Protective effect of chicory and/or artichoke leaves extracts on carbon tetrachloride and gamma-irradiation-induced chronic nephrotoxicity in rats.

The prevalence of chronic kidney disease (CKD) is in progress that causes kidney failure, leading to global problems. This manuscript investigated the nephroprotective effects of chicory (CLE) and/or artichoke (ALE) leaves extracts on carbon tetrachloride (CCl4 ) and gamma-irradiation (Rad)-induced chronic nephrotoxicity in rats. Rats were divided into 10 groups (10 animals/group): group 1: control, groups 2-7 rats were treated with CLE, ALE, CLE/ALE, CCl4 , Rad, and CCl4 /Rad, respectively. Groups 8 to 10, rats were intoxicated with CCl4 /Rad, and treated with CLE, ALE, and CLE/ALE extracts, respectively, for 4 weeks. The data demonstrated that CCl4 administration or Rad exposure induced high levels of urea and creatinine, with low levels of total protein and albumin in the serum. However, high levels of malondialdehyde (MDA), nitric oxide (NO), hydrogen peroxide (H2 O2 ), some pro-inflammatory markers such as interleukins (IL-1ß, IL-2, IL-6), TNF-α, NF-κB, the fibrotic marker; TGF-ß1, calcium, and copper, low contents of reduced glutathione (GSH), iron, and zinc, and suppression of the antioxidant enzymes' activity, superoxide dismutase (SOD), and catalase (CAT) were observed. In addition, the Wnt and ß-catenin protein expression ratios were up-regulated in the kidney tissues of the CCl4 , and Rad intoxicated animals. However, the combined treatment CCl4 /Rad augmented these measurements. On the other hand, CLE, ALE, and CLE/ALE treatments demonstrated nephroprotection in the kidney tissues of CCl4 /Rad intoxicated animals, in the order of CLE/ALE>ALE>CLE by ameliorating the investigated parameters. Kidney tissues' histopathological examinations confirmed these results. In conclusion, CLE and/or ALE demonstrated nephroprotection against CCl4 /Rad co-toxicity mediated by down-regulation of renal Wnt/ß-catenin protein expressions.

Investigation of the applicability of the zebrafish model for the evaluation of aristolochic acid-related nephrotoxicity.

BACKGROUND: The risk of compounds/drugs, including aristolochic acid-induced nephrotoxicity remains high and is a significant public health concern. Therefore, it is particularly important to select reasonable animal models for rapid screening and evaluation of different samples with complex chemical systems. The zebrafish (Danio rerio) has been used to study chemical-induced renal toxicity. However, most of the published literature was performed on individual components or drugs, and the key evidence confirming the applicability of zebrafish larvae for the evaluation of aristolochic acid-related nephrotoxicity in complex chemical systems, such as in traditional Chinese medicine (TCM), was insufficient. METHODS: High-performance liquid chromatography (HPLC) was used to determine the content of aristolochic acid (AA) in herbs and Chinese patent medicines. The zebrafish larvae at 4 days post-fertilization (dpf) were used to evaluate the nephrotoxicity of various samples, respectively, based on the phenotype of the kidney and histological, and biochemical. Transcriptome technology was used to investigate the related signaling pathways and potential mechanisms after treatment with AA, which was verified by RT-PCR technology. RESULTS: The results showed that the total amounts of AAI, AAII, and ALI ranged from 0.0004 to 0.1858 g·g-1( %) from different samples, including Aristolochia debilis, Fibraurea recisa, Asarum, Wantongjingu tablets, Jiuweiqianghuo granules, and Xiaoqinglong granules in descending order. Moreover, compared with the negative/blank control, substantial changes in phenotype, histomorphology and biochemical parameters of renal function were observed in the groups challenged with the sublethal concentration of drugs. The transcriptomics results showed the upregulation of most genes in PERK/ATF4/CHOP, ATM/Chk2/p53, Caspase/Bax/Bcl-2a, TGF/Smad/ERK, PI3K/Akt, induced by aristolochic acid analogues, which were essentially consistent with those of the q-RT-PCR experiments, highlighting the similar toxicity response to the previously published article with the other traditional evaluation model. CONCLUSION: The stability, accuracy and feasibility of the zebrafish larval model in screening and evaluating the nephrotoxicity of TCM were validated for the first time on the AAs-related drugs in a unified manner, confirming and promoting the applicability of zebrafish in assessing nephrotoxicity of samples with complex chemical character.

Dietary intake of n-3 polyunsaturated fatty acids alters the lipid mediator profile of the kidney but does not attenuate renal insufficiency.

The efficacy of n-3 polyunsaturated fatty acids (PUFAs) in improving outcomes in a renal ischemia-reperfusion injury (IRI) model has previously been reported. However, the underlying mechanisms remain poorly understood and few reports demonstrate how dietary n-3 PUFAs influence the composition of membrane phospholipids in the kidney. Additionally, it has not been elucidated whether perilla oil (PO), which is mainly composed of the n-3 alpha-linolenic acid, mitigates renal IRI. In this study, we investigated the effect of dietary n-3 PUFAs (PO), compared with an n-6 PUFA-rich soybean oil (SO) diet, on IRI-induced renal insufficiency in a rat model. Levels of membrane phospholipids containing n-3 PUFAs were higher in the kidney of PO-rich diet-fed rats than the SO-rich diet-fed rats. Levels of blood urea nitrogen and serum creatinine were significantly higher in the ischemia-reperfusion group than the sham group under both dietary conditions. However, no significant differences were observed in blood urea nitrogen, serum creatinine, or histological damage between PO-rich diet-fed rats and SO-rich diet-fed rats. In the kidney of PO-rich diet-fed rats, levels of arachidonic acid and arachidonic acid-derived pro-inflammatory lipid mediators were lower than SO-rich diet-fed rats. Eicosapentaenoic acid and eicosapentaenoic acid-derived lipid mediators were significantly higher in the kidney of PO-rich than SO-rich diet-fed rats. These results suggest that dietary n-3 PUFAs alter the fatty acid composition of membrane phospholipids and lipid mediators in the kidney; however, this does not attenuate renal insufficiency or histological damage in a renal IRI model.

The Pharmacology, Efficacy, and Safety of Rivaroxaban in Renally Impaired Patient Populations.

Rivaroxaban is a factor Xa inhibitor oral anticoagulant first approved for use in the United States in 2011. Under the drug class commonly termed direct oral anticoagulants, rivaroxaban is approved for the most indications within its class, 7 indications, which are: (1) reduction of risk of stroke and systemic embolism (SE) in nonvalvular atrial fibrillation, (2) treatment of deep vein thrombosis (DVT), (3) treatment of pulmonary embolism (PE), (4) reduction in the risk of recurrence of DVT and/or PE, (5) prophylaxis of DVT following hip or knee replacement surgery, (6) prophylaxis of venous thromboembolism in acutely ill medical patients at risk for thromboembolic complications not at high risk of bleeding, and (7) reduction of risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease. Considering the relationship between cardiovascular disease, renal impairment, and the use of oral anticoagulants, the following targeted review was created. This review reports the results of the primary pharmacology, pharmacokinetic modeling, clinical safety and efficacy, and real-world postmarketing effectiveness and safety of rivaroxaban in patients with various degrees of renal impairment. Based on these data, rivaroxaban is a viable option for when anticoagulation is needed in patients who have both cardiovascular disease and renal impairment. However, as with any therapy, the benefits and risks of intervention should be carefully assessed and balanced. Patients treated with rivaroxaban for several of its approved indications should have their kidney function assessed prior to and during continued therapy to ensure consistency with the drug label.

Therapeutic Drug Monitoring Can Improve Linezolid Dosing Regimens in Current Clinical Practice: A Review of Linezolid Pharmacokinetics and Pharmacodynamics.

Linezolid is an antibiotic used to treat infections caused by drug-resistant gram-positive organisms, including vancomycin-resistant Enterococcus faecium, multi-drug resistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus. The adverse effects of linezolid can include thrombocytopenia and neuropathy, which are more prevalent with higher exposures and longer treatment durations. Although linezolid is traditionally administered at a standard 600 mg dose every 12 hours, the resulting exposure can vary greatly between patients and can lead to treatment failure or toxicity. The efficacy and toxicity of linezolid are determined by the exposure achieved in the patient; numerous clinical and population pharmacokinetics (popPK) studies have identified threshold measurements for both parameters. Several special populations with an increased need for linezolid dose adjustments have also been identified. Therapeutic Drug Monitoring (TDM) is a clinical strategy that assesses the response of an individual patient and helps adjust the dosing regimen to maximize efficacy while minimizing toxicity. Adaptive feedback control and model-informed precision dosing are additional strategies that use Bayesian algorithms and PK models to predict patient-specific drug exposure. TDM is a very useful tool for patient populations with sparse clinical data or known alterations in pharmacokinetics, including children, patients with renal insufficiency or those receiving renal replacement therapy, and patients taking co-medications known to interact with linezolid. As part of the clinical workflow, clinicians can use TDM with the thresholds summarized from the current literature to improve linezolid dosing for patients and maximize the probability of treatment success.

Inflammation both increases and causes resistance to FGF23 in normal and uremic rats.

Fibroblast growth factor 23 (FGF23) increases phosphorus excretion and decreases calcitriol (1,25(OH)2D) levels. FGF23 increases from early stages of renal failure. We evaluated whether strict control of phosphorus intake in renal failure prevents the increase in FGF23 and to what extent inflammation impairs regulation of FGF23. The study was performed in 5/6 nephrectomized (Nx) Wistar rats fed diets containing 0.2-1.2% phosphorus for 3 or 15 days. FGF23 levels significantly increased in all Nx groups in the short-term (3-day) experiment. However, at 15 days, FGF23 increased in all Nx rats except in those fed 0.2% phosphorus. In a second experiment, Nx rats fed low phosphorus diets (0.2 and 0.4%) for 15 days received daily intraperitoneal lipopolysaccharide (LPS) injections to induce inflammation. In these rats, FGF23 increased despite the low phosphorus diets. Thus, higher FGF23 levels were needed to maintain phosphaturia and normal serum phosphorus values. Renal Klotho expression was preserved in Nx rats on a 0.2% phosphorus diet, reduced on a 0.4% phosphorus diet, and markedly reduced in Nx rats receiving LPS. In ex vivo experiments, high phosphorus and LPS increased nuclear ß-catenin and p65-NFκB and decreased Klotho. Inhibition of inflammation and Wnt signaling activation resulted in decreased FGF23 levels and increased renal Klotho. In conclusion, strict control of phosphorus intake prevented the increase in FGF23 in renal failure, whereas inflammation independently increased FGF23 values. Decreased Klotho may explain the renal resistance to FGF23 in inflammation. These effects are likely mediated by the activation of NFkB and Wnt/ß-catenin signaling.

Key role of organic cation transporter 2 for the nephrotoxicity effect of triptolide in rheumatoid arthritis.

Tripterygium wilfordii Hook. F. (TwHF), a traditional Chinese Medicine, is effective in treating rheumatoid arthritis (RA), but its severe nephrotoxicity limits its extensive application. The nephrotoxic mechanism of Triptolide (TP), the main pharmacological and toxic component of TwHF, has not been fully revealed. This study was designed to explore the nephrotoxicity of TP in the RA state and the potential molecular mechanism. A rat collagen-induced arthritis (CIA) model was constructed and administered with TP for 28 days in vivo. Results showed that the kidney injury induced by TP was aggravated in the CIA state, the concentration of TP in the renal cortex was higher than that of the medulla after TP administration in the CIA rats, and the expression of organic cation transporter 2 (Oct2) in kidney was up-regulated under CIA condition. Besides, rat kidney slice study demonstrated that TP was transported by Oct2 and this was confirmed by transient silencing and overexpression of OCT2 in HEK-293T cells. Furthermore, cytoinflammatory models on HK-2 and HEK-293T cell lines were constructed by exposure of TNF-α or IL-1ß to further explore the TP's renal toxicity. Results suggested that TNF-α exposure aggravated TP's toxicity and up-regulated the protein expression of OCT2 in both cell lines. TNF-α treatment also increased the function of OCT2 and finally OCT2 silencing confirmed OCT2 mediated nephrotoxicity of TP in HEK-293T cells. In summary, the exposure of TNF-α in RA state induced the expression of OCT2, which transported more TP into kidney cortex, subsequently exacerbated the kidney injury.

Effect of fatty acids from ethanol extract of Moringa oleifera seeds on kidney function impairment and oxidative stress induced by gentamicin in rats.

Gentamicin, an aminoglycoside drug, used for the treatment of Gram-negative bacterial infections. Despite its potency against bacterial infections, its clinical use is limited owing to nephrotoxicity effect. However, the study investigated the nephroprotective effect of fatty acids from ethanolic extract of Moringa oleifera seeds (EEMOS) against gentamicin-induced kidney injury in rats. Forty-five male Wistar rats, 100-160 g, were divided into 5 groups as follows: Group 1 (control), 5 rats, received 0.2 ml/100 g/day of propylene glycol orally for 28 days. Group 2, 10 rats, received 100 mg/kg/day (i.p) of gentamicin (GENT) for 8 days. Group 3-5, 10 rats each, treated with EEMOS orally for 28 days at graded doses of 100, 200 and 400 mg/kg respectively after GENT treatment. Twenty four after treatment, five rats from each group were sacrificed. The remaining 5 rats were sacrificed after 2 weeks recovery period from the drugs. The result showed that GENT elicited polyuria, elevated plasma creatinine, urea, and lower plasma electrolytes and creatinine clearance levels. Measurements of 24 h urinary output demonstrated marked decrease in creatinine and potassium levels in the GENT-treated group, whereas sodium level remain unchanged. Also, GENT caused significant decrease in superoxide dismutase and an increase in malondialdehyde levels in the kidney of the rats. Histopathological examination revealed evidence of necrosis of the kidney. Treatment with EEMOS significantly ameliorated the alterations caused by GENT in the plasma, urine and kidney homogenate of the rats. Hence, the mono- and poly-unsaturated fatty acids present in EEMOS were responsible for its renoprotective ability.

Aging, metabolic acidosis and renal failure: Interactive accelerating processes.

In this article, we hypothesize that eating a low acid (and particularly a low phosphate) diet and/or supplementing the diet with base precursors such as bicarbonate would have a number of helpful effects on aging, by:Although the present data is mainly from studies in invertebrate and small animal models, extrapolation of these results, as well as some associated results in human studies, suggests that low acid diets, or neutralization of the low grade metabolic acidosis seen in aging human subjects would possibly allow us to live longer and remain healthier.

Clinical Use of Digitalis: A State of the Art Review.

The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium-potassium adenosine triphosphatase (Na+/K+-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.

Does dietary nitrate say NO to cardiovascular ageing? Current evidence and implications for research.

CVD are characterised by a multi-factorial pathogenesis. Key pathogenetic steps in the development of CVD are the occurrence of endothelial dysfunction and formation of atherosclerotic lesions. Reduced nitric oxide (NO) bioavailability is a primary event in the initiation of the atherosclerotic cascade. NO is a free radical with multiple physiological functions including the regulation of vascular resistance, coagulation, immunity and oxidative metabolism. The synthesis of NO proceeds via two distinct pathways identified as enzymatic and non-enzymatic. The former involves the conversion of arginine into NO by the NO synthases, whilst the latter comprises a two-step reducing process converting inorganic nitrate into nitrite and subsequently NO.Inorganic is present in water and food, particularly beetroot and green leafy vegetables. Several investigations have therefore used the non-enzymatic NO pathway as a target for nutritional supplementation ( salts) or dietary interventions (high- foods) to increase NO bioavailability and impact on cardiovascular outcomes. Some studies have reported positive effects of dietary on systolic blood pressure and endothelial function in patients with hypertension and chronic heart failure. Nevertheless, results have been inconsistent and the size of the effect appears to be declining in older individuals. Additionally, there is a paucity of studies for disorders such as diabetes, CHD and chronic kidney failure. Thus, whilst dietary supplementation could represent an effective and viable strategy for the primary and secondary prevention of age-related cardiovascular and metabolic diseases, more large-scale, robust studies are awaited to confirm or refute this notion.

[Novel hormones related to the calcium and phosphate homeostasis in kidney disease].

Calcium and phosphate levels are regulated by a complex interplay between parathyroid hormone (PTH), calcitriol, fibroblast growth factor 23 (FGF23) and its co-receptor αKlotho. Kidney failure causes severe disturbances in the mineral and bone homeostasis resulting in phosphate retention, hypocalcaemia and high plasma levels of FGF23 and PTH, and the patients develop fragile bones and vascular calcifications. Today's treatments aim to lower the levels of phosphate and PTH. Future studies need to clarify, if lowering the FGF23 level or supplementation with αKlotho will improve survival for patients with chronic kidney disease.

Vitamin D protection from rat diabetic nephropathy is partly mediated through Klotho expression and renin-angiotensin inhibition.

OBJECTIVE: We hypothesised that vitamin D has a beneficial renal protective effect from diabetic nephropathy (DN). METHODS: Four rat groups were included: normal control (control), type 2 diabetes for eight weeks (DM), treated group with angiotensin receptor blocker losartan (DM + L), and vitamin D-treated group started from the onset of diabetes (DM + Vit D). RESULTS: In the both treated groups, we found a significant (p < .05) reduction in the renal pro-inflammatory and profibrotic markers induced by diabetes. Vitamin D caused more reduction in monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGFß-1), and renin-angiotensin levels that gave better kidney function compared to the DM + L group. CONCLUSION: Vitamin D may have a valuable role in the renal protective effect from DN, this may occur via expression of its VDR, Klotho and blocking renin-angiotensin activation, so vitamin D should be considered as a target in renal prophylactic measures against DN.

Protective effects of Mentha piperita L. leaf essential oil against CCl4 induced hepatic oxidative damage and renal failure in rats.

BACKGROUND: Mentha piperita L. is a flowering plant belonging to the Lamiaceae family. Mentha plants constitute one of the main valuable sources of essential oil used in foods and for medicinal purposes. METHODS: The present study aimed to investigate the composition and in vitro antioxidant activity of Mentha piperita leaf essential oil (MpEO). A single dose of CCl4 was used to induce oxidative stress in rats, which was demonstrated by a significant rise of serum enzyme markers. MpEO was administrated for 7 consecutive days (5, 15, 40 mg/kg body weight) to Wistar rats prior to CCl4 treatment and the effects on serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and γ -glutamyl transpeptidase (γ-GT) levels, as well as the liver and kidney superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity and thiobarbituric acid reactive substances (TBARS) levels were evaluated. In addition, histopathological examinations of livers and kidneys was performed. RESULTS: The in vitro antioxidant activity of MpEO was lower than that of silymarin. Pretreatment of animals with MpEO at a dose of 5 mg/kg did not have a significant effect on ALT, AST, ALP, LDH, γGT, urea or creatinine levels in CCl4-induced stress. Whereas pretreatment with MpEO at doses of 15 and 40 mg/kg prior to CCl4, significantly reduced stress parameters (ALT, AST, ALP, LDH, γGT, urea and creatinine) compared to the CCl4-only group. Moreover, a significant reduction in hepatic and kidney lipid peroxidation (TBARS) and an increase in antioxidant enzymes SOD, CAT and GPx was also observed after treatment with MpEO (40 mg/kg) compared to CCl4-treated rats. Furthermore, pretreatment with MpEO at 40 mg/kg can also markedly ameliorate the histopathological hepatic and kidney lesions induced by administration of CCl4. CONCLUSIONS: We could demonstrate with this study that MpEO protects liver and kidney from CCl4-induced oxidative stress and thus substantiate the beneficial effects attributed traditionally to this plant.

Chemoprotective effects of curcumin on doxorubicin-induced nephrotoxicity in wistar rats: by modulating inflammatory cytokines, apoptosis, oxidative stress and oxidative DNA damage.

Doxorubicin (DXR) is one of the most important chemotherapeutic agent. However, nephrotoxicity reduces its clinical utility in humans. The aim of the study was to investigate protective effects of curcumin (CMN) against DXR-induced nephrotoxicity. Rats were subjected to oral treatment of CMN (100 and 200 mg/kg body weight) for 7 days. Nephrotoxicity was induced by single intra peritoneal injection of DXR (40 mg/kg body weight) on the fifth day and then the experiment was terminated on the eighth day. Nephroprotective effects of CMN were associated with decrease in serum toxicity markers and increase in antioxidant enzyme activities. CMN was able to reduced the levels of inflammatory markers such as TNF-α, NF-κB, IL-1ß, iNOS and COX-2 in the rats. It also reduced the expressions of apoptotic marker including caspase-3, and oxidative DNA damage marker including 8-OHdG. Collectively, these findings indicated that CMN protect against DXR-induced nephrotoxicity.

Euterpe oleracea Mart. seed extract protects against renal injury in diabetic and spontaneously hypertensive rats: role of inflammation and oxidative stress.

PURPOSE: Euterpe oleracea Mart. (açaí) seed extract (ASE), through its anti-hypertensive, antioxidant and anti-inflammatory properties, may be useful to treat or prevent human diseases. Several evidences suggest that oxidative stress and inflammation contribute to the pathogenesis of diabetic nephropathy; therefore, we tested the hypothesis that ASE (200 mg/kg-1day-1) prevents diabetes and hypertension-related oxidative stress and inflammation, attenuating renal injury. METHODS: Male rats with streptozotocin (STZ)-induced diabetes (D), and spontaneously hypertensive rats with STZ-induced diabetes (DH) were treated daily with tap water or ASE (D + ASE and DH + ASE, respectively) for 45 days. The control (C) and hypertensive (H) animals received water. RESULTS: The elevated serum levels of urea and creatinine in D and DH, and increased albumin excretion in HD were reduced by ASE. Total glomeruli number in D and DH, were increased by ASE that also reduced renal fibrosis in both groups by decreasing collagen IV and TGF-ß1 expression. ASE improved biomarkers of renal filtration barrier (podocin and nephrin) in D and DH groups and prevented the increased expression of caspase-3, IL-6, TNF-α and MCP-1 in both groups. ASE reduced oxidative damage markers (TBARS, carbonyl levels and 8-isoprostane) in D and DH associated with a decrease in Nox 4 and p47 subunit expression and increase in antioxidant enzyme activity in both groups (SOD, catalase and GPx). CONCLUSION: ASE substantially reduced renal injury and prevented renal dysfunction by reducing inflammation, oxidative stress and improving the renal filtration barrier, providing a nutritional resource for prevention of diabetic and hypertensive-related nephropathy.

Dietary Supplementation with Virgin Coconut Oil Improves Lipid Profile and Hepatic Antioxidant Status and Has Potential Benefits on Cardiovascular Risk Indices in Normal Rats.

Research findings that suggest beneficial health effects of dietary supplementation with virgin coconut oil (VCO) are limited in the published literature. This study investigated the in vivo effects of a 5-week VCO-supplemented diet on lipid profile, hepatic antioxidant status, hepatorenal function, and cardiovascular risk indices in normal rats. Rats were randomly divided into 3 groups: 1 control and 2 treatment groups (10% and 15% VCO-supplemented diets) for 5 weeks. Serum and homogenate samples were used to analyze lipid profile, hepatorenal function markers, hepatic activities of antioxidant enzymes, and malondialdehyde level. Lipid profile of animals fed VCO diets showed significant reduction in total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels; high-density lipoprotein (HDL) level increased significantly (p < .05) compared to control; and there were beneficial effects on cardiovascular risk indices. The level of malondialdehyde (MDA), a lipid peroxidation marker, remarkably reduced and activities of hepatic antioxidant enzymes-superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)-were markedly increased in VCO diet-fed rats. The VCO diet significantly modulated creatinine, sodium (Na+), potassium (K+), chloride (Cl-), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) compared to control. The findings suggest a beneficial effect of VCO on lipid profile, renal status, hepatic antioxidant defense system, and cardiovascular risk indices in rats.

Biological effects of MRI contrast agents: gadolinium retention, potential mechanisms and a role for phosphorus.

No discussion of challenges for chemistry in molecular imaging would be complete without addressing the elephant in the room-which is that the purest of chemical compounds needs to interact with a biological system in a manner that does not perturb normal biology while still providing efficacious feedback to assist in diagnosis of disease. In the past decade, magnetic resonance imaging (MRI) agents long considered inert have produced adverse effects in certain patient populations under certain treatment regimens. More recently, inert blood pool agents have been found to deposit in the brain. Release of free metal is often suspected as the culprit but that hypothesis has yet to be validated. In addition, even innocuous agents can cause painful side effects during injection in some patients. In this brief review, we summarize known biological effects for gadolinium- and iron-based MRI contrast agents, and discuss some of the potential mechanisms for the observed biological effects, including the potential role of phosphorus imbalance, related to kidney disease or cancer, in destabilizing gadolinium-based chelates and precipitating free gadolinium.This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

Lucerastat, an Iminosugar for Substrate Reduction Therapy: Pharmacokinetics, Tolerability, and Safety in Subjects With Mild, Moderate, and Severe Renal Function Impairment.

Lucerastat, an inhibitor of glucosylceramide synthase, has the potential for substrate reduction therapy in glycosphingolipid storage disorders such as Fabry disease. In pharmacokinetic studies in rats, dogs, and healthy subjects, the main route of elimination was renal. The pharmacokinetics, tolerability, and safety of lucerastat were evaluated in subjects with mild (group A), moderate (group B), and severe (group C) renal impairment. Group D included healthy subjects. Thirty-two subjects (8 per group) were included in this single-center, open-label study and received a single oral dose of 1000 mg lucerastat in groups A and B and 500 mg in groups C and D. The degree of renal impairment of the subjects was based on estimated glomerular filtration rate. Plasma lucerastat concentrations (dose-corrected) were higher in groups B and C compared to group D. The elimination phase half-life was slower in groups B (9.6 hours) and C (16.1 hours) compared to group D (7.0 hours). Increased exposure to lucerastat was observed in subjects from groups B and C with ratio of geometric means (90%CI) of 1.60 (1.29, 1.98) for group B vs D and 3.17 (2.76, 3.65) for group C vs D. There were no clinically relevant abnormalities in vital signs, 12-lead electrocardiograms, and clinical laboratory values. Four nonserious adverse events were reported by 4 subjects (1 in group A, 3 in group D). Lucerastat was well tolerated in all dose groups. Dose adjustment is warranted in subjects with moderate and severe renal impairment.

Net Reclassification Index and Integrated Discrimination Index Are Not Appropriate for Testing Whether a Biomarker Improves Predictive Performance.

One of the goals of the Critical Path Institute's Predictive Safety Testing Consortium (PSTC) is to promote best practices for evaluating novel markers of drug induced injury. This includes the use of sound statistical methods. For rat studies, these practices have centered around comparing the area under the receiver-operator characteristic curve for each novel injury biomarker to those for the standard markers. In addition, the PSTC has previously used the net reclassification index (NRI) and integrated discrimination index (IDI) to assess the increased certainty provided by each novel injury biomarker when added to the information already provided by the standard markers. Due to their relatively simple interpretations, NRI and IDI have generally been popular measures of predictive performance. However recent literature suggests that significance tests for NRI and IDI can have inflated false positive rates and thus, tests based on these metrics should not be relied upon. Instead, when parametric models are employed to assess the added predictive value of a new marker, following (Pepe, M. S., Kerr, K. F., Longton, G., and Wang, Z. (2013). Testing for improvement in prediction model performance. Stat. Med. 32, 1467-1482), the PSTC recommends that likelihood based methods be used for significance testing.