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Pits of dates (Phoenix dactylifera L.) have numerous nutritional benefits that could have wide-ranging applications. This study aimed to examine the effects of administering three extracts from powdered date pits on some basic physiological parameters, plasma constituents, reproductive hormones, and testicular histology in CD1 male mice. Three groups received doses of 100 mg/kg/day of lyophilized extract, a nonpolar fraction, and a polar fraction of date pits by oral gavage for 28 consecutive days. For the control, one group was administered a 1 mL/kg concentration of distilled water. The three different extracts significantly increased the plasma testosterone level but showed no significant effect on estradiol or luteinizing hormone levels, except for estradiol reduction in the polar extract group. The measured physiological or biochemical parameters or testicular histology also demonstrated no significant differences between the control mice and those mice treated with the three extracts, except for reductions in plasma urea in all extracts and in total protein in the nonpolar extract. Therefore, date pit extracts may potentially be used as a safe and effective dietary supplement. However, further investigation is needed.
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Phoeniceae , Extractos Vegetales , Ratones , Masculino , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Testículo , Estradiol/farmacologíaRESUMEN
BACKGROUND/AIMS: SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). METHODS: CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. RESULTS: Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1ß, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. CONCLUSION: Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.
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Adenina/efectos adversos , Canagliflozina/farmacología , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Adenina/farmacología , Animales , Biomarcadores/orina , Ratas , Ratas Wistar , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/prevención & control , Insuficiencia Renal Crónica/orinaRESUMEN
BACKGROUND/AIMS: The effect of treatment with gum acacia (GA), a prebiotic shown previously to ameliorate chronic kidney disease (CKD), in diabetic and non - diabetic rats with adenine - induced CKD has been investigated using several conventional and novel physiological, biochemical, and histopathological parameters. METHODS: Diabetes mellitus was induced in rats by a single injection of streptozotocin (STZ). Diabetic and non - diabetic rats were randomly divided into several groups, and given either normal food or food mixed with adenine (0.25% w/w, for five weeks) to induce CKD. Some of these groups were also concomitantly treated orally with GA in the drinking water (15% w/w). RESULTS: Rats fed adenine alone exhibited physiological (decreased body weight, increased food and water intake and urine output), biochemical (increase in urinary albumin/creatinine ratio, plasma urea and, creatinine, indoxyl sulfate and phosphorus), inflammatory biomarkers (increased in neutrophil gelatinase-associated lipocalin, transforming growth factor beta -1, tumor necrosis factor alpha, adiponectin, cystatin C and interleukin-1ß), oxidative biomarkers (8-isoprostane, 8 -hydroxy -2-deoxy guanosine), nitrosative stress biomarkers (nitrite and nitrate) and histopathological (increase in tubular necrosis and fibrosis) signs of CKD. STZ - induced diabetes alone worsened most of the renal function tests measured. Administration of adenine in STZ - diabetic rats further worsened the renal damage induced by adenine alone. GA significantly ameliorated the renal actions of adenine and STZ, given either singly or in combination, especially with regards to the histopathological damage. CONCLUSION: GA is a useful dietary agent in attenuating the progression of CKD in rats with streptozotocin-induced diabetes.
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Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Goma Arábiga/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Acacia/química , Adenina , Animales , Diabetes Mellitus Experimental/patología , Modelos Animales de Enfermedad , Goma Arábiga/química , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/patología , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Estrés Nitrosativo/efectos de los fármacos , Ratas , Ratas Wistar , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/patologíaRESUMEN
The present study investigated the effect of diminazene, lisinopril, or valsartan on adenine-induced chronic kidney disease (CKD) in rats. The animals were divided into five groups (n = 6). The first and second groups received normal diet and adenine in the feed at a dose of 0.25% w/w for 35 days, respectively. The third, fourth, and fifth groups were treated as the second group but also received diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), and valsartan (30 mg/kg/day), respectively, for 35 days. Adenine significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL), calcium, phosphorus, and uric acid. In addition, adenine increased urinary albumin/creatinine ratio and N-Acetyl-ß-D-glucosaminidase (NAG)/creatinine ratio and reduced creatinine clearance. Adenine also significantly increased the plasma concentrations of inflammatory cytokines (plasma tumor necrosis factor-alpha [TNF-α] and interleukin-1beta [IL-1ß]) and significantly reduced antioxidant indices (catalase, glutathione reductase [GR], and superoxide dismutase [SOD]). Histopathologically, renal tissue from adenine-treated rats showed necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. All drugs ameliorated adenine-induced biochemical and histopathological changes. The protective effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Our results show that administration of diminazene, lisinopril, or valsartan had a comparable effect on the reversal of the biochemical and histopathological indices of adenine-induced CKD in rats.
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Diminazeno , Insuficiencia Renal Crónica , Ratas , Animales , Diminazeno/efectos adversos , Adenina/toxicidad , Creatinina , Enzima Convertidora de Angiotensina 2/farmacología , Enzima Convertidora de Angiotensina 2/uso terapéutico , Lisinopril/efectos adversos , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/tratamiento farmacológico , Riñón , Antioxidantes/farmacologíaRESUMEN
This study aimed to investigate the potential protective effects of diminazene, an activator of angiotensin II converting enzyme (ACE2), on kidney function and structure in rats with acute kidney injury (AKI) induced by the anticancer drug doxorubicin (DOX). The impact of diminazene was compared to that of two other drugs: the ACE inhibitor lisinopril and the angiotensin II type 1 (AT1) receptor blocker valsartan. Rats were subjected to a single intraperitoneal injection of DOX (13.5 mg/kg) on the 5th day, either alone or in combination with diminazene (15 mg/kg/day), lisinopril (10 mg/kg/day), or valsartan (30 mg/kg/day) for 8 consecutive days. Various markers related to kidney function, oxidative stress, and inflammation were measured in plasma and urine. Additionally, kidney tissues were assessed histopathologically. DOX-induced nephrotoxicity was confirmed by elevated levels of plasma urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL). DOX also led to increased urinary N-acetyl-ß-D-glucosaminidase (NAG) activity and decreased creatinine clearance, albumin levels, and osmolality. Moreover, DOX caused a reduction in renal oxidative stress markers, including superoxide dismutase (SOD), glutathione reductase (GR), and catalase activities, while increasing malondialdehyde (MDA) levels. It also raised plasma inflammatory markers, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß). Concurrently administering diminazene significantly mitigated these DOX-induced changes, including histopathological alterations like renal tubule necrosis, tubular casts, shrunken glomeruli, and increased renal fibrosis. Similar protective effects were observed with lisinopril and valsartan. These protective effects, at least in part, appear to result from the anti-inflammatory and antioxidant properties of these drugs. In summary, this study suggests that the administration of diminazene, lisinopril, or valsartan had comparable effects in ameliorating the biochemical and histopathological aspects of DOX-induced acute kidney injury in rats.
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INTRODUCTION: The diuretic agent furosemide (FUR, 25 and 50 mg/kg) has been shown in a single report to act as an anti-stressor agent in two models of acute stress in mice, viz. electric foot-shock stress and immobilization (IMS). The present work aimed to investigate the possible anti-stressor action of FUR on two models of acute stress in mice, cold-water stress (CWS) and IMS, and tried to determine whether gender has any impact on the effect of FUR. METHODS: FUR (40 mg/kg) was injected intraperitoneally, and after 30 minutes, mice were subjected to CWS (4°C for three minutes) or IMS (fixing movement for two and a half hrs using adhesive tape). Motor and exploratory activities, neuromuscular coordination, and thermal nociception were then tested. Blood was collected from the mice and used to measure the concentrations of three stress hormones (corticosterone, epinephrine and prolactin). RESULTS: Mice subjected to CWS and IMS had significantly reduced motor and exploratory activities, neuromuscular coordination, and increased nociception. CWS and IMS also significantly increased the plasma concentrations of the three hormones. FUR pretreatment significantly mitigated these stress-induced hormonal changes. There was no significant sex difference when CWS or IMS was applied. DISCUSSION: IMS and CWS stimuli in male and female mice caused significant elevations in the plasma concentrations of corticosterone, epinephrine, and prolactin, accompanied by a significant reduction of motor and exploratory activities, neuromuscular coordination, and thermal nociception. There were no sex differences when IMS was applied. In stressed mice, prior administration of FUR (40 mg/kg) significantly decreased the concentrations of stress hormones, and this effect significantly mitigated the stress-induced behavioural and motor changes.
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This work aimed to investigate whether treatment with the antidiabetic drug metformin would affect adenine-induced chronic kidney disease (CKD) in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Rats were randomly divided into eight groups, and given either normal feed, or feed mixed with adenine (0.25% w/w, for five weeks) to induce CKD. Some of these groups were also simultaneously treated orally with metformin (200 mg/kg/day). Rats given adenine showed the typical signs of CKD that included detrimental changes in several physiological and traditional and novel biochemical biomarkers in plasma urine and kidney homogenates such as albumin/creatinine ratio, N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, 8-isoprostane, adiponectin, cystatin C, as well as plasma urea, creatinine, uric acid, indoxyl sulfate, calcium, and phosphorus. Several indices of inflammation and oxidative stress, and renal nuclear factor-κB and nuclear factor erythroid 2-related factor 2 levels were also measured. Histopathologically, adenine caused renal tubular necrosis and fibrosis. The activation of the intracellular mitogen-activated protein kinase signaling pathway was inhibited in the groups that received metformin and STZ together, with or without adenine induced-CKD. Induction of diabetes worsened most of the actions induced by adenine. Metformin significantly ameliorated the renal actions induced by adenine and STZ when these were given singly, and more so when given together. The results suggest that metformin can be a useful drug in attenuating the progression of CKD in both diabetic and non-diabetic rats.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Riñón/metabolismo , Metformina/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Adenina/efectos adversos , Adenina/farmacología , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Riñón/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratas , Ratas Wistar , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/patologíaRESUMEN
Cisplatin (CP) is nephrotoxic, and this side effect is used as an animal model for acute kidney injury (AKI). Earlier research has been focused on CP-induced AKI, with relatively little attention being paid to its ability to progress to chronic kidney disease (CKD) on repeated administration. We aimed here to test the dose dependency of its nephrotoxic actions by comparing various physiological, biochemical, molecular, and histopathological indices using repeated increasing doses of CP in rats. Furthermore, we investigated whether these doses of CP would result in the development of CKD. Biochemical, molecular, and histopathological measurements were conducted in plasma, urine, and/or kidneys of rats treated with increasing doses of CP at 1.6, 3.2, and 4.8 mg kg-1 weekly for four consecutive weeks. These doses induced significant and dose-dependent elevations in most of the measured renal indices. These included increased renal fibrosis, as suggested histopathologically and biochemically by the significant increase in transforming growth factor-ß1, significant decrease in actin alpha 2, and variable actions of collagen I and IV. CP also dose-dependently increased nuclear factor (erythroid-derived 2)-like 2 and caspase-3. Multiple repeated doses of CP (1.6 to 4.8 mg kg-1) induced multiple episodes of AKI, leading to CKD after the 4th weekly dose and confirmed that this dosage regimen could be used as an experimental animal model of AKI progressing to CKD. These actions were driven by inflammation, oxidative, and nitrosative stress.
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Lesión Renal Aguda/inducido químicamente , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Modelos Animales de Enfermedad , Insuficiencia Renal Crónica/inducido químicamente , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Albuminuria/sangre , Albuminuria/inducido químicamente , Albuminuria/patología , Albuminuria/orina , Animales , Antineoplásicos/efectos adversos , Caspasa 3 , Cisplatino/efectos adversos , Creatinina/sangre , Creatinina/metabolismo , Creatinina/orina , Citocinas , Relación Dosis-Respuesta a Droga , Proteínas de Unión a Ácidos Grasos/metabolismo , Indicán/sangre , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Fósforo/sangre , Ratas Wistar , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Urea/sangre , Ácido Úrico/sangreRESUMEN
This study examined the effect of levosimendan on streptozotocin-induced early diabetic nephropathy. Rats were distributed into four groups and treated for six weeks. The first and third group received either vehicle or levosimendan (1 mg/kg/day) for the last three weeks, respectively. The second and fourth groups were rendered diabetic by a single intraperitoneal injection of streptozotocin (60 mg/kg) and were treated as the first and third groups, respectively. In the untreated diabetic group, there was a significant decrease in body weight, polyuria and hyperglycemia as well as, increased urinary albumin/creatinine ratio (UACR) and N-acetyl-ß-D-glucosaminidase (NAG)/creatinine ratio (UNCR) with no change in creatinine clearance. In addition, diabetes was associated with increased oxidative stress as evidenced by reduced plasma total antioxidant capacity (TAC) and catalase activity and increased plasma malondialdhyde (MDA) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α). Kidneys from streptozotocin-treated rats showed focal clear renal tubular cells affecting proximal convoluted tubules and mild interstitial fibrosis at the cortico-medullary junction. Levosimendan significantly attenuated the streptozotocin-induced physiological and biochemical changes and there was less clear renal tubular cells. This study shows that levosimendan ameliorated some of the changes seen in streptozotocin-induced early diabetic nephropathy in rats. This could be partly due to its antioxidative and anti-inflammatory effects.
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Cardiotónicos/uso terapéutico , Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Simendán/uso terapéutico , Animales , Antioxidantes/metabolismo , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/patología , Fibrosis , Hiperglucemia/tratamiento farmacológico , Riñón/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Poliuria/tratamiento farmacológico , Ratas , Ratas Sprague-DawleyRESUMEN
Treatment with the chemotherapeutic agent, doxorubicin (DOX), is limited by nephrotoxicity. We investigated the possible protective effect of infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor on DOX-induced nephrotoxicity. Rats were treated with a single intraperitoneal (ip) injection of DOX (17.5 mg/kg) in the absence or presence of infliximab (5 mg/kg, i.p.). Plasma and urinary markers of kidney function, oxidative stress, and inflammation were measured. Kidney and heart tissue was evaluated histopathologically. DOX-induced nephrotoxicity was confirmed by increased plasma urea, creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and clusterin concentrations. In addition, DOX increased urinary albumin/creatinine ratio, N-acetyl-ß-D-glucosaminidase (NAG) activity, kidney injury molecule (KIM-1) concentrations, and reduced creatinine clearance. DOX significantly reduced renal antioxidants and increased plasma inflammatory markers and adiponectin concentrations. Concomitant treatment with infliximab did not significantly affect DOX-induced changes in plasma creatinine, cystatin C, or creatinine clearance. However, infliximab significantly reduced DOX-induced action on plasma urea, NGAL, clusterin, and adiponectin. Infliximab also significantly reduced urinary albumin/creatinine ratio, NAG activity, and KIM-1 concentrations, as well as the occurrence of fibrotic lesions in kidney tissue. Fibrosis detected in the heart was unchanged. In addition, infliximab reduced DOX-induced effects on plasma inflammatory markers, renal superoxide dismutase (SOD) and total antioxidant capacity. Our results show that infliximab is partially effective in mitigating DOX-induced nephrotoxicity in rats.
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Antineoplásicos , Doxorrubicina , Infliximab/uso terapéutico , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adiponectina/sangre , Animales , Interleucina-6/sangre , Riñón/efectos de los fármacos , Riñón/patología , Enfermedades Renales/patología , Masculino , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Ratas WistarRESUMEN
The aim of this study was to investigate some biochemical indices of inflammation and oxidative and nitrosative stresses in the gastrointestinal tract of mice with experimental chronic kidney disease (CKD) and treated with gum arabic (GA). Male CD1 mice (n = 28) were randomly distributed into four groups and treated for four consecutive weeks: group 1: Control: received the same diet without treatment until the end of the study; group 2: Adenine: switched to a powder diet containing adenine (0.2% w/w in feed); group 3: Gum acacia (GA): given normal feed and GA in drinking water at a concentration of 15% w/v; and group 4: Adenine + GA: given adenine in the feed as in the second group plus GA in the drinking water at concentration of 15% w/v. CKD was induced to mice by adenine feeding and concomitantly treated with the prebiotic dietary fiber gum acacia, GA (15% in drinking water). Duodenal mucosa from CKD mice had significantly higher concentrations of TNF-alfa, IL- 6, and TGF-beta-1 and lipid peroxidation. Moreover, low concentrations of IL-10, some antioxidants (catalase, glutathione reductase, total antioxidant capacity, and superoxide dismutase), and nuclear factor erythroid 2-related factor 2 were found in the duodenum. The levels of nitrosative stress (nitrite, nitrate, and total nitrate) were significantly increased by CKD, as well as the concentrations of ammonia and urea creatinine in the cecal content. Concomitant GA treatment significantly mitigated these harmful effects. Taken together, GA reduces inflammation and duodenal oxidative and nitrosative stress in the gastrointestinal tract of mice with CKD.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Ciego/efectos de los fármacos , Duodeno/efectos de los fármacos , Goma Arábiga/farmacología , Mediadores de Inflamación/metabolismo , Estrés Oxidativo/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Adenina , Animales , Biomarcadores/sangre , Biomarcadores/orina , Ciego/metabolismo , Modelos Animales de Enfermedad , Duodeno/metabolismo , Interleucina-6/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Estrés Nitrosativo/efectos de los fármacos , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Cisplatin (CP) is a potent anticancer drug used to treat solid tumors. Its use, however, is dose-limited by its nephrotoxicity. We aimed to compare the effect of melatonin and curcumin given singly, with that of a combination of these two agents on CP-induced nephrotoxicity in rats. CP (6 mg/kg, given once intraperitoneally) induced nephrotoxicity as evidenced by several significant adverse physiological, biochemical and histopathological actions that included a reduction in body weight, increased urine production, and significant alterations in some conventional and novel renal damage indices in plasma, urine and kidneys. CP also elevated several pro-inflammatory cytokines and caused renal oxidative/nitrosative stress. Supplementation with either curcumin (200 mg/kg) or melatonin (10 mg /kg) given singly by oral gavage for eight consecutive days prior to CP injection and four days thereafter, significantly mitigated the adverse renal effects of CP, by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in renal tissues of CP- treated rats. When curcumin and melatonin were given together, the ameliorative effect was augmented in some of the measured indices e.g. tumor necrosis factor alpha, cystatin C, uric acid, phosphorus in plasma and, urine creatinine and creatinine clearance. Renal platinum concertation was reduced more with curcumin than that with melatonin, while the reduction was maximized when both melatonin and curcumin were given. Pending further pharmacological and toxicological studies, a combination of these two agents is likely to be mor effective in mitigating the adverse renal effects of CP administered to cancer patients.
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Cisplatino/toxicidad , Curcumina/farmacología , Enfermedades Renales/prevención & control , Melatonina/farmacología , Animales , Antineoplásicos/toxicidad , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Curcumina/administración & dosificación , Citocinas/metabolismo , Quimioterapia Combinada , Mediadores de Inflamación/metabolismo , Enfermedades Renales/inducido químicamente , Masculino , Melatonina/administración & dosificación , Estrés Nitrosativo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
We investigated some reproductive actions of hookah smoke (HS) exposure (30 min/day, for 30 days) in male mice, and the possible mitigative effect of the prebiotic agent gum acacia (GA) thereon. Control mice were air-exposed (AE). Twenty-four hours after the last exposure, the levels of some plasma reproductive hormones, biochemical markers of inflammation, oxidative and nitrosative stress and testicular histopathology were assessed. The urinary level of cotinine, a major nicotine metabolite, was also measured. HS exposure induced significant decreases in testosterone, estradiol, luteinizing hormone, and androgen binding protein, as well as glutathione reductase activity and levels of nitrite and total nitrite. Plasma inhibin B, alkaline phosphatase, lipopolysaccharide binding protein, uric acid, lactate dehydrogenase, lipid peroxidation, 8-oxo-2'-deoxyguanosine, and cytochrome C were significantly increased following HS exposure. In testicular homogenate, nuclear factor-κB (NF-ĸB), nuclear factor erythroid 2-related factor 2 (Nrf2), interleukin- 6 (IL-6), interleukin-1ß (IL-1ß), transforming growth factor-ß1(TGF- ß1), and tumor necrosis factor-α (TNF- α) were all significantly elevated, and the steroidogenic acute regulatory protein (StAR) significantly decreased. Histopathologically, there was slight impairment and disorganization of spermatogenesis. Urinary cotinine concentration was elevated significantly in the HS-exposed group compared with the air-exposed group. GA co-administration mitigated the adverse actions of HS measured. In conclusion, daily exposure to HS at the above dose induced adverse actions on the reproductive system of male mice. GA co-administration significantly mitigated these effects by reducing the inflammation, oxidative and nitrosative stress, via a mechanism involving Nrf2, and reduction of StAR expression.
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Goma Arábiga/farmacología , Enfermedades Testiculares/prevención & control , Testículo/efectos de los fármacos , Contaminación por Humo de Tabaco/efectos adversos , Tabaco para Pipas de Agua/efectos adversos , Animales , Hormonas Gonadales/sangre , Goma Arábiga/uso terapéutico , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Fosfoproteínas/metabolismo , Espermatogénesis , Enfermedades Testiculares/etiología , Testículo/metabolismo , Testículo/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Canagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor that is currently available for the management of type 2 diabetes mellitus. The present study investigated the effect of canagliflozin on cisplatin (CP)-induced nephrotoxicity in mice. The animals were divided into four groups (n = 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) cisplatin (20 mg/kg) on day 7, respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (20 mg/kg) on day 7 and canagliflozin (10 mg/kg/day) and (30 mg/kg/day), for 10 days, respectively. At day 11, animals were anesthetized and blood collected and kidneys were removed. CP significantly increased the plasma urea, creatinine, cystatin C, and clusterin concentrations and neutrophil gelatinase-associated lipocalin (NGAL) activity. In addition, CP increased urinary albumin/creatinine ratio, N-acetyl-ß-D-glucosaminidase (NAG) activity, and liver-type fatty acid-binding protein (L-FABP) concentrations and reduced creatinine clearance. CP also significantly increased the plasma concentration of inflammatory cytokines [plasma tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß)] and significantly reduced antioxidant indices [catalase, glutathione reductase (GR), and superoxide dismutase (SOD)]. Histopathologically, CP caused a remarkable renal damage compared with control. Canagliflozin significantly ameliorated CP-induced biochemical and histopathological changes. The protective effect of canagliflozin is most likely due to anti-inflammatory and antioxidant effects. Our results show that administration of canagliflozin reversed the biochemical and histopathological indices of CP-induced nephrotoxicity in mice.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antineoplásicos/toxicidad , Antioxidantes/uso terapéutico , Canagliflozina/uso terapéutico , Cisplatino/toxicidad , Enfermedades Renales/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Canagliflozina/farmacología , Catalasa/metabolismo , Clusterina/sangre , Creatinina/sangre , Cistatina C/sangre , Citocinas/sangre , Glutatión Reductasa/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Lipocalina 2/sangre , Lipocalina 2/orina , Masculino , Ratones , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Superóxido Dismutasa/metabolismo , Urea/sangre , Ácido Úrico/sangreRESUMEN
We investigated the effect of levosimendan on cisplatin (Cis)-induced nephrotoxicity. Rats were divided into four groups (n = 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) cisplatin (6 mg/kg) on day 7, respectively. The third and fourth groups received a single intraperitoneal (i.p.) injection of Cis on day 7 and levosimendan (1 mg/kg/day, orally) or vehicle for 10 days, respectively. At day 11, animals were anaesthetized and blood collected and kidneys removed. Another four groups were treated the same as the previous four groups to measure renal blood flow. Cis induced nephrotoxicity as evidenced by biochemical, histopathological and hemodynamic changes. Levosimendan partially reduced Cis-induced increase in plasma urea, creatinine and neutrophil gelatinase-associated lipocalin (NGAL) levels and decrease in creatinine clearance. Levosimendan partially reduced Cis-induced increase in urinary albumin/creatinine ratio, N-Acetyl-ß-D-Glucosaminidase (NAG) and kidney Injury Molecule-1 (KIM-1). Levosimendan significantly attenuated the effect of Cis on plasma concentration of plasma tumor necrosis factor-alpha (TNF-α), antioxidant indices [catalase and superoxide dismutase (SOD)] and lipid peroxidation. Cis induced acute tubular necrosis with tubular dilatation, interstitial edema and congestion. Levosimendan attenuated the remarkable renal damage and reduced renal blood flow induced by Cis. In conclusion this study shows that levosimendan has a partial protective effect on Cis-induced nephrotoxicity. The protective effect of levosimendan is shown to be related to its anti-inflammatory, antioxidant and vasodilator effects.
RESUMEN
The aim of this study was to examine the effect of tocilizumab, an interleukin-6 (IL-6) inhibitor on streptozotocin-induced diabetic nephropathy. Male Sprague-Dawley rats (n = 36) were distributed into six groups and treated for 4 weeks. Groups 1, 3, 5 received either saline, tocilizumab (2 mg/kg), or tocilizumab (8 mg/kg) injection intraperitoneally (i.p.), every 2 weeks, respectively. Groups 2, 4, 6 were rendered diabetic by a single i.p. injection of streptozotocin (65 mg/kg) and were treated as in groups 1, 3, 5, respectively. Biochemical parameters were measured in plasma, urine, and kidneys. In the untreated diabetic group, there was a significant decrease in body weight, polyuria, and increased kidney weight. There was increased urinary albumin/creatinine ratio (UACR) and N-acetyl-ß-D-glucosaminidase (NAG)/creatinine ratio (UNCR). Streptozotocin also induced a significant increase in creatinine clearance. In addition, diabetes was associated with increased oxidative stress [reduced renal glutathione reductase (GR), superoxide dismutase (SOD), catalase activities, and increased malondialdhyde (MDA)] and increased plasma tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) concentrations. Kidneys from streptozotocin-treated rats showed marked vacuolation of the proximal tubular epithelium with focal tubular necrosis and the glomeruli showing increase in mesangial cells. Tocilizumab significantly mitigated the increase in UACR and UNCR, renal MDA, plasma TNF-α, IL-6 and NO levels, and the decrease in renal SOD and catalase activities in diabetic rats. Tocilizumab did not significantly improve creatinine clearance; however, it attenuated the histopathological changes induced by streptozotocin. This study shows that tocilizumab was able to ameliorate some of the changes seen in streptozotocin-induced early diabetic nephropathy in rats. This is mainly due to its anti-inflammatory and antioxidative effects.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/prevención & control , Hipoglucemiantes/farmacología , Interleucina-6/antagonistas & inhibidores , Animales , Antiinflamatorios/farmacología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antioxidantes/farmacología , Peso Corporal/efectos de los fármacos , Nefropatías Diabéticas/patología , Hipoglucemiantes/administración & dosificación , Inyecciones Intraperitoneales , Riñón/patología , Masculino , Tamaño de los Órganos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
We assessed the effect of treatment with the dipeptidyl peptidase-4 inhibitor, sitagliptin, on adenine-induced chronic kidney disease (CKD). Six equal groups of rats were given either normal food or food mixed with adenine (0.25% w/w for five weeks) to induce CKD. Some of these groups were also simultaneously treated with sitagliptin (2.5 and 10 mg/kg/day, by gavage). Rats given adenine showed elevation of blood pressure, decreased body weight and increased relative kidney weight. Adenine also significantly increased plasma urea, creatinine, cystatin C, liver-type fatty acid-binding protein concentrations and neutrophil gelatinase-associated lipocalin activity by 404%, 354%, 667%, 91% and 281% respectively and reduced plasma α-Klotho by 50%. In addition, adenine significantly increased albumin/creatinine ratio and N-acetyl-ß-d-glucosaminidase activity by 3553% and 400% respectively and reduced creatinine clearance by 91%. Adenine feeding also significantly elevated the plasma concentration of inflammatory cytokines (plasma tumor necrosis factor-alpha, interleukin-1beta and transforming growth factor beta-1) and significantly reduced antioxidant indices (catalase, glutathione reductase and superoxide dismutase). Histopathologically, adenine caused renal fibrosis, inflammation and atrophy. When given concomitantly with adenine, sitagliptin ameliorated all the measured adenine-induced physiological and biochemical changes but not the histopathological changes. Sitagliptin (10 mg/kg/day) reduced plasma urea and creatinine by 32% and 25% respectively and increased creatinine clearance by 248%. These findings suggest a renoprotective action of sitagliptin on adenine-induced CKD.
Asunto(s)
Adenina/toxicidad , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/prevención & control , Fosfato de Sitagliptina/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Sustancias Protectoras/uso terapéutico , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/patologíaRESUMEN
There is a worldwide increase in the popularity of water pipe (shisha) tobacco smoking including in Europe and North America. However, little is known about the effects of water pipe smoke (WPS) exposure on male reproductivity. We have recently demonstrated that WPS exposure in mice induces testicular toxicity including inflammation and oxidative stress. Nootkatone, a sesquiterpenoid found in grapefruit, has antioxidant and anti-inflammatory effects. However, the possible protective effect of nootkatone on WPS-induced testicular toxicity has not been reported before. Here, we tested the effects of treatment of mice with nootkatone on WPS-induced testicular toxicity. Mice were exposed to normal air or WPS (30 minutes/day, for 30 days). Nootkatone (90 mg/kg) was given orally to mice by gavage, 1 h before WPS or air exposure. Nootkatone treatment significantly ameliorated the WPS-induced increase in plasma levels of inhibin, uric acid, and lactate dehydrogenase activity. Nootkatone also significantly mitigated the decrease in testosterone, androgen-binding protein, and estradiol concentrations in the plasma induced by WPS. In testicular homogenates, WPS exposure caused a decrease in the total nitric oxide level and an increase in the proinflammatory cytokine interleukin-1ß level and oxidative stress markers including malondialdehyde, cytochrome C, and 8-Oxo-2'-deoxyguanosine. All the latter effects were significantly alleviated by nootkatone treatment. Moreover, in testicular homogenate, nootkatone inhibited the expression of nuclear factor-kappaB induced by WPS. Likewise, histological examination of mouse testes showed that nootkatone treatment ameliorated the deterioration of spermatogenesis induced by WPS exposure. We conclude that nootkatone ameliorated the WPS-induced testicular inflammation and oxidative stress and hormonal and spermatogenesis alterations.
Asunto(s)
Sesquiterpenos Policíclicos/uso terapéutico , Testículo/patología , Fumar en Pipa de Agua/efectos adversos , Animales , Masculino , Ratones , Sesquiterpenos Policíclicos/farmacologíaRESUMEN
This study aimed at investigating the possible ameliorative effects of sitagliptin in mice with gentamicin (GEN) nephrotoxicity. Sitagliptin was given to the animals at an oral dose of 10mgkg-1 per day for 10days, and in some of these mice, GEN was injected intraperitoneally at a dose of 100mgkg-1 per day during the last seven days of the treatment. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically by measuring several indices in plasma, urine and renal cortex homogenates. GEN treatment induced nephrotoxicity as evidenced by significantly (P<0.0001) increasing the plasma concentrations of urea, creatinine, circulatory cytokines, cystatin C, sclerostin, and TNFα. Treatment with GEN also significantly elevated urinary N-acetyl-ß-d glucosaminidase (NAG) concentration (P<0.0001). Moreover, GEN caused significant increase in oxidative stress in the kidneys (P<0.0001). Histopathological examination revealed massive tubular injury, necrosis, infiltration of inflammatory cells and intraluminal hyaline casts in mice treated with GEN. Sitagliptin alone did not significantly affect any of the indices measured. However, concomitant treatment with sitagliptin and GEN significantly mitigated most of the nephrotoxic actions of GEN. Pending further studies, sitagliptin may potentially be useful as a nephroprotectant agent.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Gentamicinas/toxicidad , Enfermedades Renales/prevención & control , Fosfato de Sitagliptina/farmacología , Administración Oral , Animales , Antibacterianos/administración & dosificación , Antibacterianos/toxicidad , Creatinina/sangre , Cistatina C/sangre , Citocinas/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Femenino , Gentamicinas/administración & dosificación , Inyecciones Intraperitoneales , Riñón/efectos de los fármacos , Riñón/patología , Corteza Renal/efectos de los fármacos , Corteza Renal/patología , Enfermedades Renales/inducido químicamente , Ratones , Estrés Oxidativo/efectos de los fármacos , Fosfato de Sitagliptina/administración & dosificación , Urea/sangreRESUMEN
Fructose administration can induce hypertension, insulin resistance and hypertriglyceridemia. Here, we investigated the possible protective effect of infliximab (IFX), a tumor necrosis factor alpha (TNF-α) inhibitor, or tocilizumab (TOC), an interleukin-6 (IL6) inhibitor, on fructose-induced increase in blood pressure, insulin resistance and hyperlipidemia in rats. The animals were fed a 60% fructose diet in the absence or presence of IFX (5â¯mg/kg, i.p., once weekly) or TOC (8â¯mg/kg, i.p., once every two weeks). Fructose significantly increased blood pressure, heart rate and homeostatic model assessment of insulin resistance (HOMA-IR). Fructose also significantly raised the concentrations of fasting plasma insulin, triglycerides, total cholesterol, uric acid, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), malondialdhyde (MDA) and nitric oxide. Fructose also significantly decreased plasma superoxide dismutase (SOD) and catalase activities. In addition, fructose significantly increased aortic endothelin and nitric oxide concentrations. Both IFX and TOC attenuated the fructose-induced increase in blood pressure, insulin resistance, and the concentrations of uric acid, MDA and IL-6. TOC significantly reduced fructose-induced increase in triglycerides and cholesterol. In addition, IFX increased plasma SOD and catalase activities. Our results showed that both IFX and TOC were partially successful in reversing fructose - induced changes.