The Effect of Dextrose Hypotonic vs Saline Hydration on Methotrexate-Induced Nephrotoxicity in Male and Female Rats.

Background: High-dose methotrexate (HDMTX) as a cytotoxic agent might cause various side effects. Hyperhydration has been implemented as the major strategy to decrease the potential risk of toxicities induced by HDMTX. This study aims to assess the renoprotective effect of hydration with dextrose water (DW) 5% versus normal saline (N/S) 0.9% against methotrexate (MTX) induced nephrotoxicity. Materials and Methods: This experimental animal study has been conducted on 36 Wistar rats (200-250 g) categorized into six groups, including male (n = 6) and female (n = 6) rats receiving sodium chloride 0.9% saline plus MTX, DW 5% plus MTX, or MTX alone. By the fifth day after the MTX injection, biochemical indexes were measured. The rats were also sacrificed and renal specimens were evaluated microscopically to determine kidney tissue damage (KTD). Results: The groups were not significantly different with regard to blood urea nitrogen (BUN) (P = 0.5), creatinine (Cr) (P = 0.24), kidney weight (P = 0.34), and urine flow (UF) (P = 0.5), while KTD score was remarkably less in the hydrated groups (P < 0.001). Weight loss in DW-treated rats was significantly more than N/S-treated ones, and creatinine clearance (CrCl) and urine load (UL) of Cr were statistically similar between males and females in the control group, but significantly lower among the DW5% treated males. Conclusion: Based on the findings of this study, hydration with N/S was superior to DW5% for the prevention from HDMTX-induced nephrotoxicity. Besides, we found insignificant differences between male versus female rats in response to the hydration for HDMTX-induced renoprotection; however, females probably benefit more.

Synthesis and pharmacological characterization of conformationally restricted 2-amino-Adipic acid analogs and carboxycyclopropyl glycines as selective metabotropic glutamate 2 receptor agonists.

The metabotropic glutamate (Glu) receptors (mGluRs) are G-protein coupled receptors, which play a central role in modulating excitatory neurotransmission in the central nervous system (CNS). Thus, the development of tool compounds thereto, continues to interest the scientific community. In this study, we report the design and synthesis of new conformationally restricted 2-aminoadipic acid (2AA) 2-4, and glutamic acid 5, 6 analogs, which share the cyclopropane ring as the restrictor. The analogs were characterized at rat mGlu1-8 in an IP-One functional assay. While the 2AA analogs 3a, 4a and CCG-I analog 5a were shown to be selective mGlu2 agonists with low micromolar potencies, CCG-II analog 5b was shown to be a potent full agonist at mGlu2 (EC50 = 82 nM) with ∼15-fold selectivity over mGlu3, >25-fold selectivity over group III, and >60-fold selectivity over group I subtypes. An in silico study was performed to address this significant change (>3500 fold) in potency upon introduction of this methyl group (L-CCG-II vs 5b).

Nutritional Support Following Traumatic Brain Injury: A Comprehensive Review.

Traumatic brain injury (TBI) can contribute to extensive dysbiosis of the gastrointestinal system, leading to worsened outcomes. The importance of nutrition in recovery is underappreciated but highly important. In this focused review, we discuss the timing of nutritional interventions with supporting data. We highlight routes of administration that are important given the extent of injury often seen in TBI. The increased energy demands can be met through these approaches. Furthermore, patients need increased vitamins, minerals, and supplements. These interventions are constantly being refined. The current standards are reviewed with an emphasis on evidence-based practices.

Effects of isochronal induced feed restriction during the transition period on mRNA abundance of the hepatic genes related to lipid metabolism in fat-tailed ewes.

The process of fat mobilization during the transition period (TP) requires deep re-orchestration of the energy indices, and understanding its mechanism has generated considerable interest among the TP-related studies. The present study aims to validate the effect of feed restriction and TP on the mRNA abundance of hepatic genes related to fat metabolism in fat-tailed sheep. Twenty pregnant ewes with the age of 40.8 ± 6.2 (mean ± standard error) month were randomly assigned to control (n = 10) or restriction (n = 10), and investigated from week - 5 to 5 relative to parturition. Control animals received 100% DM during the trial. Restriction animals received 100% DM through weeks - 5, - 1, 1 and 5 and were fed with 50, 65, and 80% DM in the weeks - 4, - 3, - 2 and 2, 3, and 4, respectively. On the third week of experiment (65%) during both pre- and post-partum, the hepatic tissue was biopsied, and the mRNA load of the fatty acid synthase, acetyl-CoA carboxylase, carnitine palmitoyltransferase (CPT) 1, CPT2, and acyl-CoA synthase long-chain family member-1 genes was quantified by the TaqMan qPCR technique. Data were analyzed using the mixed model procedure of SAS. The mRNA abundance of the target genes was not influenced by feed restriction, during the pre- and post-partum periods. Parturition suppressed the mRNA abundance of target genes in both groups. It can be concluded that the fat-tailed sheep are well adapted to feed scarcity in the harsh environment and would have a higher capacity for the metabolism of fat mobilization during the negative energy balance.

Semi-Synthesis of New 1,2,3-Triazole Derivatives of 9-Bromonoscapine and their Anticancer Activities.

Novel 1,2,3-triazole-tethered 9-bromonoscapine derivatives were synthesized by the propargylation of N-nornoscapine followed by Huisgen's 1,3-dipolar cycloaddition of the terminal alkynes with different azides. Cytotoxicity of the products was studied by MTT assay against the MCF-7 breast cancer cell line. Most of the compounds revealed a better cytotoxicity than N-nornoscapine and 9-bromonornoscapine as the parent compounds. Among the synthesized compounds, those with a hydroxylated aliphatic side chain (5p, 5q, and 5r) showed the highest activities (IC50s: 47.2, 37.9, and 32.3 µg/mL, respectively). Molecular docking studies showed that these compounds also had the highest docking scores and effective interactions with binding sites equal to -8.074, -7.425 and -7.820 kcal/mol, respectively.

The effect of the various doses of atorvastatin on renal tubular cells; an experimental study.

BACKGROUND: Recent retrospective observational studies suggest that high-potency statin therapy might increase the risk of acute kidney injury, however data on this subject is scares. OBJECTIVES: This study, was designed to investigate the renal tubular cell effect of different doses of atorvastatin to detect the possible aggravation of renal function or morphology of the kidney. MATERIALS AND METHODS: In this experimental study 24 male Wistar rats were designated into 4 equal groups and treated as follows. Control group received phosphate buffer as the vehicle of atorvastatin for 7 days. Groups 1, II and III received atorvastatin at doses of 10, 50 and 150 mg/kg daily for 7 days, then on the day 8, all rats were anesthetized using ketamine and the blood samples were collected for evaluation of creatinine (Cr) and blood urea nitrogen (BUN) levels and then all rats were sacrificed, then the animals' kidneys were dissected out and histopathological studies were performed. RESULTS: Mean (±SD) of scores of injury to renal tubular cells in control group was 4.2 ± 2.2 and in groups I, II and III were 6.44 ± 4.9, 15.4 ± 8.5 and 25.8 ± 12.7 respectively. Group III which received 150 mg/kg/day of atorvastatin had significant renal damage in comparison to control group (P < 0.001). There was no significant difference of renal injury score between control group with groups of I and II. CONCLUSIONS: In the present study we found, atorvastatin with a dose of 150 mg/kg/day for 7 days was nephrotoxic for rats, while lower doses at 10 mg/kg/day or 50 mg/kg/day for 7 days were not accompanied by renal injury. These findings imply further attention to the administration of higher doses of atorvastatin in clinical conditions.

Association between serum myeloperoxidase levels and coronary artery disease in patients without diabetes, hypertension, obesity, and hyperlipidemia.

BACKGROUND: Myeloperoxidase (MPO) is an enzyme, elevated in the atheroma and serum of a patient with atherosclerotic vessels. The aim of this study is to investigate whether the serum MPO level is related to the presence of plaque in patients without risk factors, such as, diabetes, hypertension, obesity, and hyperlipidemia. MATERIALS AND METHODS: A serum sample was collected from patients who referred for angiography. The MPO level was measured in the serum samples of 40 patients without risk factors for atherosclerosis using the enzyme-linked immunosorbent assay (ELISA). RESULTS: The MPO level was 245.5 ± 13.8 (ng/ml) in patients with atherosclerosis and 213.9 ± 8.9 (ng/ml) in patients without atherosclerosis. There was a significant difference between the groups (P = 0.002). The odds ratio was 0.67 (0.95 CI, 0.17 - 2.5) for patients with and without coronary atherosclerosis. CONCLUSION: Although the MPO concentration is higher in patients suffering from atherosclerosis, it is not a predictor of coronary artery disease in patients without diabetes, hypertension, obesity, and hyperlipidemia.

Paradoxical effects of atorvastatin on renal tubular cells: an experimental investigation.

INTRODUCTION: Atorvastatin has antioxidant activity and has been reported to increase blood antioxidant capacity. This study aimed to evaluate the effect of different doses of atorvastatin on gentamicin-induced kidney injury. MATERIALS AND METHODS: In this experimental study, 30 male Wistar rats were designated into 6 equal groups for a 7-day period of intraperitoneal injections of gentamicin and atorvastatin. Group 1 received gentamicin, 80 mg/kg. Group 2 received phosphate buffer as the vehicle of atorvastatin. All rats in groups 3, 4, and 5 received gentamicin, 80 mg/kg/d, and then, after a 1-hour interval, atorvastatin was injected for 7 days as follow: group 3, 10 mg/kg/d; group 4, 50 mg/kg/d; and group 5, 150 mg/kg/d. Rats in group 6 received only 150 mg of atorvastatin. On the 8th day, blood samples were collected for evaluation of creatinine and blood urea nitrogen levels, and the animals' kidneys were dissected out for histopathological examinations. RESULTS: Morphological damages to the tubular cells in groups 3 and 4 were less than those in groups 1 and 5. Injuries to the renal tubular cells in the rats of group 5 (gentamicin and atorvastatin, 150 mg/kg/d) and in group 6 (atorvastatin 150 mg/kg/d alone) were more extensive than those in group 1. CONCLUSIONS: The none-dose-dependent effect of atorvastatin in inducing renal tubular cell protection and renal tubular toxicity of atorvastatin in higher dose suggest administration of low-dose atorvastatin in critical conditions associated with renal tubular cell protection.

Aqueous concentrations of VEGF and soluble VEGF receptor-1 in diabetic retinopathy patients.

BACKGROUND: The aim of this study was to simultaneously measure the concentrations of vascular endothelial growth factor (VEGF) and soluble VEGF receptor-1 (sVEGFR-1, also known as sFlt-1) in the aqueous humor of patients with non-proliferative diabetic retinopathy (NPDR) and to investigate whether aqueous levels of vascular endothelial growth factor (VEGF) and VEGFR-1 are related to diabetic macular edema. MATERIALS AND METHODS: Aqueous humor was collected from 27 diabetic patients and 33 age- and sex-matched normoglycemic controls and analyzed for pro-angiogenic VEGF and angiogenic inhibitor VEGFR-1 by enzyme-linked immunosorbent assay (ELISA). The mean foveal thickness was measured by optical coherence tomography (OCT). RESULTS: There was no significant difference in the aqueous levels of VEGF in patients with NPDR compared with control subjects (P > 0.05), while the NPDR patients had significantly lower sVEGFR-1 in their aqueous humor. Furthermore, a significant (P < 0.01) positive correlation was observed between VEGF/sVEGFR-1 concentration and the mean foveal thickness measured on OCT. CONCLUSION: The results suggest that decreased chelating effect of sVEGFR-1 may be the preliminary event allowing VEGF to activate the proangiogenic endothelial cell state and to induce permeability. The imbalance between angiogenic agent (VEGF) and the antiangiogenic factors (sFlt-1), which is disturbed in the diabetic state, may determine the fate of diabetic macular edema.