Nephrotoxic Properties Research Articles

Evaluation of apoptosis gene expression and morphological changes in kidney tissue under acrylamide exposure and prophylactic drug correction

Introduction. Acrylamide is a well-known toxicant, contact with which occurs both in industrial and domestic conditions. It has been found to have nephrotoxic properties. The purpose of the work is to evaluate the expression of the Casp7, Chek1 genes and changes in the structure of the kidney tissue in rats under long-term exposure to acrylamide and preventive correction. Materials and methods. The experiment used sixty white outbred male rats. Acrylamide was administered intragastrically at a dose of 5 mg/kg body weight for 90 days. Correction of possible violations was carried out 1 hour before the administration of the toxicant with complex compounds of hydroxymethyluracil. Gene expression was studied using real-time PCR. SPSS Statistics 21.0 software (IBM, USA) was used for statistical data analysis. Morphological studies of the structure of rat kidneys were carried out using standard methods. Results. Studies have shown that exposure to acrylamide for 3 months at a dose of 5 mg/kg body weight causes structural changes in the kidney tissue in rats. With long-term exposure to acrylamide, there is a tendency to increase the expression of the Chek1 and Casp7 genes, which may indicate cell damage and activation of repair and apoptosis processes in them. The combination of hydroxymethyluracil with acetylcysteine had the greatest protective effect on the structure of the kidneys and the expression of the Casp7 gene. Limitations are that morphological changes in kidney tissue during long-term exposure to acrylamide were correlated with the expression of only two apoptotic genes. For a more complete understanding of the pathogenetic changes during the damaging effect of acrylamide on the kidneys, it is necessary to conduct a multivariate analysis taking into account other toxicological and genetic indicators. Conclusion. Acrylamide, when ingested for a long time at a dose of 5 mg/kg body weight, has a nephrotoxic effect, which is confirmed by data from morphological studies and a tendency to increase the expression of the main apoptosis genes in kidney tissue. The best protective effect according to the studied parameters was observed with the prophylactic administration of a complex compound of hydroxymethyluracil with acetylcysteine.

Kidney REPLACEment therapies in patients with acute kidney injury and RHABDOmyolysis (ReplaceRhabdo): a pilot trial

BackgroundRhabdomyolysis is frequently associated with acute kidney injury (AKI). Due to the nephrotoxic properties of myoglobin, its rapid removal is relevant. If kidney replacement therapy (KRT) is necessary for AKI, a procedure with effective myoglobin elimination should be preferred. This pilot trial was designed to compare different KRT modes that enable myoglobin elimination.MethodsIn this prospective randomized single-center study, 15 patients with rhabdomyolysis and severe AKI requiring KRT were randomized 1:1:1 into three groups: continuous veno-venous hemofiltration (CVVH), continuous veno-venous hemodialysis (CVVHD) using a high cut-off dialyzer (CVVHD-HCO), or CVVHD using a high-flux dialyzer in combination with the adsorber CytoSorb (CVVHD-CS). Concentrations of serum myoglobin, urea, creatinine, β2-microglobulin, interleukin-6, and albumin were measured before and after the dialyzer 1, 6, 12, and 24 h after initiating KRT.ResultsThere was no significant difference in the median myoglobin clearance between the KRT modes during the 24-h study period. Nevertheless, the CVVHD-CS group showed a significantly higher myoglobin elimination compared to the other modes in the first hours of treatment. However, as a greater decline in clearance performance was observed over time, no better performance was detected over the whole study period. Simulation of different device combinations showed the highest myoglobin clearance for CVVHD-HCO combined with CS with a 12-hourly adsorber exchange interval.ConclusionsAll tested modes showed an effective myoglobin elimination capacity. The time-dependent elimination performance could be further increased by combining KRT with more frequent adsorber exchange.Trial registrationGerman Clinical Trials Registry (DRKS00023998); date of registration 03/03/2021.

In Vivo Effectiveness of Pleurotus ostreatus in Degradation of Toxic Metabolites of Filamentous Fungi Such as Aflatoxin B1 and Zearalenone.

Mycotoxins, secondary metabolites synthesized by filamentous fungi, have been classified as dangerous substances and proven to be carcinogenic, as well as to have genotoxic, nephrotoxic, hepatotoxic, teratogenic, and mutagenic properties. Despite numerous trials to develop an effective and safe-for-human-health method of detoxification, there is still a high risk associated with the occurrence of these toxins in food and feed. Biological methods of food preservation are an alternative option to conventional chemical and physical methods, characterized by their less negative impact on human health as well as their high efficiency against filamentous fungi and other foodborne pathogens. Mycoremediation is a new biotechnique based on the capability of fungi to detoxify matrices from various pullulans. Ligninolytic enzymes produced by white rot fungi (WRF) characterize a high efficiency in the degradation of various mycotoxins. In our study, Pleurotus ostreatus, as a representative of WRF, was cultivated on a medium contaminated by AFB1 and ZEN (mushroom substrate and maize) in a few variants of concentration. After the cultivation, medium and fruiting bodies were collected and analyzed with the usage of HPLC and LC/MS methods. The reduction oscillated between 53 and 87% (AFB1) and 73 and 97% (ZEN) depending on the initial concentration of toxins in the medium. Grown fruiting bodies contained insignificant amounts of both toxins. These findings confirm the potential of P. ostreatus as an effective biological agent for reducing mycotoxins in contaminated medium, highlighting its applicability in developing sustainable and safe methods for detoxification.

Two-dimensional liquid chromatography based on different modulations for the determination of Aristolochic Acid Ⅰ in Asari Radix et Rhizoma

Asari Radix et Rhizoma (ARR) is a traditional Chinese herbal medicine derived from the genus Asarum in the Aristolochiaceae family, which has been widely used for years. Aristolochic acids in it significantly restrict the clinical application of ARR due to its nephrotoxic and carcinogenic properties, of which aristolochic acid I (AA I) is the most representative. The present paper describes two 2D-LC systems modulated by a sample loop and a trap column respectively for the detection of trace aristolochic acid I in ARR. An Inertsil ODS-3 C18 column and a Luna 3u Phenyl-Hexyl column were separately utilized in the first-dimension (1D) and second-dimension (2D) chromatography. A mixed-mode column with reversed-phase and ion-exchange was selected for trap column modulation of 2D-LC system. Method validation results showed that these two 2D-LC methods performed well in terms of repeatability, linearity, intra/interday precision, stability, and accuracy, which were demonstrated qualified for the simultaneous determination of trace AA I in ARR. The AA Ⅰ contents in three batches of ARR were 0.466∼0.812 μg/g by the two 2D-LC methods, which were below the limit requirement in the Chinese Pharmacopoeia. The comprehensive comparison between the two methods showed that a significant solute focusing effect was obtained by trap column modulation, which led to four-time lower LOD compared with loop modulation, while the loop-modulation-based method achieved higher analytical efficiency when analyzing a large batch of samples.

Assessment of sweet whey fortified with Bifidobacteria and selenium on reduction of pesticide liver toxicity in albino rats

Deltamethrin (DLM) represents one of the most commonly used pesticides. It passes through milk, vegetables, and fruits to humans or through animals (veterinary drugs and feeding on contaminated forage) to milk; it can escape from skin to blood and be secreted in breast milk in lactating women. It is believed to have neurotoxic, nephrotoxic, and hepatotoxic properties. To investigate deltamethrin-induced hepatotoxicity, 64 rats were divided into eight groups. The control group did not receive any treatment. The groups were as follows: D 30 mg DLM/kg body weight (BW) dissolved in corn oil; B 1 mL whey (1010 cfu/mL of Bifidobacterium longum ATCC 15707); S 1 mL whey (0.5 ppm selenium); BS 1 mL whey (1010 cfu/mL of B. longum ATCC 15707 + 0.5 ppm selenium); BD 1 mL whey (1010 cfu/mL of B. longum ATCC 15707 + DLM); SD 1 mL whey (0.5 ppm selenium) + DLM; and BSD 1 mL whey (1010 cfu/mL of B. longum ATCC 15707) + 0.5 ppm selenium + DLM. Results revealed that the manipulation of Bifidobacteria with selenium triggered a significant improvement in AST (U/mL), ALT (U/mL), GSH (mg/g), TNF-α (pg/mL), NF-κB (ng/mL), and BCL2 (ng/mL) from 166.7 ± 6.42, 30.67 ± 0.55, 0.252 ± 0.005, 17.18 ± 0.42, 1.14 ± 0.10, and 1.77 ± 0.06 versus 334.9 ± 4.7, 72.83 ± 2.49, 0.108 ± 0.005, 33.57 ± 0.59, 2.58 ± 0.05, and 1.04 ± 0.04, respectively, compared to DLM group. As well as reduction in histopathological necrosis, congestion, and degradation. Whey beverages fortified with B. longum and selenium implicated a reduction in oxidative stress and histopathological degradation that accomplished DLM toxicity. The utilization of whey (a byproduct of cheese making) is considered a recycling process that supports eco-friendly practices and sustainability, thus encouraging its use as a protective tool in animal feed or manipulation by humans, especially workers in pesticide plants.

The Role of MicroRNA in the Pathogenesis of Acute Kidney Injury.

Acute kidney injury (AKI) describes a condition associated with elevated serum creatinine levels and decreased glomerular filtration rate. AKI can develop as a result of sepsis, the nephrotoxic properties of several drugs, and ischemia/reperfusion injury. Renal damage can be associated with metabolic acidosis, fluid overload, and ionic disorders. As the molecular background of the pathogenesis of AKI is insufficiently understood, more studies are needed to identify the key signaling pathways and molecules involved in the progression of AKI. Consequently, future treatment methods may be able to restore organ function more rapidly and prevent progression to chronic kidney disease. MicroRNAs (miRNAs) are small molecules that belong to the non-coding RNA family. Recently, numerous studies have demonstrated the altered expression profile of miRNAs in various diseases, including inflammatory and neoplastic conditions. As miRNAs are major regulators of gene expression, their dysregulation is associated with impaired homeostasis and cellular behavior. The aim of this article is to discuss current evidence on the involvement of miRNAs in the pathogenesis of AKI.

Study of Antibacterial Drugs’ Nephrotoxicity in the RPTEC Cell Line

The created cell line of human proximal renal tubules RPTEC/TERT1 showed maximum compliance with primary human RPTEC, which makes it optimal for use in studies of the nephrotoxic properties of xenobiotics. Transepithelial resistance measurement (TEER) is a valuable non-invasive method that can be used to quantify the integrity of the cell barrier at various stages of cell growth and differentiation, as well as to predict the toxicity and permeability of drugs.The aim of the study was to examine the dynamics of changes in transepithelial resistance in the model of the RPTEC/TERT1 cell line during incubation with drugs with nephrotoxic effects.Material and methods. The human proximal renal tubule cell line RPTEC/TERT was obtained from the ATCC cell culture bank. Cells at passage 14 were used in the experiment. The following drugs were studied: cisplatin: 2.5 mcg/ml; vancomycin: 50 mcg/ml; doripenem — 20mcg/ml; cefepim — 150mcg/ml. 4–5 repetitions were performed for each concentration of the drug in the experiment. THEER measurements were carried out 4–5 times for each well.Results. Cisplatin, vancomycin, doripenem, and cefepim in the concentrations used do not show a cytotoxic effect on the RPTEC cell line according to TEER dynamics.

Assessment of osteopontin as an early nephrotoxicity indicator in human renal proximal tubule cells and its application in evaluating lanthanum-induced nephrotoxicity

Nephrotoxicity is a common adverse effect induced by various chemicals, necessitating the development of reliable toxicity screening models for nephrotoxicity assessment. In this study, we assessed a group of nephrotoxicity indicators derived from different toxicity pathways, including conventional endpoints and kidney tubular injury biomarkers such as clusterin (CLU), kidney injury molecule-I (KIM-1), osteopontin (OPN), and neutrophil gelatinase-associated lipocalin (NGAL), using HK-2 and induced pluripotent stem cells (iPSCs)-derived renal proximal tubular epithelial-like cells (PTLs). Among the biomarkers tested, OPN emerged as the most discerning and precise marker. The predictive potential of OPN was tested using a panel of 10 nephrotoxic and 5 non-nephrotoxic compounds. The results demonstrated that combining OPN with the half-maximal inhibitory concentration (IC50) enhanced the diagnostic accuracy in both cellular models. Additionally, PTLs cells showed superior predictive efficacy for nephrotoxicity compared to HK-2 cells in this investigation. The two cellular models were utilized to evaluate the nephrotoxicity of lanthanum. The findings indicated that lanthanum possesses nephrotoxic properties; however, the degree of nephrotoxicity was relatively low, consistent with the outcomes of in vivo experiments.

Evaluation of Nephrotoxic Properties of Favipiravir Using the RPTEC cell model

Scientific relevance. Favipiravir is an antiviral RNA polymerase inhibitor used to treat COVID-19. An adverse drug reaction associated with the use of favipiravir is renal disorder.Aim. This study aimed to investigate favipiravir nephrotoxicity by assessing its effects on the integrity of a monolayer formed by renal proximal tubular epithelial cells (RPTECs).Materials and methods. This study focused on an RPTEC monolayer culture that was seeded at a density of 6×104 cells/cm2 on plates with membrane inserts with 0.4 μm pores. Favipiravir was added to the plate wells at a concentration of 5, 10, or 15 μg/mL. The nephrotoxicity evaluation relied on measuring the transepithelial electrical resistance (TEER) of the RPTEC monolayer. A TEER value of 120–140 Ω×cm2 was considered an indication of nephrotoxicity.Results. RPTEC incubation with favipiravir led to a dose-dependent decrease in the TEER values. However, the TEER values after 6 days of incubation ranged within 250–280 Ω×cm2 and were above the critical thresholdof 120–140 Ω×cm2.Conclusions. The results of this study indicate that favipiravir has no pronounced effect on the TEER of the RPTEC monolayer.

Determination of 22 mycotoxins in milk by liquid chromatography-quadrupole/orbitrap mass spectrometry

Mycotoxins have carcinogenic, mutagenic, hepatotoxic, nephrotoxic, immunotoxic, neurotoxic, and teratogenic properties. Thus, these substances have attracted significant attention because they pose a threat to human health. As research on mycotoxins deepens, new structural analogues of mycotoxins are constantly being discovered. In this study, a method based on high performance liquid chromatography-quadrupole/orbitrap mass spectrometry was established for the simultaneous determination of 22 mycotoxins in milk. A simple, effective, and rapid pretreatment method was optimized by focusing on the solvent type, extractant volume, and extracting salt based on the characteristics of the mycotoxins and sample matrix. The analytes were extracted using 0.5% formic acid acetonitrile solution and added with sodium chloride to separate fats from water. The samples were centrifuged at 8000 r/min (4 ℃) for 5 min using a centrifuge and then concentrated using nitrogen. The dry residue was dissolved with 50% methanol aqueous solution. Twenty-two mycotoxins were separated on a ZORBAX Eclipse Plus C18 chromatographic column (100 mm×2.1 mm, 1.7 μm), and quantitative analysis was performed using the isotope internal standard method. The analytes were determined by liquid chromatography-quadrupole/orbitrap mass spectrometry in positive electrospray ionization mode. Qualitative analyses of the compounds were performed in full mass spectrometry/data-dependent tandem mass spectrometry (MS/dd-MS2) mode. Good linearities in the range of 0.5-100.0 μg/L were observed for the 22 mycotoxins, and the correlation coefficients (R2) were greater than 0.999. The limits of detection (S/N=3) and quantification (S/N=10) ranged from 0.3 to 0.5 μg/kg and from 1.0 to 1.5 μg/kg, respectively. The average recoveries of the 22 mycotoxins at three spiked levels of 1.5, 5.0, and 15 μg/kg were between 84.7% and 100.8%, with relative standard deviations (RSDs) of 1.2%-9.9%. These findings indicate that the method has high sensitivity and accuracy as well as good precision. Finally, the method was applied to the detection and analysis of mycotoxins in 25 actual commercial milk samples. The results revealed that the selected samples were not contaminated with any of the mycotoxins analyzed. Thus, the proposed method is useful as a quick preprocessing and confirmatory method for the simultaneous determination of mycotoxins in milk.

Insights into Repeated Renal Injury Using RNA-Seq with Two New RPTEC Cell Lines.

Renal proximal tubule epithelial cells (RPTECs) are a primary site for kidney injury. We created two RPTEC lines from CD-1 mice immortalized with hTERT (human telomerase reverse transcriptase) or SV40 LgT antigen (Simian Virus 40 Large T antigen). Our hypothesis was that low-level, repeated exposure to subcytotoxic levels of 0.25-2.5 μM cisplatin (CisPt) or 12.5-100 μM aflatoxin B1 (AFB1) would activate distinctive genes and pathways in these two differently immortalized cell lines. RNA-seq showed only LgT cells responded to AFB1 with 1139 differentially expressed genes (DEGs) at 72 h. The data suggested that AFB1 had direct nephrotoxic properties on the LgT cells. However, both the cell lines responded to 2.5 μM CisPt from 3 to 96 h expressing 2000-5000 total DEGs. For CisPt, the findings indicated a coordinated transcriptional program of injury signals and repair from the expression of immune receptors with cytokine and chemokine secretion for leukocyte recruitment; robust expression of synaptic and substrate adhesion molecules (SAMs) facilitating the expression of neural and hormonal receptors, ion channels/transporters, and trophic factors; and the expression of nephrogenesis transcription factors. Pathway analysis supported the concept of a renal repair transcriptome. In summary, these cell lines provide in vitro models for the improved understanding of repeated renal injury and repair mechanisms. High-throughput screening against toxicant libraries should provide a wider perspective of their capabilities in nephrotoxicity.

Susceptibility of HEK293 and RPTEC Cell Lines to Nephrotoxic Effects of Cefuroxime and Cefepime: A Comparative Study

Researchers need to identify the nephrotoxic properties of medicinal products both during preclinical development and when exploring options to optimise pharmacotherapy. The main challenge is to find an experimental model for assessing drug-induced nephrotoxicity that reflects in vivo conditions as closely as possible.The aim of the study was to compare the susceptibility of HEK293 and RPTEC cell lines used as experimental models for assessing the nephrotoxicity of cefuroxime and cefepime.Materials and methods. The study investigated HEK293 and RPTEC cell lines cultured on plates with 0.4 µm pore membrane inserts. The cell lines were incubated for 3 days with cefuroxime and cefepime (cephalosporins excreted primarily by the kidneys). The medicinal products were added to the basal part of the well at concentrations of 50 and 150 µg/mL (cefuroxime) or 30 and 120 µg/mL (cefepime) twice a day. After incubating the cells with cefuroxime and cefepime for 24, 48, and 72 hours, the authors determined the expression levels of the SLC22A6 and SLC22A8 genes encoding organic anion transporters by a reverse transcription polymerase chain reaction. The authors considered caspase 3 and caspase 7 activation indicative of the nephrotoxic effect of cephalosporins; they evaluated this indicator by a fluorometric assay after 24, 48, and 72 hours of incubation.Results. According to the study, the expression of the SLC22A6 and SLC22A8 genes decreased with cephalosporin transport in both cell lines. The decrease occurred in the RPTEC cell line earlier than in the HEK293 cell line. The authors observed caspase 3 and caspase 7 activation only in the RPTEC cell line after incubation with cefuroxime and cefepime at low concentrations (50 and 30 µg/mL, respectively) for 72 hours and at high concentrations (150 and 120 µg/mL, respectively) for 24 hours.Conclusions. The RPTEC cell line exhibits higher susceptibility to cefuroxime and cefepime toxic effects than the HEK293 cell line due to higher transporter gene expression. Higher cephalosporin concentrations accelerate caspase 3 and caspase 7 activation in the RPTEC cell line. The experimental model based on the RPTEC cell line is a promising tool for the analysis of the nephrotoxic properties of a wide range of medicinal products.

Ochratoxin A degrading enzymes of Stenotrophomonassp. 043-1a.

Ochratoxin A is a secondary metabolite that acts as a mycotoxin and is produced by Aspergillus, Penicillium, and other fungal species. It is a threat to animal and human health due to nephrotoxic, carcinogenic, and genotoxic properties and its widespread incidence in agricultural products. To reduce this threat, biological remediation processes are of growing interest. The aerobic gram-negative bacterium Stenotrophomonassp. 043-1a, isolated from soil, was previously shown to degrade ochratoxin A into the non-toxic ochratoxin α and l-phenylalanine (Schatzmayr et al. 2002). However, the enzyme or enzymes catalyzing this reaction in this strain remained elusive. Here, we report the targeted purification of Stenotrophomonassp. 043-1a lysate via ammonium sulfate precipitation, size-exclusion chromatography, and hydrophobic interaction chromatography to identify the ochratoxin A degrading enzymes by subsequent peptide fragment fingerprinting. The metallo-dependent hydrolase Chr1_3858681_3267 and a member of the peptidase S9 family, Chr1_3858681_771, were shown to degrade ochratoxin A. This was, to our knowledge, the first report of an ochratoxin A degrading enzyme from the peptidase S9 family.

ПАТОМОРФОЛОГИЧЕСКИЕ ИЗМЕНЕНИЯ В ОРГАНАХ ДЕТОКСИКАЦИИ БЕЛЫХ МЫШЕЙ ПРИ ВСПЫШКЕ «ГАФФСКОЙ» БОЛЕЗНИ

Gaff disease (paroxysmal-toxic alimentary myoglobinuria, Yuksovsky or Sartlan disease) is a foodborne toxicosis. Occurs in predatory fish, carnivorous animals and birds, in humans. The aim of the work was to study the changes in the internal organs of white mice eating offal of fish from Andreevsky and Ishmenevsky lakes during an outbreak of Gaff disease, performed in the laboratories of the Department of Anatomy and Physiology of the Federal State Budgetary Educational Institution of Higher Education of the State Agrarian University of the Northern Trans-Urals. The liver, kidneys, stomach and duodenum of white mice eating fish from the unfavorable lakes Andreevsky and Ishmenevsky during the outbreak of Guff disease, as well as the control group, were selected for morphological and histological studies. The material was selected for anatomical, morphological and histological studies. As a result of the research, it was found that in white mice with pronounced signs of Gaff disease (eating offal of fish from Lake Ishmenevsky and Lake Andreevsky), with a standard bioassay, pathoanatomical changes include: 1. catarrhal inflammation of the stomach, degenerative changes in the glandular part of the stomach, enteritis; 2. acute congestive hyperemia of the liver, a decrease in its relative mass, areas of necrosis and necrobiosis, protein degeneration, small foci of hemorrhages in the parenchyma, swelling and expansion of Disse spaces; 3. necrotizing nephrosis, glomerular atrophy and swelling of epitheliocytes, and in 20 % of cases, lymphocytic infiltration of the parenchyma and granular degeneration. All these changes indicate the hepato- and nephrotoxic properties of the toxin, as well as a decrease in the barrier properties of the gastrointestinal tract, which further opens the gate for the active development of opportunistic microflora.

Development of a Prediction Model for Acute Kidney Injury after Colistin Treatment for Multidrug-resistant Acinetobacter baumanii Ventilator-Associated Pneumonia: A Pilot Study

Objective: Multidrug-resistant Acinetobacter baumanii (MDR-AB) ventilator-associated pneumonia (VAP) is the major complication following hospital admission in Thailand, increasing morbidity and prolonging hospital stay duration. Treatment of MDR-AB VAP usually requires colistin which has highly nephrotoxic properties. Therefore, we aimed to develop a pilot prediction model for acute kidney injury (AKI) after colistin treatment.Material and Methods: We conducted a retrospective cohort study. All MDR-AB VAP patients who received colistin for at least 72 hours in Suratthani Hospital from January to July 2017 were eligible for inclusion. The primary outcome was the overall presence of AKI on days 3, 5 or 7 after colistin administration. Multivariable logistic regression analysis was used to develop the final prediction model.Results: Of 85 MDR-AB VAP patients, 51 (61%) developed AKI after colistin treatment. Nine factors, female, intensive care unit (ICU) admission, diabetes mellitus, systolic blood pressure (SBP), diastolic blood pressure (DBP), serum sodium, creatinine, blood urea nitrogen (BUN) and glomerular filtration rate were potential predictors of AKI. Multivariable logistic regression with backward stepwise selection revealed the best prediction model had four predictors: female, ICU admission, BUN, and DBP. The area under the receiver operating characteristic curve for the model in predicting AKI among MDR-AB VAP patients was 0.801 (95% confidence interval: 0.703, 0.898).Conclusion: The prediction model containing four predictors, female gender, ICU admission, BUN level, and DBP had fair to good performance in predicting AKI after colistin treatment among MDR-AB VAP patients.

Aristolochic acid I as an emerging biogenic contaminant involved in chronic kidney diseases: A comprehensive review on exposure pathways, environmental health issues and future challenges

Described in the 1950s, Balkan Endemic Nephropathy (BEN) has been recognized as a chronic kidney disease (CKD) with clinical peculiarities and multiple etiological factors. Environmental contaminants – aromatic compounds, mycotoxins and phytotoxins like aristolochic acids (AAs) – polluting food and drinking water sources, were incriminated in BEN, due to their nephrotoxic and carcinogenic properties. The implication of AAs in BEN etiology is currently a highly debated topic due to the fact that they are found within the Aristolochiaceae plants family, used around the globe as traditional medicine and they were also incriminated in Aristolochic Acid Nephropathy (AAN). Exposure pathways have been investigated, but it is unclear to what extent AAs are acting alone or in synergy with other cofactors (environmental, genetics) in triggering kidney damage. Experimental studies strengthen the hypothesis that AAI, the most studied compound in the AAs class, is a significant environmental contaminant and a most important causative factor of BEN. The aim of this review is to compile information about the natural exposure pathways to AAI, via traditional medicinal plants, soil, crop plants, water, food, air. Data that either supports or contradicts the AAI theory concerning BEN etiology was consolidated and available solutions to reduce human exposure were discussed. Because AAI is a phytotoxin with physicochemical properties that allow its transportation in environmental matrices from different types of areas (endemic, nonendemic), and induce CKDs (BEN, AAN) and urinary cancers through bioaccumulation, this review aims to shed a new light on this compound as a biogenic emerging pollutant.

Proteomic analysis reveals rattlesnake venom modulation of proteins associated with cardiac tissue damage in mouse hearts

Snake envenomation is a common but neglected disease that affects millions of people around the world annually. Among venomous snake species in Brazil, the tropical rattlesnake (Crotalus durissus terrificus) accounts for the highest number of fatal envenomations and is responsible for the second highest number of bites. Snake venoms are complex secretions which, upon injection, trigger diverse physiological effects that can cause significant injury or death. The components of C. d. terrificus venom exhibit neurotoxic, myotoxic, hemotoxic, nephrotoxic, and cardiotoxic properties which present clinically as alteration of central nervous system function, motor paralysis, seizures, eyelid ptosis, ophthalmoplesia, blurred vision, coagulation disorders, rhabdomyolysis, myoglobinuria, and cardiorespiratory arrest. In this study, we focused on proteomic characterization of the cardiotoxic effects of C. d. terrificus venom in mouse models. We injected venom at half the lethal dose (LD50) into the gastrocnemius muscle. Mouse hearts were removed at set time points after venom injection (1 h, 6 h, 12 h, or 24 h) and subjected to trypsin digestion prior to high-resolution mass spectrometry. We analyzed the proteomic profiles of >1300 proteins and observed that several proteins showed noteworthy changes in their quantitative profiles, likely reflecting the toxic activity of venom components. Among the affected proteins were several associated with cellular deregulation and tissue damage. Changes in heart protein abundance offer insights into how they may work synergistically upon envenomation. SignificanceVenom of the tropical rattlesnake (Crotalus durissus terririficus) is known to be neurotoxic, myotoxic, nephrotoxic and cardiotoxic. Although there are several studies describing the biochemical effects of this venom, no work has yet described its proteomic effects in the cardiac tissue of mice. In this work, we describe the changes in several mouse cardiac proteins upon venom treatment. Our data shed new light on the clinical outcome of the envenomation by C. d. terrificus, as well as candidate proteins that could be investigated in efforts to improve current treatment approaches or in the development of novel therapeutic interventions in order to reduce mortality and morbidity resulting from envenomation.

Quality Control of Paracetamol Generic Tablets Marketed in Benin and Search of Its Two Impurities P-Aminophenol and P-Nitrophenol by HPLC-UV/Visible

In this work, we evaluated the quality of paracetamol generic tablets while seeking its two main impurities namely 4-para-aminophenol (4-AP) and 4-para-nitrophenol (4-NP) which have nephrotoxic and teratogenic properties. Ninety-four (94) samples were collected at various levels of the medicine supply chain and illegal markets in Benin for quality control tests such as visual inspection, pharmacotechnical tests as mass variation, disintegration test, dissolution test, followed by HPLC UV-Vis identification and assay of paracetamol, 4-AP and 4-NP. The analytes were separated on C18 Lichrocart column (250 mm × 4.0 mm i.d, 5 μm); the mobile phase was MeOH:10 mM ammonium acetate buffer pH 6.8 (35:65) pumped at a flow rate of 1 ml/min. The detection was done at 245 nm. Analysis of our results shows that 77.7% of the samples did not comply with the visual inspection test requirements, 2.1% did not pass the mass variation test, 24.3% of the sample batches didn’t comply with the disintegration test requirements. In addition none of these uncomply batches passed the dissolution test, even if the identification test indicated that all samples contained paracetamol. None contained 4-NP (acceptance limit < 0.05% m/m; BP), while 3 of 94 samples contained 4-AP but within acceptance limit (4-AP < 0.1% m/m; BP). As for the paracetamol assay, 80.9% complied with the specifications of the pharmacopoeias taken as reference (90% - 110%; USP). Further, broader studies should be conducted according to the same rules of good practice for a more comprehensive analysis of the situation. Generally the quality control of paracetamol in most African countries, particularly in Benin, is based on pharmacotechnical tests and paracetamol assay. This work, in addition to the usual tests, showed the importance to search for paracetamol and other drugs’ impurities during their routine quality control.

Detection, Contamination, Toxicity, and Prevention Methods of Ochratoxins: An Update Review.

Ochratoxins (OTs) with nephrotoxic, immunosuppressive, teratogenic, and carcinogenic properties are thermostable fungal subordinate metabolites. OTs contamination can occur before or after harvesting, during the processing, packing, distribution, and storage of food. Mold development and mycotoxin contamination can occur in any crop or cereal that has not been stored properly for long periods of time and is subjected to high levels of humidity and temperature. Ochratoxin A (OTA) presents a significant health threat to creatures and individuals. There is also a concern of how human interaction with OTA will also express the remains of OTA from feedstuffs into animal-derived items. Numerous approaches have been studied for the reduction of the OTA content in agronomic products. These methods can be classified into two major classes: inhibition of OTA adulteration and decontamination or detoxification of food. A description of the various mycotoxins, the organism responsible for the development of mycotoxins, and their adverse effects are given. In the current paper, the incidence of OTA in various fodder and food materials is discussed, which is accompanied by a brief overview of the OTA mode of synthesis, physicochemical properties, toxic effects of various types of ochratoxins, and OTA decontamination adaptation methods. To our knowledge, we are the first to report on the structure of many naturally accessible OTAs and OTA metabolism. Finally, this paper seeks to be insightful and draw attention to dangerous OTA, which is too frequently neglected and overlooked in farm duplication from the list of discrepancy studies.

Nephrotoxicity Biomarkers: Role and Significance in the Diagnosis of Drug-Induced Kidney Injury

Drug-induced kidney injury (DIKI) accounts for 8 to 60% of episodes of acute kidney injury (AKI) among hospital patients. Early DIKI detection and timely adjustment of therapy will help reduce the kidney injury incidence and mortality. The aim of the study was to analyse scientific literature on the biomarkers used in DIKI diagnosis. The study revealed that the use of such kidney damage markers as serum creatinine, urinary output, urea nitrogen, sodium excretion, urinary sediment microscopy is limited because they do not give a full picture of the kidney injury degree and progression and do not allow for early AKI diagnosis. It was demonstrated that some of the most promising biomarkers are KIM-1, L-FABP, NAG, NGAL, cystatin C, clusterin, β2-microglobulin, МСР-1, IGFBP7, and TIMP-2. However, recommendations for determination of these biomarkers’ urine or blood concentrations for AKI diagnosis are somewhat preliminary, because there have been insufficient clinical and preclinical studies to establish validity of such tests. No precise algorithms based on determination of the biomarkers levels in urea and/or blood serum have been developed for AKI risk assessment, diagnosis, monitoring, and treatment. Thus, further research is necessary to investigate different AKI biomarkers and improve experimental models (both in vivo and in vitro), which will support assessment of potential nephrotoxic properties of existing and new medicinal products.