Increase In Kidney Weight Research Articles

Protective Effect of Apelin-13 on Kidney and Platelet Functions in Adenine-Induced Chronic Renal Failure in Rats

AbstractBackground: Apelin and angiotensin I receptor-related protein J receptor (APJ) were found to be expressed in the kidney. Also, in cases of Chronic Renal Failure (CRF), platelet function was found to be affected. Apelin-13 treatment effect on both kidney and platelet functions in cases of CRF was not fully understood.Aim of Study: To investigate the possible protective effect of apelin-13 on kidney and platelet function in adenine-induced CRF in rats.Material and Methods: Rats were divided into three groups of eight rats each as follow: Intact control group received a standard diet for 28 days, adenine treated group received a standard diet added to it adenine (0.75% w/w) for 28 days, and adenine + apelin treated group received a standard diet added to it adenine as in the adenine treated group with a concomitant treatment with apelin-13 for 28 days. Apelin-13 was dissolved in saline immediately before use and was given at a dose of 5μg/kg body weight/day subcutaneously. 24-hour urine samples were collected, and 24-hour water intake was estimated on the 28th day of the study, while each rat was kept in a separate metabolic cage. The collected urine samples were measured for volume, total protein, and creatinine levels. After 28 days from the start of the experimental period, rats were fasted overnight, and their blood pressure was measured using the Power Lab. Blood samples were collected and a part of it was placed in heparinized tubes to investigate platelet indices and another part of blood was kept in non-heparinized tubes which were left to clot for 30min at room temperature. Clotted blood was centrifuged at 3000rpm for 15min. The supernatant serum was pipetted off using fine tipped automatic pipettes and stored at –20oC until assayed.Results: Treatment with adenine (0.75%, w/w) for 28 days caused a significant decrease (p<0.001) in Body Mass Index (BMI) and a significant increase (p<0.001) of the relative kidney weight when compared with that of the control group. On concomitant treatment with apelin-13 and adenine significantly mitigated (p<0.001) the adenine-induced reduction in BMI and the increase in relative kidney weight. Water intake and urine output of adenine treated rats were signifi-cantly higher (p<0.001) than that in control rats, while, simultaneous treatment with adenine and apelin-13 signifi-cantly decreased (p<0.001) both in comparison to adenine treated group. Also, in comparison with control group, the serum levels of creatinine, uric acid and urea were enhanced significantly (p<0.001) in adenine treated group, indicating that adenine-induced CRF model has been successfully estab-lished in this experiment. However, these enhancements were significantly decreased (p<0.001) by concomitant treatment with apelin-13. On the other hand, there was a significant decrease (p<0.001) in the creatinine clearance in adenine treated group in comparison to the control one, however, simultaneous treatment with adenine and apelin-13 signifi-cantly deteriorated this effect. Also, in this study, comparing to those of normal group, the Superoxide Dismutase (SOD) and Glutathione Reductase (GR) levels in adenine treated group were significantly decreased (p<0.001) while, Malonal-dehyde (MDA) was significantly increased (p<0.001). The alteration of SOD, GR and MDA serum levels was remarkably reversed by concomitant treatment with apelin-13. A significant increase (p<0.001) in platelet count, Mean Platelet Volume (MPV), Platelet Distribution Width (PDW) and plateletcrit, but a significant decline (p<0.001) in bleeding time in adenine treated group in comparison to the control one. These changes were significantly reversed (p<0.001) by the concomitant treatment with adenine and apelin-13 in comparison to the adenine treated group.Conclusion: Apelin-13 treatment improved both kidney and platelet functions, and may give a promising strategy for slowing the progression of CRF and its complications.

Pentoxifylline May Restore Kanamycin-Induced Renal Damage in Rats

Background: Kidney damage can be caused by many factors, such as using certain drugs in high doses or over the longterm. The use of one such group of drugs, aminoglycosides, which act as Gram-negative antibacterial therapeutic agents,can lead to nephrotoxicity. It has been hypothesized that aminoglycoside-induced nephrotoxicity might be prevented byusing pentoxifylline, which has antioxidant and anti-inflammatory effects and improves microcirculation. The objectiveof this present research was to determine the protective effects of pentoxifylline on kanamycin-induced kidney damage.Materials, Methods &amp; Results: Thirty-two male Wistar rats were divided into four groups as follows: control, pentoxifylline,kanamycin, and kanamycin + pentoxifylline. The control group received intraperitoneal (IP) injections of 0.5 mL normalsaline solution once a day (d) (SID) for 20 d; the pentoxifylline group received IP injections of 50 mg/kg pentoxifyllinetwice a day (BID) for 20 d, the kanamycin group received subcutaneous (SC) injections of 500 mg/kg kanamycin SID for20 d, and the kanamycin + pentoxifylline group received both SC injections of 500 mg/kg kanamycin SID and IP injectionsof 50 mg/kg pentoxifylline BID for 20 d. At the end of 20 d, blood samples were taken from the heart by cardiac punctureunder general anesthesia. After euthanizing the rats by cervical dislocation under anesthesia, the kidneys were immediatelyremoved, relative kidney weights were calculated, and routine pathologic evaluations were conducted. Hemogramparameters were measured using a blood cell count apparatus and serum biochemical parameters were measured usingan autoanalyzer. Kanamycin also caused (P &lt; 0.05) tubular degeneration and tubular dilatation. Although pentoxifyllinesignificantly reduced the level of kanamycin-induced tubular degeneration (P &lt; 0.05), it did not significantly reduce tubulardilatation. Increases in relative kidney weights (P &lt; 0.05) and in interstitial mononuclear cell (MNC) infiltrates wereobserved in the kanamycin and kanamycin + pentoxifylline groups compared to those in the control and pentoxifyllinegroups. Statistically significant changes were determined in the levels of some hemogram and biochemical parameterswithin reference ranges (P &lt; 0.05).Discussion: In this study, both tubular degeneration and dilatation were observed in the kanamycin group. Pentoxifyllineinhibited (P &lt; 0.05) kanamycin-induced tubular degeneration and appeared to also reduce tubular dilatation, although thisreduction was not significant. Tubular necrosis, epithelial edema of proximal tubules, tubular fibrosis, and perivascularinflammation might also be observed in aminoglycoside-induced nephrotoxicity. In current research, pentoxifylline preventedtubular damage induced by kanamycin, but did not inhibit infiltration by MNCs. Pentoxifylline also amelioratedamikacin- or gentamycin-induced histopathologic changes, especially those associated with tubular structures. The protectiveeffects of pentoxifylline on kanamycin-induced tubular nephrotoxicity in this research might be a result of its stimulatingthe production of prostaglandin, a vasodilator, and of its improving microcirculation. Although the anti-inflammatoryeffects of pentoxifylline have been reported, these did not inhibit kanamycin-induced infiltration by interstitial MNCs inthe present study. These results could indicate that the anti-inflammatory effects of pentoxifylline are not obvious and/orare dose dependent. Statistically significantly changes were determined in the levels of some hemogram and biochemicalparameters in reference ranges. However, these changes were within the reference ranges for rats. These results suggestedthat kanamycin-induced tubular degeneration and dilatation might be prevented by administering pentoxifylline.

Novel Rat Models of Diabetic Nephropathy Displaying Pronounced Tubular Fibrosis and Glomerular Alterations

Diabetic nephropathy (DN) is a long-term complication of diabetes characterized by proteinuria and loss of kidney function. Up to one third of patients with diabetes develop DN, and no new therapies targeting DN have been introduced for more than a decade. The lack of treatment options may, in part, be caused by the scarcity of translatable rodent models. We have established a surgically induced rat model of non-insulin dependent type 1-like diabetes (90% pancreatectomy, Px), displaying a stable blood glucose of &amp;gt;20 mmol/L. In addition, both Px and uninephrectomy (UNx) was performed simultaneously to potentially increase progression of renal pathological changes. Kidneys in the Px diabetic rat model displayed hypertrophy of glomeruli, cortex, and medulla 11 weeks post-surgery. Renal fibrosis was significantly increased in Px rats vs. nondiabetic control animals, as determined by quantitative histology following picro-sirius red staining of collagen (total kidney collagen, Px vs. controls; 127 ± 8 mg vs. 39 ± 5 mg, p&amp;lt;0.001). Plasma urea was increased in Px rats compared to nondiabetic animals (8.3 ± 0.6 vs. 5.5 ± 0.3 mmol/L, p&amp;lt;0.01). Finally, gene expression of the kidney injury markers NGAL and KIM1 as well as gene expression of pro-fibrotic macrophage markers (mannose receptor, MGL1, and CD163) was increased in Px rat kidneys. Px-UNx rats developed a diabetic phenotype similar to that observed in Px rats. In contrast, a highly increased kidney weight was detected with the more advanced surgical approach. Detailed histological analyses will establish whether glomerular and tubular pathology is exacerbated to a comparable extent. In conclusion, our data suggest that the Px model develops profound renal hypertrophy and fibrosis, and that renal hypertrophy is exacerbated in the Px-UNx model. Thus, Px alone and Px-UNx in rats may represent novel, strong alternatives to streptozotocin-induced diabetes and genetic models for the study of DN drug candidates. Disclosure T. Secher: Employee; Self; Gubra. Employee; Spouse/Partner; Novo Nordisk A/S. T.T. Johansen: None. M.V. Oestergaard: None. P.J. Pedersen: None. N.E. Zois: Employee; Self; Gubra. T.X. Pedersen: Employee; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Fosgerau: Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S.

Effects of β-glucan and Folium mori Extract Combinations in STZ-induced Diabetic Rats: Effectiveness of Various BGFM Complex Compositions in Treating Diabetes

Background: The hypoglycaemic effects of β-glucan (BG) extracts from some mushrooms and Folium mori (FM) has been reported. Objective: To determine the most effective composition of combined β-glucan originated from Aureobasidium and Folium mori extract (BGFM) for treating diabetes and complicated hepatopathy and nephropathy using streptozotocin (STZ)-induced diabetic rats. Methods: Six days after STZ dosing, rats (n = 5 per group) were selected based on body weight and blood glucose levels. BGFM was orally administered once a day for 28 days (Qd × 28), and changes in blood glucose levels, body weight, liver and kidney weight, and levels of serum blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured. Results: The diabetic control group exhibited dramatic decreases in body weight, and increase in liver and kidney weight, and blood glucose, serum BUN, creatinine, AST, and ALT levels compared to the non-diabetic sham group. However, these hyperglycaemic changes were markedly reduced in the Folium mori extract single group (S-FM) and some groups that received a mixed composition. Additionally, the changes related to the complicated hepatopathy and nephropathy of body weight were attenuated in the β-glucan single (S-BG) and some mixed groups compared to the diabetic control group. The anti-diabetic effects of β-glucan composition increased with its dose, and similarly, the hypoglycaemic effects of FM composition increased with its dose. Of the 11 types of mixed composition and single formulations, the BG:FM 1:4 composition was considered most effective for dual efficacy in terms of its hypoglycaemic and anti-diabetic effects. Conclusion: The greatest synergistic effects of the BGFM complex in treating the hyperglycaemic and complicated hepatopathy and nephropathy of STZ were obtained using a BG:FM 1:4 ratio.

Protective Effect of Ixora Coccinea Flowers against Cadmium Chloride induced Nephrotoxicity Model in Rats

The present study was carried out to evaluate the protective effects of the aqueous extract of Ixora coccinea flowers (AICF) against CdCl2 induced renal toxicity in rats. The study was performed using 30 (rats), divided into five groups i.e control group, CdCl2 treated group and plant extract at a dose of 100, 200 and 400 mg/kg body weight along with CdCl2 treated groups. The exposure to CdCl2 exhibit marked destruction in kidney function characterized by decrease in the body weight, increase in kidney weight and increase in serum creatinine, urea and uric acid levels, decrease of total protein levels and histopathological variations. The pretreatment of AICF at a dose of 100, 200 and 400 mg/kg body weight for eight days significantly improved the various biochemical parameters in a dose dependent manner. Furthermore, the histological alterations were also ameliorated by AICF. The AICF showed apparent dose dependent proactive effect on CdCl2 induced nephrotoxicity model in rats.

Bone Morphogenetic Proteins 2/4 Are Upregulated during the Early Development of Vascular Calcification in Chronic Kidney Disease.

Vascular calcification is a main cause of increased cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study aimed to investigate the role of the bone morphogenetic protein (BMP) signaling pathway in the early development of vascular calcification in CKD. A CKD vascular calcification rat model was established by providing rats with a 1.8% high-phosphorus diet and an intragastric administration of 2.5% adenine suspension. The kidney and aortic pathologies were analyzed. Blood biochemical indicators, serum BMP-2 and BMP-4 levels, and aortic calcium content were determined. The expression levels of BMP-2, BMP-4, bone morphogenetic protein receptor-IA (BMPR-IA), and matrix Gla protein (MGP) in aorta were examined by quantitative real-time polymerase chain reaction and immunohistochemistry. Compared with the normal control (Nor) rats, the CKD rats exhibited a significantly decreased body weight and an increased kidney weight as well as abnormal renal function and calcium-phosphorus metabolism. Aortic von Kossa and Alizarin red staining showed massive granular deposition and formation of calcified nodules in aorta at 8 weeks. The aortic calcium content was significantly increased, which was positively correlated with the serum BMP-2 (r = 0.929; P < 0.01) and serum BMP-4 (r = 0.702; P < 0.01) levels in CKD rats. The rat aortic BMP-2 mRNA level in the CKD rats was persistently increased, and the BMP-4 mRNA level was prominently increased at the 4th week, declining thereafter. Strong staining of BMP-2, BMP-4, BMPR-IA, and MGP proteins was observed in the tunica media of the aorta from the 4th week after model induction. In conclusion, activation of the BMP signaling pathway is involved in the early development of vascular calcification in CKD. Therefore, elevated serum BMP-2 and BMP-4 levels may serve as serum markers for CKD vascular calcification.

Protective Effect of Safflower Seed on Cisplatin-Induced Renal Damage in Mice via Oxidative Stress and Apoptosis-Mediated Pathways.

Cisplatin, a platinum chelate with potent antitumor activity against cancers of the testis, ovary, urinary bladder, prostate, and head and neck, has adverse effects on the kidney, bone marrow, and digestive organs, and its use is particularly limited by nephropathy as a side effect. In the present study, safflower seed extract was administered to a mouse model of cisplatin-induced acute renal failure to investigate its activity. Cisplatin (20[Formula: see text]mg/kg body weight) was administered by intraperitoneal injection to mice that had received oral safflower seed extract (100 or 200[Formula: see text]mg/kg body weight per day) for the preceding 2 days. Three days after the cisplatin injection, serum and renal biochemical factors; oxidative stress, inflammation, and apoptosis-related protein expression; and histological findings were evaluated. Cisplatin-treated control mice showed body-weight, food intake and water intake loss, and increased kidney weight, whereas the administration of safflower seed extract attenuated these effects ([Formula: see text], [Formula: see text]). Moreover, safflower seed extract significantly decreased the renal functional parameters urea nitrogen and creatinine in the serum ([Formula: see text] and [Formula: see text], respectively). Safflower seed extract also significantly reduced the enhanced levels of reactive oxygen species in the kidney observed following cisplatin treatment, with significance. The expression of proteins related to the anti-oxidant defense system in the kidney was down-regulated following cisplatin treatment, but safflower seed extract significantly up-regulated the expression of the anti-oxidant enzyme catalase. Furthermore, safflower seed extract reduced the overexpression of phosphor (p)-p38, nuclear factor-kappa B p65, cyclooxygenase-2, inducible nitric oxide synthase, ATR, p-p53, Bax, and caspase 3 proteins, and mice treated with safflower seed extract exhibited less renal histological damage. These results provide important evidence that safflower seed extract exerts a pleiotropic effect on several oxidative stress- and apoptosis-related parameters and has a renoprotective effect in cisplatin-treated mice.

The Potential Ameliorative Effect of Nano-Zinc and Zinc Against Copper Hepatorenal Toxicosis in Rats

This study was designed to evaluate the effect of Nano-Zinc (N-Zn) and Zinc (Zn) against copper (Cu) toxicosis in rats. Sixty male albino rats were randomly divided into 6 groups (n=10); control group, Cu-treated group: orally received CuSo4 (100 mg/kg bwt/day ), N-Zn-treated group: intraperitoneally (IP) injected with N-ZnO (5 mg/kg bwt/day), Zn-treated group: IP injected with ZnO (5 mg/kg bwt/day), Cu+N-Zn - and Cu+Zn -treated groups received the same previous doses and routes. All the experimental treatments were given 3 times / week and continued for eight weeks. Results showed that Cu- treated group caused a significant decrease in body weight and a significant increase in relative liver and kidney weights. Also, Cu caused a significant decrease in red blood cells (RBCs) count, hemoglobin (Hb) concentration, mean corpuscular hemoglobin concentration (MCHC) and platelets count with a significant increase in mean corpuscular volume (MCV) without any changes in leukocytic count. Biochemical analysis showed a significant elevation in serum liver enzymes, total and indirect bilirubin with a significant decrease in serum levels of total proteins and albumin. Also, there was a significant elevation in serum urea and creatinine levels. Cu induced a significant increase in renal and hepatic malondialdhyde (MDA) and a significant decrease in reduced glutathione (GSH). Histopathologically, Cu revealed severe degenerative and necrotic lesions in the livers and kidneys. N-Zn and Zn- treatments attenuated Cu-induced oxidative damage, alterations in the liver and kidney function tests and histopathology. Moreover, Zn treatment showed better protection against Cu-induced toxicity as compared to N-Zn.

Frankincense administration antagonizes adenine-induced chronic renal failure in rats

Background: Chronic renal failure (CRF) treatment through kidney transplantation or dialysis is restricted because of economic and medical resources deficiency. Thus, demand for using dietary supplements that can delete or ameliorate uremia or even to delay the need for dialysis is rising. Objectives: This study is the first one conducted to evaluate the efficacy of frankincense aqueous extract on CRF induced by adenine in rats. Materials and Methods: Forty male Sprague-Dawley rats were divided into four equal groups: control, frankincense, adenine, and frankincense + adenine. Kidney function tests, liver function tests, minerals' levels, antioxidant status, and histopathological alterations were investigated. Results: Results showed significant increases in relative kidney weight, serum level of urea, creatinine, blood urea nitrogen (BUN), uric acid, phosphorous, cholesterol, total bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in adenine group, as well as significant decreases in body weight, calcium, total protein, and albumin. Significant elevation was also demonstrated in lipid peroxidation marker associated with depletion in activities of superoxide dismutase (SOD) and catalase in tissues of kidney and liver. In addition, there were marked histopathological changes of kidney and liver. Conclusion: Study results demonstrated that co-administration of frankincense aqueous extract with adenine is an effective way to reduce the signs of adenine-induced CRF and have returned them to almost completely normal levels. Abbreviations used: CRF: Chronic renal failure; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; SOD: Superoxide dismutase; CKD: Chronic kidney disease; ROS: Reactive oxygen species; MDA: Malondialdehyde; H and E: Hematoxylin and eosin; BUN: Blood urea nitrogen; PTH: Parathyroid hormone.

Zinc supplementation alleviates the progression of diabetic nephropathy by inhibiting the overexpression of oxidative-stress-mediated molecular markers in streptozotocin-induced experimental rats

Zinc deficiency during diabetes projects a role for zinc nutrition in the management of diabetic nephropathy. The current study explored whether zinc supplementation protects against diabetic nephropathy through modulation of kidney oxidative stress and stress-induced expression related to the inflammatory process in streptozotocin-induced diabetic rats. Groups of hyperglycemic rats were exposed to dietary interventions for 6 weeks with zinc supplementation (5 times and 10 times the normal level). Supplemental-zinc-fed diabetic groups showed a significant reversal of increased kidney weight and creatinine clearance. There was a significant reduction in hyperlipidemic condition along with improved PUFA:SFA ratio in the renal tissue. Expression of the lipid oxidative marker and expression of inflammatory markers, cytokines, fibrosis factors and apoptotic regulatory proteins observed in diabetic kidney were beneficially modulated by zinc supplementation, the ameliorative effect being concomitant with elevated antiapoptosis. There was a significant reduction in advanced glycation, expression of the receptor of the glycated products and oxidative stress markers. Zinc supplementation countered the higher activity and expression of polyol pathway enzymes in the kidney. Overexpression of the glucose transporters, as an adaptation to the increased need for glucose transport in diabetic condition, was minimized by zinc treatment. The pathological abnormalities in the renal architecture of diabetic animals were corrected by zinc intervention. Thus, dietary zinc supplementation has a significant beneficial effect in the control of diabetic nephropathy. This was exerted through a protective influence on oxidative-stress-induced cytokines, inflammatory proliferation and consequent renal injury.

Efficacy of feed additives to reduce the effect of naturally occurring mycotoxins fed to turkey hen poults reared to 6 weeks of age

Corn with naturally occurring aflatoxin (AF), wheat with naturally occurring doxynivalenol (DON), and barley with naturally occurring zearalenone (ZEA) were used to make rations for feeding turkey hen poults to 6 weeks of age. Control rations with equal amounts of corn, wheat, and barley were also fed. The control rations did contain some DON while both sets of rations contained ZEA. Within each grain source, there were 4 treatments: the control ration plus 3 rations each with a different feed additive which were evaluated for the potential to lessen potential mycotoxin effects on bird performance and physiology. The additives were Biomin BioFix (2lb/ton), Kemin Kallsil (4lb/ton), and Nutriad UNIKE (3lb/ton). The mycotoxin rations reduced poult body weight (2.31vs. 2.08 ± 0.02kg) and increased (worsened) poult feed conversion (1.47vs. 1.51 ± 0.01) at 6 wk. Feeding the poults the mycotoxin feed also resulted in organ and physiological changes typical of feeding dietary aflatoxin although a combined effect of AF, DON, and ZEA which cannot be dismissed. The feed additives resulted in improved feed conversion to 6 wk in both grain treatment groups. The observed physiological effect of feeding the additives was to reduce relative gizzard weight for both groups and to lessen the increase in relative kidney weight for the birds fed the mycotoxin feed. In conclusion, the feed additives used in this study did alleviate the effect of dietary mycotoxins to some degree, especially with respect to feed conversion. Further studies of longer duration are warranted.

Manifestations of Renal Impairment in Fructose-induced Metabolic Syndrome.

IntroductionInternational studies show an increased incidence of chronic kidney disease (CKD) in patients with metabolic syndrome (MS). It is assumed that the major components of MS - obesity, insulin resistance, dyslipidemia, and hypertension - are linked to renal damage through the systemic release of several pro-inflammatory mediators, such as uric acid (UA), C-reactive protein (CRP), and generalized oxidative stress. The aim of the present study was to investigate the extent of kidney impairment and manifestations of dysfunction in rats with fructose-induced MS.MethodsWe used a model of high-fructose diet in male Wistar rats with 35% glucose-fructose corn syrup in drinking water over a duration of 16 weeks. The experimental animals were divided into two groups: control and high-fructose drinking (HFD). Serum samples were obtained from both groups for laboratory study, and the kidneys were extracted for observation via light microscopy examination.ResultsAll HFD rats developed obesity, hyperglycemia, hypertriglyceridemia, increased levels of CRP and UA (when compared to the control group), and oxidative stress with high levels of malondialdehyde and low levels of reduced glutathione. The kidneys of the HFD group revealed a significant increase in kidney weight in the absence of evidence of renal dysfunction and electrolyte disturbances. Under light microscopy, the kidneys of the HFD group revealed amyloid deposits in Kimmelstiel-Wilson-like nodules and the walls of the large caliber blood vessels, early-stage atherosclerosis with visible ruptures and scarring, hydropic change (vacuolar degeneration) in the epithelial cells covering the proximal tubules, and increased eosinophilia in the distant tubules when compared to the control group.ConclusionUnder the conditions of a fructose-induced metabolic syndrome, high serum UA and CRP correlate to the development of early renal disorders without a clinical manifestation of renal dysfunction. These phenomena are of particular importance for assessing the risk of developing future CKD.

A 90-day subchronic gavage toxicity study in Fischer 344 rats with 3-methylfuran

A 90-day gavage study was conducted with 0.0, 0.02, 0.075, 0.25, 1.0 and 4.0 mg/kg bw/day dose groups of 3-methylfuran to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects including changes in gross anatomy, histopathology, clinical biochemistry and hematology. There were significant changes in the serum clinical biochemistry markers related to liver injury where males were more affected than the females for most parameters analysed. The serum liver injury marker γ−glutamyltransferase, alanine and aspartate aminotransferases were significantly increased in males in the 4.0 mg/kg dose group. Alkaline phosphatase was increased in females and males. There were increases in both gross and histological lesions in the liver of both sexes in addition to statistical differences in female liver weights at the 4.0 mg/kg bw/day dose. Significant increases in spleen weights were found in both genders. This was accompanied by a dose–dependent atrophy of both B- and T-cell regions in which the males were more affected. There were no significant changes in male kidney weights but there was microscopically decreased protein in the proximal tubules and crowding of their nuclei in the 4.0 mg/kg bw/day dose group. There were also significant changes in the kidney serum biomarkers including various electrolytes, blood urea nitrogen, creatinine and uric acid. A small, but significant increase in female kidney weights was observed and which increase was accompanied by changes in electrolytes, kidney specific markers and a dose-dependent increase in mineralization. In both genders, amylase decreased whereas lipase increased but these were not accompanied by any histological changes in the pancreas.Histopathological changes in the liver were observed consistently in male and female rats in the 0.25 mg/kg dose group and higher. Hence, a lowest observed adverse effect level (LOAEL) of 0.25 mg/kg bw/d and a no observed adverse effect level (NOAEL) of 0.075 mg/kg bw/day are proposed for 3-methylfuran-induced hepatic lesions in this study. Benchmark dose modelling based on a BMR of 10% change in lesion incidence, generated BMDLs10 of 0.08 mg/kg bw/day in male rats and 0.05–0.17 mg/kg bw/day in female rats for increased incidence of liver lesions.

EFFECT OF SILYMARIN EXTRACTED FROM SILYBUM MARIANUM ON NICKEL HEMATOTOXICITY AND NEPHROTOXICITY IN MALE ALBINO WISTAR RATS

Objective: The objective of this study was to investigate the effect of silymarin extract from Silybum marianum against nickel-induced alterations in haematological indices, kidney dysfunction and renal antioxidant defence system.Methods: Male albino Wistar rats were divided into four groups seven each. Control, silymarin, nickel and nickel plus silymarin. Silymarin was administrated orally (100 mg/kg b. wt) and nickel as nickel sulfate (NiSO4 6H20) was given intraperitoneally (20 mg/kg b. wt) at alternative days. The experiment continued for three consecutive weeks. Body weight was recorded regularly. After overnight fasting, animals were killed and serum creatinine, serum urea, serum uric acid, hematological parameters and renal antioxidant markers were determined.Results: The treatment with nickel led to a significant decrease in body weight with an increase in both absolute and relative kidney weights and a significant increase in renal markers, which confirmed by histopathological alteration. A microcytic anemia was also observed, which was manifested by a reduction of red blood cells count (RBC), hemoglobin (Hb) concentration, platelet counts (Plt), hematocrit and white blood cells counts (WBC). The level of lipid peroxidation was increased. Whereas, GSH concentration and enzymatic antioxidants SOD, GSH-Px and CAT activities were decreased. The co-treatment with methanolic extract of milk thistle attenuated the variation in the hematological and renal markers, decreasing renal lipid peroxidation (p&lt;0.05) with a concomitant increasing reduced glutathione content (p&lt;0.01) and restoring the antioxidant enzymes (SOD, CAT, GSH-Px) in kidney, as well as an improvement in histological changes compared to those previously noticed in nickel group.Conclusion: To conclude, these findings demonstrated that silymarin extract effectively improved heamatotoxicity and nephrotoxicity caused by nickel.

Protective effect of proanthocyanidins against doxorubicin-induced nephrotoxicity in rats.

Doxorubicin (DOX) exerts toxic effects in several organs particularly kidney. The present study aimed to assess the protective effect of proanthocyanidins (PAs) against DOX-induced nephrotoxicity in rats. A single dose of DOX (7.5mg/kg, i.v.) significantly increased kidney weight, kidney/body weight ratio, serum urea, creatinine, tumor necrosis factor alpha levels, and kidney contents of malondialdehyde, nitric oxide, cyclooxygenase-2, and caspase-3 activity with significant reduction in final body weight, serum albumin, kidney contents of reduced glutathione (GSH), and superoxide dismutase activity as compared with control group. In contrast, pretreatment with PAs (200mg/kg, p.o.) for 14 days before DOX and for 7 days after DOX ameliorated kidney function and oxidative stress parameters. Histopathological evidence confirmed the protective effects of PAs from the tissue damage induced by DOX. In conclusion, PAs have a multi-nephroprotective effect that might be attributed to its antioxidant, anti-inflammatory, and antiapoptoic activities.

Re-evaluation of glutamic acid (E620), sodium glutamate (E621), potassium glutamate (E622), calcium glutamate (E623), ammonium glutamate (E624) and magnesium glutamate (E625) as food additives.

The EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion re‐evaluating the safety of glutamic acid–glutamates (E 620–625) when used as food additives. Glutamate is absorbed in the intestine and it is presystemically metabolised in the gut wall. No adverse effects were observed in the available short‐term, subchronic, chronic, reproductive and developmental studies. The only effect observed was increased kidney weight and increased spleen weight; however, the increase in organ weight was not accompanied by adverse histopathological findings and, therefore, the increase in organ weight was not considered as an adverse effect. The Panel considered that glutamic acid–glutamates (E 620–625) did not raise concern with regards to genotoxicity. From a neurodevelopmental toxicity study, a no observed adverse effect level (NOAEL) of 3,200 mg monosodium glutamate/kg body weight (bw) per day could be identified. The Panel assessed the suitability of human data to be used for the derivation of a health‐based guidance value. Although effects on humans were identified human data were not suitable due to the lack of dose–response data from which a dose without effect could be identified. Based on the NOAEL of 3,200 mg monosodium glutamate/kg bw per day from the neurodevelopmental toxicity study and applying the default uncertainty factor of 100, the Panel derived a group acceptable daily intake (ADI) of 30 mg/kg bw per day, expressed as glutamic acid, for glutamic acid and glutamates (E 620–625). The Panel noted that the exposure to glutamic acid and glutamates (E 620–625) exceeded not only the proposed ADI, but also doses associated with adverse effects in humans for some population groups.

Time-Dependent Alterations of Vancomycin-Induced Nephrotoxicity in Mice.

Vancomycin hydrochloride (VCM) is a glycopeptide antibiotic that is commonly used against methicillin-resistant, Gram-positive cocci despite the nephrotoxic side effects. VCM-induced nephrotoxicity has been reported in 5-28% of recipient patients. Therefore, renal failure induced by VCM has become an important clinical problem. However, the exceedingly complex mechanism of VCM-induced nephrotoxicity is not fully understood. Therefore, this study was designed to clarify time-dependent alterations of VCM-induced nephrotoxicity in mice as a step toward decreasing the risks of kidney injury associated with VCM therapy. VCM was injected intraperitoneally into mice at a dose of 400 mg/kg body weight at 24-h intervals for 3, 5, 7, and 14 d. At 24 h after the last injection, we examined histopathological alterations of the kidney as well as blood biochemistry. VCM administration resulted in a decrease of body weight and increase of kidney weight. Histological examination revealed renal damage such as dilated proximal tubules with occasional casts and interstitial fibrosis in VCM-treated mice. Furthermore, immunohistochemical staining with anti-CD10 and anti-single-stranded DNA antibodies highlighted damaged renal proximal tubules with marked dilatation as well as numerous apoptotic cells as early as day 4 of VCM-treatment. The severity of symptoms progressed until day 15. These results suggest that VCM-induced renal damage and incipient renal failure begin soon after the start of treatment and progressively worsen. This is the first report describing the time-dependence of VCM-induced nephrotoxicity in mice and depicting a model that clarifies the mechanisms of this tissue damage.

Effect of Nandrolone Decanoate (Anabolic Steroid) on the Liver and Kidney of Male Albino Rats and the Role of Antioxidant (Antox-Silymarin) as Adjuvant Therapy

Background and objective: The present study is determining the effect of Nandrolone Decanoate (ND) administration on the liver and kidney of white male albino rats. In addition, study the possible protective effect of administration of Antox and Silymarin on ND. Methods: The sample consisted of 110 male albino rats that divided into eleven groups treated by Nandrolone Decanoate at a dose of 7.93 mg/kg and 11.9 mg/kg then treated by Silymarin or Antox or both for 8 weeks. The variations in the body weight and weight of liver & kidney organs of rats are determined in all different groups in addition to the variation in liver enzymes (ALT-AST), bilirubin level, kidney function tests: Creatinine and blood urea level among different study groups are measured. The present study represents the hepatic and renal histological changes observed among the different groups. Results: The highest increase in liver weight the group was treated by ND low dose while the least value of liver weight noted at group is treated by ND high dose. The combination of Silymarin and Antox with ND at high and low dose showed the best results of liver weight. The highest increase in kidney weight showed at ND high dose group while the best result in reduce the kidney weight showed in rats treated by ND low dose with Antox. The highest increase of liver enzymes showed among ND high dose group while the more decrease in liver enzymes showed in groups treated with the combination of Silymarin and Antox with ND at low and high dose. The highest value showed in the group treated by ND high dose while the more decrease in kidney function tests showed in groups treated by the combination of Silymarin and Antox with ND at low and high dose. Conclusion: The combination of Silymarin and Antox with ND showed the best improvement in liver and renal tissue changes, these means synergistic action to protect the hepato-renal cells against harmful effect of ND by their antioxidant and free radical scavenging activities.

Acute and sub-chronic toxicity of Cajanus cajan leaf extracts

Context: The leaves of Cajanus cajan (L.) Millsp. (Fabaceae) have diverse bioactivities, but little safety data are reported. Objective: This study examines the toxicological profiles of C. cajan leaf extracts. Materials and methods: The leaves were extracted by water or 90% ethanol to obtain water or ethanol extract (WEC or EEC). EEC was suspended in water and successively fractionated into dichloroform and n-butanol extracts (DEC and BEC). Marker compounds of the extracts were monitored by high-performance liquid chromatography (HPLC). Kunming mice were administered with a single maximum acceptable oral dose (15.0 g/kg for WEC, EEC and BEC and 11.3 g/kg for DEC) to determine death rate or maximal tolerated doses (MTDs). In sub-chronic toxicity investigation, Sprague–Dawley rats were orally given WEC or EEC at 1.5, 3.0 or 6.0 g/kg doses for four weeks and observed for two weeks after dosing to determine toxicological symptoms, histopathology, biochemistry and haematology. Results: Flavonoids and stilbenes in the extracts were assayed. In acute toxicity test, no mortality and noted alterations in weight and behavioural abnormality were observed, and the maximum oral doses were estimated as MTDs. In sub-chronic toxicity study, no mortality and significant variances in haematological and biochemical parameters or organ histopathology were observed, but increased kidney weight in 3.0 g/kg WEC- or 3.0 and 6.0 g/kg EEC-treated female rats, and reduced testes and epididymis weight in EEC-treated male rats were recorded. These changes returned to the level of control after recovery period. Conclusion: Acute and sub-chronic toxicity of Cajanus cajan leaf extracts was not observed.

Transcriptional Profile of Kidney from Type 2 Diabetic db/db Mice.

Diabetic nephropathy (DN), a common diabetic microvascular complication, is characterized by progressive glomerular sclerosis and tubulointerstitial fibrosis. However, the underlying mechanisms involved in DN remain to be elucidated. We explored changes in the transcriptional profile in spontaneous type 2 diabetic db/db mice by using the cDNA microarray. Compared with control db/m mice, the db/db mice exhibited marked increases in body weight, kidney weight, and urinary albumin excretion. Renal histological analysis revealed mesangial expansion and thickness of the basement membrane in the kidney of the db/db mice. A total of 355 differentially expressed genes (DEGs) were identified by microarray analysis. Pathway enrichment analysis suggested that biological oxidation, bile acid metabolism, and steroid hormone synthesis were the 3 major significant pathways. The top 10 hub genes were selected from the constructed PPI network of DEGs, including Ccnb2 and Nr1i2, which remained largely unclear in DN. We believe that our study can help elucidate the molecular mechanisms underlying DN.