Nephroprotective effect of date fruit extract against dichloroacetic acid exposure in adult rats

The aim of this study was to investigate the protective effects of aqueous date extract (ADE) on dichloroacetic acid (DCA)-induced nephrotoxicity. In vitro, total phenolic content estimated in the ADE were 417.71 mg gallic acid equivalents/100 g fresh weights (FW), while total flavonoid and tannins contents were 285.23 and 73.65 mg catechin equivalents/100 g FW, respectively. The ADE has strong scavenging activity. Ferulic, caffeic and p-coumaric acids are the major’s compounds. Nephrotoxicity was induced in male Wistar rats by the administration of 0.5 and 2 g/L DCA as drinking water. Some of these rats received also by gavage ADE (4 mL/kg) before the administration of DCA. After two months of experiment, DCA administration caused elevated levels of renal MDA, significant depletion of GSH levels, altered the antioxidant enzyme activities and deteriorated the renal functions as assessed by the increased plasma urea, uric acid and creatinine levels compared to control rats. The treatment with the ADE significantly normalized the increased plasma levels of creatinine, urea and uric acid, reduced the elevated MDA levels, significantly normalized the antioxidant enzyme activities and GSH level and restored the altered kidney histology in rats treated with DCA. Therefore, it was speculated that ADE protects rats from kidney damage through its antioxidant capacity.     

Effect of oleuropein against chemotherapy drug-induced histological changes,oxidative stress,and DNA damages in rat kidney injury

Cisplatin-based chemotherapy is responsible for a large number of renal failures, and it is still associated with high rates of mortality today. Oleuropein (OLE) presents a plethora of pharmacological beneficial properties. In this study we investigated whether OLE could provide sufficient protection against cisplatin-induced nephrotoxicity. With this aim, Sprague-Dawley rats were divided into eight groups: control; 7 mg/kg/d cisplatin, 50 mg/kg, 100 mg/kg, and 200 mg/kg OLE; and treatment with OLE for 3 days starting at 24 hours following cisplatin injection. After exposure to the chemotherapy agent and OLE, oxidative DNA damage was quantitated in the renal tissue of experimental animals by measuring the amount of 8-hydroxy-2′-deoxyguanosine (8-OHdG) adducts. Malondialdehyde (MDA) level, total oxidative stress (TOS), and total antioxidant status (TAS) were assessed to determine the oxidative injury in kidney cells. The histology of the kidney was examined using four different staining methods: hematoxylin-eosin (H&E), periodic acid Schiff (PAS), Masson trichrome, and amyloid. In addition, the blood urea nitrogen (BUN), uric acid (UA), and creatinine (CRE) levels were established. Our experimental data showed that tissue 8-OHdG levels were significantly higher in the cisplatin group when compared to the control group. The glomerular cells were sensitive to cisplatin as tubular cells. In addition, treatment with cisplatin elevated the levels of BUN, UA, CRE, and TOS, but lowered the level of TAS compared to the control group. The OLE therapy modulated oxidative stress in order to restore normal kidney function and reduced the formation of 8-OHdG induced by cisplatin. Furthermore, the OLE treatment significantly reduced pathological findings in renal tissue. We demonstrate for the first time that OLE presents significant cytoprotective properties against cisplatin-induced genotoxicity by restoring the antioxidant system of the renal tissue. According to our findings, OLE is a promising novel natural source for the prevention of serious kidney damage in current chemotherapies.     

姜黄素对顺铂所致大鼠肾毒性的防护作用

目的研究姜黄素(CMN)对顺铂(CDDP)所致肾损害的防护作用,并探讨其可能机制。方法将42只大鼠按体重随机分6组,分别为对照组、CMN组、CDDP组、CMN(204、0和80 mg/kg) CDDP组。CMN连续给予大鼠灌胃3 d,第2天灌胃后1 h腹腔注射CDDP(5.5 mg/kg)。CDDP处理后,分别在第1、3和5天采血,测定血清尿素氮(BUN)和肌酐(CRE)。第5天采血后处死动物,测定肾脏系数、肾皮质匀浆丙二醛(MDA)、谷胱甘肽(GSH)含量和谷胱甘肽过氧化物酶(GSH-Px)活力以及肾组织铂(Pt)含量等。同时利用体外实验观察对抗增殖作用的影响。结果CMN预处理可减轻CDDP引起的肾脏系数升高及BUN、CRE水平升高;能抑制CDDP引起的MDA形成增高;并能提升CDDP引起的GSH含量和GSH-Px活力下降。CMN低剂量的上述作用明显(P<0.05或P<0.01)。CMN防护组与CDDP组的人卵巢癌细胞系和膀胱癌细胞系的半数抑制浓度差异无显著性。结论CMN经口给予能防护CDDP所致的肾损害,其机制可能与其抗氧化作用和清除自由基活性有密切关系。较高剂量CMN未见防护CDDP所致肾毒性的作用,其原因可能与其助氧化作用有关。CMN对CDDP抗肿瘤细胞增殖作用无明显影响。     

The impact of gallic acid on the methotrexate-induced kidney damage in rats

Prolonged use of an antineoplastic agent methotrexate (MTX), can cause numerous side effects such as nephrotoxicity. The aim of this study was to examine the effects of MTX on kidneys and demonstrate the protective effects of gallic acid (GA). Twenty-four, male, rats distributed into three groups. Each groups consisted eight rats and only saline was administered to the control group. The MTX group received a single dose (20 mg/kg) MTX intraperitoneally. The MTX + GA group received same dose MTX and 100 mg/kg GA orally during the 7 days. Renal functions, oxidative stress markers, histopathological and immunohistochemical changes were evaluated at the end of the experiment. Blood urea nitrogen, creatinine, uric acid levels and tissue oxidative stress markers, total oxidant status and oxidative stress index levels significantly increased and total antioxidant status levels significantly decreased in MTX group compared with the control group. At the histopathological examination hemorrhages, tubular cell necrosis, glomerulosclerosis, inflammatory cell infiltrations and proteinous materials in tubules were noticed in MTX group. Immunohistochemical examination revealed that increased expressions of serum amyloid A (SAA), tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE-2) and C-reactive protein (CRP) in tubular epithelial cells of kidneys in this group. There were no immunoreaction with SAA and CRP, only small number of PGE-2 and TNF-α positive tubular epithelial cells were observed in MTX + GA group. In conclusion, all evidence suggested that oxidative stress caused MTX-induced nephrotoxicity and GA prevent the kidney from the nephrotoxicity due to its antioxidant and anti-inflammatory activities.     

Role of non-selective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin-induced nephrogonadal toxicity in rats

1. It is well documented that cisplatin (CDDP) treatment increases the expression of adenosine A(1) receptors in both kidney and testes. However, the effect of adenosine at these receptors is controversial. Adenosine A(1) receptors have been documented to be involved in either cytoprotection or aggravation of nephrotoxicity. The aim of the present study was to examine the effect of the non-selective adenosine receptor inhibitor theophylline and the phosphodiesterase inhibitor pentoxifylline on CDDP-induced renal and testicular toxicity. 2. Male Wister rats were divided into six groups. Two control groups received plain drinking water and a third control group received theophylline 0.8 mg/mL in the drinking water for 2 weeks. One group of animals drinking plain water was injected intraperitoneally (i.p.) with pentoxifylline 50 mg/kg per day for 2 weeks. The remaining groups were treated in the same manner and received single dose of CDDP 7 mg/kg, i.p., 1 week after starting theophylline and pentoxifylline treatment and all animals were killed 1 week after CDDP treatment. 3. Rats treated with CDDP developed nephrotoxicity, as demonstrated by increased kidney and testes weight as a percentage of total bodyweight, blood urea nitrogen and serum creatinine levels and decreased serum calcium and albumin levels. In addition, CDDP treatment resulted in an increase in the production of malondialdehyde (MDA) and decreases in total nitrate/nitrite levels, as well as depletion of reduced glutathione (GSH) content and glutathione peroxidase (GPX) activity in both the kidney and testes. Administration of theophylline in the drinking water to CDDP-treated rats resulted in exacerbation of the indices of nephrotoxicity, depletion of GSH content and GPX activity levels, with increased MDA production and platinum accumulation in both the kidney and testes. However, pentoxifylline administration reduced CDDP-induced biochemical changes and reduced platinum accumulation in both organs. Histopathological examination of the kidney revealed that CDDP treatment produced multifocal tubular atrophy, atypical reparative changes of the tubular epithelium and marked tubular necrosis. Animals treated with the theophylline/CDDP combination showed extensive widespread damage with intratubular calcification. However, pentoxifylline treatment ameliorated the overt changes induced by CDDP treatment. 4. Theophylline exacerbates the deleterious effects of CDDP on rat kidney and testes. However, pentoxifylline alleviates CDDP-induced renal and testicular toxicity.     

Effect of dimethyl sulfoxide on gentamicin-induced nephrotoxicity in rats

Nephrotoxicity of gentamicin (GM) has been suggested to be mediated by the generation of reduced oxygen metabolites. The present study investigated the possible protective role of the free radical scavenger dimethyl sulfoxide (DMSO) on some indices of GM nephrotoxicity in rats. The antibiotic was injected intramuscularly (i.m.) at a dose of 100 mg/kg for six consecutive days, either with or without treatment with DMSO (12.5%, 25% or 50% in saline) at an intraperitoneal (i.p.) dose of 2 ml/kg 4 days before GM, and concomitantly with GM treatment thereafter. DMSO (25% in saline) was also given as above to rats treated with GM at i.m. doses of 25, 50 or 100 mg/kg for six consecutive days. GM caused dose-dependent significant increases in the concentrations of urea and creatinine in plasma, and in thiobarbituric acid reactive substances (TBARS) level in the kidney cortex and also caused significant decreases in the concentrations of reduced glutathione (GSH) and superoxide dismutase (SOD) activity. In GM-treated rats, DMSO dose-dependently lowered the elevated plasma urea and creatinine concentrations, and the rise in cortical TBARS. It also restored the levels of GSH and SOD activity to near normal. DMSO (25%) was effective in completely preventing the development of signs of nephrotoxicity of G (50 mg/kg). Treatment of the rats with DMSO alone, at any of the above doses, did not alter significantly any of the renal or hepatic function tests studied, and did not appear to adversely affect the kidney or liver histology. However, the efficacy and safety of DMSO require further studies. It is suggested that DMSO has potential protective effect against GM nephrotoxicity in rats.     

Protective effects of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice

Context: Currently, the outcomes of the use of cisplatin in cancer therapy is limited by nephrotoxicity.

Objective: This study aims to investigate the nephroprotective role of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice.

Materials and methods: Adult female Wistar Albino mice were divided into eight groups (n?=?8). Group I served as normal control. Groups II, III and IV received apigenin (3?mg/kg, i.p.), myricetin (3?mg/kg, i.p.) or their combination respectively, for seven days. Group V served as positive control group, received vehicles for seven days and cisplatin (7.5?mg/kg, i.p.) for three days starting at day five. Groups VI, VII and VIII received apigenin, myricetin or their combination, respectively for seven days as well as cisplatin injection for three days starting at day five. by the end of the experimental period, a biochemical study involving, nephrotoxicity markers [serum creatinine (Cr) and blood urea nitrogen (BUN)], apoptotic marker [caspase 3], inflammatory mediators [tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), cyclooxygenase I and II (COXI, COXII)] and oxidative stress biomarkers [malondialdehyde (MDA), reduced glutathione (GSH) and catalase] was conducted. In addition, renal histopathological alterations were evaluated.

Results: Apigenin, myricetin and their combination significantly reduced blood BUN, serum Cr, caspase-3TNF-α, IL-6, COXI and COXII, MDA levels and significantly increased GSH level and catalase activity parallel to, histopathological improvement in kidney tissues.

Discussion and conclusion: Apigenin and myricetin exhibited a protective and promising preventive strategy against cisplatin-induced nephrotoxicity due to their antioxidant and anti-inflammatory effects.     

Effect of sodium butyrate on gastric ulcer aggravation and hepatic injury inflicted by bile duct ligation in rats

Background and AimCholestasis is positively associated with an increased risk of peptic ulceration. The present study investigated the aggravating effect of cholestasis on piroxicam-induced gastric ulceration. The study also evaluated the effect of sodium butyrate (SoB) on piroxicam-induced gastric ulceration in cholestatic animals and its effect on hepatic tissues and both effects were compared to ursodeoxycholic acid (UDCA) as a standard anticholestatic drug.MethodsBile duct ligation was adopted for induction of cholestasis in rats. The cholestatic animals received saline, SoB (P.O, 400 mg/kg, twice daily) or UDCA (P.O, 30 mg/kg/day) for 4 days starting from the first day of surgery. On the 4th day, blood samples were collected for determination of serum hepatic markers, then gastric ulcers were induced by piroxicam administration (P.O, 50 mg/kg) and 4 h later, the stomach was isolated and gastric mucosa was collected for biochemical determinations. The ulcer indices for the investigated drugs were compared to omeprazole as a standard acid suppressive drug.ResultsPiroxicam-induced ulceration was exacerbated in cholestatic rats. Gastric mucosa showed a significant elevation of MDA and TNF-α together with a significant decrease in GSH &VEGF levels. SoB treatment significantly attenuated ulcer development. The afforded protection was higher than that provided by UDCA and was not significantly different from that afforded by omeprazole. SoB significantly decreased gastric mucosal MDA and TNF-α level, whereas UDCA failed to alter these parameters. Both drugs significantly elevated GSH, VEGF and IL10 levels. Similar to UDCA, SoB showed a significant reduction in AST, ALT, GGT, ALP and bilirubin level. Histopathological examination confirmed the attenuating effect of SoB on gastric and hepatic injury.ConclusionsSodium butyrate effectively protected gastric and hepatic tissues against cholestasis-induced damage. Gastroprotection was mediated through antioxidant, anti-inflammatory and angiogenic activities.     

Effects of gemcitabine on cisplatin-induced nephrotoxicity in rats: schedule-dependent study.

The effects of gemcitabine (dFdC) on the lipid peroxidation and kidney histopathology in the nephrotoxicity of an antitumour drug cisplatin (CDDP) were studied in rats. dFdC was administered intraperitoneally (i.p.) at single doses of 90 mgkg(-1) while CDDP was administered i.p. at single doses of 6 mgkg(-1). Both drugs were injected either alone or sequentially in combination. In one case, CDDP preceded dFdC by 4 h and 24 h and in the other case, dFdC preceded CDDP by 4 h and 24 h. Seven days after CDDP administration, the nephrotoxicity was manifested biochemically by elevation of serum creatinine, blood urea nitrogen and an increase in the kidney weight as a percentage of total body weight. In addition, marked decreases in serum albumin and calcium levels were observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde (MDA) production level and kidney glutathione (GSH) content, which were increased and depleted, respectively. Administration of dFdC 4 h and 24 h after CDDP administration did not significantly change the indices of CDDP-induced nephrotoxicity or the kidney platinum concentration levels in comparison with those animals treated with CDDP alone. On the contrary, administration of dFdC 4 h and 24 h prior to CDDP administration significantly aggravated CDDP-induced nephrotoxicity which was manifested by severe increases in the serum creatinine and blood urea nitrogen levels as well as kidney weight as a percentage of total body weight. In addition, kidney tissue showed severe GSH depletion and increases in the MDA production and platinum concentration levels. Moreover, treatment of rats with dFdC 24 h prior to CDDP resulted in much more aggravation of CDDP-induced nephrotoxicity in comparison with those animals treated with dFdC 4 h prior to CDDP. Histopathological examination demonstrated tubular atrophy, tubular necrosis and drug-induced nuclear changes in the CDDP-treated group. However, pretreatment of rats with dFdC 4 h and 24 h prior to CDDP revealed extensive interstitial nephritis, renal tubular atrophy and tubular necrosis with 'sloughing off' of the lining cells, especially with those rats treated with dFdC 24 h prior to CDDP. These results might suggest that administration of dFdC prior to CDDP enhanced the lipid peroxidation in kidney tissue and aggravated CDDP-induced nephrotoxicity.     

Ligustrazine modulates renal cysteine biosynthesis in rats exposed to cadmium

The objective of this study was to determine the effect of ligustrazine (TMP) on cadmium (Cd)-induced nephrotoxicity and its relevant mechanism. TMP (50 mg/kg) was injected intraperitoneally (i.p.) into rats 1 h prior to CdCl₂ exposure (at a Cd dose of 0.6 mg/kg). TMP reversed Cd-induced nephrotoxicity, evidenced by the relatively normal architecture of the renal cortex. Additionally, TMP alleviated renal oxidative stress of rats that were exposed to Cd, evidenced by the decreased levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), elevated levels of glutathione (GSH) and GSH/GSSG (glutathione disulfide) ratios. Furthermore, TMP also raised the decreased levels of S-adenosylmethionine (SAM) and cystathionine involved in cysteine biosynthesis in rats exposed to Cd. Further analysis revealed that TMP treatment upregulated expression of several proteins involved in cysteine biosynthesis including methionine adenosyltransferases (MATs) and cystathionine-beta-synthase (CBS). Taken together, these results suggest that TMP remodeled metabolomics of cysteine biosynthesis in rat kidneys and attenuated Cd-induced nephrotoxicity.     

Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions. Cisplatin (CDDP) elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion. Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis (NASH), however, associated changes to substrate toxicity is unknown. To test this, a methionine- and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics, transporter expression, and toxicity. NASH rats administered CDDP (6 mg/kg, i.p.) displayed 20% less nephrotoxicity than healthy rats. Likewise, CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min, renal secretion decreased from 6.23 to 2.80 mL/min, and renal CDDP accumulation decreased by 15%, relative to healthy rats. Renal copper transporter-1 expression decreased, and organic cation transporter-2 and ATPase copper transporting protein-7b increased slightly, reducing CDDP secretion. Hepatic CDDP accumulation increased 250% in NASH rats relative to healthy rats. Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats, although no drug-related toxicity was observed. These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance, which may alter nephrotoxicity.     

Protective effect of lycopene on gentamicin-induced oxidative stress and nephrotoxicity in rats

A potential therapeutic approach to protect or reverse gentamicin-induced oxidative stress and nephrotoxicity would have more importance for clinical consequences. Therefore, the present study was designed to investigate the possible protective effects of lycopene against gentamicin-induced renal damage in rats. Male Sprague-Dawley rats were divided into four groups of six rats in each one; first group served as control. The other groups were treated intraperitoneally with gentamicin alone (100 mg kg(-1) per day) for six successive days, gentamicin for 6 days following 10 days of orally lycopene (4 mg kg(-1) per day) pre-treatment and 6-days of simultaneous lycopene and gentamicin. Biochemical and histopathological examinations were utilized for evaluation of the oxidative stress and renal nephrotoxicity. Creatinine, urea, Na(+) and K(+) levels in plasma and malondialdehyde (MDA), reduced glutathione (GSH) levels and glutathione peroxidase (GSH-Px) and catalase (CAT) activities were determined in kidney tissue. Administration of gentamicin to rats induced a marked renal failure, characterized by a significant increase in plasma creatinine and urea concentrations. The animals treated with gentamicin alone showed a significantly higher kidney MDA and lower GSH-Px and CAT activities but unaffected GSH concentrations when compared with the control group. Pre-treatment with lycopene produced amelioration in biochemical indices of nephrotoxicity in plasma. However, little changes were observed in the kidney MDA and GSH levels and GSH-Px and CAT activities when compared with the gentamicin treated group. The histological structures of the renal proximal tubules showed similar patterns. On the other hand, administration of simultaneous lycopene to rats produced amelioration in MDA and GSH levels and GSH-Px and CAT activities when compared with gentamicin group. In addition, simultaneous lycopene was found to reduce the degree of kidney tissue damage in histopathological findings. These results indicate that specially simultaneous treatment of lycopene might have produced amelioration in biochemical indices and oxidative stress parameters against gentamicin-induced nephrotoxicity, but pre-treatments with lycopene had no beneficial effects on these parameters. It was concluded that lycopene as a novel natural antioxidant might have protective effects against gentamicin-induced nephrotoxicity and oxidative stress in rats.     

Preventive effect of tert-butylhydroquinone on cisplatin-induced nephrotoxicity in rats

Cis-diamminedichloroplatinum II (CDDP)-induced nephrotoxicity is associated with the overproduction of reactive oxygen species. tert-Butylhydroquinone (tBHQ) is a compound widely used as food antioxidant. The purpose of this study was to investigate the ability of tBHQ to prevent the nephrotoxic effect of CDDP in rats as well as the mechanisms involved. Thirty-six Wistar rats divided in the following groups were used: control, tBHQ (12.5 mg/kg), CDDP (7.5 mg/kg) and tBHQ + CDDP. Twenty-four h urine was collected at the beginning and at the end of the experiment and the rats were sacrificed 72 h after CDDP-administration. Histological studies were performed and markers of renal function and oxidative/nitrosative stress were measured. In addition, the activity of the following antioxidant enzymes was measured: glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione reductase (GR) and glutathione-S-transferase (GST). CDDP-induced renal dysfunction, structural damage and oxidative/nitrosative were prevented by tBHQ. In addition, tBHQ completely prevented the CDDP-induced fall in GPx and GST activities. In conclusion, the present study indicates that the antioxidant activity of tBHQ is associated with its nephroprotective effect against CDDP-induced acute kidney injury in rats.     

The effect of ascorbic acid supplementation on brain oxidative events in experimental diabetes

Increased oxidant stress plays an important role in the etiopathogenesis of chronic complications of diabetes. This study aimed to examine the effects of ascorbic acid (vitamin C, AA) supplementation on the oxidant and antioxidant processes in the brain of diabetic rats. Wistar albino rats were divided into four groups: group 1 (control), group 2 (ascorbic acid, AA, vitamin C), group 3 (diabetes), and group 4 (diabetes + AA). The rats were treated with a single dose of streptozotocin (45 mg/kg, intraperitoneal) to induce diabetes. After 48 h, the rats whose fasting blood glucose levels exceeded 200 mg/100 mL were included in the diabetes groups. The rats in the AA and diabetes + AA groups were treated with AA (20 mg/kg/day), administered intragastrically for 21 days. At the end of the experiment, malondialdehyde (MDA), glutathione (GSH), AA, and total nitric oxide (NOx) levels in the liver tissues were determined. Analysis of variance (ANOVA) and Mann–Whitney U tests were used for statistical analyses. Whereas the MDA levels increased in the diabetes group, the NOx levels decreased. The NOx levels increased in the diabetes + AA group compared with the control subjects. There were no significant differences in the diabetes + AA group in terms of GSH levels. In conclusion, vitamin C or vitamin C preparations may be beneficial in the treatment of diabetic patients for maintenance of the brain cells against oxidative damage.     

维生素C对顺铂所致大鼠肾损伤的保护作用

目的研究维生素C（Vit C）对顺铂所致肾损伤的保护作用,并探讨其可能的机制。方法将40只成年雌性SD大鼠按体重分成5组,分别为正常对照组（A组,生理盐水）、Vit C对照组（B组,500mg／kg）、顺铂化疗模型组（C组,6mg／kg）、顺铂（6mg／kg）＋Vit C（50mg／kg或500mg／kg）干预组（D1组及D2组）。腹腔注射Vit C进行前、中、后期全程保护,并于顺铂给药5d后采血处死动物,测定血清尿素氮（BUN）、肌酐（Cr）、肾皮质匀浆丙二醛（MDA）含量及谷胱甘肽过氧化物酶（GSH—Px）、超氧化物歧化酶（SOD）活力的变化。结果与C组相比,D1组及D2组的血清Cr及BUN、肾皮质匀浆MDA含量明显下降（P〈0．01或P〈0．05）,GSH—Px和SOD活力略有增加。结论Vit C可以减轻顺铂所致肾损伤,作用机制可能与其抗氧化作用和清除自由基活性密切相关。     

1,2-Diazole prevents cisplatin-induced nephrotoxicity in experimental rats

BackgroundCisplatin (a platinum-compound) is a anti-neoplastic drug used in the treatment of various cancers but eventually results in severe adverse effects namely nephrotoxicity or renal disorder through generation of reactive oxygen species (ROS). This biochemical measurements and histopathology analysis investigated a possible protective effect of 1,2-diazole with regards to cisplatin-induced nephrotoxicity in experimental animals.MethodsAnimals were divided into four groups of six mice each. Group A: normal control, vehicle (1 % (w/v) gum acacia in phosphate buffer saline (PBS)). Group B: cisplatin group, vehicle + cisplatin (7.5 mg/kg). Group C: 1,2-diazole (10 mg/kg) + cisplatin and Group D: silymarin (50 mg/kg) + cisplatin. Each vehicle/drug treatment was given daily via intraperitoneal (ip) injection for 10 consecutive days starting from day 1. On group B, C and D cisplatin was given in single dose only on day 5 one hour post drug administration. Animals were allowed till 10^th day and on day 11 all four groups animals were anesthetized. Blood samples were collected and serum was isolated for biochemical measurements. The rats were then euthanized by cervical dislocation and their kidney was recovered and then prepared for biochemical measurements and histopathology analyses.ResultsPretreatment with 1,2-diazole prevented nephrotoxicity induced by cisplatin through a protective mechanism that involved reduction of increased oxidative stress by significantly increasing the enzymatic and non enzymatic antioxidant enzymes such as glutathione peroxidase (GPx), glutathione (GSH) and diminishing the lipid peroxidation (LPO). The pretreatment with 1,2-diazole does not affect superoxide dismutase (SOD), catalase (CAT), serum urea and creatinine level during nephrotoxicity when compared to cisplatin-induced group. Moreover, the 1,2-diazole animals shown significant decrease in urine volume and kidney weight when compared with cisplatin-induced group. Histopathological findings reveals the protective efficacy of 1,2-diazole that restores histopathological changes against nephrotoxicity.ConclusionThese analysis will provide a critical evidence that 1,2-diazole could provide a new protective strategy against cisplatin-induced nephrotoxicity.     

cis-Dichlorodiammineplatinum nephrotoxicity: Time course and dose response of renal functional impairment

Although administration of cis-dichlorodiammineplatinum (CDDP) is known to induce acute proximal tubular necrosis, more subtle functional damage of the kidney could occur. This study was initiated to examine the renal functional correlates of CDDP nephrotoxicity in male F-344 rats receiving a single iv dose of 0, 1.25, 2.5, 5, 10, or 15 mg/kg CDDP. When compared to pair-fed controls, the following effects were observed 2 days following CDDP treatment: (a) increased 24-hr uv (5, 10, and 15 mg/kg), (b) reduced U_osm (2.5 and 5 mg/kg), (c) increased 24-hr urinary K⁺ excretion (10 and 15 mg/kg), (d) glucosuria, accompanied by hyperglycemia (10 and 15 mg/kg), and (e) elevated BUN (15 mg/kg). On Day 4, increased 24-hr uv and reduced U_osm persisted in surviving drug treated animals (2.5 or 5 mg/kg). In addition, glucosuria, unaccompanied by hyperglycemia, was observed in the 2.5 and 5 mg/kg group and an elevated BUN was apparent only in the latter treatment group. C_inulin (GFR) and C_PAH (ERPF) were significantly compromised in drug-treated animals (5 mg/kg) on Day 4, findings consistent with the increased BUN. CDDP administration did not impair the ability of renal cortical slices to accumulate a prototype organic anion (p-aminohippurate) or cation (tetraethylammonium) in vitro on Day 4. However, accumulation of these organic ions was significantly depressed in kidney slices obtained from untreated animals when 500 or 600 μg/ml CDDP was added to incubation medium. Inasmuch as alterations in urinary excretory function, but not BUN, were apparent in the lower dosage groups on Day 2, these results suggest that urine analyses may provide a more sensitive test for the early detection of CDDP nephrotoxicity than the commonly used measurement of BUN.     

In vitro and in vivo toxicity evaluation of cationic PDMAEMA-PCL-PDMAEMA micelles as a carrier of curcumin

Polymeric micelles have attracted significant attention because of their potential application as promising drug-delivery systems. In the present study cationic micelles, based on triblock copolymer poly(dimethylaminoethyl methacrylate) - poly(e-caprolactone) - poly(dimethylaminoethyl methacrylate) were prepared and loaded with curcumin. In vitro cytotoxicity of empty and curcumin loaded polymer micelles was investigated on two cell culture models, human hepatoma cell line HEP G2 and freshly isolated rat hepatocytes, following their viability and lactate dehydrogenase (LDH) leakage. MTT dye reduction assay and LDH release study showed that empty cationic micelles did not cause significant changes in cell viability and membrane integrity at the concentration range from 10.0 to 80.0 μg/ml. Our special attention was focused on the effects of empty and curcumin loaded micelles on oxidative stress markers malondialdehyde (MDA) and reduced glutathione (GSH). The increase in the micelles concentration to 100 μg/ml was accompanied by GSH depletion and increased levels of MDA production in isolated rat hepatocytes. The in vivo toxicity of polymeric micelles was examined in male Wistar rats. The results showed that neither single (7.5 mg/kg, i.p.), nor repeated (3.5 mg/kg, i.p., 14 days) exposure to empty or curcumin loaded polymeric micelles induced any toxicity changes, e.g. hematopoietic and liver tissue damages.     

The Role of Urotensin Receptors in the Paracetamol‐Induced Hepatotoxicity Model in Mice: Ameliorative Potential of Urotensin II Antagonist

We aimed to evaluate the possible protective effect of a UTR antagonist and to determine the effect of the antagonist on ALT and AST levels in serum, the mRNA expression level of UTR, tumour necrosis factor‐alpha (TNF‐α) and IL‐1β and SOD activity, GSH and MDA levels in liver tissues, which are important mediators or markers for the hepatotoxicity animal model in mice. Animals fasted overnight and were divided into seven equal groups (n = 12). The first group was the healthy group (administered 0.1% DMSO intraperitoneally). Group 2 received only paracetamol (PARA) (administered orally at a dosage of 300 mg/kg). Groups 3 and 4 were treated with only AGO (AC7954, UTR agonist) 15 and 30 mg/kg intraperitoneally, respectively. Groups 5 and 6 were treated with only ANTA (SB657510, UTR antagonist) 30 and 60 mg/kg intraperitoneally, respectively. Group 7 was treated with AGO 30 mg/kg and ANTA 60 mg/kg intraperitoneally. One hour after the pre‐treatment drugs were administered, groups 3 through 7 were given PARA. After the experimental period, the mice were killed 6 and 24 hr after PARA was administered. Antagonist administration significantly decreased the ALT and AST levels, while agonist administration did not. In addition, SOD activity and GSH levels increased, and the MDA level decreased with the pre‐treatment of two antagonist doses. The increased UTR gene expression through PARA was significantly lower in both doses of the antagonist groups at 24 hr when compared with the agonist and PARA groups. This study showed that UTR antagonists have hepatoprotective and anti‐inflammatory effects on high‐dose PARA‐induced hepatotoxicity in mice.     

Caffeic acid phenethyl ester ameliorates imidacloprid-induced acute toxicity in the rat cerebral cortex

This study aimed to investigate the role of caffeic acid phenethyl ester (CAPE), a compound found in propolis, on imidacloprid (IMI), a nicotinic acetylcholine receptor agonist that causes cerebral toxicity. 60 adult rats were randomly divided into five groups: control, IMI (100 mg/kg), and IMI+CAPE (1, 5, 10 mg/kg). Cerebral cortex tissue was examined histopathologically, biochemically, spectrophotometrically and immunohistochemically. The results showed that IMI caused toxicity in the cerebral cortex. However, CAPE (5 and 10 mg/kg) attenuated the deteriorated histopathological score and normalized the apoptotic markers (Bax and Caspase-3). Additionally, CAPE dose-dependently normalized the levels of TNF-α, dopamin, GFAP and NGF, and at the highest dose (10 mg/kg) also normalized the balance of oxidative parameters (MDA, SOD, CAT, and GSH). In conclusion, the antioxidant, anti-inflammatory, and anti-apoptotic effects of CAPE may be a promising treatment for acute IMI-induced cerebral cortex toxicity.