RESUMEN
We have addressed in the current study the potential of L-carnitine (LC) to extenuate the reproductive toxic insults of carbendazim (CBZ) in male rats, and the molecular mechanisms whereby carnitine would modify the spermatogenic and steroidogenic derangements invoked by the endocrine disruptor. Herein, animals received daily doses of carbendazim (100 mg/kg) by gavage for 8 weeks. Another CBZ-challenged group was co-supplemented with LC (500 mg/kg, IP) twice weekly for 8 weeks. Sperm quantity and quality (morphology, motility and viability), serum testosterone and gonadotropins, and thyroid hormone levels were assessed. Serum tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) concentrations were determined by ELISA. Oxidant/antioxidant status in rat testis was investigated via measuring testicular contents of malondialdehyde (MDA) and reduced glutathione (GSH), as well as the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Immunohistochemical localizations of the junctional protein; occludin, and inflammatory markers; inducible nitric oxide synthase (iNOS) and nuclear factor kappa beta (NF-κB) were further analyzed. A host of transduction genes that regulate spermatogenic and steroidogenic pathways, and their encoded proteins namely, Steroidogenic Acute Regulatory Protein (StAR), Fatty acid binding protein 9 (FABP9) and P38-mitogen activated protein kinase (P38-MAPK) were assessed by real time quantitative (RT-qPCR) and Western blot. LC improved rat spermiogram, testicular histological alterations and endocrine perturbances, and modulated genes' expressions and their respective proteins. In conclusion, LC effects appear to reside for the most part on its endocrine-preserving, anti-oxidant and anti-inflammatory properties through a myriad of interlaced signal transductions that ultimately recapitulated its beneficial effects on spermatogenesis and steroidogenesis.
Asunto(s)
Bencimidazoles/toxicidad , Carbamatos/toxicidad , Carnitina/farmacología , Proteínas de Unión a Ácidos Grasos/biosíntesis , Estrés Oxidativo/fisiología , Fosfoproteínas/biosíntesis , Testículo/metabolismo , Animales , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Disruptores Endocrinos/toxicidad , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Distribución Aleatoria , Ratas , Recuento de Espermatozoides/métodos , Testículo/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Ischemia-reperfusion (I/R) injury is a pathological process which magnifies with the ensuing inflammatory response and endures with the increase of oxidants especially during reperfusion. The present study was conducted to assess the possible modulatory effects of plumbagin, the active constituent extracted from the roots of traditional medicinal plant Plumbago zeylanica L., on the dire role of high mobility group box 1 (HMGB1) as well as the associated inflammation, oxidative stress and apoptotic cell death following hepatic I/R. Four groups of rats were included: sham-operated, sham-operated treated with plumbagin, I/R (30â¯min ischemia and 1â¯h reperfusion) and I/R treated with plumbagin. Pretreatment with plumbagin markedly improved hepatic function and structural integrity compared to the I/R group, as manifested by depressed plasma transaminases and lactate dehydrogenase (LDH) activities as well as alleviated tissue pathological lesions. Plumbagin prominently hampered HMGB1 expression and subsequently quelled inflammatory cascades, as nuclear factor κB (NF-κB), tumor necrosis factor-alpha (TNF-α) and myeloperoxidase (MPO) activity. It also interrupted reactive oxygen species (ROS)-HMGB1loop as evident by restored liver reduced glutathione (GSH), elevated glutathione peroxidase (GPx) activity, along with decreased liver lipid peroxidation. Simultaneously, plumbagin significantly ameliorated apoptosis by amending the mRNA expressions of both anti-apoptotic (Bcl-2) and pro-apoptotic (Bax). The present results revealed that plumbagin is endowed with hepatoprotective activity ascribed to its antioxidant, anti-inflammatory and anti-apoptotic properties which are partially mediated through dampening of HMGB1 expression.
Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Proteína HMGB1/metabolismo , Hepatitis/prevención & control , Hígado/efectos de los fármacos , Naftoquinonas/farmacología , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/prevención & control , Animales , Biomarcadores/sangre , Citoprotección , Modelos Animales de Enfermedad , Enzimas/sangre , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Hepatitis/metabolismo , Hepatitis/patología , Mediadores de Inflamación/sangre , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacosRESUMEN
The anti-inflammatory potential and vasoprotective effects of an Iberis amara extract in a rat model of arthritis were investigated. I. amara, or bitter candytuft, has long been known for its anti-inflammatory properties on account of its active constituents, including cucurbitacins, kaempferol, and sinapic acid. The present study was intended to explore more in depth its anti-inflammatory activity in both acute (carrageenan rat paw edema) and chronic (adjuvant-induced arthritis) models of inflammation. An extract of I. amara dose-dependently reduced the extent of edema in both models. In the chronic model, this was associated with a reduction in the inflammation mediators tumor necrosis factor-α, interleukin-1ß, and prostaglandin E2 and in the antioxidant biomarkers malondialdehyde and total nitrate/nitrite. Because arthritis was reported both clinically and experimentally to contribute towards different vascular complications, it was of interest to study ex vivo the sensitivity of aortic rings in our experimental setup towards norepinephrine, acetylcholine, and sodium nitroprusside. The aortic rings from arthritic rats showed no change in sensitivity to norepinephrine, but showed a reduced sensitivity to sodium nitroprusside and acetylcholine. To show whether the treatment of the arthritis would restore endothelial function, I. amara extract was shown to markedly reduce the reactivity to norepinephrine, but not to appreciably affect the reactivity towards sodium nitroprusside and it had a tendency towards normalizing reactivity to acetylcholine. Taken collectively, the findings imply an improvement in endothelial function and lend support to the use of the extract in rheumatic inflammatory conditions to help safeguard the integrity of the endothelium and reduce the risk of vascular complications.
Asunto(s)
Antiinflamatorios/farmacología , Brassicaceae/química , Mediadores de Inflamación/metabolismo , Extractos Vegetales/farmacología , Animales , Antioxidantes/metabolismo , Artritis Experimental/tratamiento farmacológico , Carragenina/efectos adversos , Dinoprostona/metabolismo , Edema/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Interleucina-1beta/metabolismo , Masculino , Ratas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Many screening procedures for agents with potential usefulness in functional dyspepsia (FD) rely on animals exposed to stress early in life (neonatal maternal separation, NMS) or in adulthood (restraint stress, RS). PURPOSE: Since many clinical cases of FD have been associated with stress in early life followed by stress in adulthood, a sequential model simulating the clinical situation is described. To explore the validity of the model, the efficacy of STW5, a multicomponent herbal preparation of proven usefulness in FD, was tested. STUDY DESIGN/METHODS: A sequential stress model established where rats are exposed to NMS after birth followed later by RS in adulthood. Stress hormones and ghrelin were measured in plasma, while responsiveness of stomach fundus strips to smooth muscle stimulants and relaxants was assessed ex-vivo. The effectiveness of treatment with STW5 a few days before and during exposure to RS in preventing changes induced by the stress model is reported and compared to its efficacy when used in animals subjected to RS alone. RESULTS: Responses to both stimulants and relaxants were reduced to various extents in the studied models, but treatment with STW5 tended to normalize gastric responsiveness. Plasma levels of ghrelin, corticosterone releasing factor, and corticosterone were raised by RS as well as the sequential model. Treatment with STW5 tended to prevent the deranged parameters. CONCLUSION: The sequential stress model has a place in drug screening for potential usefulness in FD as it simulates more the clinical setting. Furthermore, the findings shed more light on the mechanisms of action of STW5 in FD.
Asunto(s)
Modelos Animales de Enfermedad , Dispepsia/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Estrés Psicológico , Animales , Corticosterona/sangre , Hormona Liberadora de Corticotropina/sangre , Femenino , Motilidad Gastrointestinal , Ghrelina/sangre , Masculino , Privación Materna , Ratas , Ratas Wistar , Restricción FísicaRESUMEN
BACKGROUND: Paracetamol overdose causes severe hepatotoxicity that leads to liver failure in both humans and experimental animals. The present study investigates the protective effect of honey against paracetamol-induced hepatotoxicity in Wistar albino rats. We have used silymarin as a standard reference hepatoprotective drug. METHODS: Hepatoprotective activity was assessed by measuring biochemical parameters such as the liver function enzymes, serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST). Equally, comparative effects of honey on oxidative stress biomarkers such as malondialdyhyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx) were also evaluated in the rat liver homogenates. We estimated the effect of honey on serum levels and hepatic content of interleukin-1beta (IL-1ß) because the initial event in paracetamol-induced hepatotoxicity has been shown to be a toxic-metabolic injury that leads to hepatocyte death, activation of the innate immune response and upregulation of inflammatory cytokines. RESULTS: Paracetamol caused marked liver damage as noted by significant increased activities of serum AST and ALT as well as the level of Il-1ß. Paracetamol also resulted in a significant decrease in liver GSH content and GPx activity which paralleled an increase in Il-1ß and MDA levels. Pretreatment with honey and silymarin prior to the administration of paracetamol significantly prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines. Histopathological evaluation of the livers also revealed that honey reduced the incidence of paracetamol-induced liver lesions. CONCLUSION: Honey can be used as an effective hepatoprotective agent against paracetamol-induced liver damage.
Asunto(s)
Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Antioxidantes/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Miel , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Interleucina-1beta/sangre , Interleucina-1beta/metabolismo , Hígado/metabolismo , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo , Ratas , Ratas Wistar , Silimarina/uso terapéuticoRESUMEN
PURPOSE: An herbal preparation, STW 5, used clinically in functional dyspepsia and irritable bowel syndrome, has been shown to possess properties that may render it useful in inflammatory bowel disease (IBD). The present work was conducted to study its effectiveness in a rat model of IBD. METHODS: An experimental model reflecting ulcerative colitis in man was adopted, whereby colitis was induced in Wistar rats by feeding them 5 % dextran sulfate sodium (DSS) in drinking water for one week. STW 5 and sulfasalazine (as a reference standard) were administered orally daily for 1 week before colitis induction and continued during DSS feeding. The animals were then sacrificed, and the severity of colitis was evaluated macroscopically and microscopically. Colon samples were homogenized for determination of reduced glutathione, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-3 as well as myeloperoxidase, glutathione peroxidase, and superoxide dismutase. In addition, colon segments were suspended in an organ bath to test their reactivity towards carbachol, KCl, and trypsin. RESULTS: STW 5 and sulfasalazine were both effective in preventing the shortening of colon length and the increase in both colon mass index and total histology score as well as the changes in biochemical parameters measured except changes in dismutase activity. DSS-induced colitis led to marked depression in colonic responsiveness to the agents tested ex vivo, an effect which was normalized by both drugs. CONCLUSIONS: The findings point to a potential usefulness of STW 5 in the clinical setting of ulcerative colitis.
Asunto(s)
Colitis/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Colitis/patología , Colitis/fisiopatología , Colon/efectos de los fármacos , Colon/enzimología , Colon/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Motilidad Gastrointestinal/efectos de los fármacos , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Técnicas In Vitro , Inflamación/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
A multitarget herbal preparation, STW 5, has been used clinically in different gastro-intestinal disorders including functional dyspepsia and irritable bowel syndrome. Previous studies have shown that it possesses properties that may render it useful in gastro-oesophageal reflux disease (GERD). We performed this study to test this compound in an acute model of reflux oesophagitis in rats. Oesophagitis was induced surgically by ligating the pyloric end and fore-stomach. Lower oesophageal pH was measured 3 h later in conscious animals. Five hours after surgery, animals were sacrificed and the oesophagi were examined macroscopically and histologically. Selected markers of inflammation were measured in oesophageal homogenates. STW 5 was given orally for 5 days before induction of oesophagitis. Pantoprazole was used as a reference standard. Ligated animals showed a high incidence of ulcerative lesions associated with a marked increase in myeloperoxidase, thiobarbituric acid-reactive substances, tumor necrosis factor-alpha, and interleukin-1beta. STW 5 did not affect oesophageal pH, but dose-dependently reduced the severity of the oesophageal lesions and normalized the deranged level of the inflammation markers. The beneficial effects were confirmed histopathologically. STW 5 proved to be effective in protecting against inflammatory lesions in this model of oesophagitis, thus warranting further investigation of its potential therapeutic usefulness in GERD.