RESUMEN
This study aimed to evaluate the possible ameliorative effects of saroglitazar (SAR) on aspects of hepatic injury in dexamethasone (DEX)-induced nonalcoholic steatohepatitis (NASH) in rats. Wistar rats received SAR (2 or 4 mg/kg/day, orally) or metformin (MET, 500 mg/kg/day, orally) for one week before and concurrently with DEX administration (8 mg/kg/day, i.p., for 6 days. Control and drug control groups received vehicle or the higher dose of SAR, respectively. At the end of the experiment, an oral glucose tolerance test (OGTT) was conducted, serum hepatic function parameters and lipid profile were assessed, and hepatic histological changes were evaluated. Moreover, hepatic p-Akt/Akt ratios, malondialdehyde (MDA) content, SREBP-1, FOXO1, LC3, cleaved caspase-3, and p-MLKL protein levels were determined. Furthermore, hepatic immunohistochemical expressions of FOXO1, caspase-3, Bcl-2, LC3, and P62 were examined. SAR (mainly at 4 mg/kg/day) significantly improved Area under the OGTT curve (P < 0.0001), hepatic function parameters, lipid profile, and hepatic histopathological features in DEX-administered rats. Moreover, SAR significantly attenuated DEX-induced increases in hepatic MDA content (P < 0.05), SREBP-1 levels (P < 0.0001), and nuclear FOXO1, caspase-3, LC3, P62, and p-MLKL protein expressions (P < 0.0001). Furthermore, SAR significantly enhanced hepatic p-Akt/Akt ratio and Bcl-2 protein expression in DEX-administered rats (P < 0.0001). The higher dose of SAR showed greater hepatoprotective effects compared to its corresponding lower dose and MET in most assessments, approaching levels similar to the control group. SAR mitigated hepatic injury associated with DEX-induced NASH in rats, suggesting it might be a potential hepatoprotective drug for patients with or at high risk of NASH.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Fenilpropionatos , Pirroles , Humanos , Ratas , Animales , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Caspasa 3 , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Necroptosis , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Dexametasona/farmacología , Lípidos , AutofagiaRESUMEN
PURPOSE: This research was designed to investigate the effects and mechanisms of flavocoxid (FCX) on vascular calcification (VC) in rats. METHODS: Vitamin D3 and nicotine were administered to Wistar rats, which then received FCX (VC-FCX group) or its vehicle (VC group) for 4 weeks. Control and FCX groups served as controls. Systolic (SBP) and diastolic (DBP) blood pressures, heart rate (HR), and left ventricular weight (LVW)/BW were measured. Serum concentrations of calcium, phosphate, creatinine, uric acid, and alkaline phosphatase were determined. Moreover, aortic calcium content and aortic expression of runt-related transcription factor (Runx2), osteopontin (OPN), Il-1ß, α-smooth muscle actin (α-SMA), matrix metalloproteinase-9 (MMP-9), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α) were assessed. Oxidative status in aortic homogenates was investigated. RESULTS: Compared to untreated VC rats, FCX treatment prevented body weight loss, reduced aortic calcium deposition, restored normal values of SBP, DBP, and HR, and attenuated LV hypertrophy. FCX also improved renal function and ameliorated serum levels of phosphorus, calcium, and ALP in rats with VC. FCX abolished aortic lipid peroxidation in VC rats. Moreover, VC-FCX rats showed marked reductions in aortic levels of Il-1ß and osteogenic marker (Runx2) and attenuated aortic expression of TNF-α, iNOS, and MMP-9 proteins compared to untreated VC rats. The expression of the smooth muscle lineage marker α-SMA was greatly enhanced in aortas from VC rats upon FCX treatment. CONCLUSION: These findings demonstrate FCX ability to attenuate VDN-induced aortic calcinosis in rats, suggesting its potential for preventing arteiocalcinosis in diabetic patients and those with chronic kidney disease.
Asunto(s)
Nicotina , Calcificación Vascular , Ratas , Animales , Nicotina/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismo , Ratas Sprague-Dawley , Metaloproteinasa 9 de la Matriz/metabolismo , Calcio , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas Wistar , Calcificación Vascular/inducido químicamente , Calcificación Vascular/tratamiento farmacológico , Calcificación Vascular/prevención & control , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismoRESUMEN
Design, synthesis and pharmacological activities of a group of 1,3,5-trisubstituted pyrazolines were reported. The chemical structures of the synthesized compounds have been assigned on the basis of IR, MS, (1)H NMR, and (13)C NMR spectral analyses. The synthesized 1,3,5-trisubstituted pyrazoline derivatives were evaluated in vivo for anti-inflammatory, analgesic activities and in vitro for COX-1/2 inhibition assay. Among the tested compounds, derivatives 4h, 6e, 7a, 7e, and 9 showed more potent anti-inflammatory and analgesic activities than the reference drug celecoxib. On the basis of their higher activities in the in vivo studies compared with celecoxib, the five compounds 4h, 6e, 7a, 7e and 9 were selected to test their inhibitory activities against ovine COX-1/2 using an in vitro cyclooxygenase inhibition assay. Docking study of compounds 7a, 7e and 9 into the COX-2 binding site revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Ciclooxigenasa 1/efectos de los fármacos , Pirazoles/farmacología , Analgésicos/síntesis química , Animales , Antiinflamatorios/síntesis química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Simulación del Acoplamiento Molecular , Pirazoles/síntesis química , RatasRESUMEN
Both human ether-à-go-go-related gene (hERG1) and the closely related human ether-à-go-go (hEAG1) channel are aberrantly expressed in a large proportion of human cancers. In the present study, we demonstrate that transfection of hERG1 into mouse fibroblasts is sufficient to induce many features characteristic of malignant transformation. An important finding of this work is that this transformation could be reversed by chronic incubation (for 2-3 weeks) with the hERG channel blocker dofetilide (100 nM), whereas more acute applications (for 1-2 days) were ineffective. The hERG1 expression resulted in a profound loss of cell contact inhibition, multiple layers of overgrowing cells, and high saturation densities. Cells also changed from fibroblast-like to a more spindle-shaped morphology, which was associated with a smaller cell size, a dramatic increase in cell polarization, a reduction in the number of actin stress fibers, and less punctate labeling of focal adhesions. Analysis of single-cell migration and scratch-wound closure clearly demonstrated that hERG1-expressing cells migrated more rapidly than vector-transfected control cells. In contrast to previous studies on hEAG1, there were no increases in rates of proliferation, or loss of growth factor dependency; however, hERG1-expressing cells were capable of substrate-independent growth. Allogeneic transplantation of hERG1-expressing cells into nude mice resulted in an increased incidence of tumors. In contrast to hEAG1, the mechanism of cellular transformation is dependent on ion conduction. Trafficking-deficient and conduction-deficient hERG1 mutants also prevented cellular transformation. These results provide evidence that hERG1 expression is sufficient to induce cellular transformation by a mechanism distinct from hEAG1. The most important conclusion of this study is that selective hERG1 channel blockers have therapeutic potential in the treatment of hERG1-expressing cancers.
Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Actinas/metabolismo , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Fibroblastos/efectos de los fármacos , Adhesiones Focales/metabolismo , Humanos , Ratones , Ratones Desnudos , Células 3T3 NIH , Fibras de Estrés/metabolismo , TransfecciónRESUMEN
Several in vivo and in vitro studies reported a favorable effect of piperine (PIP) on vascular function. However, the potential impacts of PIP on macrovasculopathy in streptozotocin (STZ)-diabetic rats have not yet been studied. Thirty-two Sprague Dawley rats were used (n= 8/group). STZ-administered rats (50 mg/kg once, i.p) received PIP (30 mg/kg/day, orally) or its vehicle starting from day 15 till the end of the study (10 weeks). Control groups consisted of age-matched normal rats with or without PIP treatment. Metabolic and oxidative stress parameters were biochemically determined. Aortas were histologically examined. Ex vivo aortic reactivity to phenylephrine and acetylcholine was studied. Components of the TXNIP-NLRP3 pathway were assessed using real-time PCR, ELISA, and immunohistochemistry. Two-way ANOVA was used to compare groups. Statistical significance was set at P < 0.05. PIP treatment of diabetic rats significantly reduced levels of fasting glycemia, HbA1c, and serum AGEs, TGs, TC, and LDL-C compared to control diabetic group. PIP diminished aortic endothelial denudation and fibrous tissue proliferation compared to control STZ aortas. PIP lessened aortic contractility to phenylephrine and improved aortic relaxation to acetylcholine relative to untreated STZ group. PIP administration to diabetic rats elicited significant enhancements in GSH and SOD levels, eNOS expression, and total nitrate/nitrite bioavailability compared to untreated STZ rats. Moreover, PIP attenuated aortic contents of ROS, MDA, TXNIP protein and mRNA, NF-κB p65 mRNA, NLRP3 mRNA, IL-1ß protein, and caspase-3 and TNF-α expressions compared to untreated STZ levels. In conclusion, PIP might ameliorate diabetes-associated functional and structural aortic remodeling by targeting TXNIP-NLRP3 signaling.
Asunto(s)
Diabetes Mellitus Experimental , Enfermedades Vasculares , Ratas , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas Sprague-Dawley , Inflamasomas/metabolismo , Estreptozocina , Diabetes Mellitus Experimental/metabolismo , Acetilcolina , FN-kappa B/metabolismo , Aorta/metabolismo , Fenilefrina , Proteínas de Ciclo CelularRESUMEN
This work aimed to investigate a possible mechanism that may mediate the hepatoprotective effects of pomegranate fruit extract (PFE) against thioacetamide (THIO)-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly allocated into four groups (n = 8 each): control; PFE (150 mg/kg/day, orally); THIO (200 mg/kg, i.p, 3 times a week); and THIO and PFE-treated groups. Oral PFE treatment decreased liver/body weight ratio by 12.4%, diminished serum function levels of ALT, AST, ALP, LDH, and total bilirubin, increased serum albumin, boosted hepatic GSH (by 35.6%) and SOD (by 17.5%), and significantly reduced hepatic levels of ROS, MDA, 4-HNE, AGEs, and RAGE in THIO-fibrotic rats relative to untreated THIO group. Moreover, PFE administration downregulated the hepatic levels of profibrotic TGF-ß1 (by 23.0%, P < 0.001) and TIMP-1 (by 41.5%, P < 0.001), attenuated α-SMA protein expression, decreased serum HA levels (by 41.3%), and reduced the hepatic levels of the fibrosis markers hydroxyproline (by 26.0%, P < 0.001), collagen type IV (by 44.3%, P < 0.001) and laminin (by 43.4%, P < 0.001) compared to the untreated THIO group. The histopathological examination has corroborated these findings, where PFE decreased hepatic nodule incidence, attenuated portal necroinflammation and reduced extent of fibrosis. These findings may suggest that oral PFE administration could slow the progression of hepatic fibrogenesis via reducing hepatic levels of AGEs, RAGE, ROS, TGF-ß1, and TIMP-1.
RESUMEN
The current work explored the influences of nifuroxazide, an in vivo inhibitor of signal transducer and activator of transcription-3 (STAT-3) activation, on tubulointerstitial fibrosis in rats with obstructive nephropathy using unilateral ureteral obstruction (UUO) model. Thirty-two male Sprague Dawley rats were assigned into 4 groups (n = 8/group) at random. Sham and UUO groups were orally administered 0.5% carboxymethyl cellulose (CMC) (2.5 mL/kg/day), while Sham-NIF and UUO-NIF groups were treated with 20 mg/kg/day of NIF (suspended in 0.5% CMC, orally). NIF or vehicle treatments were started 2 weeks after surgery and continued for further 2 weeks. NIF treatment ameliorated kidney function in UUO rats, where it restored serum creatinine, blood urea, serum uric acid and urinary protein and albumin to near-normal levels. NIF also markedly reduced histopathological changes in tubules and glomeruli and attenuated interstitial fibrosis in UUO-ligated kidneys. Mechanistically, NIF markedly attenuated renal immunoexpression of E-cadherin and α-smooth muscle actin (α-SMA), diminished renal oxidative stress (↓ malondialdehyde (MDA) levels and ↑ superoxide dismutase (SOD) activity), lessened renal protein expression of phosphorylated-STAT3 (p-STAT-3), phosphorylated-Src (p-Src) kinase, the Abelson tyrosine kinase (c-Abl) and phosphorylated nuclear factor-kappaB p65 (pNF-κB p65), decreased renal cytokine levels of transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and monocyte chemoattractant protein-1 (MCP-1) and reduced number of cluster of differentiation 68 (CD68) immunolabeled macrophages in UUO renal tissues, compared to levels in untreated UUO kidneys. Taken together, NIF treatment suppressed interstitial fibrosis in UUO renal tissues, probably via inhibiting STAT-3/NF-κB signaling and attenuating renal oxidative stress and inflammation.
Asunto(s)
Fibrosis/metabolismo , Hidroxibenzoatos/farmacología , Nitrofuranos/farmacología , Animales , Fibrosis/tratamiento farmacológico , Hidroxibenzoatos/metabolismo , Inflamación , Riñón/patología , Enfermedades Renales/patología , Masculino , FN-kappa B/metabolismo , Nitrofuranos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Obstrucción Ureteral/patología , Ácido Úrico/metabolismoRESUMEN
This research aimed to investigate the reno-protective impact of the tyrosine kinase inhibitor dasatinib (DAS) against renal fibrosis induced by unilateral ureteral obstruction (UUO) in rats. DAS administration improved renal function and mitigated renal oxidative stress with paralleled reduction in the ligated kidney mass index, significant retraction in renal histopathological alterations and suppression of renal interstitial fibrosis. Nevertheless, DAS administration attenuated renal expression of phosphorylated Src (p-Src), Abelson (c-Abl) tyrosine kinases, nuclear factor-kappaB (NF-κB) p65, and phosphorylated signal transducer and activator of transcription-3 (p-STAT-3)/STAT-3 with paralleled reduction in renal contents of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and monocyte chemoattractant protein-1 (MCP-1). DAS diminished interstitial macrophage infiltration and decreased renal profibrotic transforming growth factor-ß1 (TGF-ß1) levels and suppressed interstitial expression of renal α-smooth muscle actin (α-SMA) and fibronectin. Collectively, DAS slowed the progression of renal interstitial fibrosis, possibly via attenuating renal oxidative stress, impairing Src/STAT-3/NF-κB signaling, and reducing renal inflammation.
Asunto(s)
Dasatinib/uso terapéutico , Sustancias Protectoras/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Obstrucción Ureteral/tratamiento farmacológico , Animales , Citocinas/inmunología , Dasatinib/farmacología , Modelos Animales de Enfermedad , Fibrosis , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-abl/metabolismo , Ratas Sprague-Dawley , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Obstrucción Ureteral/inmunología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patología , Familia-src Quinasas/metabolismoRESUMEN
This work explored influences of protocatechuic acid (PCA) on type 2 diabetes (T2D)-associated hepatic insulin resistance and other metabolic, hepatic and vascular irregularities using the rat model of high fat diet (HFD)+high fructose+low dose streptozotocin (STZ). Twenty-four male Wister rats were used. Twelve rats were ad libitum supplied with HFD and high fructose drinking water (25 % w/v) for 60 days. On day 30, they received a single injection of STZ (35 mg/kg, i.p). On day 32, they were divided into two subgroups (n = 6/each): T2D + PCA, received PCA (100 mg/kg/day, orally) and T2D, received PCA vehicle till the end of experiment. Rats provided with regular diet and fructose-free drinking water, with or without PCA treatment, served as PCA and control groups (n = 6/each), respectively. PCA treatment significantly reduced the elevated levels of fasting glycemia and insulin, AUCOGTT, AUCITT, and HOMA-IR index, while it boosted HOMA-ß and insulinogenic index values in T2D rats. PCA ameliorated serum lipid levels and hepatic function parameters and mitigated hepatosteatosis in T2D rats. Mechanistically, PCA mitigated hepatic lipid peroxidation and restored reduced glutathione (GSH) and superoxide dismutase (SOD) to near-normal levels. Moreover, PCA enhanced hepatic protein levels of P-AKTser473 and hepatic mRNA expression of insulin receptor substrate 1 (IRS1), phosphatidylinositol 3 kinase (PI3K)-p85 and AKT2. Furthermore, PCA ameliorated aortic oxidative stress in T2D rats, possibly via reducing serum levels of advanced glycation end products (AGEs) and diminishing vascular expression of RAGE and NOX4 mRNA. Collectively, PCA may improve hepatic insulin resistance and vascular oxidative status by modulating IRS1/PI3K/AKT2 and AGE-RAGE-NOX4 pathways, respectively.
Asunto(s)
Aorta Torácica/efectos de los fármacos , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hidroxibenzoatos/farmacología , Resistencia a la Insulina , Hígado/efectos de los fármacos , Animales , Aorta Torácica/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Productos Finales de Glicación Avanzada/sangre , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Hígado/metabolismo , Masculino , NADPH Oxidasa 4/genética , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Ratas Wistar , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
This study was undertaken to investigate the possible ameliorative influences of febuxostat (FEB) on vitamin D3 plus nicotine (VDN)-induced vascular calcification (VC) in Wistar rats. VDN rats received a single dose of vitamin D3 (300.000 IU/kg, I.M) and two oral doses of nicotine (25 mg/kg) on day 1. They were then administrated FEB, in two doses (10 and 15 mg/kg/day, orally), or the drug vehicle, for 4 weeks. Age-matched normal rats served as control. At the end of the experiment, body weight, kidney function parameters, serum ionic composition, cardiovascular measures, aortic calcium deposition and aortic levels of oxidative stress markers, interleukin 1ß (IL-1ß), runt-related transcription factor 2 (Runx2) and osteopontin (OPN) were determined. Aortic immunoexpressions of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP-9) and α-smooth muscle actin (α-SMA) were evaluated. FEB significantly restored body weight loss, ameliorated kidney function and diminished serum disturbances of calcium and phosphorus in VDN rats. Moreover, FEB reduced VDN-induced elevations in aortic calcium deposition, SBP and DBP. FEB (15 mg/kg) markedly decreased left ventricular hypertrophy and bradycardia in VDN group. Mechanistically, FEB dose-dependently improved oxidative damage, decreased levels of IL-1ß and Runx2, lessened expression of TNF-α, iNOS and MMP-9 and enhanced expression of OPN and α-SMA in VDN aortas relative to controls. These findings indicate that FEB, mainly at the higher administered dose (15 mg/kg), successfully attenuated VDN-induced VC. FEB may be useful in reducing VC in patients at high risk, including those with chronic kidney disease and diabetes mellitus.
Asunto(s)
Colecalciferol , Calcificación Vascular , Animales , Febuxostat , Humanos , Nicotina , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Calcificación Vascular/inducido químicamente , Calcificación Vascular/tratamiento farmacológicoRESUMEN
Vascular complications are a leading cause of morbidity and mortality among diabetic patients. This work aimed to investigate possible influences of dimethyl fumarate (DMF) on streptozotocin (STZ) diabetes-associated vascular complications in rats, exploring its potential to modulate ROS-TXNIP-NLRP3 inflammasome pathway. Two weeks after induction of diabetes (via a single injection of 50 mg/kg STZ, i.p.), diabetic rats were administered either DMF (25 mg/kg/day) or its vehicle for further eight weeks. Age-matched normal and DMF-administered non-diabetic rats served as controls. DMF treatment elicited a mild ameliorative effect on diabetic glycemia. DMF reduced serum TG and AGE levels and enhanced serum HDL-C concentrations in diabetic rats. Moreover, DMF significantly diminished aortic levels of ROS and MDA and restored aortic GSH, SOD and Nrf2 to near-normal levels in STZ rats. Aortic mRNA levels of TXNIP, NLRP3 and NF-κB p65 in diabetic rats were significantly reduced by DMF treatment. Serum and aortic protein levels of TXNIP and aortic contents of IL-1ß, iNOS, NLRP3 and TGF-ß1 were significantly lower in DMF-diabetic animals than non-treated diabetic rats. Furthermore, protein expression of TNF-α and caspase-3 in diabetic aortas was greatly attenuated by DMF administration. DMF enhanced eNOS mRNA and protein levels and increased bioavailable NO in diabetic aortas. Functionally, DMF attenuated contractile responses of diabetic aortic rings to KCl and phenylephrine and enhanced their relaxant responses to acetylcholine. DMF also mitigated diabetes-induced fibrous tissue proliferation in aortic tunica media. Collectively, these findings demonstrate that DMF offered vasculoprotective influences on diabetic aortas via attenuation of ROS-TXNIP-NLRP3 inflammasome pathway.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Angiopatías Diabéticas/tratamiento farmacológico , Angiopatías Diabéticas/metabolismo , Dimetilfumarato/uso terapéutico , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Aorta/metabolismo , Aorta/patología , Biomarcadores/metabolismo , Caspasa 3/metabolismo , Proteínas de Ciclo Celular/sangre , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Angiopatías Diabéticas/sangre , Dimetilfumarato/farmacología , Interleucina-1beta/metabolismo , Masculino , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oxidación-Reducción , Ratas Sprague-Dawley , Estreptozocina , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Bleomycin (BLM) is one of the most common anti-cancer drugs used to treat numerous types of tumors. However, pulmonary toxicity is considered the most dramatic effect of BLM. Therefore, BLM has been frequently used for induction of pulmonary fibrosis. This study aimed to evaluate the effect of nicorandil on BLM-induced pulmonary fibrosis and explore the possible mechanisms. BLM was instilled intratracheally into male Sprague-Dawley rats as a single dose (5 mg/kg) and oral nicorandil was given (30 mg/kg/day) for 6 weeks after BLM challenge. At the end of experimental period, rats were sacrificed, and lung histopathology and biochemical parameters were evaluated. Nicorandil therapy attenuated lung inflammation and fibrosis elicited by BLM. Nicorandil significantly reduced total protein content, lactate dehydrogenase (LDH) activity and total and differential cell counts. Moreover, nicorandil diminished lung levels of malondialdehyde and total nitrite/nitrate, in addition to increasing lung contents of reduced glutathione and superoxide dismutase activity. Nicorandil reduced lung and bronchoalveolar lavage fluid contents of hypoxia inducible factor-1α (HIF-1α) and lung content of thioredoxin-interacting protein (TXNIP). Besides, nicorandil significantly improved histological lesions and reduced collagen deposition as well as hydroxyproline content. Immunohistochemical examination revealed that nicorandil-treated rats exhibited significant diminutions in protein expression levels of transforming growth factor beta-1(TGF-ß1) and inducible nitric oxide synthase (iNOS) and enhanced pulmonary protein expression of endothelial NOS (eNOS). In conclusion, these results illustrate the possible potential effects of nicorandil for managing pulmonary fibrosis caused by BLM.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Bleomicina/toxicidad , Proteínas de Ciclo Celular/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Nicorandil/farmacología , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Fibrosis Pulmonar/inducido químicamente , Animales , Líquido del Lavado Bronquioalveolar/química , Proteínas de Ciclo Celular/análisis , Subunidad alfa del Factor 1 Inducible por Hipoxia/análisis , L-Lactato Deshidrogenasa/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Nicorandil/uso terapéutico , Nitratos/análisis , Óxido Nítrico/análisis , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Nitritos/análisis , Fibrosis Pulmonar/tratamiento farmacológico , Ratas , Ratas Sprague-DawleyRESUMEN
The purpose of this work was to compare the influences of sulforaphane (SFN) to those of the standard insulin sensitizer pioglitazone (PIO) on high fructose diet (HFrD)-induced insulin resistance, dyslipidemia, hepatosteatosis, and vascular dysfunction in rats. Male Sprague Dawley rats (150-200 g) were fed on a standard diet (control) or a high fructose diet (HFrD, 60% w/w fructose) for 60 days. From day 16, two subgroups of HFrD-fed rats received either SFN (0.5 mg/kg/day, orally) or PIO (5 mg/kg/day, orally) along with HFrD until the end of the experiment. Fructose-fed rats showed significant decreases in food intake, body weight and feeding efficiency; effects that were not altered by either treatment. Data from insulin tolerance test (ITT), oral glucose tolerance test (OGTT), and HOMA-IR and HOMA-ß indices demonstrated impaired insulin sensitivity and glucose utilization in HFrD-fed rats. SFN and PIO treatments significantly reduced OGTTAUC (Glass's Delta values = 1.12 and 0.84, respectively), decreased ITTAUC (Glass's Delta values = 1.05 and 0.71, respectively), significantly diminished HOMA-IR index (by 55.6% and 77.6%, respectively), and increased HOMA-ß value (by 1.8 and 1.3 fold, respectively) compared to the HFrD rats. Moreover, SFN and PIO ameliorated hepatic oxidative stress and reduced serum levels of C-reactive protein and lactate dehydrogenase in HFrD-fed rats. Furthermore, SFN and PIO administrations improved insulin resistance-associated heaptosteatosis and enhanced vascular responsiveness to acetylcholine-induced relaxations. However, only SFN was able to enhance serum HDL-C levels in HFrD group. These finding suggests that SFN elicited insulin-sensitizing, hepatoprotective, and vasculoprotective effects in HFrD insulin-resistant rats that were comparable to those exerted by PIO.
Asunto(s)
Aorta Torácica/efectos de los fármacos , Dislipidemias/tratamiento farmacológico , Hígado Graso/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Isotiocianatos/uso terapéutico , Pioglitazona/uso terapéutico , Animales , Aorta Torácica/fisiología , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Proteína C-Reactiva/análisis , Dislipidemias/sangre , Dislipidemias/patología , Hígado Graso/sangre , Hígado Graso/patología , Fructosa/administración & dosificación , L-Lactato Deshidrogenasa/sangre , Masculino , Ratas Sprague-Dawley , SulfóxidosRESUMEN
This research was conducted to investigate possible protective influences of levocetirizine, a nonsedating H1 antihistamine, against lipopolysaccharide (LPS)-induced lung injury in rats. Male Sprague Dawley rats received either levocetirizine (1 mg/kg/day, orally) or the vehicle of the drug (2 ml/kg/day, orally) for 1 week before a single IP injection of LPS (7.5 mg/kg). A group of normal rats served as control. The experiments were terminated 18 h after the LPS challenge. Serum C-reactive protein levels were determined. Moreover, total cell count, lactate dehydrogenase (LDH) activity, protein levels, and total NOx were evaluated in bronchoalveolar lavage fluid (BALF). Pulmonary edema was evaluated as the wet/dry lung weight ratio. Lung tissue homogenate was assessed for antioxidant/pro-oxidant status. BALF and lung tissue levels of tumor necrosis factor-α (TNF-α) were assessed. Lungs were examined for histological alterations. LPS-mediated lung injury was manifested by pulmonary edema, leukocyte infiltration, oxidative stress, and inflammation. Levocetirizine attenuated lung edema and mitigated the increases in BALF protein levels, LDH activity, and lung leukocyte recruitment in LPS-challenged rats. Additionally, TNF-α protein levels in BALF and lung tissue were diminished by levocetirizine administration. Levocetirizine also exhibited a potent antioxidant activity as indicated by a decrease in lung tissue levels of malondialdehyde and an enhancement of superoxide dismutase activity. Histological examination of lung tissues confirmed the beneficial effect of levocetirizine against LPS-induced histopathological alterations. In conclusion, levocetirizine may offer protection against lung tissue damage and inflammation in LPS-challenged rats.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Cetirizina/farmacología , Antagonistas de los Receptores Histamínicos H1 no Sedantes/farmacología , Inflamación/tratamiento farmacológico , Pulmón/inmunología , Animales , Líquido del Lavado Bronquioalveolar , Lipopolisacáridos , Pulmón/patología , Masculino , Neumonía , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfaRESUMEN
The effects of cinnamaldehyde (CIN), a commonly consumed food flavor, against high-cholesterol diet (HCD)-induced vascular damage in rabbits were evaluated. Male New Zealand rabbits (n = 24) were allocated to four groups at random: control, fed with standard rabbit chow; CIN, fed with standard diet and administered CIN; HCD, fed with 1% cholesterol-enriched diet; and HCD-CIN, fed with HCD and treated with CIN. CIN was orally given at a dose of (10 mg/kg/day) concomitantly with each diet type from day 1 until the termination of the experimental protocol (4 weeks). HCD elicited significant elevations in serum levels of total cholesterol (TC), triglycerides (TGs), and high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively) compared with control rabbits. Moreover, aortic levels of nitric oxide metabolites (NOx) and antioxidant enzyme activities were significantly lower, while aortic levels of malondialdehyde (MDA) and myeloperoxidase (MPO) activity were significantly higher, in HCD-fed rabbits relative to control animals. CIN administration mitigated or completely reversed HCD-induced metabolic alterations, vascular oxidative stress, and inflammation. Moreover, CIN ameliorated HCD-induced vascular functional and structural irregularities. Aortic rings from HCD-CIN group showed improved relaxation to acetylcholine compared to aortas from HCD group. Moreover, CIN decreased atherosclerotic lipid deposition and intima/media (I/M) ratio of HCD aortas. CIN-mediated effects might be related to its ability to attenuate the elevated aortic mRNA expression of cholesteryl ester transfer protein (CETP) and MPO in HCD group. Interestingly, the vasculoprotective effects of CIN treatment in the current study do not seem to be mediated via Nrf2-dependent mechanisms. In conclusion, CIN may mitigate the development of atherosclerosis in hypercholestrolemic rabbits via cholesterol-lowering, antiinflammatory and antioxidant activities.
Asunto(s)
Acroleína/análogos & derivados , Hipercolesterolemia/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Acroleína/farmacología , Acroleína/uso terapéutico , Animales , Aorta/efectos de los fármacos , Aorta/patología , Aorta/fisiología , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Aterosclerosis/patología , Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol/genética , Colesterol en la Dieta/administración & dosificación , Regulación de la Expresión Génica , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Masculino , Óxido Nítrico/metabolismo , Peroxidasa/genética , Peroxidasa/metabolismo , Sustancias Protectoras/farmacología , Conejos , Triglicéridos/sangreRESUMEN
The aim of the present work was to explore possible protective effects of sulforaphane (SFN) against atherosclerosis development and endothelial dysfunction in hypercholesterolemic rabbits. Rabbits were assigned to three groups of five: group I fed normal chow diet for four weeks, group II fed 1% high cholesterol diet (HCD) and group III fed HCD + SFN (0.25 mg/kg/day). Blood samples were collected for measurement of serum triglycerides (TGs), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), lactate dehydrogenase (LDH) and C-reactive protein (CRP). Aortic malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and total nitrite/nitrate (NOx) were measured. Vascular reactivity and intima/media (I/M) ratio were analyzed. Nuclear factor-kappa B (NF-κB) activation in aortic endothelial cells was identified immunohistochemically. HCD induced significant increases in serum TGs, TC, LDL-C, LDH, and CRP, and aortic MDA and SOD. Moreover, HCD caused significant reductions in serum HDL-C, aortic GSH and NOx. SFN administration significantly decreased HCD-induced elevations in serum TC, LDL-C, CRP, and LDH. while significantly increased HDL-C and GSH levels and normalized aortic SOD and NOx. Additionally, SFN significantly improved rabbit aortic endothelium-dependent relaxation to acetylcholine. Moreover, SFN significantly reduced the elevation in I/M ratio. This effect was confirmed by aortic histopathologic examination. The expression of NF-κB in aortic tissue showed a marked reduction upon treatment with SFN. In conclusion, this study reveals that SFN has the ability to ameliorate HCD-induced atherosclerotic lesions progression and vascular dysfunction, possibly via its lipid-lowering and antioxidant effects and suppression of NF-κB-mediated inflammation.
Asunto(s)
Anticolesterolemiantes/administración & dosificación , Antioxidantes/administración & dosificación , Aterosclerosis/prevención & control , Hipercolesterolemia/complicaciones , Isotiocianatos/administración & dosificación , Animales , Aorta/patología , Proteína C-Reactiva/análisis , Dieta Aterogénica , Histocitoquímica , Inmunohistoquímica , L-Lactato Deshidrogenasa/sangre , Lípidos/sangre , Masculino , FN-kappa B/análisis , Conejos , Suero/química , Sulfóxidos , Túnica Íntima/patología , Túnica Media/patologíaRESUMEN
This work was designed to investigate the effects of levocetirizine, a histamine H1 receptor antagonist, on diabetes-induced nephropathy and vascular disorder, in comparison to an angiotensin II receptor antagonist, losartan. Diabetes was induced in male Sprague Dawley rats by a single intraperitoneal injection of streptozotocin (50mg/kg). Diabetic rats were divided into three groups; diabetic, diabetic-levocetirizine (0.5mg/kg/day) and diabetic-losartan (25mg/kg/day). Treatments were started two weeks following diabetes induction and continued for additional eight weeks. At the end of the experiment, urine was collected and serum was separated for biochemical measurements. Tissue homogenates of kidney and aorta were prepared for measuring oxidative stress, nitric oxide (NO), transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor-α (TNF-α). Moreover, histological analyses were conducted and aortic vascular reactivity was investigated. Levocetirizine improved renal function in diabetic rats (evidenced by mitigation of diabetes-induced changes in kidney to body weight ratio, serum albumin, urinary proteins and creatinine clearance). Moreover, levocetirizine attenuated the elevated renal levels of TNF-α and TGF-ß1, ameliorated renal oxidative stress and restored NO bioavailability in diabetic kidney. These effects were comparable to or surpassed those produced by losartan. Moreover, levocetirizine, similar to losartan, reduced the enhanced responsiveness of diabetic aorta to phenylephrine. Histological evaluation of renal and aortic tissues further confirmed the beneficial effects of levocetirizine on diabetic nephropathy and revealed a greater attenuation of diabetes-induced vascular hypertrophy by levocetirizine than by losartan. In conclusion, levocetirizine may offer comparable renoprotective effect to, and possibly superior vasculoprotective effects than, losartan in streptozotocin-diabetic rats.
Asunto(s)
Aorta/efectos de los fármacos , Cetirizina/farmacología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/fisiopatología , Nefropatías Diabéticas/complicaciones , Losartán/farmacología , Animales , Aorta/metabolismo , Aorta/patología , Aorta/fisiopatología , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0.0001 versus control group), 114.50 ± 78.63 (P < 0.05 versus CIS group), and 60.91 ± 14.30 (P < 0.001 versus CIS group) mg/dl, respectively). Histological analysis of renal tissues also demonstrated that febuxostat offered a dose-dependent renoprotection. The present study suggests that antioxidant, anti-inflammatory, and cytoprotective mechanisms potentially mediate the renoprotective effects of febuxostat in CIS-administered rats, presenting febuxostat as a promising combinatorial strategy for cancer patients undergoing CIS chemotherapy.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Cisplatino , Febuxostat/farmacología , Riñón/efectos de los fármacos , Agentes Urológicos/farmacología , Lesión Renal Aguda/sangre , Lesión Renal Aguda/patología , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Biomarcadores/metabolismo , Creatinina/sangre , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Glutatión/metabolismo , Mediadores de Inflamación/metabolismo , Riñón/metabolismo , Riñón/patología , L-Lactato Deshidrogenasa/sangre , Masculino , Malondialdehído/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteinuria/inducido químicamente , Proteinuria/prevención & control , Ratas Sprague-Dawley , Albúmina Sérica/metabolismo , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismoRESUMEN
The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose-dependent protection by febuxostat against LPS-induced lung inflammation in rats.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Febuxostat/uso terapéutico , Edema Pulmonar/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/patología , Animales , Antiinflamatorios/farmacología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Proteína C-Reactiva/análisis , Relación Dosis-Respuesta a Droga , Febuxostat/farmacología , Glutatión/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Recuento de Leucocitos , Lipopolisacáridos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Masculino , Malondialdehído/metabolismo , Óxido Nítrico/metabolismo , Edema Pulmonar/inducido químicamente , Edema Pulmonar/inmunología , Edema Pulmonar/patología , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
Sulforaphane (SFN), a dietary phase-2 enzyme inducer that mitigates cellular oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) activation, is known to exhibit beneficial effects in the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, a major event in atherosclerosis and restenosis after angioplasty. In particular, SFN attenuates the mitogenic and pro-inflammatory actions of platelet-derived growth factor (PDGF) and tumor necrosis factor-α (TNFα), respectively, in VSMCs. Nevertheless, the vasoprotective role of SFN has not been examined in the setting of obesity characterized by hyperleptinemia and insulin resistance. Using the mouse model of western diet-induced obesity, the present study demonstrates for the first time that subcutaneous delivery of SFN (0.5mg/Kg/day) for~3weeks significantly attenuates neointima formation in the injured femoral artery [↓ (decrease) neointima/media ratio by~60%; n=5-8]. This was associated with significant improvements in metabolic parameters, including ↓ weight gain by~52%, ↓ plasma leptin by~42%, ↓ plasma insulin by~63%, insulin resistance [↓ homeostasis model assessment of insulin resistance (HOMA-IR) index by~73%], glucose tolerance (↓ AUCGTT by~24%), and plasma lipid profile (e.g., ↓ triglycerides). Under in vitro conditions, SFN significantly decreased leptin-induced VSMC proliferation by~23% (n=5) with associated diminutions in leptin-induced cyclin D1 expression and the phosphorylation of p70S6kinase and ribosomal S6 protein (n=3-4). The present findings reveal that, in addition to improving systemic metabolic parameters, SFN inhibits leptin-induced VSMC proliferative signaling that may contribute in part to the suppression of injury-induced neointima formation in diet-induced obesity.