Metformin Is Associated with the Inhibition of Renal Artery AT1R/ET-1/iNOS Axis in a Rat Model of Diabetic Nephropathy with Suppression of Inflammation and Oxidative Stress and Kidney Injury.

Diabetes is the most common cause of end-stage renal disease, also called kidney failure. The link between the renal artery receptor angiotensin II type I (AT1R) and endothelin-1 (ET-1), involved in vasoconstriction, oxidative stress, inflammation and kidney fibrosis (collagen) in diabetes-induced nephropathy with and without metformin incorporation has not been previously studied. Diabetes (type 2) was induced in rats and another group started metformin (200 mg/kg) treatment 2 weeks prior to the induction of diabetes and continued on metformin until being culled at week 12. Diabetes significantly (p < 0.0001) modulated renal artery tissue levels of AT1R, ET-1, inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and the advanced glycation end products that were protected by metformin. In addition, diabetes-induced inflammation, oxidative stress, hypertension, ketonuria, mesangial matrix expansion, and kidney collagen were significantly reduced by metformin. A significant correlation between the AT1R/ET-1/iNOS axis, inflammation, fibrosis and glycemia was observed. Thus, diabetes is associated with the augmentation of the renal artery AT1R/ET-1/iNOS axis as well as renal injury and hypertension while being protected by metformin.

MiR-155 Dysregulation Is Associated with the Augmentation of ROS/p53 Axis of Fibrosis in Thioacetamide-Induced Hepatotoxicity and Is Protected by Resveratrol.

Liver fibrosis is a hallmark of thioacetamide (TAA) intoxications. MicroRNAs (miRs), such as miR-155, have been implied in the pathogenesis of liver disease, and regulated by the antioxidant and anti-inflammatory compound resveratrol (RES). The link between reactive oxygen species (ROS), tumour suppressor p53 (p53), and liver fibrosis-during the pathogenesis of TAA-induced liver injury-associated with miR-155 dysregulation with and without RES incorporation has not been previously studied. Therefore, one group of rats received TAA injections of 200 mg/kg; twice a week at the beginning of week 3 for 8 weeks (TAA group; or model group), whereas the protective group was pretreated daily with RES suspension (20 mg/kg; orally) for the first two weeks and subsequently sustained on receiving both RES and TAA until being sacrificed at the 10th week. Liver injuries developed in the model group were confirmed by a significant (p < 0.0001) elevation of hepatic tissue levels of miR-155, ROS, p53, and the profibrogenic biomarkers: tissue inhibitor of metalloproteinases-1 and α-smooth muscle actin, as well as collagen deposition (fibrosis). All these parameters were significantly (p ≤ 0.0234) protected by resveratrol (RES + TAA). In addition, we observed a significant (p < 0.0001) correlation between ROS/p53 axis mediated liver fibrosis and miR-155. Thus, TAA intoxication induced miR-155 imbalance and ROS/p53-mediated liver fibrosis, with resveratrol, conversely displaying beneficial hepatic pleiotropic effects for a period of 10 weeks.

Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin-Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis.

The intermediate filament protein desmin is essential for maintaining the structural integrity of sarcomeres, the fundamental unit of cardiac muscle. Diabetes mellitus (DM) can cause desmin to become dysregulated, following episodes of nitrosative stress, through the activation of the iNOS/mTOR/TIMP-1 pathway, thereby stimulating collagen deposition in the myocardium. In this study, type 2 diabetes mellitus (T2DM) was induced in rats. One group of animals was pre-treated with metformin (200 mg/kg) prior to diabetes induction and subsequently kept on metformin until sacrifice at week 12. Cardiac injuries developed in the diabetic rats as demonstrated by a significant (p < 0.0001) inhibition of desmin immunostaining, profound sarcomere ultrastructural alterations, substantial damage to the left ventricular tissue, collagen deposition, and abnormal ECG recordings. DM also significantly induced the cardiac expression of inducible nitric oxide synthase (iNOS), mammalian target of rapamycin (mTOR), and the profibrogenic biomarker tissue inhibitor of metalloproteinase-1 (TIMP-1). The expression of all these markers was significantly inhibited by metformin. In addition, a significant (p < 0.0001) correlation between desmin tissue levels/sarcomere damage and glycated hemoglobin, heart rate, iNOS, mTOR, and fibrosis was observed. These findings demonstrate an association between damage of the cardiac contractile unit­desmin and sarcomere­and the iNOS/mTOR/TIMP-1/collagen axis of fibrosis in T2DM-induced cardiomyopathy, with metformin exhibiting beneficial cardiovascular pleiotropic effects.

Suppression of diabetes-induced renal inflammatory cell infiltration by metformin associated with the amelioration of renal injury biomarkers / Supresión de la infiltración de células inflamatorias renales de diabetes-inducida, por metformina asociada con la mejora de los biomarcadores de lesión renal

SUMMARY: Diabetes and hypertension account for the majority of chronic kidney injury cases that can lead to renal failure. The link between the leukocytes common antigen (CD45) and diabetic kidney disease (DKD) with and without metformin incorporation in an animal model has not been investigated before. Therefore, we sought to assess the extent of leukocytes infiltration into kidney tissues 10 weeks following the induction of diabetes in rats treated with metformin. In addition, we monitored blood and urine parameters associated with diabetes. The model group of rats received streptozotocin (STZ; 50 mg/kg) injection after being fed for 14 days on a high-fat diet (HFD) and continuously fed a HFD until they were culled, at week 12. The protective group was treated in the same way except that these animals were put from day 1 on metformin (200 mg/kg) until being culled, on week 12. Kidneys were immunostained with CD45 as a marker of leukocytes infiltration and examined by light microscopy. Urine samples were tested for urine albumin and collected blood was analyzed for sugar, urea, creatinine, and oxidative stress and antioxidants biomarkers. Kidney injury secondary to diabetes was developed as demonstrated by (i) increased blood glucose, urea, and malondialdehyde (MDA) as a marker of lipid peroxidation; and (ii) kidney tissue damage and marked increase in kidney tissues expressing CD45 positive cells. The above markers were inhibited (p0.0006) by metformin. Also, a significant correlation was observed between CD45 score and glycemia, urea, MDA, and the antioxidant superoxide dismutase (SOD). Thus, our data demonstrate an association between the infiltration of CD45+ inflammatory cells into kidney tissues and biomarkers of kidney damage in a rat model of DKD, which was effectively protected by metformin.

RESUMEN: La diabetes y la hipertensión representan la mayoría de los casos de lesión renal crónica que pueden provocar insuficiencia renal. El vínculo entre el antígeno común de los leucocitos (CD45) y la enfermedad renal diabética (DKD) con y sin incorporación de metformina en un modelo animal no se había anteriormente investigado. El objetivo fue evaluar el grado de infiltración de leucocitos en los tejidos renales 10 semanas después de la inducción de diabetes en ratas tratadas con metformina. Además, monitoreamos los parámetros de sangre y orina asociados con la diabetes. El grupo modelo de ratas recibió una inyección de estreptozotocina (STZ; 50 mg/kg) después de ser alimentadas durante 14 días con una dieta alta en grasas (HFD) y continuamente alimentadas con un HFD hasta que fueron sacrificadas, en la semana 12. El grupo protector fue tratado de la misma manera excepto que estos animales fueron recibieron desde el día 1 metformina (200 mg/kg) hasta ser sacrificados, en la semana 12. Los riñones fueron inmunoteñidos con CD45 como marcador de infiltración de leucocitos y examinados por microscopía óptica. Las muestras de orina se analizaron en busca de albúmina y la sangre recolectada se analizó en busca de glucosa, urea, creatinina y biomarcadores de estrés oxidativo y antioxidantes. La lesión renal secundaria a la diabetes se desarrolló como lo demuestra (i) el aumento de la glucosa en sangre, la urea y el malondialdehído (MDA) como marcador de la peroxidación lipídica; y (ii) daño del tejido renal y marcado aumento en los tejidos renales que expresan células positivas para CD45. Los marcadores anteriores fueron inhibidos (p≤0.0006) por metformina. Además, se observó una correlación significativa entre la puntuación de CD45 y la glucemia, la urea, la MDA y la superóxido dismutasa antioxidante (SOD). Por lo tanto, nuestros datos demuestran una asociación entre la infiltración de células inflamatorias CD45+ en los tejidos renales y biomarcadores de daño renal en un modelo de rata con DKD, que fue protegido de manera efectiva por metformina.

Paracetamol poisoning induces acute liver injury in rats: inhibition of miR-155/cd45 axis-mediated antioxidant depletion and hepatotoxicity using quercetin and resveratrol / La intoxicación por paracetamol induce daño hepático agudo en ratas: inhibición de la depleción de antioxidantes mediado por el eje miR-155/cd45 y hepatotoxicidad usando quercetina y resveratrol

SUMMARY: Ingestion of an overdose of paracetamol (also called acetaminophen, or APAP) induces hepatotoxicity that can lead to liver failure. The link between the pro-inflammatory microRNA-155 (miR-155) and leukocyte infiltration (CD45) in APAP- antioxidant depletion and liver toxicity with and without the natural polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) has not been previously studied. Therefore, acute hepatic injury was induced in rats by 2 g/kg APAP (single dose, orally) and another group started QUR (50 mg/kg) plus RES (30 mg/kg) treatment one week prior to APAP ingestion. Animals were culled 24 hours post the paracetamol treatment. APAP overdose induced hepatic and blood levels of miR-155 expression, CD45 (leukocyte common antigen) immunostaining, degenerated hepatocytes, and hepatic injury enzymes; alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which were markedly decreased by QUR+RES. Whereas, APAP intoxication ameliorated liver tissue levels of the antioxidants, glutathione peroxidase and superoxide dismutase that were augmented by QUR+RES. Moreover, a significant (p<0.05) correlation between miR-155/CD45 axis and liver tissue injury was observed. These findings show that paracetamol intoxication augments miR- 155/CD45 axis-mediated modulation of antioxidants and liver injury in rats, and is protected by QUR+RES.

RESUMEN: La ingestión de una sobredosis de paracetamol (también llamado acetaminofeno o APAP) induce hepatotoxicidad que puede provocar insuficiencia hepática. El vínculo entre el microARN-155 proinflamatorio (miR-155) y la infiltración de leucocitos (CD45) en el agotamiento de APAP- antioxidante y la toxicidad hepática con y sin los compuestos polifenólicos naturales, quercetina (QUR) más resveratrol (RES) no ha sido previamente investigado. En este estudio, se indujo daño hepático agudo en ratas con 2 g/kg de APAP (dosis única, por vía oral) y otro grupo comenzó el tratamiento con QUR (50 mg/ kg) más RES (30 mg/kg) una semana antes de la ingestión de APAP. Los animales se sacrificaron 24 horas después del tratamiento con paracetamol. La sobredosis de APAP indujo niveles hepáticos y sanguíneos de expresión de miR-155, inmunotinción de CD45 (antígeno leucocitario común), degeneración de los hepatocitos y daño hepático enzimático; alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST), disminuyeron notablemente con QUR+RES. Mientras que la intoxicación con APAP mejoró los niveles de antioxidantes, glutatión peroxidasa y superóxido dismutasa en el tejido hepático los que aumentaron con QUR+RES. Además, se observó una correlación significativa (p<0,05) entre el eje miR-155/CD45 y la lesión del tejido hepático. Estos hallazgos muestran que la intoxicación por paracetamol aumenta la modulación mediada por el eje miR-155/CD45 de los antioxidantes y la lesión hepática en ratas, y está protegida por QUR+RES.

Tramadol Biological Effects: 4: Effective Therapeutic Efficacy of Lagenaria siceraria Preparation (Gamal & Aref1) and Melatonin on Cell Biological, Histochemical, and Histopathological Changes in the Kidney of Tramadol-Induced Male Mice.

Tramadol is used worldwide and is listed in many medical guidelines to treat both acute and chronic pains. There is a growing evidence of abuse of tramadol in some African and West Asian countries. Tramadol has some side effects. The present study designed to follow up the treatment of the cellular responses which might be induced in the kidney of tramadol mice. Treated mice received daily injection of tramadol dose (125 µg/100 g b.wt) for 20 and 40 days. Other mice received tramadol for 40 days and then were divided into three groups: the first received distilled water, the second received Lagenaria siceraria, and the third received melatonin daily for 40 days. Both the daily injection of tramadol for 20 and 40 days resulted in radical, extensive, and severe alterations in the normal histological architecture of the kidney. Treatment with Lagenaria siceraria or melatonin after tramadol administration for a long-term, markedly changed the collagen content and other chemical components, that may reach nearly normal levels. Such findings propose that although tramadol has many cytological and histopathological side effects on the kidneys of male mice, the treatments via Lagenaria siceraria and melatonin have effective therapeutic impacts on the tramadol side effects.

Effects of dried okra fruit (Abelmoschus esculentus L.) powder on growth, carcass characteristics, blood indices, and meat quality of stored broiler meat.

The present study investigated the impacts of dried okra fruit powder (DOFP), used as a natural feed supplement, on growth, carcass, blood, and meat quality parameters of broilers. A total of 240 unsexed, one-week-old chicks were randomly allotted to 4 equal groups with 6 replicates in each group (i.e., 10 birds/replicate). The dietary treatments consisted of the basal diet as control, and 3 DOFP groups, supplemented with 1.0, 2.0, and 3.0 g DOFP/kg feed, respectively. The results showed that the highest values of live body weight and body weight gain were observed in the group with 1.0 g of DOFP/kg of feed during the fifth week of age and between 1 and 5 wk of age, respectively. During 1 to 3 wk of age, daily feed consumption of chicks fed DOFP-supplemented diets increased numerically with increasing DOFP levels. Dietary treatments significantly depressed liver, thigh, and dressing fat percentages. Chicks fed the diet containing 1.0 g of DOFP/kg of feed had the lowest values for serum urea and creatinine compared with the other treatment group. In addition, the concentration of liver enzymes decreased with increasing DOFP levels, except for the groups fed 3.0 and 1.0 g of DOFP/kg of diet. Oxidative rancidity of broiler meat samples containing DOFP in their diets was lower than that of the control samples, throughout the storage period. It can be concluded that DOFP is a useful phytogenic additive, which can lower the percentage of abdominal fat of the carcass, as well as alanine aminotransferase, urea, and creatinine in the blood. Furthermore, all sensory characteristics of the meat were improved by the addition of DOFP to broiler diets. It could be concluded that DOFP can be used as a natural supplement in broiler diets for improving growth performance and reducing abdominal fat, blood creatinine, and urea.

Potential use of chromium to combat thermal stress in animals: A review.

Heat stress (HS) has adverse effects on the body: it decreases body weight, feed efficiency, feed intake, carcass quality, and nutrient digestibility. Chromium (Cr) can prevent lipid peroxidation induced by HS through its strong antioxidant activities, especially when it is added to the poultry diet. It improves the action of insulin and nutrient metabolism (of lipids, proteins, nucleic acid, and carbohydrates) through activation of enzymes associated with such pathways. The results of the studies on Cr added to diets with concentrations of 0.05 mg Cr/kg of Cr-methionine led to improved feed efficiency and DM intake by cows and Holstein dairy calves exposed to high environmental temperatures. Moreover, calves that received Cr at levels of 0.05 mg/kg of body weight tended to have higher serum concentrations of glucose and higher ratios of insulin to glucose. In heat-stressed pigs, Cr addition (200 ppb) increased blood neutrophils by about 37%. Several studies have asserted that Cr can inhibit inflammation in lactating cows by promoting the release of Hsp72, assisting production of IL-10 and inhibiting degradation of IκBα in HS conditions. In addition, Cr supplementation was observed to possibly have positive impacts on both cell-mediated and humeral immunity in heat-stressed buffalo calves. Studies over the last two decades have shown with certainty that chromium supplementation has an impact on many variables in chickens. Moreover, Cr is believed to increase insulin action in insulin-sensitive tissues (i.e., adipose and muscles), resulting in increased farm animal productivity through the improvement of feed intake, growth rate, carcass quality, reproductive parameters and immune functions.