Antioxidant preserving effects of l-arginine at reducing the hemodynamic toxicity of gentamicin-induced rat nephrotoxicity: pathological and biochemical findings

Nephrotoxicity results from an abrupt decline in glomerular functions of the kidney and is regarded as a major cause of concern for limiting therapeutic uses of gentamicin in hospital settings. Recent evidences suggest that both endothelial nitric oxide synthesis (eNOS) and inducible NOS (iNOS)-derived nitric oxide (NO) vasodilators reduce renal toxicity, restoring normal glomerular functions and hemodynamic stability, but this has not been adequately investigated in gentamicin nephrotoxicity. To determine the isoform of NOS that plays a predominant role in the control of glomerular vasodilation under the oxidative stress of nephrotoxicity, we conducted a controlled, randomized study in five equal groups of ten Sprague–Dawley rats. All animals were given a corresponding dose of either normal saline, only l-arginine, only gentamicin, or a combination thereof with and without N-3-aminomethyl benzylacetamidine (a selective iNOS inhibitor, 1400W) for 9?days. After 6?days, gentamicin-treated rats developed nephrotoxic alterations evident by a significant fall in renal blood flow and glomerular filtration rate, increased urinary excretion of gamma glutamyl transpeptidase and serum concentration of inflammatory interleukins (IL-6 and IL-8) as well as a decrease in the tissue antioxidant activity of superoxide dismutase. Changes in these biochemical variables were completely inhibited by supplemented l-arginine up to 9?days. However, a combination of 1400W partially removed protective effects of l-arginine on the glomerular hemodynamics of the kidney. Our results suggest that at irradiation of eNOS developed by increased oxidative process, administration of l-arginine increases iNOS-derived NO production and glomeruli infiltration on its direct antioxidant effects counteracting the undesirable effects of peroxynitrite formation on the kidney.     

Electron microscopic evaluation of milk thistle,chicory, and vitamin E effects on gentamicin-induced nephrotoxicity in rat

Gentamicin is an aminoglycoside with nephrotoxic effects; however, it seems that antioxidants such as vitamin E, milk thistle, and chicory extracts can reduce these effects. To test this, 60 male Wistar rats (200–250 g) were randomly allocated into six groups (n = 10). Each animal received intraperitoneal injections daily for 14 days: group 1—distilled water (1 ml) (control); group 2—gentamicin; group 3—gentamicin and milk thistle; group 4—gentamicin and chicory; group 5—gentamicin and vitamin E; and group 6—gentamicin, vitamin E, milk thistle, and chicory. At termination, blood was taken, to measure the serum levels of blood urea nitrogen (BUN) and creatinine, and the kidneys were taken, sampled, and processed for examination using a transmission electron microscope. Using milk thistle, chicory and vitamin E all showed a decrease in both dense bodies and damage to the nucleus. These observations were more pronounced in the group that received milk thistle, chicory, and vitamin E together. The levels of BUN and creatinine in all treatment groups were significantly lower compared to those of the gentamicin group (group 2). In conclusion, milk thistle, chicory, and vitamin E, individually, can reduce kidney damage caused by gentamicin, but they have a greater effect in reducing damage if used together.     

Effects of co-supplementation of vitamins E and C on gentamicin-induced nephrotoxicity in rat

Gentamicin (GM) is an effective antibiotic against severe gram-negative infections. However it can produce nephrotoxicity in human. Reactive oxygen species (ROS) have been proposed as the causative factors of the renal side effects the drug. This study was performed to investigate the protective role of antioxidant vitamins against GM-mediated nephropathy in an in situ model of isolated rat kidney. Male Sprague-Dawley rats were randomly assigned to one of the following groups of seven rats: group 1 (Control) was perfused with Tyrode solution; group 2 (GM), 200 microg ml(-1) GM was added to the perfusate; group 3 (GM + Vit C), as group 2 with vitamin C added to the drinking water for 3 days (200 mg l(-1)) and to the perfusate (100 mg l(-1)); group 4 (GM + Vit E), as group 2 with vitamin E (100 mg (100 g body weight)(-1), i.m.) injected 12 h before the start of the experiment; group 5 (GM + Vit C + Vit E) as group 2 with vitamin E and C co-administered (concentrations and conditions as in groups 3 and 4). To compare the groups, urinary lactate dehydrogenase (LDH), N-acetyle-beta-D-glucosaminidase (NAG) and alkaline phosphatase (ALP) activities, inulin clearance (glomerular filtration rate, GFR) and renal tissue glutathione (GSH) content were measured. GM caused a significant nephrotoxicity demonstrated by an increase in urinary LDH, NAG and ALP activities. Reduction in GSH content and a marked decrease in GFR were observed compared to controls. Vitamin C inhibited the GM-induced increase in urinary enzyme activities but did not show a significant effect on the GSH content or GFR. Vitamin E prevented the GM-induced reduction in GSH level without a significant improvement in GFR. Co-administration of vitamins C and E significantly prevented the GM-induced nephrotoxicity demonstrating by preservation of GFR and GSH levels and prevention of increase in urinary enzyme activities. We conclude that co-administration of moderate doses of vitamins C and E has beneficial effects on renal preservation in GM-induced nephrotoxicity.     

Protective effects of corn silk extract administration on gentamicin-induced nephrotoxicity in rat

The objective of this study was to evaluate effect of corn silk against gentamicin (GM)-induced nephrotoxicity. Sixty Wistar rats were divided into ten equal groups as follow: (1) control group, 0.1 ml/kg given intraperitoneally (i.p.) per day of isotonic saline. (2) GM group, 100 mg/kg i.p. per day of GM. (3) corn silk groups (3–6), 200, 300, 400, and 500 mg/kg, i.p. (4) Corn silk + GM groups (7–10), corn silk extract was injected the same as corn silk groups and after1 h, 100 mg/kg GM was injected i.p. to rats. All animals were treated for 8 days. Plasma creatinine and urea levels significantly increased in GM group. Corn silk administration (200 and 300 mg/kg) with GM injection significantly decreased serum creatinine, but not urea, levels compared with GM group. Acute tubular necrosis (ATN), hyaline casts in tubular lumen, interstitial nephritis, and glomerular changes were histopathologically detected in the GM group. Co-treatment of corn silk with GM considerably decreased the interstitial nephritis, but not ATN and hyaline casts formation, compared with the GM group. Also, high dose of corn silk caused hyaline cast formation, apoptosis, congestion, and swelling of renal tubules. In conclusion, the results showed that corn silk may ameliorate nephropathy during prolonged therapeutic use of GM and related aminoglycosides.     

Antioxidant protecting effects of vitamin B6 at reducing hemodynamic toxicity of gentamicin in rat model of nephrotoxicity

Routine therapeutic use of gentamicin in patients with preexisting renal failure may confront us with the toxic effects of aminoglycosides in the kidney known as nephrotoxicity. It is a common and often overlooked clinical entity that presents itself in the setting of oxidative stress-associated diseases in older individuals with renal failure. In this study, we investigated the antioxidant protecting effects of vitamin B₆ in the kidney, with a view on vasoregulatory role of renal pyridoxal 5′-phosphate at reducing the hemodynamic toxicity of gentamicin. Hence, 50 male Sprague–Dawley rats were randomly assigned in five groups to receive a corresponding dose of either normal saline, vitamin B₆ (100 mg/kg/bw; i.m.) or gentamicin alone (80 mg/kg/bw; i.m.), or in combination with vitamin B₆ at low (100 mg/kg/bw; i.m.) and high dose (200 mg/kg/bw; i.m.) for 10 days as animal model of nephrotoxicity. Daily administration of gentamicin at a dose of 80 mg/kg resulted in a significant increase in local and systemic oxidative stress and a decrease in glomerular functions as result of early hemodynamic toxicity. Histopathological examinations of renal tissues revealed acute tubular necrosis with hyaline cast formation triggered by gentamicin over 9 days of the experiment, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies in HVB group showed the protecting effects of supplemented vitamin B₆ at a high dose, including a slowdown in urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and ATPase activity up to 50 % when compared to low-dose rats and controls. In high-dose animals, normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that antioxidant properties of vitamin B₆ consistently increase with dose intensity. The present study also provided evidence that high dose of vitamin B₆ prevented both functional and histological renal changes induced by gentamicin in rats, more efficient than low dose of the vitamin.     

Protective effects of nigella sativa against gentamicin-induced nephrotoxicity in rats

The aim of this study was focused on investigating the possible protective effect of NS against GS-induced nephrotoxicity. Twenty four Wistar-albino rats were divided into four equal groups as follows: control group, GS group (100 mg/kg intraperitoneal – i.p.), NSL+GS group (0.2 ml/kg+100 mg/kg i.p.) and NSH+GS group (0.4 ml/kg+100 mg/kg i.p.). Plasma creatinine and urea levels significantly increased as a result of nephrotoxicity in the GS group. Also, creatinine and urea levels significantly decreased in NSL+GS and NSH+GS groups. In the GS group, plasma MDA and NO levels increased significantly (p<0.05) and erythrocyte SOD and GSH-Px activities decreased significantly (p<0.05) when compared with control group. NS administration with GS injection resulted in significantly decreased MDA and NO generation and increased SOD and GSH-Px activities when compared with GS group. Proximal tubular necrosis, vacuolation, desquamation and degeneration in epithelial cells of the proximal tubules, hyaline casts in tubular lumen, mononuclear cell infiltration, glomerular and basement membrane alterations were histopathologically detected in the kidneys of the GS group. Co-treatments with NS (low and high dose) considerably decreased the renal damage when compared with the GS group. In conclusion, NS acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GS both in the biochemical and histopathological parameters.     

Vitamin B6 dose-dependently ameliorates renal hemodynamic toxicity of cisplatin in rat model of nephrotoxicity: the histopathologic and biochemical findings

Despite its significant anticancer activity, the clinical use of cisplatin is often limited by its undesirable side effects in the kidney known as nephrotoxicity. It is a common and often overlooked clinical entity that presents itself in the setting of oxidative stress-associated diseases in older individuals with renal failure. In this study, we investigated the antioxidant-protecting effects of vitamin B₆ in the kidney, with a view on the vasoregulatory role of renal pyridoxal 5′-phosphate at reducing the hemodynamic toxicity of cisplatin. Hence, 50 male Sprague–Dawley rats were randomly assigned in one of five groups of the study to receive a corresponding dose of either normal saline, vitamin B₆ (200 mg/kg/bw; i.m.) or cisplatin alone (7 mg/kg/bw; i.m.), or in combination with vitamin B₆ at low (100 mg/kg/bw; i.m.) and high dose (200 mg/kg/bw; i.m.) for 10 days as animal model of renal failure. Daily administration of cisplatin at a dose of 7 mg/kg/bw resulted in a significant increase in local and systemic oxidative stress of the kidney and a decrease in glomerular function as a result of early hemodynamic toxicity. Histopathological examinations of renal tissues revealed acute tubular necrosis with hyaline cast formation triggered by cisplatin over 9 days of the study, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies in HVB group showed the protecting effects of supplemented vitamin B₆ at a high dose, including a slowdown in urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and ATPase activity up to 50 % when compared to the low-dose rats and controls. In high-dose animals, the normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that the antioxidant property of vitamin B₆ consistently increases with the dose intensity. The present study also provided evidence that high dose of vitamin B₆ prevented both functional and histological renal changes induced by cisplatin in rats, more efficient than low dose of the vitamin.     

Vitamin C dose-dependently ameliorates renal hemodynamic toxicity of cisplatin in adult Swiss albino rats: a histopathologic and biochemical study

Nephrotoxicity is usually thought of as a common invariable consequence of hemodynamic toxicity whose effects, including oliguria and dysuria, has largely limited the clinical use of cisplatin. In this study, we investigated the protective effects of low and high dose of vitamin C against cisplatin-induced rat nephrotoxicity. Hence, 50 adult male Swiss albino rats were randomly divided into five equal groups to receive a corresponding dose of either normal saline as control, vitamin C (600 mg/kg/BW, i.v.), or cisplatin alone (7 mg/kg/BW, i.p.) or in combination with vitamin C at low dose (200 mg/kg/BW, i.v.) and high dose (600 mg/kg/BW, i.v.) for 9 days. Daily administration of cisplatin at a dose of 7 mg/kg/BW resulted in a significant increase in oxidative stress in renal tissues and plasma and a concomitant decrease in the creatinine clearance and renal blood flow as a result of early hemodynamic toxicity. Histopathological examination revealed acute tubular necrosis with hyaline cast formation triggered by cisplatin over 9 days of experiment. Further biochemical studies showed protecting effects of supplemented vitamin C at a high dose, illustrated by slowdown in the urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and the ATPase activity up to 50 % when compared to controls and rats receiving low-dose. In high-dose animals, normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that antioxidant property of vitamin C increases with dose, and, therefore, high dose of vitamin C prevents both functional and histological renal changes induced by cisplatin in rats, more efficient than low dose of the vitamin.     

Exaggerated response to gentamicin-induced nephrotoxicity in Sprague-Dawley rats: identification of a highly sensitive outlier population

A number of factors have been shown to predispose patients treated with aminoglycosides to nephrotoxicity. In a previous study in our laboratory investigating the interaction of prior renal dysfunction with gentamicin toxicokinetics, 9.4% of rats in all treatment groups were relatively more sensitive to gentamicin-induced nephrotoxicity. To determine if these outliers had an underlying disease or physiological abnormality, serum was collected from 99 Sprague-Dawley rats prior to daily treatment with 75 mg/kg gentamicin for seven days. Urea nitrogen, creatinine, Na, K, Ca, Mg, P, total protein, albumin, aspartate transaminase, serum osmolality, total white and red blood cell count, hematocrit, hemoglobin, blood gases, and thyroxine were measured. Blood was collected one and four hours after the first dose of gentamicin for pharmacokinetic analysis. Elevations in post-treatment creatinine and nitrogen were significantly greater in the outliers (4.10 +/- 0.24 mg/dl (n = 12) vs 1.92 +/- 0.06 mg/dl (n = 87) and 146.4 +/- 7.2 mg/dl (n = 12) vs 71.5 +/- 2.0 mg/dl (n = 87); both p = 0.0001) and served as criteria for identifying this subgroup. Post-treatment creatinine and urea nitrogen were not normally distributed in the entire study population. However, when the population was divided into normal and sensitive subgroups, both subgroup values were normally distributed. The gentamicin pharmacokinetic profiles were similar in both groups. Postmortem histopathology showed significant increases in tubular casts and tubular necrosis (p = 0.01) in the sensitive rats, compared to the normally responding subgroup.(ABSTRACT TRUNCATED AT 250 WORDS)     

Model of gentamicin-induced nephrotoxicity and its amelioration by calcium and thyroxine

The exact mechanism of gentamicin-induced acute renal failure is presently unknown; various mechanisms have been proposed but there is no proposed commonality between them. In animals, dietary calcium loading and L-thyroxine administration have been shown to ameliorate toxicity, with again no common process. A mechanism of competitive displacement of calcium and other cations from anionic phospholipids at the plasma and organelle membrane level, resulting in a decrease in Na+ -K+ ATPase, adenylate cyclase, mitochondrial function and ATP production, protein synthesis, solute reabsorption and overall cellular function is proposed. A further proposal is dietary calcium loading and thyroxine (which increases intracellular calcium) reverse gentamicin-induced acute renal failure by increasing the calcium and solute flux, thereby competitively inhibiting the primary lesion: anionic phospholipid binding.     

Effects of the calcium-channel blocker diltiazem on gentamicin-induced nephrotoxicity in rats

Injection of diltiazem (40 mg/kg/d) to gentamicin (75 mg/kg/d = G 75 or 100 mg/kg/d = G 100) treated rats enhances aminoglycoside-induced nephrotoxicity. As a result of this combination, acute renal failure becomes systematic and is often irreversible. The lesion is of tubular origin and is characterized by a large increase in the urinary N-acetyl-beta-D-glucosaminidase (u-NAG) activity and its NAG-B isoenzyme level. The phenomenon is twice as marked with G 75 (u-NAG x 6.8, NAG-B x 2.2) as with G 100 (u-NAG x 3.1, NAG-B x 1.1). The effect seems to be attenuated if diltiazem is administered as a preventive treatment or in drinking water. As well as its diuretic properties, diltiazem may aggravate the renal toxicity of gentamicin by reducing the proximal tubular availability of calcium. Diltiazem inhibits reabsorption and behaves like a non-competitive inhibitor of calcium. This deficiency favours the proximal tubular binding and the non-specific penetration of gentamicin in the cytosol and cellular organelles (microsomes, mitochondria). The tubular toxic symptoms which ensure (inactivation of membranaceous enzyme, reduction of microsomal protein synthesis and ATP level, decreased of solute reabsorptive flux) lead in turn to proximal tubular necrosis and acute renal failure.     

Protective effect of Moringa oleifera leaves against gentamicin-induced nephrotoxicity in rabbits

Oxidative stress due to abnormal production of reactive oxygen species has been implicated in the nephrotoxicity induced by gentamicin. The nephroprotective effect of aqueous-ethanolic extract of Moringa oleifera leaves (150 and 300 mg/kg) was evaluated against gentamicin-induced (80 mg/kg) renal injury in rabbits. Serum urea and creatinine levels were evaluated as the markers of renal nephrotoxicity. At the end of the experiment, the kidneys of rabbits were excised for histological examinations and determination of lipid peroxidation levels. Serum urea and creatinine levels were reduced in the M. oleifera (150 and 300 mg/kg) plus gentamicin treated groups. On histological examinations, kidney of intoxicated rabbits groups which received M. oleifera extract showed reparative tendencies. A highly significant (p < 0.01) elevation was observed in lipid peroxidation (LPO) level in the kidneys of gentamicin-intoxicated rabbits whereas combined treatment of M. oleifera and gentamicin group showed a highly significant (p < 0.01) depletion in LPO. The present study indicates that aqueous-ethanolic extract of M. oleifera leaves attenuates renal injury in rabbits treated with gentamicin, possibly by inhibiting lipid peroxidation.     

Gentamicin nephrotoxicity in rats. I. Acute biochemical and ultrastructural effects.

This investigation characterizes the acute biochemical and ultrastructural alterations within the rat kidney following the single injection of 10, 40, 80, or 160 mg. of gentamicin per kilogram of rat weight. Gentamicin was given intraperitoneally and rats were killed 80 minutes later. To assess a possible inhibitory effect upon protein synthesis 3H-leucine was injected 20 minutes postantibiotic and renal cortex was assayed for whole tissue and the protein fraction amino acid uptake. To exclude the possibility of gentamicin-induced lysosomal membrane instability with subsequent release of acid hydrolases, the activity of acid phosphatase was assayed in the supernatant and the residue of cortical homogenates containing the lysosomal fraction. Ultrastructural changes were concomitantly studied. To determine the intracellular localization of gentamicin, levels of the antibiotic were measured in subcellular fractions of cortical homogenates obtained from rats 2 hours following a single subcutaneous injection of 20 mg. of gentamicin per kilogram of rat weight. No gentamicin-induced alterations either of protein synthesis or of acid phosphatase distribution were demonstrated. Ultrastructural changes were most marked at 160 mg. per kg. consisting mainly of dilation of the endoplasmic reticulum, altered mitochondria, and increased cytosegresomes. Significant quantities of gentamicin were distributed within the nuclear, mitochondrial, and microsomal fractions. These studies indicate that although cytoplasmic alterations are prominent within the proximal tubular epithelial cells, they are not likely the result of either inhibition of protein synthesis or release of acid phosphatase from lysosomes.     

A morphological and biochemical study of the effects of L-cysteine on the renal uptake and nephrotoxicity of cadmium.

In JCLR and Wistar-Porton rats renal concentrations of Cd2+ were maximal (21-22 micrograms Cd2+/g wet wt tissue) at 1 and 4 h respectively after the administration of CdCl2 (10 micromol, 1-12 mg Cd2+/kg body wt) together with L-cysteine (5 mmol/kg body wt). Synthesis of metallothionein in the kidney in response to the uptake of Cd2+, which occurred between 2 and 7 h after treatment in the Wistar-Porton rat, affected the distribution of Cd2+ between proteins of the renal soluble fraction, but not between the particulate components and, at both times, about 40% of the total Cd2+ was associated with the heterogeneous nuclei + cell debris fraction. Autoradiographic studies with 109CdCl2 revealed that Cd2+, accumulated by the kidney under these conditions, was not uniformly distributed throughout the renal cortex, but was concentrated unevenly in proximal tubules in the outer stripe of the outer zone of the medulla. Pathological changes, which were correlated with the concentrations of accumulated Cd2+ and were limited to the S3 segments of the proximal tubules, were apparent by light microscopy at 4 h after the administration of Cd2+ + cysteine and progressed with time. Thus by 7 h the lesion had extended to include almost the whole of the outer stripe of the outer zone of the medulla and, by 24 h the cells of the affected epithelia showed extensive necrosis and karyorrhexis. At this, as at earlier times, the cortex appeared to be undamaged. Neither these nor other morphological changes were observed in the kidneys of animals that had been dosed with either Cd2+, or L-cysteine alone. Within 60 min of the administration of Cd2+ + cysteine an increase in the number of endocytotic vesicles in the apical cytoplasm of the proximal tubular epithelium was observed by electron microscopy. Subsequent cytoplasmic vesiculation, which was conspicuous at 2 h, was extensive and widespread in both the apical and basal regions of the cytoplasm at 4 h. In some cells at this time the nuclei were irregular in shape; the mitochondria were swollen and their cristae were disorganized. As, after the administration of either Cd2+ or cadmium-metallothionein, damage is known to occur in the S1 and S2 segments of proximal tubules throughout the cortex, the Cd2+ + cysteine combination does not provide an exact model which reproduces in a short time the effects of long-term, low level exposure to Cd2+. Nevertheless it is suggested that the toxic mechanisms are the same after either treatment with Cd2+ + cysteine or continual exposure to Cd2+, but are limited to different segments of the proximal tubules. Possible mechanisms of toxicity are discussed.     

Preventive effect of aminoguanidine compared to vitamin E and C on cisplatin-induced nephrotoxicity in rats

In this study, the antioxidant effect of aminoguanidine on nephrotoxicity of a single dose of cisplatin is investigated and compared with the effects of well-known antioxidants vitamin C and E combination. Tubular damage and perivascular inflammation were observed in kidney samples of the cisplatin-administered groups. Aminoguanidine and vitamin C–E combination are found to be capable of preventing these effects of cisplatin. Liver tissues of all groups were intact. Cisplatin-induced oxidative stress was evidenced by significant decrease in glutathione and significant increase in malondialdehyde levels in kidney samples. Antioxidants with cisplatin decreased malondialdehyde levels. Antioxidants with cisplatin prevented the decrease in liver glutathione levels. The nephrotoxicity was confirmed biochemically by significant elevation of serum urea and creatinine levels. Both vitamin C–E combination and aminoguanidine prevented the increase in serum urea levels according to the cisplatin group.     

Anti-oxidant and anti-inflammatory effects of apigenin in a rat model of sepsis: an immunological,biochemical, and histopathological study

Objective: We hypothesize that apigenin may inhibit some cellular process of sepsis-induced spleen injury and simultaneously improve inflammation and oxidative stress. Therefore, the aim of this study was to investigate the potential protective effects of apigenin in a polymicrobial sepsis rat model of by cecal ligation and puncture.

Materials and methods: 64 female Wistar albino rats were divided into 8 groups. The pro-inflammatory (tumor necrosis factor-alpha, interleukin-6, and interleukin-1-beta) and anti-inflammatory (tumor growth factor-beta and interleukin-10) cytokine levels were measured by enzyme-linked immunosorbent assay. CD3, CD68, and nuclear factor kappa B (NF-κB) positivity rates were detected by immunohistochemical methods. Oxidative stress parameters were measured by tissue biochemistry.

Results: Sepsis caused a significant increase in TNF-alpha, IL-1-beta, IL-6, and TGF-beta levels whereas it reduced IL-10 level. Additionally, it led to an increase in CD3, CD68, and NF-κB positivity rates as well as oxidative stress parameters levels. However, apigenin inhibited the inflammation process, increased the IL-10 level and normalized the oxidative stress parameters.

Discussion and conclusion: Pretreatment with apigenin results in a significant reduction in the amount of inflammatory cells. The beneficial effect of apigenin on spleen injury also involved inhibition of NF-κB pathway, suppression of proinflammatory cytokines, and induction of anti-inflammatory cytokine production. Additionally, it led to a decrease in oxidative stress in spleen tissue. Taking everything into account, apigenin may be an alternative therapeutic option for prevention of sepsis-induced organ.     

Dose-related effects of oestradiol on rat thymic and splenic T-lymphocyte responsiveness to mitogens.

The dose-related effects of oestradiol on responses of thymic and splenic lymphocytes to mitogenic stimulation were studied in immature female Wistar rats. An attempt was made to relate responses not merely to dose but also to the circulating levels of the steroid. Lymphocytes were prepared from thymus and spleen and stimulated with phytohaemagglutinin (PHA) and concanavalin A (Con A) prior to measurement of 3H-thymidine incorporation. Oestradiol suppressed lymphoid tissue weight and cell number in a dose-related manner, but it was found, unexpectedly, that the dose of oestradiol used actually stimulated responsiveness of lymphocytes to mitogenic stimulation. Log dose-response curves indicate that the effects of oestradiol on responsiveness are complex, and the results suggest that the atrophic effects of oestradiol on lymphoid tissue and its enhancement of response to mitogens might be mediated by different mechanisms. Since the stimulant effects of the steroid were observed with serum levels of oestradiol attained both physiologically and pharmacologically, the results suggest a possible mechanism of action of oestradiol in abnormal cell proliferation, as occurs in neoplastic tissues, and might also help to explain certain sex-linked immune-related disorders.     

Ischaemia-reperfusion injury of rat ovary and the effects of vitamin C,mannitol and verapamil

BACKGROUND: In this prospective controlled study, the aim was to examine the effects of vitamin C, mannitol and verapamil on adnexial ischaemia-reperfusion injury in the rat ovary. METHODS: Thirty-six female Wistar rats were used. In the controls (group 1), only laparotomy was performed. In group 2, ovarian ischaemia was produced and the bilateral ovaries were surgically removed 4 h later. In group 3, an ischaemic period of 4 h was followed by reperfusion for 1 h; the bilateral ovaries were then removed. In groups 4, 5 and 6, after 4 h of ischaemia, either vitamin C, mannitol or verapamil respectively was infused before reperfusion; after 1 h of reperfusion the ovaries were removed. Thiobarbituric acid reactive substance (TBARS) levels were measured in all ovary tissues. RESULTS: TBARS levels of the reperfusion group were significantly higher than those of groups treated with vitamin C or mannitol (P = 0.013 and P = 0.045 respectively), but not of the verapamil group. CONCLUSIONS: Vitamin C and mannitol were found to be effective in reducing ischaemia-reperfusion injury of the ovary during its early stages, but verapamil was ineffective.     

Effect of vitamin C deficiency and excess on the liver: a histopathological and biochemical study in guinea pigs fed normal or high cholesterol diet

When guinea pigs were kept on a restricted vitamin C intake of only 0.5 mg daily, their serum ascorbic acid fell to 0.16 +/- 0.06 mg/d1 in 16 weeks as compared to 0.73 +/- 0.11 in control. This was associated with significant increase in liver cholesterol and triglycerides. When they were simultaneously challenged with a high cholesterol load, this fat accumulation was markedly exaggerated. The weight of the liver now increased by almost two-and-half times. Liver cholesterol rose to 12.90 +/- 2.63 mg/gm as compared to 3.23 +/- 0.56 mg/gm with low vitamin C alone. Histopathology showed marked distension and vacuolation of hepatocytes, focal necrosis and fibroplasia. Administration of excess vitamin C (100 mg daily) significantly countered these changes. The vitamin C-lipid relationship has important clinical bearings and liver could be an important site of vitamin C action.