Hepatoprotective Effect of Nicotinamide Versus Lead-Motivated Hepatotoxicity in Rats via Correcting Effect on Nuclear Factor-kß Pathway and Glutathione Metabolism.

Lead (Pb) poisoning is one of the pivotal environmental issues and prompts liver dysfunction by elevating oxidative stress and inflammation. Nicotinamide (NA) deficiency enhances sensitivity to Pb toxicity. So, we investigated the effect of nicotinamide (NA) on the rat's liver histopathological and biochemical profiles in a rat model of Pb toxicity. Thirty-six rats were divided into four groups (nine rats at each): normal (N), lead toxicity (Pbt), and NA-treated N and Pbt groups. Treated groups took NA (180 mg/L in drinking water for one month). Pb intoxication was motivated in rats by acquiring 50 mg/L lead acetate in drinking water. Oxidative stress markers (advanced oxidation protein products and malondialdehyde), antioxidant markers (total glutathione, reduced glutathione to oxidized glutathione ratio, ferric ion reducing power, catalase, and paraoxonase-1), and inflammatory markers (hepatic nuclear factor-kß expression, interleukin 1ß level, and myeloperoxidase activity) in sera and liver homogenates were determined. In addition, the biochemical parameters of the liver function were measured. Finally, the liver of rats was evaluated by histopathological observation. NA corrected lead-persuaded biochemical and histopathological changes in the rat's liver. In addition, treatment decreased Pb, oxidative stress, and inflammatory markers in the sera and liver homogenates of N and Pbt groups. In addition, it elevated antioxidant markers (p < 0.001). NA prevented Pb-induced liver histopathological alternations and reduced liver dysfunction by reducing Pb, oxidative stress, and inflammation. Moreover, raising GSH/GSSG and diminishing the hepatic NF-kß pathway are cardinal mechanisms of the treatment against Pb-motivated hepatotoxicity in rats.

Crocetin ameliorative effect on diabetic nephropathy in rats through a decrease in transforming growth factor-ß and an increase in glyoxalase-I activity.

BACKGROUND & AIMS: Glycation, oxidative stress, and inflammation due to the elevation of transforming growth factor-ß1 (TGF-ß1) participate in diabetic nephropathy (DN). Thus, we investigated for the first time the effect of crocetin (Crt) on the renal histopathological parameters, TGF-ß1 and glycation, oxidative stress, as well as inflammatory markers in the DN rat model. METHODS: Forty male Wistar rats were randomly divided into 4 equal groups: normal (N), N + Crt, DN, and DN + Crt. DN was induced in rats with a combination of nephrectomy and streptozotocin. Treated groups received 100 mg/kg of Crt via intraperitoneal injection monthly for 3 months. Different glycation (glycated albumin, glycated LDL, Methylglyoxal, and pentosidine), oxidative stress (advanced oxidation protein products, malondialdehyde, glutathione, and paraoxonase-I (PON-1)), and inflammatory markers (tumor necrosis factor-α, myeloperoxidase, and TGF-ß1), blood glucose, insulin, lipid profile, creatinine in the serum, and proteinuria, as well as the glyoxalase-1 (GLO-1) activity, was determined. RESULTS: Crt decreased renal biochemical (Cre and PU) and histopathological (glomerulosclerosis) renal dysfunction parameters, diverse glycation, oxidative stress, and inflammatory markers in the DN rats. Furthermore, the treatment corrected glycemia, insulin resistance, and dyslipidemia as well as induced the activities of GLO-1 and PON-1. Over and above, the treatment decreased TGF-ß1 in their serum (p > 0.001). CONCLUSIONS: Crocetin improved DN owing to an advantageous effect on metabolic profile. Further, the treatment with a reducing effect on TGF-ß1, oxidative stress, glycation, and inflammation markers along with an increase in Glo-1 activity showed multiple protective effects on kidney tissue.

Glutamine Defended the Kidneys Versus Lead Intoxication Via Elevating Endogenous Antioxidants, Reducing Inflammation and Carbonyl Stress, as well as Improving Insulin Resistance and Dyslipidemia.

Kidneys are primarily sensitive to lead (Pb) poisoning due to their cardinal role in lead excretion. Then, we studied the effect of glutamine (Gln) on lead nephrotoxicity in rats by assessing the histopathological and biochemical parameters (the renal NF-kß expression, metabolic profile, oxidative stress, inflammatory markers, methylglyoxal (MGO), and glyoxalase-I activity). Forty rats were allotted into four groups (ten rats in each): normal (N), Gln-treated N, Pb intoxication (Pbi), and Gln-treated Pbi. The treated groups took 0.1% Gln in drinking water for 1 month. To motivate lead poisoning, rats gained 50 mg/l lead acetate in drinking water for 1 month. Oxidative stress indices (total glutathione, its reduced and oxidized forms, their ratios, advanced protein oxidation products, malondialdehyde, and ferric ion reducing power) and inflammatory markers (renal nuclear factor-kß expression, interleukin 1ß level, and myeloperoxidase activity) were measured. Furthermore, metabolic profile (fasting blood sugar, insulin, insulin resistance, lipid profile, and atherogenic index) and renal dysfunction parameters were determined. Pb-induced renal histopathological alterations were investigated by a pathologist. In the kidney of Pbi rats, the glomerulus was damaged. Gln prevented kidney damage and reduced kidney dysfunction parameters. In addition, Gln decreased oxidative stress and inflammation in sera and kidney homogenates. In addition, it improved insulin resistance, dyslipidemia, and carbonyl stress (p < 0.001). Gln guarded the kidneys versus lead intoxication by improving insulin resistance and dyslipidemia, elevating antioxidant markers, and diminishing inflammation and carbonyl stress.

Exogenous glutamine ameliorates diabetic nephropathy in a rat model of type 2 diabetes mellitus through its antioxidant and anti-inflammatory activities.

This study aimed to evaluate the effects of glutamine (Gln) on diabetic nephropathy and other complications in a rat model of type 2 diabetes mellitus. Streptozotocin/nicotinamide induced diabetic rats were enrolled as an animal model of type 2 diabetes mellitus. Animals were divided into control, diabetic, and Gln (1000 mg/l in drinking water, eight weeks) treated diabetic groups. Gln alleviated renal inflammatory and oxidative stress biomarkers (tumour necrosis factor-alpha, interleukin 6, glutathione peroxidase, total superoxide dismutase, and glutathione), decreased serum uric acid and creatinine, and restored renal histopathological changes (glomerular volume, sclerosis, and leukocyte infiltration). Additionally, Gln ameliorated other complications, including systemic oxidative stress (serum malondialdehyde and nitric oxide, serum and liver glutathione, glutathione peroxidase, and total superoxide dismutase, and liver catalase), insulin resistance, hyperglycaemia, and hyperlipidaemia. Collectively, Gln attenuates diabetic nephropathy and other complications in type 2 diabetes mellitus in rats through its antioxidant and anti-inflammatory activities.

Protective effect of acetylcysteine, histidine, and their combination against diabetes vascular complications in type-2 diabetic rats via reducing NF-kß pathway signaling.

Purpose: The nuclear factor-kappa B (NF-κB) signaling participates in diabetes complications. Therefore, the reduction of NF-κB signaling may be a goal to prevent or improve them. Thus, we investigated the effects of acetylcysteine (AC), histidine (His), and their combination on the NF-κB expression and its different activators in type 2 diabetic rats. Methods: The survey was performed on 50 rats that were allotted equally into five groups composed of control, diabetic, diabetic treated with (AC, 0.06%), (His, 0.1%), and (AC & His) groups. Treated groups have received the treatments daily in drinking water for two months. Metabolic profile (glucose, insulin resistance indices, lipid profile, and cardiovascular indices) and renal dysfunction parameters (creatinine and urinary protein excretion) were measured. Plus, diverse glycation (early, intermediate, and end), oxidative stress (Oxidized LDL, Reduced glutathione), and inflammatory markers (interleukine-1ß, myeloperoxidase, and NF-kß expression) were determined. Results: Glucose, insulin resistance indices, cardiovascular indices, renal dysfunction parameters, different markers of glycation, oxidative stress, and inflammation as well as NF-κB expression, were the lowest in the (AC & His) treated diabetic rats. Besides, the cited parameter was lower in the Ac treated one than His treated (p > 0.001). Conclusion: The combination of AC and His had the most protective effect against diabetes complications and advantageous effect on metabolism, ß-cell activity, and insulin function due to the most reductive effect on the NF-κB pathway rather than More than any of the amino acids alone.

1,8 cineole protects type 2 diabetic rats against diabetic nephropathy via inducing the activity of glyoxalase-I and lowering the level of transforming growth factor-1ß.

Purpose: Diabetes leading to the production and circulation of glycation products along with the reduction of the activity of glyoxalase-I (GLO-I) contribute to diabetic nephropathy. Therefore, we studied the effect of 1,8 cineole (Cin) on the formation of diverse glycation products and the activity of GLO-I as well as renal histopathological alterations in the type-2 diabetic rat. Methods: Type 2 diabetes was induced in rats with a combination of streptozotocin and nicotinamide (55 + 200 mg/kg). Two groups of rats, normal and diabetic, were treated intragastrically with Cin (200 mg/kg) once daily for 2 months. Fasting blood sugar, insulin resistance index, lipid profile, the activity of GLO-I, glycation products (Glycated albumin, Glycated LDL, Methylglyoxal, and advanced glycation end products), and oxidative stress (Advanced oxidation protein products, malondialdehyde, oxidized LDL, and reduced glutathione), inflammatory markers (Tumor necrosis factor-α and Transforming growth factor-1ß), creatinine in the serum (Cre), and proteinuria (PU) in the urine of all rats was determined as well as renal histopathological alterations were investigated. Results: Cin reduced biochemical (Cre and PU) and histopathological (glomerulosclerosis) indicators of renal dysfunction in the diabetic rat compared to untreated diabetic rats. Moreover, the treatment decreased different glycation, oxidative stress, and pro-inflammatory markers (p < 0.001). Further, Cin had an advantageous effect on glucose and lipid metabolism. Conclusions: Cin ameliorated diabetic nephropathy via reduction of TGF-1ß following to decrease the formation of different glycation products, oxidative stress, and inflammatory process with the induction of the activity of glyoxalase-I in type 2 diabetic rats.

Glutamine Is a Superior Protector Against Lead-Induced Hepatotoxicity in Rats via Antioxidant, Anti-inflammatory, and Chelating Properties.

Lead acetate-motivated oxidative stress can affect all organ systems, particularly the liver. Glutamine (Gln) has both antioxidant and chelating properties. Therefore, we investigated for the first time the effect of Gln on the biochemical and histopathological alternations in a rat model of lead toxicity. Thirty-two rats were divided into four groups (eight rats in each): untreated normal, lead poisoning, and two similar groups receiving Gln (0.1% in drinking water for 4 weeks). To induce lead poisoning, rats received 50 mg/L lead acetate in drinking water for 4 weeks. Oxidative stress indices (total glutathione, the ratio of reduced glutathione to oxidized glutathione, advanced protein oxidation products, malondialdehyde, and ferric ion reducing power) and inflammatory markers (hepatic nuclear factor-kß expression, interleukin 1ß level, and myeloperoxidase activity) were measured. Furthermore, biochemical markers of hepatotoxicity (alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin, total protein, albumin, and globulins) were measured. Histopathological examination evaluated lead-induced liver damage. The treatment compensated lead-induced biochemical and histopathological alternations in rat liver. Furthermore, it decreased lead acetate level, the NF-kß gene expression, oxidative stress, and inflammatory markers. Moreover, the treatment elevated total glutathione and reduced glutathione in the sera and liver homogenates of treated groups (p < 0.001). Glutamine could protect the liver against lead intoxication via antioxidant, anti-inflammatory, and chelating properties. In addition, its downregulating effect on the hepatic NF-kß signaling pathway confirms its hepatoprotective activity.

Protection of CCl4-induced hepatic and renal damage by linalool.

The aim of the current study is to determine the protective and therapeutic effects of linalool against carbon tetrachloride (CCl4)-induced hepatoxicity and nephrotoxicity. Six-week-old male Wistar rats were divided into five groups: Control group (a regular diet); CCl4 group (1 ml/kg dissolved in olive oil, intraperitoneally at 14th day); pretreatment group (25 mg/kg linalool daily + CCl4 14thday); post-treatment group (25 mg/kg linalool 2, 6, 24, and 48 h after the injection of CCl4 at 14th day); and linalool group (25 mg/kg linalool daily, orally). All animals were sacrificed, tissue and blood samples were collected to analysis. Administration of CCl4 resulted in a marked increase in hepatic (aspartate aminotransferase, alanine transaminase, and alkaline phosphatase) and renal (blood urea nitrogen and creatinine) markers. Also, CCl4 resulted in pathological damages, a significant increase in the concentration of malondialdehyde , tumor necrosis factor-alpha, and Interleukin 6 , expression of nuclear factor kappa-light-chain-enhancer of activated B cells and a significant decrease in the levels of serum total protein, serum albumin, and antioxidants. However, in pretreatment and post treatment groups, linalool significantly inhibited CCl4- induced hepatic and nephric damages. These results demonstrate that linalool has protective and therapeutic effects in an in vitro model of CCL4-induced hepatic and nephric damage, proposing linalool as a potential therapeutic agent against chemical and drug induced hepatotoxicity and nephrotoxicity.

Preventive Effect of Eucalyptol on the Formation of Aorta Lesions in the Diabetic-Atherosclerotic Rat.

BACKGROUND: Glycation, inflammation, and oxidative stress are the cardinal motivators of diabetes vascular complications. Here, we studied the effect of eucalyptol (EUC) on the formation of atheromatous lesions, glycation, oxidative stress, and inflammatory markers as well as insulin resistance, lipid profile, and activity of glyoxalase-1 (GLO-I) in the atherosclerotic rat model. METHODS: Diabetic-atherosclerosis induced in rats with a combination of streptozotocin and atherogenic diet. Two groups of rats, normal and diabetic-atherosclerotic, were treated intragastrically with EUC (200 mg/kg) once daily for 3 months. Fasting blood sugar (FBS), insulin, insulin resistance index, lipid profile, the activity of GLO-I, low-density lipoprotein (LDL) glycation and oxidation markers, inflammatory markers, creatinine in the serum, and proteinuria in the urine of all rats were determined. RESULTS: EUC inhibited the formation of any atheromatous lesions in atherosclerotic rats. Further, EUC displayed the lowering effect on glycemia, insulin resistance, LDL glycation, and oxidation products, and tumor necrosis factor (TNF)-α as well as it exhibited the improving effect on lipid profile, the activity of GLO-I, and renal function in the diabetic rat (P < 0.001). CONCLUSIONS: EUC prevented the formation of the atheromatous lesions and improved renal function in the atherosclerotic rat model due to a reduction of glycation, oxidative stress, and inflammatory mediators.

Thiamine reduced metabolic syndrome symptoms in rats via down-regulation of hepatic nuclear factor-kß and induction activity of glyoxalase-I.

OBJECTIVES: Metabolic syndrome (MS) is a cause of death worldwide. The hepatic nuclear factor- NF-kß (NF-kß) is the cardinal player of hepatic homeostasis, insulin sensitivity, and lipid metabolism. Thus, we investigated the effect of thiamine on hepatic gene expression of NF-kß and its levels of activators in MS rats. MATERIALS AND METHODS: Male Wistar rats were randomly divided into 4 equal groups (ten rats in each group): normal, MS, and two alike groups under thiamine treatment. MS was induced in rats with a high sucrose solution (40 % in drinking water) for 4 months. Treated groups of rats received 0.18 % of thiamine daily in drinking water. Hematoxylin-Eosin stains were employed to determine the histopathological changes of the liver. Metabolic profile, glycation products, oxidative stress, inflammatory markers, the activity of glyoxalase-I, as well as NF-kß hepatic expression of all rat groups, were determined. RESULTS: Acute hepatitis was not observed in the livers of the thiamine treated MS rats. Besides, the treatment showed an advantageous effect on glucose, lipid metabolism, and body weight via down-regulation of hepatic NF-kß and induction of glyoxalase system activity. Furthermore, the treatment decreased diverse glycation, oxidative stress, and inflammatory markers (P>0.001). CONCLUSION: Thiamine decreased body weight and improved metabolism and activity of glyoxalase-I in MS rats with anti-glycation, antioxidant, and anti-inflammatory activities. Further, the treatment had a hepato-protective effect via reduction of NF-kß signaling.

Thiamine pyrophosphate improved vascular complications of diabetes in rats with type 2 diabetes by reducing glycation, oxidative stress, and inflammation markers.

Background: Thiamine deficiency contributes to hyperglycemia and diabetes complications. Thus, in this study, the effect of thiamine pyrophosphate (TPP) on the in vivo and in vitro formation of glycation, oxidative stress, and inflammatory markers (the main contributors of vascular diabetes complications) was examined in type 2 diabetes rat model. Methods: Type 2 diabetes was induced in rats with a combination of streptozotocin and nicotinamide (55+200 mg/kg). Two groups of rats, healthy and diabetic, were treated with 0.1% TPP in drinking water daily for 3 months and the 2 others received water only. The glucose, insulin, early to end glycation products, the activity of glyoxalase system, lipid profile, LDL oxidation markers, inflammatory markers, creatinine in the serum, and proteinuria in the urine of all rats were determined. Moreover, albumin and LDL were incubated with glucose in the presence and absence of TPP, and the samples were investigated for glycation and oxidation products. Different variables in all 4 groups were compared with multiple analysis of variance (MANOVA-Tukey) test using SPSS version 16. Significance level was set at p<0.05. Results: TPP decreased the formation of diverse glycation and oxidation products in both in vivo (glycated LDL= 144.50±3.48 and oxidized LDL= 54.08±2.67 µmol/l) and in vitro (glycated LDL= 107.00±2.82 and oxidized LDL= 50.83±1.22 µmol/l). In addition, the vitamin reduced fasting blood sugar (9.23±0.29), insulin resistance (9.10±0.50), tumor necrosis factor-α (285.43±15.97), interleukin-6 (257.65±13.06), and improved the lipid profile, the activity of Glo system (Glo-I= 31.65±1.06 and Glo-II= 27.01±0.90 U/mL) and renal function in the diabetic rat (p<0.001). Conclusion: TPP decreased the major risk factors for diabetic complications and corrected the alternations of glucose and lipid metabolism in type 2 diabetic rats; thus, it is recommended for diabetes treatment.

Ameliorative effects of histidine on oxidative stress, tumor necrosis factor alpha (TNF-α), and renal histological alterations in streptozotocin/nicotinamide-induced type 2 diabetic rats.

OBJECTIVES: The present study sought to evaluate the beneficial effects of histidine (His) on oxidative stress, tumor necrosis factor alpha (TNF-α), renal histological alterations and anti-oxidant enzymes gene expressions in type 2 diabetic rats. MATERIALS AND METHODS: Streptozotocin/nicotinamide (STZ/NA) induced diabetic rats were used as an animal model of type 2 diabetes. One group of rats received daily His (1000 mg/l) in drinking water for 8 weeks, whereas other groups (control and untreated diabetic groups) received only water. Different parameters such as glucose, insulin, insulin resistance, lipid profile, cardiac risk ratios, renal functional markers, and oxidative stress were determined in all groups. Moreover, renal histological alterations, mRNA expressions of anti-oxidant enzymes, and TNF-α were evaluated in the rats. RESULTS: His exhibited a protective effect on glucose, insulin, insulin resistance, lipid profile, cardiac risk ratios, renal functional markers, oxidative stress, and TNF-α. Furthermore, His restored the renal histological alterations and normalized the augmented mRNA expressions of renal anti-oxidant enzymes (glutathione peroxidase (GPX) and Cu-Zn superoxide dismutase (Cu-Zn SOD)) and TNF-α. CONCLUSION: His could ameliorate diabetes complications related to oxidative stress, inflammation, dyslipidemia, hyperglycemia, insulin resistance, and nephropathy. Hence, the use of this amino acid is recommended for diabetic patients in order to reduce diabetes complications.

Protective Effect of Thioctic Acid on Renal Ischemia-reperfusion Injury in Rat.

BACKGROUND: We investigated the effect of thioctic acid (TA) on kidney function, oxidative stress, and inflammatory status in serum and kidney homogenates of a rat subjected to ischemia-reperfusion injury (IRI). MATERIALS AND METHODS: Thirty male Wistar rats were randomly divided into three equal groups: sham, IR, and IR + TA in 50 mg/kg once-daily intraperitoneal injection for 2 weeks, before IR induction. The levels of urea and creatinine (Cr) in the serum of rats were measured. Malondialdehyde and nitric oxide (NO) as stress oxidative markers; tumor necrosis factor-α, interleukin-6, and myeloperoxidase as inflammatory markers, as well as activities of superoxide dismutase, glutathione peroxidase and catalase, and glutathione (GSH) level in both serum and kidney homogenates were determined. RESULTS: Cr and urea increased in serum of IR group. Furthermore, levels of oxidative stress and inflammatory markers in serum and kidney homogenates of the cited group were higher than the sham group. TA not only decreased the levels of Cr, urea, oxidative stress, and inflammation but also elevated the level of GSH and activities of antioxidant enzymes (P < 0.001). CONCLUSIONS: The findings showed that TA protected IR rat against kidney dysfunction and IRI due to reinforcing endogenous antioxidant and subtracting of inflammatory markers.