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Objectives: In this study, we investigated the possible useful effectiveness of Sinapic acid on rat kidney and lung tissues in an experimental cecal ligation puncture (CLP) model. Methods: CLP model was created for the rats in the CLP group. 20 mg/kg of Sinapic acid was given in the CLP-Sinapic acid group. At the end of the experiment, lung and kidney tissues were collected and biochemical analyzes were evaluated. Results: For the lung and kidney tissue samples; antioxidant levels decreased, and oxidant levels increased in the CLP group. When the immunohistochemical parameters were evaluated, IL-1β, caspase-3, and TNF-α immunopositivity were severe levels in CLP group. But immunopositivity of these parameters have been observed as attenuated in CLP-Sinapic acid group compared to CLP group. Conclusion: The results of our study showed that Sinapic acid has useful effectiveness on the sepsis model caused by CLP in the lung and kidney tissues.

Doxorubicin (DOXO) is a cytostatic agent used in the chemotherapy protocol of several cancers for more than 40 years, but usage of this drug in cancer treatment has been limited due to severe renal and cardiac tissue toxicities that may result in death in patients. Fluvastatin (FV) is a fully synthetic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor used as a cholesterol-lowering agent in patients with hypercholesterolemia. Previous studies revealed that FV also exhibits antioxidant, anti-inflammatory, and antitumor activity. Additionally, our previous study indicated that FV exerts a prophylactic effect on DOXO-induced testicular toxicity by preventing lipid peroxidation, supporting the antioxidant system, and regulating the blood-testis barrier-associated genes expression. Herein, we purposed to evaluate the possible therapeutic and the protective effects of FV on the DOXO-induced cardiac and renal toxicitiy model by histochemical, immunohistochemical, biochemical, and real-time polymerase chain reaction (real-time PCR) analyses. Results point out protective use of FV exerts a beneficial effect by repressing lipid peroxidation and by regulating the inducible nitric oxide synthase (iNOS), nitric oxide synthase endothelial (eNOS), nuclear factor kappa-B (NF-kappa B), and Caspase-3 (Casp3) protein and mRNA expressions, which play an important role in mediating DOXO-induced renal and cardiac toxicity mechanisms. In conclusion, FV may be a candidate agent for the prevention of renal and cardiac toxicities in cancer patients receiving DOXO chemotherapy., Ege University Scientific Research Projects Coordination Unit [18-TIP-016], This study was supported by the Ege University Scientific Research Projects Coordination Unit [grant number 18-TIP-016 (to FO)].

Background: Favipiravir (FPV), an effective antiviral agent, is a drug used to treat influenza and COVID-19 by inhibiting the RNA-dependent RNA polymerase (RdRp) of RNA viruses. FPV has the potential to increase oxidative stress and organ damage. The purpose of this study was to demonstrate the oxidative stress and inflammation caused by FPV in the liver and kidneys of rats, as well as to investigate the curative effects of vitamin C (VitC).Methods: A total of 40 Sprague-Dawley male rats were randomly and equally divided into the following five groups: 1st; Control, 2nd; FPV = 20 mg/kg, 3rd; FPV = 100 mg/kg, 4th; FPV = 20 mg/kg + VitC (150 mg/kg), and 5th; FPV = 100 mg/kg + VitC (150 mg/kg) groups. Rats were given either FPV (orally) or FPV plus VitC (intramuscular) for 14 days. Rat blood, liver, and kidney samples were collected at 15 days to be analyzed for oxidative and histological changes.Results: FPV administration resulted in an increase in proinflammatory cytokines (TNF-alpha and IL-6) in the liver and kidney, as well as oxidative and histopathologic damage. FPV increased TBARS levels significantly (p < .05) and decreased GSH and CAT levels in liver and kidney tissues but had no effect on SOD activity. VitC supplementation significantly reduced TNF-a, IL-6, and TBARS levels while increasing GSH and CAT levels (p < .05). Furthermore, VitC significantly attenuated FPV-induced histopathological alterations associated with oxidative stress and inflammation in the liver and kidney tissues (p < .05).Conclusion: FPV caused liver and kidney damage in rats. In contrast, co-administration of FPV with VitC improved FPV-induced oxidative, pro-inflammatory, and histopathological changes.

Aim: Cisplatin is a widely used and highly effective anti-cancer agent and one of the limiting side effects of cisplatin is ocular toxicity. Achillea millefolium, also known as yarrow, is a plant that has been used for many years to treat various health problems including chemotherapy-related toxicities. Methods: The present investigation was designed to evaluate the biochemical, molecular and histopathological effects of Achillea Millefolium on cisplatin-induced oxidative and inflammatory ocular damage in rats. Twenty-four adult male rats were assigned randomly to four groups (n = 6) as (1) control, (2) cisplatin (7 mg/kg, intraperitoneally), (3) Cisplatin + Achillea millefolium (200 mg/kg, orally for 14 consecutive days), (4) Cisplatin + Achillea millefolium (400 mg/kg, orally for 14 consecutive days). Levels of total antioxidant capacity and total oxidant status, SOD, MDA, IL-1 beta, and IL-10 were measured in ocular tissue. The mRNA expressions of TNF-alpha, nuclear factor kappa B and Caspase-3 were evaluated. Also, ocular sections were evaluated histopathologically. Results: Achillea Millefolium upregulated ocular antioxidant enzymes and downregulated inflammation. The SOD activity and total antioxidant capacity increased whereas total oxidant status and MDA levels decreased significantly at high dose group. High dose Achillea millefolium treatment reduced the IL-1 beta concentrations, whereas IL-10 levels increased significantly in that group. Moreover, we observed that Achillea millefolium restored ocular histopathological structure and significantly suppressed apoptosis by reducing the expression of Caspase-3. Conclusion: Collectively, our results suggest that Achillea millefolium have protective effects against cisplatin-induced ocular toxicity and is a promising adjuvant therapy with the potential to prevent cisplatin related ocular toxicity.

Cisplatin is amongst the most potent chemotherapeutic drugs with applications in more than 50% of cancer treatments, but dose-dependent side effects limit its usefulness. Berberis vulgaris L. (B. vulgaris) has a proven role in several therapeutic applications in the traditional medicinal system. High-performance liquid chromatography was used to quantify berberine, a potent alkaloid in the methanolic root extract of B. vulgaris (BvRE). Berberine chloride in BvRE was found to be 10.29% w/w. To assess the prophylactic and curative protective effects of BvRE on cisplatin-induced nephrotoxicity, hepatotoxicity, and hyperlipidemia, in vivo toxicity trials were carried out on 25 healthy male albino Wistar rats (130&ndash, 180 g). Both prophylactic and curative trials included a single dose of cisplatin (4 mg/kg, i.p.) and nine doses of BvRE (500 mg/kg/day, orally). An array of marked toxicity effects appeared in response to cisplatin dosage evident by morphological condition, biochemical analysis of serum (urea, creatinine, total protein, alanine transaminase, aspartate transaminase, total cholesterol, and triglyceride), and organ tissue homogenates (malondialdehyde and catalase). Statistically-significant (p &lt, 0.05) variations were observed in various parameters. Moreover, histological studies of liver and kidney tissues revealed that the protective effect of BvRE effectively minimized and reversed nephrotoxic, hepatotoxic, and hyperlipidemic effects caused by cisplatin in both prophylactic and curative groups with relatively promising ameliorative effects in the prophylactic regimen. The in vitro cell viability effect of cisplatin, BvRE, and their combination was determined on HeLa cells using the tetrazolium (MTT) assay. MTT clearly corroborated that HeLa cells appeared to be less sensitive to cisplatin and berberine individually, while the combination of both at the same concentrations resulted in growth inhibition of HeLa cells in a remarkable synergistic way. The present validated the use of BvRE as a protective agent in combination therapy with cisplatin.

Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies show cisplatin generates reactive oxygen species, which impair the cell's antioxidant defense system, causing oxidative stress and potentiating injury, thereby culminating in kidney and heart failure. Understanding the molecular mechanisms of cisplatin-induced renal and cardiac toxicities may allow clinicians to prevent or treat this problem better and may also provide a model for investigating drug-induced organ toxicity in general. This review discusses some of the major molecular mechanisms of cisplatin-induced renal and cardiac toxicities including disruption of ionic homeostasis and energy status of the cell leading to cell injury and cell death. We highlight clinical manifestations of both toxicities as well as (novel)biomarkers such as kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also present some current treatment challenges and propose potential protective strategies including combination therapy with novel pharmacological compounds that might mitigate or prevent these toxicities, which include the use of hydrogen sulfide.

Cisplatin is a potent chemotherapeutic agent for the treatment of various solid-organ cancers. However, a plethora of evidence indicates that nephrotoxicity is a major side effect of cisplatin therapy. While the antineoplastic action of cisplatin is due to formation of cisplatin-DNA cross-links, which damage rapidly dividing cancer cells upon binding to DNA, its nephrotoxic effect results from metabolic conversion of cisplatin into a nephrotoxin and production of reactive oxygen species, causing oxidative stress leading to renal tissue injury and potentially, kidney failure. Despite therapeutic targets in several pre-clinical and clinical studies, there is still incomplete protection against cisplatin-induced nephrotoxicity. Hydrogen sulfide (H2S), the third discovered gasotransmitter next to nitric oxide and carbon monoxide, has recently been identified in several in vitro and in vivo studies to possess specific antioxidant, anti-inflammatory and anti-apoptotic properties that modulate several pathogenic pathways involved in cisplatin-induced nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and displays recent findings in the H2S field that could disrupt such mechanisms to ameliorate cisplatin-induced renal injury. (C) 2016 Elsevier Inc. All rights reserved.

Cisplatin is a potent chemotherapeutic agent for the treatment of various solid-organ cancers. However, a plethora of evidence indicates that nephrotoxicity is a major side effect of cisplatin therapy. While the antineoplastic action of cisplatin is due to formation of cisplatin-DNA cross-links, which damage rapidly dividing cancer cells upon binding to DNA, its nephrotoxic effect results from metabolic conversion of cisplatin into a nephrotoxin and production of reactive oxygen species, causing oxidative stress leading to renal tissue injury and potentially, kidney failure. Despite therapeutic targets in several pre-clinical and clinical studies, there is still incomplete protection against cisplatin-induced nephrotoxicity. Hydrogen sulfide (H2S), the third discovered gasotransmitter next to nitric oxide and carbon monoxide, has recently been identified in several in vitro and in vivo studies to possess specific antioxidant, anti-inflammatory and anti-apoptotic properties that modulate several pathogenic pathways involved in cisplatin-induced nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and displays recent findings in the H2S field that could disrupt such mechanisms to ameliorate cisplatin-induced renal injury. (C) 2016 Elsevier Inc. All rights reserved.

Citrinin (CIT) is a polyketide mycotoxin occurring in a variety of food and feedstuff, among which cereal grains are the most important contaminated source. Pigs and poultry are important livestock animals frequently exposed to mycotoxins, including CIT. Concerns are rising related to the toxic, and especially the potential nephrotoxic, properties of CIT. The purpose of this study was to clarify the histopathological effects on kidneys, liver, jejunum and duodenum of pigs, broiler chickens and laying hens receiving CIT contaminated feed. During 3 weeks, pigs (n = 16) were exposed to feed containing 1 mg CIT/kg feed or to control feed (n = 4), while 2 groups of broiler chickens and laying hens (n = 8 per group) received 0.1 mg CIT/kg feed (lower dose group) and 3 or 3.5 mg CIT/kg feed (higher dose group), respectively, or control feed (n = 4). CIT concentrations were quantified in plasma, kidneys, liver, muscle and eggs using a validated ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Kidneys, liver, duodenum and jejunum were evaluated histologically using light microscopy, while the kidneys were further examined using transmission electron microscopy (TEM). Histopathology did not reveal major abnormalities at the given contamination levels. However, a significant increase of swollen and degenerated mitochondria in renal cortical cells from all test groups were observed (p &lt, 0.05). These observations could be related to oxidative stress, which is the major mechanism of CIT toxicity. Residues of CIT were detected in all collected tissues, except for muscle and egg white from layers in the lowest dose group, and egg white from layers in the highest dose group. CIT concentrations in plasma ranged between 0.1 (laying hens in lower dose group) and 20.8 ng/mL (pigs). In tissues, CIT concentrations ranged from 0.6 (muscle) to 20.3 &micro, g/kg (liver) in pigs, while concentrations in chickens ranged from 0.1 (muscle) to 70.2 &micro, g/kg (liver). Carry-over ratios from feed to edible tissues were between 0.1 and 2% in pigs, and between 0.1 and 6.9% in chickens, suggesting a low contribution of pig and poultry tissue-derived products towards the total dietary CIT intake for humans.

IntroductionCT is the primary imaging option for acute abdominal pain in adults. Intravenous (IV) contrast media use improves CT quality but may cause post-contrast acute kidney injury (PC-AKI). Retrospective studies show no association between reduced baseline renal function and IV contrast CT, but, to our knowledge, no data from randomised controlled trials exist.Methods and analysisThe INCARO (INtravenous Contrast computed tomography versus native computed tomography in patients with acute Abdomen and impaired Renal functiOn) trial is a multicentre, open-label, parallel group, superiority, individually randomised controlled trial comparing IV contrast-enhanced CT to native CT in patients requiring emergency abdominal or body CT with impaired renal function defined as an estimated glomerular filtration rate (eGFR) of 15 to 45 mL/min/1.73 m2. The primary outcome is a composite of all-cause mortality or renal replacement therapy (RRT) within 90 days from CT. Secondary outcomes are AKI measured by KDIGO (The Kidney Disease: Improving Global Outcomes) criteria within 72 hours from CT, organ dysfunction defined by mSOFA (modified Sequential Organ Failure Assessment) criteria after 48 hours from CT, alive and hospital-free days within 90 days after CT, and time from imaging to definitive treatment. All-cause mortality, need for RRT and renal transplant in long-term follow-up are also measured. The calculated sample size is 994 patients. Patient recruitment is estimated to take 3 years.Ethics and disseminationThe Ethics Committee of Helsinki University Hospital approved the study. The findings will be disseminated in peer-reviewed academic journals.Trial registration numberNCT04196244

Objectives: Recently, safety guidelines for the use of intravascular iodinated contrast material have been updated, and the recommended threshold for giving prophylaxis to prevent contrast-induced nephropathy (CIN) has been reduced to estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m(2). Data on this population in the context of CIN, especially evidence for efficacy of the recommendation of prophylactic intravenous hydration, are lacking. The aim of the current study was to test implicit assumptions underlying the guideline update: (1) patients with eGFR = 30 mL/min/1.73 m(2), are at high risk of CIN and other unfavorable outcomes after intravascular iodinated contrast material administration; (2) prophylactic intravenous hydration mitigates this risk; and (3) the risk of administering prophylactic intravenous hydration does not outweigh the positive preventive effect. Materials and Methods: Retrospectively, data were collected from all patients with eGFR

Mechanisms of toxicity and cellular transport of anticancer metallodrugs, including platinum-based agents, have not yet been fully elucidated. Here, we studied the toxic effects and accumulation mechanisms of cisplatin in healthy rat kidneys ex vivo, using the Precision Cut Tissue Slices (PCTS) method. In addition, for the first time, we investigated the nephrotoxic effects of an experimental anticancer cyclometallated complex [Au(pyb-H)(PTA)Cl]PF6 (PTA = 1,3,5-triazaphosphaadamantane). The viability of the kidney slices after metallodrug treatment was evaluated by ATP content determination and histomorphology analysis. A concentration dependent decrease in viability of PCKS was observed after exposure to cisplatin or the Au(III) complex, which correlated with the increase in slice content of Pt and Au, respectively. Metal accumulation in kidney slices was analysed by ICP-MS. The involvement of OCTs and MATE transporters in the accumulation of both metal compounds in kidneys was evaluated co-incubating the tissues with cimitedine, inhibitor of OCT and MATE. Studies of mRNA expression of the markers KIM-1, villin, p53 and Bax showed that cisplatin damages proximal tubules, whereas the Au(III) complex preferentially affects the distal tubules. However, no effect of cimetidine on the toxicity or accumulation of cisplatin and the Au(III) complex was observed. The effect of temperature on metallodrug accumulation in kidneys suggests the involvement of a carrier-mediated uptake process, other than OCT2, for cisplatin; while carrier-mediated excretion was suggested in the cases of the Au(III) complex.

Summary Background Intravenous saline is recommended in clinical practice guidelines as the cornerstone for preventing contrast-induced nephropathy in patients with compromised renal function. However, clinical-effectiveness and cost-effectiveness of this prophylactic hydration treatment in protecting renal function has not been adequately studied in the population targeted by the guidelines, against a group receiving no prophylaxis. This was the aim of the AMACING trial. Methods AMACING is a prospective, randomised, phase 3, parallel-group, open-label, non-inferiority trial of patients at risk of contrast-induced nephropathy according to current guidelines. High-risk patients (with an estimated glomerular filtration rate [eGFR] of 30–59 mL per min/1·73 m 2 ) aged 18 years and older, undergoing an elective procedure requiring iodinated contrast material administration at Maastricht University Medical Centre, the Netherlands, were randomly assigned (1:1) to receive intravenous 0·9% NaCl or no prophylaxis. We excluded patients with eGFR lower than 30 mL per min/1·73 m 2 , previous dialysis, or no referral for intravenous hydration. Randomisation was stratified by predefined risk factors. The primary outcome was incidence of contrast-induced nephropathy, defined as an increase in serum creatinine from baseline of more than 25% or 44 μmol/L within 2–6 days of contrast exposure, and cost-effectiveness of no prophylaxis compared with intravenous hydration in the prevention of contrast-induced nephropathy. We measured serum creatinine immediately before, 2–6 days, and 26–35 days after contrast-material exposure. Laboratory personnel were masked to treatment allocation. Adverse events and use of resources were systematically recorded. The non-inferiority margin was set at 2·1%. Both intention-to-treat and per-protocol analyses were done. This trial is registered with ClinicalTrials.gov, number NCT02106234. Findings Between June 17, 2014, and July 17, 2016, 660 consecutive patients were randomly assigned to receive no prophylaxis (n=332) or intravenous hydration (n=328). 2–6 day serum creatinine was available for 307 (92%) of 332 patients in the no prophylaxis group and 296 (90%) of 328 patients in the intravenous hydration group. Contrast-induced nephropathy was recorded in eight (2·6%) of 307 non-hydrated patients and in eight (2·7%) of 296 hydrated patients. The absolute difference (no hydration vs hydration) was −0·10% (one-sided 95% CI −2·25 to 2·06; one-tailed p=0·4710). No hydration was cost-saving relative to hydration. No haemodialysis or related deaths occurred within 35 days. 18 (5·5%) of 328 patients had complications associated with intravenous hydration. Interpretation We found no prophylaxis to be non-inferior and cost-saving in preventing contrast-induced nephropathy compared with intravenous hydration according to current clinical practice guidelines. Funding Stichting de Weijerhorst.

The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.

Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies show cisplatin generates reactive oxygen species, which impair the cell's antioxidant defense system, causing oxidative stress and potentiating injury, thereby culminating in kidney and heart failure. Understanding the molecular mechanisms of cisplatin-induced renal and cardiac toxicities may allow clinicians to prevent or treat this problem better and may also provide a model for investigating drug-induced organ toxicity in general. This review discusses some of the major molecular mechanisms of cisplatin-induced renal and cardiac toxicities including disruption of ionic homeostasis and energy status of the cell leading to cell injury and cell death. We highlight clinical manifestations of both toxicities as well as (novel)biomarkers such as kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also present some current treatment challenges and propose potential protective strategies including combination therapy with novel pharmacological compounds that might mitigate or prevent these toxicities, which include the use of hydrogen sulfide.

Background: In the present study, the protective and therapeutic effects of quercetin (QE) on renal injury induced by methotrexate (MTX) have been examined. Materials and methods: A total of 24 male rats were divided into the following three groups: control group, MTX group, and MTX+QE group. Rats in MTX group received 20mg/kg of single dose of MTX, while those in MTX+QE group received 20mg/kg of single dose MTX, in addition to 15mg/kg of QE administered 30min prior to MTX and in the following 5-day period as a single daily dose. At the end of the experimental period, renal tissues were removed for histopathological and biochemical assessments. Results: Light microscopic examination showed a disruption of the renal structure in rats in MTX group in the form of tubular degeneration and dilation, with shedding of the tubular epithelial cells into the lumen. QE treatment was associated with less marked degenerative changes, with a similar histological appearance to that of controls. Furthermore, QE treatment resulted in decreased the number of apoptotic cells. Biochemical assessments showed significantly higher malondialdehyde (MDA) levels in MTX group as compared to control and MTX+QE groups. superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) levels showed a significant decrease in MTX group as compared to controls. However, QE significantly suppressed MDA level, compensated deficits in the anti-oxidant defenses [reduced SOD, GSH-Px, and CAT levels] in kidney tissue resulted from MTX administration. Conclusions: In conclusion, renal toxic effects of MTX may be alleviated by QE.

Cetin, Nihal/0000-0003-3233-8009; WOS: 000318732600001 PubMed: 23737712 Cisplatin causes infertility due to ovarian toxicity. the toxicity mechanism is unknown, but evidence suggests oxidative stress. in this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p.) and mirtazapine (15 mg/kg p.o.) or mirtazapine (30 mg/kg p.o.) for 10 days. After this period, six rats from each group were randomly selected, and malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), total gluthatione (tGSH), gluthatione peroxidase (GPx), superoxide dismutase (SOD), and 8-hydroxy-2 deoxyguanine (8-OH Gua) levels were measured in their ovarian tissues. Reproductive functions of the remaining rats were examined for 6 months. the MDA, MPO, NO groups and 8-OH Gua levels were higher in the cisplatin-treated groups than the controls, which was not observed in the mirtazapine and cisplatin groups. GSH, GPx, and SOD levels were reduced by cisplatin, which was prevented by mirtazapine. Cisplatin caused infertility by 70%. the infertility rates were, respectively, 40% and 10% for the 15 and 30 mg/kg mirtazapine administered groups. in conclusion, oxidative stress induced by cisplatin in the rat ovary tissue causes infertility in the female rats. Mirtazapine reverses this in a dose-dependent manner.

Peroxisome proliferator-activated receptor-α (PPARα) activation attenuates cisplatin (CP)-mediated acute kidney injury by increasing fatty acid oxidation, but mechanisms leading to reduced renal triglyceride (TG) accumulation could also contribute. Here, we investigated the effects of PPARα and CP on expression and enzyme activity of kidney lipoprotein lipase (LPL) as well as on expression of angiopoietin protein-like 4 (Angptl4), glycosylphosphatidylinositol-anchored-HDL-binding protein (GPIHBP1), and lipase maturation factor 1 (Lmf1), which are recognized as important proteins that modulate LPL activity. CP caused a 40% reduction in epididymal white adipose tissue (WAT) mass, with a reduction of LPL expression and activity. CP also reduced kidney LPL expression and activity. Angptl4 mRNA levels were increased by ninefold in liver and kidney tissue and by twofold in adipose tissue of CP-treated mice. Western blots of two-dimensional gel electrophoresis identified increased expression of a neutral pI Angptl4 protein in kidney tissue of CP-treated mice. Immunolocalization studies showed reduced staining of LPL and increased staining of Angptl4 primarily in proximal tubules of CP-treated mice. CP also increased TG accumulation in kidney tissue, which was ameliorated by PPARα ligand. In summary, a PPARα ligand ameliorates CP-mediated nephrotoxicity by increasing LPL activity via increased expression of GPHBP1 and Lmf1 and by reducing expression of Angptl4 protein in the proximal tubule.

Ashish Ranjan1, Nikorn Pothayee2,3, Mohammed N Seleem2, Ronald D Tyler Jr4, Bonnie Brenseke4, Nammalwar Sriranganathan2,4, JudyS Riffle2,3, Ramanathan Kasimanickam11Department of Large Animal Clinical Sciences, 2Institute for Critical Technology and Applied Science, 3Macromolecules and Interfaces Institute, 4Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg, VAAbstract: Pluronic based core-shell nanostructures encapsulating gentamicin were designed in this study. Block copolymers of (PAA–+Na-b-(PEO-b-PPO-b-PEO)-b-PAA– +Na) were blended with PAA– Na+ and complexed with the polycationic antibiotic gentamicin to form nanostructures. Synthesized nanostructures had a hydrodynamic diameter of 210 nm, zeta potentials of –0.7 (±0.2), and incorporated ~20% by weight of gentamicin. Nanostructures upon co-incubation with J774A.1 macrophage cells showed no adverse toxicity in vitro. Nanostructures administered in vivo either at multiple dosage of 5 µg g–1 or single dosage of 15 µg g–1 in AJ-646 mice infected with Salmonella resulted in significant reduction of viable bacteria in the liver and spleen. Histopathological evaluation for concentration-dependent toxicity at a dosage of 15 µg g–1 revealed mineralized deposits in 50% kidney tissues of free gentamicin-treated mice which in contrast was absent in nanostructure-treated mice. Thus, encapsulation of gentamicin in nanostructures may reduce toxicity and improve in vivo bacterial clearance.Keywords: gentamicin, core-shell nanostructures, Salmonella

Mercury exerts a variety of toxic effects in the body. Lipid peroxidation, DNA damage and depletion of reduced glutathione by Hg(II) suggest an oxidative stress-like mechanism for Hg(II) toxicity. Melatonin, the main secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. N-Acetylcysteine, a precursor of reduced glutathione and an antioxidant, is used in the therapy of acute heavy metal poisoning. In this study the protective effects of melatonin in comparison to that of N-acetylcysteine against Hg-induced oxidative damage in the kidney, liver, lung and brain tissues were investigated. Wistar albino rats of either sex (200-250 g) were divided into six groups, each consisting of 8 animals. Rats were intraperitoneally injected with 1) 0.9% NaCl, control (C) group; 2) a single dose of 5 mg/kg mercuric chloride (HgCl2), Hg group; 3) melatonin in a dose of 10 mg/kg, 1 hr after HgCl2 injection, Hg-melatonin group; 4) melatonin in a dose of 10 mg/kg one day before and 1 hr after HgCl2 injection, melatonin-Hg-melatonin group; 5) N-acetylcysteine in a dose of 150 mg/kg, 1 hr after HgCl2 injection, Hg-N-acetylcysteine group, and 6) N-acetylcysteine in a dose of 150 mg/kg one day before and 1 hr after HgCl2 injection, N-acetylcysteine-Hg-N-acetylcysteine group. Animals were killed by decapitation 24 hr after the injection of HgCl2. Tissue samples were taken for determination of malondialdehyde, an end-product of lipid peroxidation; glutathione (GSH), a key antioxidant, and myeloperoxidase activity, an index of neutrophil infiltration. The results revealed that HgCl2 induced oxidative tissue damage, as evidenced by increases in malondialdehyde levels. Myeloperoxidase activity was also increased, and GSH levels were decreased in the liver, kidney and the lungs. All of these effects were reversed by melatonin or N-acetylcysteine treatment. Since melatonin or N-acetylcysteine administration reversed these responses, it seems likely that melatonin or N-acetylcysteine can protect all these tissues against HgCl2-induced oxidative damage.