations in both MDA and NO2 - contents. The hepatoprotective effects were mechanistically mediated through the up-regulation of hepatic Nrf-2 and the down-regulation of Keap-1, P38MAPK, and NF- κB expression levels. In addition, an increase in Bcl-2 level with a decrease in the expression of both Bax and caspase-3 was observed. The in vitro study showed that DADS increased MTX antitumor efficacy. CONCLUSION: DADS potently alleviated MTX-induced hepatotoxicity through the modulation of Keap-1/Nrf-2, P38MAPK/NF-κB and apoptosis signaling pathways and effectively enhanced the MTX cytotoxic effects, which could be promising for further clinical trials.
Asunto(s)
Metotrexato , Factor 2 Relacionado con NF-E2 , Animales , Ratas , Compuestos Alílicos , Apoptosis , Células CACO-2 , Disulfuros , Inflamación/patología , Hígado/metabolismo , Metotrexato/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Estrés OxidativoRESUMEN
Chemotherapeutic drugs are used effectively to manage wide types of malignancies, but their therapeutic use is limited due to their associated hepatic intoxication. The current study sheds light on the effect of phytochemicals berberine (BBR) and umbelliferone (UMB) on methotrexate (MTX)-induced hepatic intoxication. Forty-eight rats were allocated to normal, BBR (50 mg/kg orally for 10 days), UMB (30 mg/kg orally for 10 days), MTX (20 mg/kg at the 5th day), BBR+MTX, and UMB+MTX. With regard to MTX, the results of this investigation reveal potent amelioration of MTX hepatotoxicity by BBR and UMB through reduction of the elevated serum levels of ALT, ALP, AST, and LDH confirmed by the attenuation of histopathological abrasion in liver tissues. BBR and UMB markedly restored antioxidant status. More importantly, BBR resulted in reducing P38 mitogen-activated protein kinase (P38MAPK), nuclear factor kappa-B (NF-κB), and Kelch-like ECH-associated protein 1 (Keap-1) genes and enhanced mRNA expression of Nrf-2 (P < 0.05). Interestingly, in silico studies via molecular docking pinpointed the binding modes of BBR and UMB to the binding pocket residues of P38MAPK, NF-κB, and Keap-1 and demonstrated a promising inhibition of Keap-1, P38MAPK, and NF-κB. BBR and UMB reduced the expression of pro-apoptotic protein Bax and apoptotic protein caspase-3 as well as increased the expression of anti-apoptotic protein Bcl-2. Therefore, BBR and UMB may denote promising therapeutic agents that can avert hepatic intoxication in patients receiving MTX.
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Berberina , Animales , Berberina/farmacología , Humanos , Metotrexato/toxicidad , Simulación del Acoplamiento Molecular , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Fitoquímicos , Ratas , Transducción de Señal , UmbeliferonasRESUMEN
Kidney injury from chemotherapy is one of the worsening problems associated with methotrexate (MTX) use. This work aims to examine the nephroprotective effects of empagliflozin (EMPA) and neohesperidin dihydrochalcone (NHD) provoked by MTX. A rat model was implemented by a single administration of MTX (20 mg/kg, i.p.). EMPA and NHD were administered in two doses (10 and 30 mg/kg, p.o.) and (40 and 80 mg/kg, p.o.), respectively for 14 consecutive days, using N-acetylcysteine (150 mg/kg, p.o.) as a reference standard. Pretreatment with EMPA and NHD showed significant attenuation in the renal function biomarkers, histopathological abrasions, and renal oxidative parameters. Also, EMPA and NHD pretreatment produced marked reductions in the expression of IL-6 and TNF-α level as proinflammatory biomarkers. Furthermore, EMPA and NHD pretreatment revealed marked decreases in the expression level of NF-ĸB, Keap1, HSP70, and caspase-3 and notable increases in Nrf2, PPARγ and HO-1 expression levels. EMPA and NHD can constrain oxidative stress liberation, inflammatory mediators proliferation, and apoptotic reactions in the renal tissue, which may be promising for further clinical applications to protect against MTX-induced renal injury or at least to reduce its adverse effects.
Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Glucósidos/uso terapéutico , Hesperidina/análogos & derivados , Inflamación/tratamiento farmacológico , Enfermedades Renales/prevención & control , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Acetilcisteína/uso terapéutico , Animales , Hesperidina/uso terapéutico , Riñón/efectos de los fármacos , Riñón/patología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Masculino , Metotrexato , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Methotrexate (MTX) is a promising chemotherapeutic agent. Its medical use is limited by induced nephropathy. Our study was designed to explore the reno-protective effect of diallyl disulfide (DADS), an organosulfur compound of garlic oil, on MTX-induced nephropathy. Adult rats were randomly divided into 4 groups; normal control, DADS (50 mg kg-1 day-1 , p.o.), MTX (20 mg/kg, i.p.) and DADS+MTX. DADS significantly decreased serum creatinine, urea, uric acid, and albumin levels with an improvement of final body weight. Additionally, DADS markedly attenuated MTX-induced elevations in renal MDA and NO2- contents with an increase in GSH content and SOD activity. Mechanistically, DADS effectively down-regulated mRNA expression level of renal p38 and NF-κB. Additionally, DADS positively regulated the NRF2 gene with a remarkable inhibition of Keap-1 gene. Furthermore, DADS up-regulated BCL2 protein and remarkably suppressed the expression of both BAX and caspase-3 proteins. Overall, DADS has favorable renal protection against MTX-induced nephropathy via modulation of Keap-1/NRF2, p38/NF-κB, and BCL2/BAX/caspase-3 signaling. PRACTICAL APPLICATIONS: Diallyl disulfide is one of the organosulfur compounds of garlic oil. Our study demonstrated that DADS substantially alleviated the decline of kidney function and renal injury induced by MTX. The antioxidative, anti-inï¬ammatory, and anti-apoptotic properties may constitute an important part of its therapeutic applications via regulation of p38/NF-κB, Keap-1/NRF2, and BCL2/BAX/caspase-3 signaling pathways. Therefore, DADS could be a potential therapeutic adjunct in cancer chemotherapy to decrease the associated side effects of MTX. It should be further explored clinically as a protective agent for MTX-treated cancer patients.
Asunto(s)
Metotrexato , Factor 2 Relacionado con NF-E2 , Compuestos Alílicos , Animales , Disulfuros/farmacología , Disulfuros/uso terapéutico , Humanos , Metotrexato/toxicidad , FN-kappa B/genética , RatasRESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. A reader reported several mistakes in the paper including duplicated images in Figures 9 and 10, incorrect names of primer sequences and reference gene, as well as unclear description of the statistical analysis. The authors requested that a corrigendum be published, however, due to the large number of corrections applied, it cannot be concluded that these changes would not alter the conclusions of the paper. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.
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Antimetabolitos Antineoplásicos/efectos adversos , Compuestos de Bencidrilo/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Glucósidos/uso terapéutico , Hesperidina/análogos & derivados , Metotrexato/efectos adversos , Sustancias Protectoras/uso terapéutico , Animales , Caspasa 3/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Proteínas del Choque Térmico HSP72/metabolismo , Hemo Oxigenasa (Desciclizante)/metabolismo , Hesperidina/uso terapéutico , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
Aims: Epidemiologic studies have shown that individuals with diabetes have a higher risk of hepatic diseases which represent a true clinical problem. The purpose of the present study was to assess the possible modulatory effect of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin on therapeutic efficiency of traditional antidiabetics, as metformin and gliclazide, regarding hepatic complications in streptozotocin (STZ)-induced diabetes in rats.Methods: Animals were divided into seven groups; normal control group, STZ control group (50 mg/kg, i.p., single dose), lovastatin group, metformin group, gliclazide group, lovastatin plus metformin group and lovastatin plus gliclazide group. Serum HMG-CoA reductase, in addition to serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) as hepatocyte integrity loss markers, hepatic tissue thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase as oxidative stress markers, as well as serum tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) and hepatic nitric oxide end products (NOx) as inflammatory markers were assessed, coupled with a confirmatory histopathological study.Results: The combined effect of lovastatin with metformin or gliclazide was significantly better than either drug alone regarding serum AST, ALP and TNF-α, and hepatic TBARS, GSH, GST, SOD and NOx levels.Conclusions: Hepatic complications associated with diabetes could be improved by combination of metformin or gliclazide with lovastatin.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipoglucemiantes/uso terapéutico , Hígado/efectos de los fármacos , Lovastatina/uso terapéutico , Animales , Biomarcadores/metabolismo , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Quimioterapia Combinada , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hipoglucemiantes/administración & dosificación , Hígado/metabolismo , Hígado/patología , Pruebas de Función Hepática , Lovastatina/administración & dosificación , Masculino , Óxido Nítrico/sangre , Ratas , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Aim: Renin-angiotensin system (RAS) is thought to have a noticeable effect in the pathophysiological injury in multiple organs by inducing different cellular and molecular reactions. The objective of the current study is to investigate the possible protective effects of perindopril against lipopolysaccharide (LPS)-induced cardiopulmonary oxidative and inflammatory damage in rats. Methods: To achieve this goal, animals were randomly divided into six groups: normal group, LPS group (3 mg/kg, i.p., single dose), perindopril-LPS treated group (1 mg/kg/day, i.p.), perindopril-LPS treated group (2 mg/kg/day, i.p.), and two perindopril negative groups (perindopril 1 or 2 mg/kg/day, i.p.) alone for seven days. Lungs and hearts tissue angiotensin II (Ang-II), angiotensin-1-7 (Ang-1-7), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were assessed using ELISA. Nuclear factor kappa-B-p65 (NF-κB-p65) was assessed using real time PCR, while protein kinase B (Akt) was evaluated by Western blot analysis. Furthermore, oxidative stress biomarkers and myeloperoxidase (MPO) enzyme were evaluated spectrophotometrically. Tissues inducible and endothelial nitric oxide synthases (iNOS and eNOS) were assessed immunohistochemically. Histopathological study was carried out to confirm our results. Results: LPS-intoxicated rats significantly elevated Ang-II, NF-κB-p65, Akt, and iNOS levels, coupled with significant down-regulation of Ang-1-7 and eNOS levels and corrected the oxidative stress biomarkers. Perindopril administration significantly attenuated the disturbances induced by LPS in a dose-dependent manner. Conclusion: Perindopril mitigates LPS-induced heart and lung damage through modulation of RAS, iNOS/eNOS, Akt, and NF-κB-p65 signaling pathways.
Asunto(s)
Lesiones Cardíacas/tratamiento farmacológico , Lipopolisacáridos/toxicidad , Lesión Pulmonar/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Perindopril/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Lesiones Cardíacas/inducido químicamente , Lesiones Cardíacas/inmunología , Lesiones Cardíacas/patología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/inmunología , Lesión Pulmonar/patología , Masculino , Estrés Oxidativo/inmunología , Ratas , Ratas Wistar , Sistema Renina-Angiotensina/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunologíaRESUMEN
Berberine (BBR) is a natural compound of plant origin belonging to isoquinoline type of alkaloid. Methotrexate (MTX) is an anti-metabolite used widely for a variety of tumors and autoimmune conditions. Clinical uses of MTX were severely limited by its concomitant renal intoxication. The current study was designed to investigate the efficacy of BBR against MTX-induced nephrotoxicity and for exploring the underlying molecular mechanisms through examining the Keap1/Nrf2, NF-κB/P38MAPK and Bax/Bcl2/caspase-3 pathways. Adults male rats were assigned to 4 groups: control, BBR, MTX and MTX + BBR. As compared to MTX-treated group, BBR effectively reduced the serum levels of creatinine, urea, uric acid and kidney/body weight ratio with a remarkable increase in serum level of albumin and the final body weight. Moreover, down-regulation of Keap1, P38MAPK and NF-κB genes along with marked up-regulation of Nrf2 gene were observed. In addition, BBR negatively regulated both Bax and caspase-3 proteins expression along with increased expression of the Bcl2 protein. Also, BBR restored GSH content and SOD activity while it decreased both TBARS and NO2- contents. Biochemical findings confirmed and markedly supported by alleviation of histopathological changes in kidney tissues. Furthermore, MTX cytotoxic activity was markedly enhanced by BBR in vitro using some human cancer cell lines. In conclusion, the current findings indicated that co-administration of BBR with MTX may be a reasonable therapeutic strategy for attenuation of MTX -induced renal damage.
Asunto(s)
Antimetabolitos Antineoplásicos/toxicidad , Berberina/farmacología , Riñón/efectos de los fármacos , Metotrexato/toxicidad , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Humanos , Proteína 1 Asociada A ECH Tipo Kelch , Riñón/patología , Masculino , Metotrexato/administración & dosificación , Metotrexato/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Gentamicin (GNT) is a potent aminoglycoside antibiotic widely used to treat life-threatening bacterial infections. We aim to investigate the potential protective effect of ursodeoxycholic acid (UDCA) against GNT-induced nephrotoxicity. In this study, 24 male Wistar rats were used and randomly divided into four groups of six animals each. Control group received 0.5% carboxymethyl cellulose orally for 15 days, GNT group received GNT 100 mg/kg/day i.p. for 8 days, UDCA group received UDCA orally for 15 consecutive days at a dose of 60 mg/kg/day suspended in 0.5% carboxymethyl cellulose and UDCA-pretreated group received UDCA orally for 7 days then co-administered with GNT i.p. for 8 days at the same fore-mentioned doses. Serum levels of kidney function parameters (urea, creatinine, uric acid and albumin) were measured. Renal tissues were used to evaluate oxidative stress markers; malonaldehyde (MDA), reduced glutathione (GSH) and the anti-oxidant enzyme superoxide dismutase (SOD) activities and nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and kidney injury molecule-1 (KIM-1) mRNA levels. Immunohistochemical expression of endothelial nitric oxide synthase (eNOS) and caspase-3 and histological and ultrastructural examination were performed. Treatment with GNT increased the serum levels of renal function parameters and renal MDA, NF-κB and KIM-1 mRNA levels, while it decreased GSH and SOD activities. Marked immunohistochemical expression of caspase-3 was observed after GNT administration while it decreased eNOS expression. Histological and ultrastructural alterations were also evident in renal corpuscles and tubules. In contrast, pretreatment with UDCA reversed changes caused by GNT administration. These results suggest that UDCA ameliorates GNT-induced kidney injury via inhibition of oxidative stress, inflammation and apoptosis.
Asunto(s)
Caspasa 3/metabolismo , Gentamicinas/efectos adversos , Riñón/patología , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ácido Ursodesoxicólico/farmacología , Animales , Biomarcadores/metabolismo , Riñón/fisiopatología , Riñón/ultraestructura , Pruebas de Función Renal , Peroxidación de Lípido/efectos de los fármacos , Masculino , FN-kappa B/genética , Óxido Nítrico/biosíntesis , Estrés Nitrosativo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/metabolismo , Ratas WistarRESUMEN
Localized tissue renin-angiotensin system (RAS) is an interesting pathway of organ damage. Here, the effect of the brain-penetrating angiotensin converting enzyme (ACE) inhibitor perindopril was studied on lipopolysaccharide (LPS)-induced brain damage, with and without exogenous angiotensin (Ang)-II administration. Animals were divided into 6 groups; a normal control group, an LPS control group (LPS, 3â¯mg/kg, i.p., single dose), two treatment groups receiving perindopril (1 and 2â¯mg/kg/day, i.p.) for 7 days before LPS administration, and two Ang-II/perindopril/LPS groups receiving perindopril and LPS, followed by a single dose of Ang-II solution (5 µl, i.c.v.). Brain tissue Ang-II, Ang-1-7, and NADPH oxidase were estimated using ELISA technique. Nuclear factor kappa-B (NF-ÆB-p65) was estimated using real time PCR technique, while phosphorylated NF-ÆB-p65 (p-NF-ÆB-p65), phosphorylated and non-phosphorylated protein kinase B (p-Akt and Akt) and phosphorylated inhibitor of kappa-B (p-IÆBa) were estimated by western blot analysis. Malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase, nitrite and myloperoxidase (MPO) were estimated colorimetrically. Brain tissue inducible and endothelial nitric oxide synthases (iNOS and eNOS) were estimated immunohistochemically, confirmed by a histopathological study. LPS-intoxicated rats showed significantly elevated Ang-II, NADPH oxidase, NF-ÆB-p65, p-NF-ÆB-p65, p-IÆBa, p-Akt, Akt, p-Akt/Akt ratio, MDA, nitrite, MPO and iNOS levels, coupled with significantly suppressed Ang-1-7, GSH, SOD, GST, catalase, and eNOS levels, which were all corrected by pre-treatment with perindopril in both doses by varying degrees. Exogenous Ang-II significantly ameliorated the protective effects of perindopril. Conclusively, perindopril ameliorates LPS-induced brain damage through modulation of RAS, iNOS/eNOS, p-Akt/Akt and NF-ÆB signaling pathways.
Asunto(s)
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/patología , Lipopolisacáridos/farmacología , Fragmentos de Péptidos/metabolismo , Perindopril/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/metabolismo , Encéfalo/patología , Lesiones Encefálicas/inducido químicamente , Lesiones Encefálicas/metabolismo , Glutatión/metabolismo , Masculino , Malondialdehído/metabolismo , Perindopril/uso terapéutico , Ratas , Ratas Wistar , Factor de Transcripción ReIA/metabolismoRESUMEN
The present study was designed to investigate the potential protective effects of diosmin (DS) and/or sildenafil against bile duct ligation (BDL). In order to achieve this goal, BDL was performed to induce liver cirrhosis, DS (100â¯mg/kg/day, p.o.) and sildenafil (10â¯mg/kg, twice daily, p.o.) were administrated alone or in combination 24â¯h after the surgical operation and lasted for 4 weeks. Liver function biomarkers, fibrotic markers, oxidative stress markers, mRNA expression of NF-κB-p65, P38-MAPK, Nrf-2, and Keap-1, as well as protein expression of cytoglobin, NF-κB-p65, Nrf-2, iNOS and eNOS were investigated concomitantly with histopathological study. The results revealed that, 4 weeks of BDL induced a significant alteration in liver functions, fibrotic and oxidative stress markers. Furthermore, up-regulation of NF-κB-p65, P38-MAPK, Keap-1 and iNOS concomitantly with down-regulation of Nrf-2, cytoglobin and eNOS expressions were observed after BDL. DS and/or sildenafil treatment significantly alleviated the disturbance induced by BDL. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of DS and sildenafil were found to significantly improved liver defects due to BDL as compared to the individual drugs. It can be concluded that, DS and sildenafil exhibit hepatoprotective effects through modulation of Keap-1/Nrf-2 and P38-MAPK/NF-κB/iNOS pathway.
Asunto(s)
Colestasis/tratamiento farmacológico , Diosmina/uso terapéutico , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Hígado/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Transducción de Señal , Citrato de Sildenafil/uso terapéutico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Colestasis/enzimología , Colestasis/metabolismo , Diosmina/farmacología , Quimioterapia Combinada , Cirrosis Hepática/enzimología , Cirrosis Hepática/metabolismo , Masculino , Ratas Wistar , Citrato de Sildenafil/farmacologíaRESUMEN
AIM: The effects of diosmin (DS), pentoxifylline (PTX) and their combination on inflammatory response, oxidant/antioxidant balance, cytoglobin and cirrhotic reaction during bile duct ligation (BDL) were investigated and explored. MAIN METHODS: Fifty adult male Wistar albino rats were randomly allocated to five groups as following, sham: received vehicle only, BDL: subjected to common BDL without treatment, BDL plus DS: received 100â¯mg/kg/day orally, BDL plus PTX: received 50â¯mg/kg/day orally, BDL plus DS plus PTX: received DS and PTX in the same manner. The test period lasted 28â¯days, liver tissues and blood samples were collected to investigate biochemical markers (liver function biomarkers, oxidative stress markers, and antifibrotic markers), mRNA expression of Nrf-2, Keap-1, NF-κB-p65 and p38-MAPK by real-time PCR, protein expression of cytoglobin and NF-κB-p65 by western blot and iNOS and eNOS by immunohistochemistry. Histopathological study was performed to confirm our results. KEY FINDINGS: Chronic BDL induced a significant alteration in liver functions, oxidative stress and fibrotic markers. Furthermore, unfavorable effects on gene and protein expression were observed after BDL. Histopathological findings of this group showed parallel effects. DS, PTX and their combination treatment significantly ameliorated the disturbance that occurred due to BDL. Similar findings were observed in liver histopathology. SIGNIFICANCE: DS and PTX could mitigate liver cirrhosis through modulation of Keap-1/Nrf-2/GSH and NF-κB-p65/p38-MAPK signaling pathways. In addition, we demonstrated that the hepatoprotective effect of DS and PTX is mediated by up-regulation of cytoglobin with inhibition of fibrotic reaction.
Asunto(s)
Diosmina/farmacología , Globinas/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Cirrosis Hepática/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Pentoxifilina/farmacología , Animales , Citoglobina , Progresión de la Enfermedad , Radicales Libres , Perfilación de la Expresión Génica , Inflamación , Hígado/metabolismo , Pruebas de Función Hepática , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oxidantes/metabolismo , Estrés Oxidativo , Ratas , Ratas Wistar , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Nephrotoxicity is the major dose-limiting adverse effect of methotrexate (MTX). Umbelliferone (UMB) is a known coumarin derivative. The current study aimed to investigate possible protective effects of UMB against MTX-induced nephrotoxicity. Adult male albino rats were divided into: control group, UMB group (30 mg/kg, p.o), MTX group (single i.p. injection of 20 mg/kg) and MTX + UMB group. Serum urea and creatinine were evaluated. The renoprotective effects of UMB were evaluated by estimation of renal Nrf-2/Keap-1 and P38MAPK/NF-κB, GSH, MDA, NO2- contents and SOD activity. Moreover, expression of Bcl-2, Bax and caspase-3 were determined. The results demonstrated that UMB significantly reduced serum creatinine and urea levels with alleviations of histopathological abrasions induced by MTX. It limited oxidative stress via lowering both renal MDA and NO2- contents and restoring renal content of reduced GSH and SOD activity with downregulation of Keap-1 and upregulation of Nrf-2. UMB downregulated P38MAPK and NF-κB expression levels. In addition, UMB increased Bcl-2 protein expression while decreasing both Bax and caspase-3 expression levels. Importantly, UMB enhanced the cytotoxic activity of MTX human cancer cell lines. In conclusion, UMB possess marked renoprotective effects against MTX-induced renal damage through modulating oxidative stress, inflammation and apoptosis with enhancement of its cytotoxic activity.
Asunto(s)
Apoptosis/efectos de los fármacos , Riñón/efectos de los fármacos , Metotrexato/toxicidad , Transducción de Señal/efectos de los fármacos , Umbeliferonas/farmacología , Animales , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Riñón/metabolismo , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Ratas , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND AND PURPOSE: So far, there is only limited information about the regulation of the endogenous synthesis of hydrogen sulfide (H(2) S), an important gaseous signalling molecule. This study was done to evaluate the redox-dependent signalling events that regulate the expression of the H(2) S synthesising enzyme cystathionine-γ-lyase (CSE) in rat mesangial cells. EXPERIMENTAL APPROACH: The effects of platelet-derived growth factor (PDGF)-BB and antioxidants on CSE expression and activity in cultured rat renal mesangial cells were assessed. Activity of nuclear factor erythroid-2-related factor-2 (Nrf2) was measured as the binding capacity to a radiolabelled consensus element by electrophoretic mobility shift assay (EMSA). Furthermore, CSE and Nrf2 expression was analysed in a rat model of anti-Thy-1-induced glomerulonephritis by immunohistochemistry. KEY RESULTS: Treatment of mesangial cells with PDGF-BB resulted in a marked time- and dose-dependent up-regulation of CSE mRNA and protein levels, as well as CSE activity accompanied with increased formation of reactive oxygen species. Remarkably, co-administration of antioxidants, such as N-acetylcysteine, ebselen or diphenylene iodonium chloride, drastically reduced PDGF-BB-induced CSE expression. PDGF-BB induced binding of Nrf2 to a corresponding consensus antioxidant element in a redox-dependent manner. Furthermore, PDGF-BB-induced CSE expression in mouse mesangial cells was completely abolished in Nrf2 knockout mice compared with wild-type mice. In a rat model of anti-Thy-1-induced proliferative glomerulonephritis, we observed a marked up-regulation of CSE protein paralleled by a stabilization of Nrf2 protein. CONCLUSIONS AND IMPLICATIONS: PDGF-BB regulated CSE via a redox-mediated activation of Nrf2. Such action would aid the resolution of glomerular inflammatory diseases. LINKED ARTICLE: This article is commented on by Gallyas, pp. 2228-2230 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.01976.x.
Asunto(s)
Cistationina gamma-Liasa/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Células Mesangiales/efectos de los fármacos , Proteínas Proto-Oncogénicas c-sis/farmacología , Animales , Antioxidantes/farmacología , Becaplermina , Células Cultivadas , Cistationina gamma-Liasa/genética , Regulación Enzimológica de la Expresión Génica/fisiología , Glomerulonefritis/inducido químicamente , Glomerulonefritis/metabolismo , Isoanticuerpos/farmacología , Macrófagos , Células Mesangiales/enzimología , Ratones , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Oxidación-Reducción , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Bazo/citologíaRESUMEN
In the present study, we have addressed the possible protective role of acetyl-L-carnitine in caerulein-induced acute pancreatitis in male Swiss albino rats. Acute pancreatitis paradigm was developed by challenging animals with a supramaximal dose of caerulein (20 microg/kg, SC) four times at hourly intervals. Caerulein induced acute pancreatitis that was well-characterized morphologically and biochemically. Severe oedema with marked increased relative pancreatic weight, marked atrophy of acini with increased interacinar spaces, vacuolization, and extensive leucocytic infiltration were diagnostic fingerprints of the pancreatitis phenotype. A biochemical test battery that confirmed the model comprised increased plasma amylase and lipase activities, calcium levels as well as increased pancreatic enzymatic myeloperoxidase and glutathione-S-transferase activities, beside increased pancreatic contents of nitric oxide and malondialdehyde and reduced pancreatic glutathione level. Prior administration of acetyl-L-carnitine (200 mg/kg, IP) for seven consecutive days ahead of caerulein challenge alleviated all the histological and biochemical manifestations of acute pancreatitis. These results suggest a possible protective role of the carnitine ester in such a murine acute pancreatitis model probably via regulation of the oxidant/antioxidant balance, beside modulation of the myeloperoxidase and nitric oxide systems, which are involved in the inflammatory cascade that most often associate the disease.