Search

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population., (© 2024 John Wiley & Sons Ltd.)

Toxicological stress in aquatic organisms is caused by the discharge of hundreds of toxic pollutants and contaminants among which the current study concentrates on the toxic effect of non-steroidal anti-inflammatory drug ibuprofen (IBF) and the trace element selenium (Se). In this study, IBF and Se toxicity on freshwater mussel Lamellidens marginalis was studied for 14 days, and in silico predictions for their degradation were made using Molecular modelling and Quantum Mechanical approaches. The degrading propensity of cytochrome c oxidase proteins from Trametes verticillatus and Thauera selenatis (Turkey tail fungi and Gram-negative bacteria) is examined into atom level. The results of molecular modelling study indicate that ionic interactions occur in the T. selenatis-HEME bound complex by Se interacting directly with HEME, and in the T. versicolor-HEME bound complex by IBF bound to a nearby region of HEME. Experimental and theoretical findings suggest that, the toxicological effects of Se and IBF pollution can be reduced by bioremediation with special emphasis on T. versicolor, and T. selenatis, which can effectively interact with Se and IBF present in the environment and degrade them. Besides, this is the first time in freshwater mussel L. marginalis that ibuprofen and selenium toxicity have been studied utilizing both experimental and computational methodologies for their bioremediation study., Competing Interests: Declaration of competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pharmaceuticals like ibuprofen (IBU) entering marine environments are of great concern due to their increasing consumption and impact on wildlife. No information on IBU toxicity to seagrasses is yet available. Seagrasses form key habitats and are threatened worldwide by multiple stressors. Here, the responses of the seagrass Cymodocea nodosa to a short-term exposure (12 days) to environmentally realistic IBU concentrations (0.25-2.5-25 µg L -1 ), both at organism (plant growth) and sub-organism level (oxidative status, photosynthetic efficiency, and specialized metabolites production), were assessed in mesocosm. Chemical analyses to detect the presence of IBU and its metabolites in seawater and plants were also performed. IBU did not affect plant growth but caused physiological alterations which varied in severity depending on its concentration. Concentrations of 0.25 and 2.5 µg L -1 resulted in oxidative stress, but an increased antioxidant enzyme activity enabled plants to tolerate stress. A concentration of 25 µg L -1 caused greater oxidative stress, reduced antioxidant enzyme activity and specialized metabolites production, and impaired photosynthetic machinery functioning (particularly PSII). IBU was detected in seawater but not in plants suggesting no bioaccumulation. These findings indicate that C. nodosa could not withstand high IBU stress, and this could reduce its resilience to additional environmental stressors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Non-steroidal anti-inflammatory drugs (NSAIDs) may cause drug-induced liver injury (DILI). However, the molecular mechanisms underlying NSAIDs hepatotoxicity remain elusive. Dysregulations of bile acids (BAs) have been implicated in various DILI. In this study, we systematically investigated the effects of ibuprofen, the most commonly used NSAID, on BA metabolism and signaling in adult male C57/BL6 mice after oral administration of ibuprofen (IBU) at clinically relevant doses (30, 100, and 200 mg/kg) for one week. Notably, IBU significantly decreased BA concentrations in the liver in a dose-dependent manner, with a concomitant increase in both mRNA and protein expression of cholesterol 7alpha-hydoxylase (CYP7A1), the rate-limiting enzyme for BA synthesis. Mechanically, IBU altered the composition of gut microbiota and increased cecal BAs, leading to reduced intestinal absorption of BAs and thus deactivated ileal farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) signaling. Additionally, diclofenac and indomethacin also induced hepatic Cyp7a1 expression in mice via their effects on gut microbiota and intestinal BA signaling. To conclude, the current findings suggest that NSAIDs-induced liver injury could be at least partially attributable to the dysregulation of BA metabolism and signaling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pharmaceuticals and Personal Care Compounds (PPCPs) are contaminants present in wastewater and in the receiving surface waters, which have no regulations and can bring on environmental risks. In this study, we evaluated the presence of six PPCPs in the Oro River Sub-basin (Colombia) and the environmental risk associated with them. We have verified that the monitored rivers show the presence of Ibuprofen, Cephalexin and Carbamazepine; the first ones (Ibuprofen and cephalexin) were those that presented higher concentrations since they are widely prescribed in Colombia. Pharmaceutical compound concentrations in the rivers downstream of the wastewater treatment plants from Floridablanca were higher than in other monitoring sites being a significant point source of contamination. This wastewater treatment plant receives hospital discharges from the city, including internationally recognized clinics accepting patients from different parts of the country. The environmental risk assessment showed that ibuprofen and Cephalexin have a higher impact on aquatic organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pharmaceuticals are found in aquatic environments due to their widespread use and environmental persistence. To date, a range of impairments to aquatic organisms has been reported with exposure to pharmaceuticals; however, further comparisons of their impacts across different species on the molecular level are needed. In the present study, the crustacean Daphnia magna and the freshwater fish Japanese medaka, common model organisms in aquatic toxicity, were exposed for 48 h to the common analgesics acetaminophen (ACT), diclofenac (DCF), and ibuprofen (IBU) at sublethal concentrations. A targeted metabolomic-based approach, using liquid chromatography-tandem mass spectrometry to quantify polar metabolites from individual daphnids and fish was used. Multivariate analyses and metabolite changes identified differences in the metabolite profile for D. magna and medaka, with more metabolic perturbations for D. magna. Pathway analyses uncovered disruptions to pathways associated with protein synthesis and amino acid metabolism with D. magna exposure to all three analgesics. In contrast, medaka exposure resulted in disrupted pathways with DCF only and not ACT and IBU. Overall, the observed perturbations in the biochemistry of both organisms were different and consistent with assessments using other endpoints reporting that D. magna is more sensitive to pollutants than medaka in short-term studies. Our findings demonstrate that molecular-level responses to analgesic exposure can reflect observations of other endpoints, such as immobilization and mortality. Thus, environmental metabolomics can be a valuable tool for selecting sentinel species for the biomonitoring of freshwater ecosystems while also uncovering mechanistic information. Environ Toxicol Chem 2024;43:1339-1351. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Ibuprofen, one of the most commonly prescribed nonsteroidal anti-inflammatory drugs, has not been fully assessed for embryonic toxicity in vertebrates. Here, we systematically assessed the embryotoxicity of ibuprofen in Xenopus laevis at various concentrations during embryogenesis. Embryos were treated with different concentrations of ibuprofen, ranging from 8 to 64 mg/L, at 23 °C for 96 h, and examined daily and evaluated at 72 hpf. Lethal or teratogenic effects were documented. For histological analysis, paraffin embedded embryos were transversely sectioned at a thickness of 10-μm and stained with hematoxylin and eosin. Total RNA was isolated from embryos at stages 6, 12, 22 and 36, and real-time quantitative PCR was performed. Ibuprofen-treated embryos showed delayed or failed dorsal lip formation and its closure at the beginning of gastrulation. This resulted in herniation of the endodermal mass after gastrulation under high concentrations of ibuprofen-treated embryos. Underdeveloped intestines with stage and/or intestinal malrotation, distorted microcephaly, and hypoplastic heart, lungs, and pronephric tubules were observed in ibuprofen-treated embryos. Cephalic, cardiac, and truncal edema were also observed in them. The severity of the deformities was observed in a concentration-dependent manner. The teratogenic index was 2.28. These gross and histological disruptions correlated well with the altered expression of each organ marker gene. In conclusion, ibuprofen induced delayed and disrupted gastrulation in the early developmental stage and multiorgan malformation later in the organogenesis stage of Xenopus laevis embryos., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Diclofenac (DCF) and ibuprofen (IBU) are pharmaceutical compounds frequently detected in aquatic compartments worldwide. Several hazard effects including developmental abnormalities and redox balance impairment have been elucidated in aquatic species, but multiple endocrine evaluations are scarce. Therefore, the present study aimed to assess the disruptive physiological effects and toxicity of DCF and IBU isolated and combined, using females of the native freshwater teleost Astyanax lacustris. In regards to NSAIDs bioavailability, the results showed absence of degradation of IBU and DCF after 7 days of exposure. IBU LC 50 for A. lacustris was 137 mgL -1 and females exposed to IBU isolated increased thyroxine (T 4 ) concentration at 24 h and decreased after 96 h; DCF exposure decreased triiodothyronine (T3) concentration at 96 h. Circulating levels of 17β-estradiol (E 2 ), cortisol (F) and testosterone (T) were not affected by any treatment. HPG and HPI axis genes fshβ, pomc and vtg were upregulated after 24 h of IBU exposure, and dio2 was downregulated in DCF fish exposed group after 96 h compared to the mixture. Protein concentration was reduced in muscle and increased in the liver by DCF and mixtures exposures at 24 h; while liver lipids were increased in the mixture groups after 96 h. The study point out the capacity of NSAIDs to affect endocrine endpoints in A. lacustris females and induce changes in energetic substrate content after acute exposure to isolated and mixed NSAIDs treatments. Lastly, the present investigation brings new insights into the toxicity and endocrine disruptive activity of NSAIDs in Latin America teleost species and the aquatic environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The aim of the study was to evaluate the effects of emerging environmental contaminants, the non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac (DCF) and ibuprofen (IBP), on physiological functions in juvenile common carp (Cyprinus carpio). Fish were exposed for 6 weeks, and for the first time, NSAIDs were administered through diet. Either substance was tested at two concentrations, 20 or 2000 μg/kg, resulting in four different treatments (DCF 20, DCF 2000, IBP 20, IBP 2000). The effects on haematological and biochemical profiles, the biomarkers of oxidative stress, and endocrine disruption were studied, and changes in RNA transcription were also monitored to obtain a comprehensive picture of toxicity. Fish exposure to high concentrations of NSAIDs (DCF 2000, IBP 2000) elicited numerous statistically significant changes (p < 0.05) in the endpoints investigated, with DCF being almost always more efficient than IBP. Compared to control fish, a decrease in total leukocyte count attributed to relative lymphopenia was observed. Plasma concentrations of total proteins, ammonia, and thyroxine, and enzyme activities of alanine aminotransferase (ALT), aspartate aminotransferase, and alkaline phosphatase (ALP) were significantly elevated in either group, as were the activities of certain hepatic antioxidant enzymes (superoxide dismutase, glutathione-S-transferase) in the DCF 2000 group. The transcriptomic profile of selected genes in the tissues of exposed fish was affected as well. Significant changes in plasma total proteins, ammonia, ALT, and ALP, as well as in the transcription of genes related to thyroid function and the antioxidant defense of the organism, were found even in fish exposed to the lower DCF concentration (DCF 20). As it was chosen to match DCF concentrations commonly detected in aquatic invertebrates (i.e., the potential feed source of fish), it can be considered "environmentally relevant". Future research is necessary to shed more light on the dietary NSAID toxicity to fish., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Case history: Two dogs presented separately to the Small Animal Hospital, University of Florida (Gainsville, FL, USA) for ingestion of ibuprofen. The first dog ingested 561.8 mg/kg ibuprofen in addition to paracetamol and caffeine and vomited prior to admission. This patient also received fluid therapy for 8 hours prior to charcoal haemoperfusion. The second dog ingested 500 mg/kg of ibuprofen and the owners induced vomiting with hydrogen peroxide prior to presentation. Due to the severity of clinical signs, both patients were treated with charcoal haemoperfusion. Clinical findings: The concentrations of ibuprofen in the blood of the dogs prior to treatment were 478 and 301 mg/L. During the treatment ibuprofen concentrations were reduced by 95.8% and 45.5%, respectively, with no treatment side effects and minimal clinical signs after treatment. Diagnosis: Toxicity due to ingestion of ibuprofen toxicity that was successfully treated with charcoal haemoperfusion. Clinical relevance: In the cases described here minimal benefit was seen after 3 hours of treatment using one haemoperfusion cartridge. This is in contrast to a previously published report in which dogs were treated for 6 hours with two charcoal haemoperfusion cartridges. This suggests that one cartridge may be sufficient. The amount of ibuprofen ingested was not a reliable predictor of the concentration in blood at the initiation of treatment. Charcoal haemoperfusion is an effective means of reducing plasma concentrations of ibuprofen, however, its use may be limited by its cost and availability. [ABSTRACT FROM AUTHOR]

Pharmaceuticals and personal care products (PPCPs) are emerging environmental contaminants and have raised significant concern due to their potential adverse impact on the environment. Ibuprofen is one of the most extensively used non-steroidal anti-inflammatory drugs (NSAIDs) and is also considered an environmental contaminant. The negative impact of ibuprofen on non-target organisms has been documented; however, the molecular mechanisms behind its reproductive toxicity remain unclear. We investigated the impact of early-life long-term ibuprofen exposure on reproductive capacity and its involvement of spermiogenesis in the non-target model organism Caenorhabditis elegans. Hermaphrodites were exposed to various ibuprofen concentrations (0.1, 1, 10, and 100 mg/L), resulting in a dose-dependent inhibition of reproduction. In addition, the lowest observed adverse effect concentration (LOAEC) for ibuprofen exposure on the total brood size of C. elegans was 0.1 mg/L, a concentration that falls within the environmentally relevant range for ibuprofen. Outcross progeny assays revealed a significant 47% reduction in total brood size for larval males (him-5) exposed to ibuprofen, while females (fog-2) exhibited only a minor effect. We found that early-life long-term ibuprofen exposure impairs spermatogenesis. The number of mitotic cells significantly reduced by 31%. The rate of sperm malformation in exposed males was 63%, much higher than in unexposed males (11%). Additionally, the percentage of sperm activation decreased from 89% to 39% in ibuprofen-exposed worms. Mechanistic insights indicated that ibuprofen downregulated mRNA levels of genes related to spermatogenesis and DAF-7/TGF-β signaling. RNAi assays provided evidence for the crucial role of the transcription factor DAF-5 in mediating the spermatogenesis impairment by ibuprofen. Our study provides insight into the environmental impacts of pharmaceutical contaminants, such as ibuprofen, on both male and female reproductive systems to safeguard environmental health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug that has been found in recent years to cause ovarian damage. The aim of this study is to explore the molecular mechanisms of IBU damage to the ovary and drugs to combat it. We established in vivo (IBU doses of 50, 100 and 200 mg/kg-day) and in vitro (IBU concentrations of 50, 100 and 200 μM in culture medium) models of ovarian damage in mice simulating clinical doses and found that IBU not only caused ovarian damage in mice in a dose-response relationship, but also decreased estradiol (E2) and prostaglandin E2 (PGE2) levels in serum/media with increasing IBU doses. In damaged ovaries, the cyclooxygenase 2 (COX2)-PGE2 pathway is inhibited, the Hippo pathway is activated, circPVT1 is decreased, and miR-149 is elevated. TT-10 is an activator of YES-associated protein (YAP)-transcriptional enhancer factor domain activity. Then, 100 μM IBU-induced ovarian damage model was selected for YAP activation (Hippo pathway inhibition) experiment, and TT-10 was found to interfere with IBU-induced ovarian damage and increase E2 level in the medium, and 10 μM of TT-10 had the best protective effect. TT-10 also inhibited the Hippo pathway, activated the COX2-PGE2 pathway, elevated circPVT1 expression, and decreased miR-149 expression in the ovary. It has been hypothesized that clinical doses of IBU damage mouse ovaries by inhibiting COX2-PGE2 and activating the Hippo pathway, whereas TT-10 protects the ovaries through the inverse regulation of these two pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

To investigate the effect of ibuprofen (IBU) on the sulfur-based and calcined pyrite-based autotrophic denitrification (SCPAD) systems, two individual reactors with the layered filling (L-SCPAD) and mixed filling (M-SCPAD) systems were established via sulfur and calcined pyrite. Effluent NO 3 - -N concentration of the L-SCPAD and M-SCPAD systems was first increased to 6.44, 0.93 mg/L under 0.5 mg/L IBU exposure and gradually decreased to 1.66 mg/L, 0 mg/L under 4.0 mg/L IBU exposure, indicating that NO 3 - -N removal performance of the M-SCPAD system was better than that of the L-SCPAD system. The variation of extracellular polymeric substances (EPS) characteristics demonstrated that more EPS was secreted in the M-SCPAD system compared to the L-SCPAD system, which contributed to forming a more stable biofilm structure and protecting microorganisms against the toxicity of IBU in the M-SCPAD system. Moreover, the increased electron transfer impedance and decreased cytochrome c implied that IBU inhibited the electron transfer efficiency of the L-SCPAD and M-SCPAD systems. The decreased adenosine triphosphate (ATP) and electron transfer system activity (ETSA) content showed that IBU inhibited metabolic activity, but the M-SCPAD system exhibited higher metabolic activity compared to the L-SCPAD system. In addition, the analysis of the bacterial community indicated a more stable abundance of nitrogen removal function bacteria (Bacillus) in the M-SCPAD system compared to the L-SCPAD system, which was conducive to maintaining a stable denitrification performance. The toxic response mechanism based on the biogeobattery effect was proposed in the SCPAD systems under IBU exposure. This study provided an important reference for the long-term toxic effect of IBU on the SCPAD systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The increasing use of chemicals and their release into aquatic ecosystems are harming aquatic biota. Despite extensive ecotoxicological research, many environmental pollutants' ecological effects are still unknown. This study examined the spatial avoidance, behavioural and biochemical impacts of ibuprofen, irgarol, and terbuthylazine on the early life stages of zebrafish (Danio rerio) under a range of ecologically relevant concentrations (0-500 μg/L). Embryos were exposed following the OECD guideline "fish embryo toxicity test" complemented with biochemical assessment of AChE activity and behavioural analyses (swimming activity) using the video tracking system Zebrabox. Moreover, spatial avoidance was assessed by exposing 120 hpf-old larvae of D. rerio to a gradient of each chemical, by using the heterogeneous multi-habitat assay system (HeMHAS). The results obtained revealed that the 3 compounds delayed hatching at concentrations of 50 and 500 μg/L for both ibuprofen and irgarol and 500 μg/L for terbuthylazine. Moreover, all chemicals elicited a dose-dependent depression of movement (swimming distance) with LOEC values of 5, 500 and 50 μg/L for ibuprofen, irgarol and terbuthylazine, respectively. Zebrafish larvae avoided the three chemicals studied, with 4 h-AC 50 values for ibuprofen, irgarol, and terbuthylazine of 64.32, 79.86, and 131.04 μg/L, respectively. The results of the HeMHAS assay suggest that larvae may early on avoid (just after 4 h of exposure) concentrations of the three chemicals that may later induce, apical and biochemical effects. Findings from this study make clear some advantages of using HeMHAS in ecotoxicology as it is: ecologically relevant (by simulating a chemically heterogeneous environmental scenario), sensitive (the perception of chemicals and the avoidance can occur at concentrations lower than those producing lethal or sublethal effects) and more humane and refined approach (organisms are not mandatorily exposed to concentrations that can produce individual toxicity)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ibuprofen (IBP) is an anti-inflammatory drug found in aquatic environments, potentially toxic for the biota. We exposed the test fish C. decemmaculatus to two environmentally relevant concentrations (50 and 100 μg IBP/L) for 4 and 12 d and evaluated the effect on some biomarkers. Micronucleus test, nuclear abnormality test and comet assay indicated cyto-genotoxicity at both concentrations and exposure periods. Oxidative stress and biochemical biomarkers were not affected, excepting muscle AChE activity for 4 d. Muscle metabolic biomarkers showed significant decrease in ETS, lipid and protein content, while carbohydrate content was not affected. The CEA index increased at the lower IBP concentration for 4 and 12 d, possibly due to changes in body energy reserves. A full-factorial GLM performed to assess the effects of IBP and exposure times showed that the metabolic and genotoxicity biomarkers were the most sensitive to IBP toxicity, mainly at 50 μg IBP/L for 4 d., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aquatic species are continuously exposed to pharmaceuticals and changeable water conditions simultaneously, which can induce changes in the toxicity of pollutants. Cyanobacterium are an organism for which less ecotoxicological tests have been performed compared to green algae. In this study, we decided to check how selected non-steroidal anti-inflammatory drugs (NSAID) affect the grow of Synechocystis salina, picocyanobacterium isolated from the Baltic Sea, with salinity as potential modulator of toxicity. S. salina was exposed to diclofenac (DCF), ibuprofen (IBF) and naproxen (NPX) (nominal 100 mg L -1 ) in BG11 medium and sea salt supplemented BG11 medium (38 PSU) over 96 h in continuous light at 23 °C. No acute toxicity was found in both tested salinity levels. The comparable grow rate in exposed culture compared to control culture over 4 days indicate lack of stress for several generations which need to be overcome with substantial energy consumption. S. salina was found to be halotolerant and can be species for ecotoxicology test where salinity in an additional stressor. Furthermore, resistant of S. salina to target NSAIDs provide a competitive advantage over other phytoplankton species., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Magda Caban reports financial support was provided by National Science Center (Poland)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Globally, the prevalence and pollution of pharmaceutical drugs in aquatic environments have been steadily increasing. This study sought to evaluate the effects of 14 days of exposure to environmental-relevant doses (ibuprofen 0.5, 5, and 50 µg/L, and carbamazepine 0.005, 1, and 10 µg/L) of the nonsteroidal anti-inflammatory drugs ibuprofen and carbamazepine in the freshwater fish Oreochromis mossambicus. The results showed a significant (P < 0.05) decrease in O. mossambicus superoxide dismutase, catalase, biotransformation enzymes, glutathione-s-transferase, glutathione peroxidase, oxidative stress lipid peroxidation, protein carbonyl activity, cellular damage metallothionine, reduced glutathione, immunological activities, and respiratory burst activity. Consequently, the acquired data revealed that O. mossambicus treated with ibuprofen and carbamazepine shows more significant alterations in metabolic depression, biochemical parameters, and oxidative stress. In addition, increased neurotoxic effects were observed in ibuprofen and carbamazepine treated O. mossambicus., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Ibuprofen (IBP) is a typical nonsteroidal anti-inflammatory drug with a wide range of applications, large dosages, and environmental durability. Therefore, ultraviolet-activated sodium percarbonate (UV/SPC) technology was developed for IBP degradation. The results showed that IBP could be efficiently removed using UV/SPC. The IBP degradation was enhanced with prolonged UV irradiation time, with the decreasing IBP concentration and the increasing SPC dosage. The UV/SPC degradation of IBP was highly adaptable to pH ranging from 4.05 to 8.03. The degradation rate of IBP reached 100% within 30 min. The optimal experimental conditions for IBP degradation were further optimized using response surface methodology. IBP degradation rate reached 97.3% under the optimal experimental conditions: 5 μM of IBP, 40 μM of SPC, 7.60 pH, and UV irradiation for 20 min. Humic acid, fulvic acid, inorganic anions, and natural water matrix inhibited the IBP degradation to varying degrees. Scavenging experiments of reactive oxygen species indicated that hydroxyl radical played a major role in the UV/SPC degradation of IBP, while carbonate radical played a minor role. Six IBP degradation intermediates were detected, and hydroxylation and decarboxylation were proposed as the primary degradation pathways. An acute toxicity test, based on the inhibition of luminescence in Vibrio fischeri, indicated that the toxicity of IBP during UV/SPC degradation decreased by 11%. An electrical energy per order value of 3.57 kWh m -3 indicated that the UV/SPC process was cost-effective in IBP decomposition. These results provide new insights into the degradation performance and mechanisms of the UV/SPC process, which can potentially be used for practical water treatment in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ibuprofen (IBU) is an emerging environmental contaminant that, in high doses, can damage reproductive organs in humans and other mammals. Recently, its effects on the uterus have been investigated. It is known that the COX2-PGE2 pathway and Yes-associated protein (YAP) are involved in female reproductive organ development and form a COX2-PGE2-EP2-Gas-β-catenin-YAP-COX2 positive feedback loop, in addition, TT-10, a pharmacological product, has been found to increase YAP. In this study, IBU was orally administrated to female mice for 7 d at doses of 0, 50, 100, and 200 mg/kg·bw/day (control, low, medium, and high doses, respectively). In addition, 0, 50, 100, and 200 μmol/L IBU was added in vitro to cultured uterine cells for 7 d at control, low, medium, and high doses, respectively; then, 0, 5, 10, and 20 μmol/L TT-10 were given to the in vitro uterine culture containing 100 μmol/L IBU to observe the effect of YAP activation. The results showed that medium and high doses of IBU inhibited the COX2-PGE2 pathway, decreasing YAP and increasing pYAP, leading to reduced circPVT1, elevated miR-149, and increased apoptosis, ultimately damaging the uterus. Conversely, 10 μmol/L TT-10 maximally enhanced YAP, which regulated COX2-PGE2 pathway activation, increased circPVT1, and decreased miR-149, and promoted cell proliferation, preventing uterine damage. This suggests that IBU may cause uterine damage by inhibiting the COX2-PGE2 pathway and YAP, and that appropriate doses of TT-10 may repair this damage by elevating YAP and stimulating COX2 via the feedback loop., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In the aim to determine neurotoxicity, new methods are being validated, including tests and test batteries comprising in vitro and in vivo approaches. Alternative test models such as the zebrafish (Danio rerio) embryo have received increasing attention, with minor modifications of the fish embryo toxicity test (FET; OECD TG 236) as a tool to assess behavioral endpoints related to neurotoxicity during early developmental stages. The spontaneous tail movement assay, also known as coiling assay, assesses the development of random movement into complex behavioral patterns and has proven sensitive to acetylcholine esterase inhibitors at sublethal concentrations. The present study explored the sensitivity of the assay to neurotoxicants with other modes of action (MoAs). Here, five compounds with diverse MoAs were tested at sublethal concentrations: acrylamide, carbaryl, hexachlorophene, ibuprofen, and rotenone. While carbaryl, hexachlorophene, and rotenone consistently induced severe behavioral alterations by ~ 30 h post fertilization (hpf), acrylamide and ibuprofen expressed time- and/or concentration-dependent effects. At 37-38 hpf, additional observations revealed behavioral changes during dark phases with a strict concentration-dependency. The study documented the applicability of the coiling assay to MoA-dependent behavioral alterations at sublethal concentrations, underlining its potential as a component of a neurotoxicity test battery., (© 2023. The Author(s).)

Pharmaceutical active compounds (PhACs) are emerging contaminants that pose a growing concern due to their ubiquitous presence and harmful impact on aquatic ecosystems. Among PhACs, the anti-inflammatory ibuprofen (IBU) and the antibiotic oxytetracycline (OTC) are two of the most used compounds whose presence has been reported in different aquatic environments worldwide. However, there is still scarce information about the cellular and molecular alterations provoked by IBU and OTC on aquatic photosynthetic microorganisms as microalgae, even more if we refer to their potential combined toxicity. To test the cyto- and genotoxicity provoked by IBU, OTC and their binary combination on Chlamydomonas reinhardtii, a flow cytometric panel was performed after 24 h of single and co-exposure to both contaminants. Assayed parameters were cell vitality, metabolic activity, intracellular ROS levels, and other programmed cell death (PCD)-related biomarkers as cytoplasmic and mitochondrial membrane potentials and caspase-like and endonuclease activities. In addition, a nuclear DNA fragmentation analysis by comet assay was carried out. For most of the parameters analysed (vitality, metabolic activity, cytoplasmic and mitochondrial membrane potentials, and DNA fragmentation) the most severe damages were observed in the cultures exposed to the binary mixture (IBU+OTC), showing a joint cyto- and genotoxicity effect. Both PhACs and their mixture caused a remarkable decrease in cell proliferation and metabolic activity and markedly increased intracellular ROS levels, parallel to a noticeable depolarization of cytoplasmic and mitochondrial membranes. Moreover, a strong increase in both caspase and endonuclease activities as well as a PCD-related loss of nuclear DNA integrity was observed in all treatments. Results analysis showed that the PhACs caused cell death on this non-target organism, involving mitochondrial membrane depolarization, enhanced ROS production and activation of PCD process. Thus, PCD should be an applicable toxicological target for unraveling the harmful effects of co-exposure to PhACs in aquatic organisms as microalgae., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used pharmaceuticals and tons of kilos are produced annually. Ibuprofen is one of the core medicines of non-steroidal anti-inflammatory drug and is primarily used for reduced pain, fever and tissue inflammation. It is also available for the treatment of osteoarthritis, rheumatoid arthritis, tendonitis, etc. It is still one of the most prescribed non-steroidal anti-inflammatory drugs in contemporary times. Although ibuprofen is a drug that has been used for years, it is also known to have various serious toxic effects., Objective: In this review, we aimed to clarify toxic and genotoxic effects of Ibuprofen by analyzing major journal indexes., Methods: The search was concentrated on the Web of Science, PubMed, Science Direct, Scopus, EBSCO Host, and Google Scholar databases, including the keyword combinations "genotoxicity", "toxicity", "teratogenicity", "side effects", "Ibuprofen"., Results: In the search procedure, a total number of 11738 studies about the topic were reviewed. Consequently, 42 studies were classified as appropriate according to the inclusion criteria and were therefore included in the review. The results presented and discussed in this review indicate that Ibuprofen might represent a toxic, genotoxic and teratogenic risk for non-target, freshwater invertebrates, vertebrates and toxic for human especially in overdose or misuse situation., Conclusion: Ibuprofen generally was found to be toxic, mutagenic, teratogenic and genotoxic agent in various organisms. In human cases mostly overdose or misuse was found to be toxic. However acute toxicity was also reported in some human clinical studies. More detailed genotoxicity, teratogenicity and especially carcinogenic potential should be investigated to reach full decision of its safety., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Pharmaceutical pollution of water bodies is among the top-notch environmental health risks all over the world. The aim of the present study was to investigate the effects of two common pharmaceuticals namely ibuprofen and gemfibrozil on zebrafish at environmentally relevant concentrations. In zebrafish liver, gemfibrozil caused a decrease in glutathione and glutathione transferase and an increase in catalase but had no effect on lipid peroxidation and protein carbonylation. Ibuprofen altered the antioxidant defense system, promoted protein carbonylation in zebrafish liver, and increased vitellogenin-like protein in the blood. Ibuprofen and particularly gemfibrozil induced lysosomes biogenesis. Lactate dehydrogenase in the blood was also found to be higher in the studied groups. Studied pharmaceuticals did not affect complex II of the electron respiratory chain. Ibuprofen affects zebrafish health status more profoundly than gemfibrozil. Our results showed that pharmaceuticals even in low, environmentally realistic concentrations, induced profound changes in the stress-responsive systems of zebrafish., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug released into water bodies causing toxic biological effects on living organisms. The current study aims to eliminate IBU from aqueous solutions by a novel carboxymethylcellulose/polypyrrole (CMC/PPY) composite with high removal efficiency. Pyrrole was polymerized to polypyrrole whose average size was about 20 nm on the CMC surface. The maximum removal percentage of IBU by CMC/PPY composite was optimized at initial concentration 10 mg/L, dosage 0.02 g, and pH 7 with adsorption capacity of 72.30 (mg/g) and removal of 83.17 %. IBU adsorption onto CMC/PPY theoretically fits into the Langmuir isotherm and Elovich-kinetic models. Fish and Phytotoxicity assessment were performed with zebrafish and seeds of Vigna mungo (VM) and Vigna radiata (VR). The toxicity study reveals that before adsorption, IBU shows high toxicity towards the zebrafish mortality (33 %), growth inhibition (58.52 % for VM, 60.84 % for VR), and germination (86.66 % for VM and 90 % for VR). As CMC/PPY adsorbs IBU, toxicity drastically decreases. Before adsorption, LC 50 was 233.02 mg/L. After adsorption, the LC 50 increases to 2325.07 mg/L as IBU molecules get adsorbed by CMC/PPY. These findings show the feasibility of preparing CMC/PPY composite to effectively remove pharmaceutical pollutant IBU from aqueous solutions with their toxicological assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

One of the main contributors to pharmaceutical pollution of surface waters are non-steroidal anti-inflammatory drugs (NSAIDs) that contaminate the food chain and affect non-target water species. As there are not many studies focusing on toxic effects of NSAIDs on freshwater fish species and specially effects after dietary exposure, we selected rainbow trout (Oncorhynchus mykiss) as the ideal model to examine the impact of two NSAIDs - diclofenac (DCF) and ibuprofen (IBP). The aim of our study was to test toxicity of environmentally relevant concentrations of these drugs together with exposure doses of 100× higher, including their mixture; and to deepen knowledge about the mechanism of toxicity of these drugs. This study revealed kidneys as the most affected organ with hyalinosis, an increase in oxidative stress markers, and changes in gene expression of heat shock protein 70 to be signs of renal toxicity. Furthermore, hepatotoxicity was confirmed by histopathological analysis (i.e. dystrophy, congestion, and inflammatory cell increase), change in biochemical markers, increase in heat shock protein 70 mRNA, and by oxidative stress analysis. The gills were locally deformed and showed signs of inflammatory processes and necrotic areas. Given the increase in oxidative stress markers and heat shock protein 70 mRNA, severe impairment of oxygen transport may be one of the toxic pathways of NSAIDs. Regarding the microbiota, an overgrowth of Gram-positive species was detected; in particular, significant dysbiosis in the Fusobacteria/Firmicutes ratio was observed. In conclusion, the changes observed after dietary exposure to NSAIDs can influence the organism homeostasis, induce ROS production, potentiate inflammations, and cause gut dysbiosis. Even the environmentally relevant concentration of NSAIDs pose a risk to the aquatic ecosystem as it changed O. mykiss health parameters and we assume that the toxicity of NSAIDs manifests itself at the level of mitochondria and proteins., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ibuprofen is a nonsteroidal anti-inflammatory drug that can be found in freshwater ecosystems. Due to its current presence in aquatic ecosystems, this pharmaceutical has aroused concerns about its impact on aquatic biota. As a result, ibuprofen is the one of the most frequently studied pharmaceuticals. However, most of these studies focus on short-term observations of biomarkers and physiological endpoints. This paper presents the outcomes of whole-life-cycle observations and six-month observations of the population dynamics of Daphnia magna reared under the influence of 1 μg/L, 2 μg/L and 4 μg/L of ibuprofen. Individuals reared under the influence of ibuprofen grew slowly, matured later and lived longer. Moreover, they displayed a higher reproduction rate and carried smaller broods but delivered larger neonates. Ibuprofen in concentrations of 1 μg/L and 2 μg/L had the most significant effect on the above traits. The observed impact of ibuprofen at the individual level did not transfer to population size and dynamics. All the populations represented a typical boom and bust cycle with restricted reproduction during the periods of highest population size. This is the first study to explore the linkage between the life histories of aquatic invertebrates and the actual response of their populations to the occurrence of ibuprofen in the environment. The study emphasizes the need to apply the protocol of whole life-cycle observation in tandem with population scrutiny, since such a protocol can reveal the virtual responses of aquatic biota to the presence of chemicals in the environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author. Published by Elsevier B.V. All rights reserved.)

Due to its ubiquitous presence in wastewaters, wastewater treatment plant effluents and even surface waters, the removal of the pharmaceutical ibuprofen from water is of special interest. Ozonation is widely applied for the treatment of micropollutants in wastewater treatment plants and is already known to also degrade ibuprofen. However, the formation of a wide range of transformation products during such oxidation steps might affect the aquatic environment. This study focuses on the acute ecotoxicological impact of the ibuprofen ozonation products on the two model organisms Daphnia magna and Desmodesmus subspicatus. For the identification of possibly ecotoxic products, a new workflow combining ecotoxicological testing, analytical methods and toxicity prediction was applied. Examination at different pH conditions with increasing ozone doses can point to respective products for further systematic examination. Seven ozonation products were confirmed in this study, two of them for the first time. Five previously postulated products were rejected. For pH 7 the inhibition of green algae growth was observed for mixtures oxidized with low ozone doses, while at pH 3 the mixtures with higher ozone doses caused toxic effects on the mobility of daphnids. Together with the analytical measurements in combination with ecotoxicity prediction, six products were identified which might have caused the toxic effect on green algae. However, no assignment to the observed toxic effects on daphnids was possible. The gained results indicate that mixture toxicity might play a role in oxidation processes and needs to be considered in ozonation studies concerning the ecotoxicological impact. Furthermore, the different observed toxicity for the two organisms underlines the importance of using multiple test systems for a comprehensive evaluation of the ecotoxicity during ozonation processes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Valentina I. Merkus reports financial support was provided by German chemical industry association VCI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The aim of this study is to assess the toxicity of ibuprofen (IBU) and propranolol (PRO) drugs using Gammarus pulex  as a model organism. Firstly, the 96 h LC 50  values of IBU and PRO were determined and then three sublethal concentrations of the drugs were exposed to  G. pulex . The activities of superoxide dismutase (SOD), catalase (CAT) and acetylcholinesterase (AChE) were evaluated. SOD activity decreased in  G. pulex  exposed to IBU and PRO compared to control. In all groups exposed to IBU, CAT activity increased at different concentrations at 24 and 96 h. In the groups exposed to different PRO concentrations, CAT activities increased after 24 h compared to the control group (p < 0.05). AChE activities increased in all application groups exposed to IBU for 96 hours (p < 0.05). In conclusion, exposure to IBU and PRO resulted in increased oxidative damage. PRO has been found to cause neurotoxicity.

Even though bivalve molluscs are recognized as bioindicators of freshwater quality, their responses to multiple stressors are unpredictable. This study aims to elucidate the inter-population peculiarities of the effect in the sub-chronic environmentally relevant exposure to novel contaminants. The specimens of Unio tumidus from reference (Pr) and contaminated (Ct) areas were treated with ibuprofen (IBU, 0.8 µg L -1 ), microplastic (MP, 1.0 mg L -1 , size 0.1-0.5 mm), or their combination (Mix) for 14 days. Untreated mussels (PrC- and CtC-groups) served as controls. The PrC-group had higher levels of antioxidants Mn-SOD, Cu,Zn-SOD, catalase, and cholinesterase (AChE) as well as lesser levels of oxidative lesions (TBARS and protein carbonyls) in digestive glands, indicating lower environmental impact than in the CtC-group. However, lysosomal stability was similar in both control groups. Among antioxidants, Mn-SOD activity was affected most prominently, increasing in all exposed Ct-groups. TBARS level was increased only in PrMP-group compared to responsive control. IBU and Mix enhanced protein carbonyl concentration in the Pr-groups, and decreased it in the Ct-groups. AChE was induced in the CtIBU- and PrMix-groups, and lysosomal integrity increased in the CtIBU and CtMix-groups. Discriminant analyses indicated lesser differences between Pr-groups, demonstrating lower cumulative stress compared to Ct-groups. Generally, the most remarkable response was revealed in the CtIBU-group, and distortion of individual effects was established in combined exposures. The qualification of stress-neutral and stress-positive populations was proposed for Pr- and Ct-populations correspondingly. Inter-site peculiarities must be taken into consideration when the environmental impact of MP and pharmaceuticals is evaluated., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The vulnerability of bivalve mollusks to micropollutants is estimated mainly in single model exposures. However, chronic environmental stress and complex exposures can modulate their responses. To evaluate the impact of population-dependent adaptations on the ability to react to common micropollutants, we compared freshwater bivalves Unio tumidus from two distinct populations, pure (Pr) and contaminated (Ct), in their exposures to microplastics (MP, 1 mg L -1 , size 0.1-0.5 mm), pharmaceutical ibuprofen (IBU, 0.8 μg L -1 ), or their combination (Mix) for 14 days. Control groups from both sites showed remarkable differences, with lower levels of total antioxidant capacity (TAC), metallothionein protein (MTSH), NADH and NAD + , cytochrome P450-related EROD, glutathione-S transferase (GST), and citrate synthase (CS) but higher levels of GSH, GSSG, caspase-3 and cathepsin D (CTD) in the Ct-control group. These data indicate a chronic stress impact in the Ct population. Under exposures, we found an almost common strategy in both populations for NAD + /NADH and MTSH suppression and CTD induction. Additionally, Mix exposure caused an increase in CS, and IBU did not change GSH in both populations. However, the expected response to IBU - the suppression of caspase-3 - was indicated only in PrIBU- and PrMix-mollusks. CTD efflux increased dramatically only in PrMP- and PrMix- groups, and suppression of EROD and GST was detected in the PrMix-group. According to discriminant analysis, exposed Pr-groups were highly differentiated from control, whereas Ct-control and exposed groups had common localization demonstrating high resistance to environmental stress. Thus, the same exposures resulted in different adverse outcome pathways depending on the population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Pharmaceutical pollutants, a vital type of emerging contaminants, have attracted researchers to study their removal from water. In this research, Corn starch nanoparticles (CSNP) have been synthesized and characterized using various analytical techniques. The synthesized CSNP was used for the biosorption of two pharmaceutical drugs, ibuprofen (IBU) and sulfamethoxazole (SUL). The influence of various experimental conditions was optimized through batch study with the removal efficiency of 86.33 % (IBU) and 85.80 % (SUL) at pH 2 and 3, initial concentration of 10 mg/L, 0.01 g of CSNP dosage. The biosorption of IBU follows Temkin, and SUL follows Langmuir isotherm models. The toxicological assessment was performed using the seeds of Vigna mungo (VM) and Vigna radiata (VR) and zebrafish to evaluate the toxic effects of pollutants on these organisms. The LC 50 of IBU and SUL on zebrafish before the biosorption process was 209.50 mg/L and 338.84 mg/L. After biosorption, the LC 50 values increase to 1435.82 mg/L for IBU and 1317.04 mg/L for SUL. Thus, CSNP is an efficient biosorbent for removing the pharmaceutical pollutants to protect ecological systems., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The major objectives of this study were to explore the long-term effects of ibuprofen (IBP) on nutrient removal, community compositions, and microbial interactions of the activated sludge system. The results showed that 1 mg/L IBP had no inhibitory effects on the removal of organic matters and nutrients. IBP significantly reduced the microbial diversity and changed the bacterial community structure. Some denitrifiers (Denitratisoma and Hyphomicrobium) increased significantly, while NOB (Nitrospira) significantly decreased under IBP stress (P < 0.05). Furthermore, molecular ecological network analysis indicated that IBP reduced the overall network size and links, but led to a closer network with more efficient communication, which might be the strategy of microbes to survive under the stress of IBP and further maintain the performance stability. Different phylogenetic populations had different responses to IBP, as a closer subnetwork with more synergistic relations was observed in Chloroflexi and a looser subnetwork with more competitive relationships was detected in Proteobacteria. The topological roles of nodes significantly changed, and the putative keystone species decreased under the stress of IBP. This study broadens our knowledge of the long-term effects of IBP on the microbial community structure and the interactions between species in the activated sludge system., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug that is noted for its favorable safety profile. It exerts its therapeutic effect through inhibition of prostaglandin (PG) production at inflammatory sites. However, the inhibition of PG synthesis at other sites is responsible for the occurrence of adverse events. Evidence regarding the effect of regular ibuprofen intake on penile PG homeostasis or penile histopathologic changes is lacking. The aim of this study was to examine the effect of regular administration of analgesic therapeutic doses of ibuprofen on penile PG E1 and F2α and penile microscopic changes of the treated rats. This study included four groups of adult male Wistar rats; a control group (I) injected intraperitoneally with saline (2 ml/kg/day) for 30 days and 3 ibuprofen-treated groups (IIa, IIb, and IIc) injected intraperitoneally with 6 mg/kg/day, 12 mg/kg/day, and 18 mg/kg/day ibuprofen, respectively, for 30 days, respectively. Mean levels of penile PGE1 and PGF2α in the control group were significantly higher than ibuprofen-treated groups IIa, IIb, and IIc. The percentage area of collagen around cavernous tissue was significantly higher in ibuprofen-treated groups IIa, IIb, and IIc than control rats. Our findings suggest that despite ibuprofen's safety profile, regular use of ibuprofen is associated with reduced penile PG and increased cavernosal fibrosis.

Background: Previous studies have raised serious concerns on cardiovascular safety of widely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore, the aim of this study was to characterize the electrophysiological effects of certain NSAIDs in an established whole heart model of proarrhythmia., Methods and Results: Thirty-eight hearts of New Zealand White rabbits were harvested and retrogradely perfused employing a Langendorff setup, and electrophysiology studies were performed to investigate action potential duration at 90% of repolarization (APD 90 ), QT intervals, and effective refractory period (ERP). After generating baseline data, hearts were perfused with ibuprofen (Group 1, n = 12; 10 and 30 μM), indomethacin (Group 2, n = 13; 10 and 20 μM) and diclofenac (Group 3, n = 13; 10 and 20 μM), respectively, and the pacing protocols were repeated for each concentration. In all groups, perfusion with the NSAIDs resulted in a significant and reproducible shortening of APD 90 and QT interval. In all groups, the arrhythmia susceptibility was significantly raised as occurrence of monomorphic ventricular tachycardia under programmed ventricular stimulation was significantly increased under perfusion with ibuprofen, indomethacin and diclofenac in all concentrations., Conclusion: The perfusion with ibuprofen, indomethacin and diclofenac in commonly used doses raised the arrhythmia susceptibility in an established rabbit whole-heart model while APD shortening and shortened ERP seem to be crucial for arrhythmogenesis., (© 2021 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Several studies highlighted the ubiquitous presence of ibuprofen and aluminum in the aquatic environment around the world and demonstrated their potential to induce embryotoxic and teratogenic defects on aquatic species individually. Although studies that evaluate developmental alterations induced by mixtures of these pollutants are scarce; and, since environmental contamination presented in the form of a mixture of toxicants with different chemical properties and toxicity mechanisms capable of generating interactions; the objective of this study was to evaluate the developmental defects, teratogenic alterations, and oxidative stress induced by individual forms and the mixture of ibuprofen (IBU) and aluminum (Al) on zebrafish embryos. Oocytes exposed to environmentally relevant concentrations of IBU (0.1-20 μg L-1) and Al (0.01-8 mg L-1) and one binary mixture. The LC50 and EC50 were obtained to calculate the teratogenic index (TI). The IBU LC50, EC50, and TI were 8.06 μg L-1, 2.85 μg L-1 and 2.82. In contrast, Al LC50 was 5.0 mg L-1with an EC50 of 3.58 mg L-1 and TI of 1.39. The main alterations observed for individual compounds were hatching alterations, head malformation, skeletal deformities, hypopigmentation, pericardial edema, and heart rate impairment. The mixture also showed significant delays to embryonic development. Moreover, oxidative stress biomarkers of cellular oxidation and antioxidant defenses at 72 and 96 hpf significantly increased. Results show that environmentally relevant concentrations of ibuprofen (IBU), aluminum (Al), and their mixture promote a series of developmental defects, teratogenic effects, and oxidative disruption on D. rerio embryos, and the interaction of both substances altered the response. In conclusion, morphological and biochemical tests are suitable tools for assessing the health risk of aquatic wildlife by exposure to individual and mixed pollutants in freshwater bodies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The article expands our knowledge on the variety of biodegraders of ibuprofen, one of the most frequently detected non-steroidal anti-inflammatory drugs in the environment. We studied the dynamics of ibuprofen decomposition and its relationship with the physiological status of bacteria and with additional carbon and energy sources. The involvement of cytoplasmic enzymes in ibuprofen biodegradation was confirmed. Within the tested actinobacteria, Rhodococcus cerastii IEGM 1278 was capable of complete oxidation of 100 μg/L and 100 mg/L of ibuprofen in 30 h and 144 h, respectively, in the presence of an alternative carbon source (n-hexadecane). Besides, the presence of ibuprofen induced a transition of rhodococci from single- to multicellular lifeforms, a shift to more negative zeta potential values, and a decrease in the membrane permeability. The initial steps of ibuprofen biotransformation by R. cerastii IEGM 1278 involved the formation of hydroxylated and decarboxylated derivatives with higher phytotoxicity than the parent compound (ibuprofen). The data obtained indicate potential threats of this pharmaceutical pollutant and its metabolites to biota and natural ecosystems., Competing Interests: The authors have declared that no competing interests exist.

We developed phospho-ERK1/2 ELISA for human and rainbow trout liver cells, employing HepG2 and RTL-W1 cell lines as models. The assay was applied to detect changes in ERK1/2 activity for nine chemicals, added over a wide concentration range and time points. Cell viability was measured to separate ERK1/2 regulation from cytotoxicity. Perfluorooctane sulfonate and carbendazim did not change ERK1/2 activity; influence on ERK1/2 due to cytotoxicity was indicated for tributyltin and cypermethrin. Mancozeb, benzo[a]pyrene, and bisphenol A stimulated ERK1/2 up to ∼2- (HepG2) and 1.5 (RTL-W1)-fold, though the kinetics differed between chemicals and cell lines. Bisphenol A and benzo[a]pyrene were the most potent concentration-wise, altering ERK1/2 activity in pM (HepG2) to nM (RTL-W1) range. While atrazine and ibuprofen increased ERK1/2 activity by ∼2-fold in HepG2, they did not initiate an appreciable response in RTL-W1. This assay proved to be a sensitive, medium- to high-throughput tool for detecting unrecognized ERK1/2-disrupting chemicals., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Due to their wide applications and extensive discharges, pharmaceuticals have recently become a potential risk to aquatic and terrestrial organisms. The uptake of pharmaceuticals have been shown to stimulate plant defense systems and induce phytotoxic effects. Signaling molecules such as plant hormones play crucial roles in plant stress and defense responses, but the relationship between these molecules and pharmaceutical uptake has rarely been investigated. In this study, two common pharmaceuticals, carbamazepine and ibuprofen, and three stress-related plant hormones, jasmonic acid, salicylic acid, and abscisic acid, were simultaneously tracked in the roots and stems of Malabar spinach (Basella alba L.) via an in vivo solid phase microextraction (SPME) method. We also monitored stress-related physiological markers and enzymatic activities to demonstrate plant hormone modulation. The results indicate that pharmaceutical uptake, subsequent stress symptoms, and the defense response were all significantly correlated with the upregulation of plant hormones. Moreover, the plant hormones in the exposure group failed to recover to normal levels, indicating that plants containing pharmaceutical residues might be subject to potential risks., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are medications used individually or as mixtures with other pharmaceuticals for the treatment of various illnesses. Their easy accessibility and high human consumption have resulted to their detection at high concentrations in South African water resources. In the present work, an extensive review of the occurrence and ecotoxicological risk assessment of NSAIDs in South African aquatic environment is provided. Reviewed literature suggested ibuprofen, naproxen, diclofenac, ketoprofen and fenoprofen as the most prominent NSAIDs in the South African aquatic environment. Among these NSAIDs, higher concentrations of ibuprofen are common in South African waters. As a result, this drug was found to pose high ecotoxicological risks towards the aquatic organisms with the highest risk quotients of 14.9 and 11.9 found for algae in surface water and wastewater, respectively. Like in other parts of the world, NSAIDs are not completely removed in wastewater treatment plants. Removal efficiencies below 0% due to higher concentrations of NSAIDs in wastewater effluents rather than influents were observed in certain instances. The detection of NSAIDs in sediments and aquatic plants could serve as the important starting step to investigate other means of NSAIDs removal from water. In conclusion, recommendations regarding future studies that could paint a clearer picture regarding the occurrence and ecotoxicological risks posed by NSAIDs in South African aquatic environment are provided., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite the ubiquitous presence of multiple pollutants in aqueous environments have been extensively demonstrated, the ecological impact of chemical cocktails has not been studied in depth. In recent years, environmental studies have mainly focused on the risk assessment of individual chemical substances neglecting the effects of complex mixtures even though it has been demonstrated that combined effects exerted by pollutants might represent a greater hazard to the biocenosis. The current study evaluates the effects on the oxidative stress status induced by individual forms and binary mixtures of ibuprofen (IBU) and aluminum (Al) on brain, gills, liver and gut tissues of Danio rerio after long-term exposure to environmentally relevant concentrations (0.1-11 μg L -1 and 0.05 mg L -1 - 6 mg L -1 , respectively). Lipid peroxidation (LPO), Protein carbonyl content (PCC) and activity of Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione Peroxidase (GPX) were evaluated. Moreover, concentrations of both toxicants and the metabolite 2-OH-IBU were quantified on test water and tissues. Results show that ibuprofen (IBU) and aluminum (Al) singly promote the production of radical species and alters the oxidative stress status in all evaluated tissues of zebrafish, nevertheless, higher effects were elicited by mixtures as different interactions take place., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A Sequencing Batch Reactor (SBR) with activated sludge was operated with synthetic wastewater containing ibuprofen (IBU) to investigate the biomass stress-responses under long-term IBU exposure. There were 3 different phases: phase I as the control without IBU for 56 days, phase II (40 days), and phase III (60 days) containing IBU at 10 and 5 mg L -1 each. The overall performance of the SBR as well as the extracellular polymeric substances (EPS) in terms of polysaccharides, proteins, and humic acid substances were estimated. Morphological parameters of microbial aggregates in the presence of IBU (phase II and phase III) were assessed by quantitative image analysis (QIA). Removal efficiencies of chemical oxygen demand (COD) and ammonium (NH 4 + ) were significantly reduced by IBU. Loosely bound EPS (LB-EPS) decreased during phase II and phase III, and tightly bound EPS (TB-EPS) was slightly higher in phase II than phase I. TB-EPS proteins were greater in phase II, perhaps to protect microbial cells from IBU exposure. These findings provided insight into both activated sludge stress-responses and EPS composition under long-term IBU exposure. Spearman correlation showed that EPS and morphological parameters significantly affected sludge settleability and flocculation. QIA also proved to be a powerful technique in investigating dysfunctions in activated sludge under IBU exposure., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The knowledge about the effects of pharmaceuticals on aquatic organisms has been increasing in the last decade. However, due to the variety of compounds presents in the aquatic medium, exposure scenarios and exposed organisms, there are still many gaps in the knowledge on how mixtures of such bioactive compounds affect exposed non target organisms. The crayfish Procambarus clarkii was used to analyze the toxicity effects of mixtures of ciprofloxacin, flumequine and ibuprofen at low and high concentrations (10 and 100 μg/L) over 21 days of exposure and to assess the recovery capacity of the organism after a depuration phase following exposure during additional 7 days in clean water. The crayfish accumulated the three compounds throughout the entire exposure in the hepatopancreas. The exposure to the mixture altered the abundance of proteins associated with different cells functions such as biotransformation and detoxification processes (i.e. catalase and glutathione transferase), carbohydrate metabolism and immune responses. Additionally changes in expression of genes encoding antioxidant enzymes and in activity of the corresponding enzymes (i.e. superoxide dismutase, glutathione peroxidase and glutathione transferase) were reported. Alterations at different levels of biological organization did not run in parallel under all circumstances and can be related to changes in the redox status of the target tissue. No differences were observed between control and exposed organisms for most of selected endpoints after a week of depuration, indicating that exposure to the drug mixture did not produce permanent damage in the hepatopancreas of P. clarkii., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Current cystic fibrosis (CF) treatment strategies are primarily focused on oral/inhaled anti-inflammatories and antibiotics, resulting in a considerable treatment burden for CF patients. Therefore, combination treatments consisting of anti-inflammatories with antibiotics could reduce the CF treatment burden. However, there is an imperative need to understand the potential drug-drug interactions of these combination treatments to determine their efficacy. Thus, this study aimed to determine the interactions of the anti-inflammatory agent Ibuprofen with each of the CF-approved inhaled antibiotics (Tobramycin, Colistin and its prodrug colistimethate sodium/Tadim) and anti-bacterial and anti-inflammatory efficacy. Chemical interactions of the Ibuprofen:antibiotic combinations were elucidated using High-Resolution Mass-Spectrometry (HRMS) and 1 H NMR. HRMS showed pairing of Ibuprofen and Tobramycin, further confirmed by 1 H NMR whilst no pairing was observed for either Ibuprofen:Colistin or Ibuprofen:Tadim combinations. The anti-bacterial activity of the combinations against Pseudomonas aeruginosa showed that neither paired nor non-paired Ibuprofen:antibiotic therapies altered the anti-bacterial activity. The anti-inflammatory efficacy of the combination therapies was next determined at two different concentrations (Low and High) using in vitro models of NuLi-1 (healthy) and CuFi-1 (CF) cell lines. Differential response in the anti-inflammatory efficacy of Ibuprofen:Tobramycin combination was observed between the two concentrations due to changes in the structural conformation of the paired Ibuprofen:Tobramycin complex at High concentration, confirmed by 1 H NMR. In contrast, the non-pairing of the Ibuprofen:Colistin and Ibuprofen:Tadim combinations showed a significant decrease in IL-8 secretion at both the concentrations. Importantly, all antibiotics alone showed anti-inflammatory properties, highlighting the inherent anti-inflammatory properties of these antibiotics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Research on the environmental impact of plastics, especially on the effect of microplastics (MPs), has become a priority issue in recent years, mainly in terrestrial ecosystems where there is a lack of studies. This work aims to assess the impact of two types of polyethylene MPs, white microbeads (W) and fluorescent blue microbeads (FB), and their interactions with two contaminants, ibuprofen (Ib) and simazine (Sz), on different organisms. A set of bioassays for Vibrio fischeri, Caenorhabditis elegans and Lactuca sativa was carried out, which helped to establish the ecotoxicological impact of those pollutants. C. elegans showed the least sensitivity, while V. fischeri and L. sativa showed a high toxicological response to MPs alone. We found that W and FB induced an inhibition of 27% and 5.79%, respectively, in V. fischeri, and the growth inhibition rates were near 70% in L. sativa for both MPs. MPs exhibited a potential role as contaminant vectors in V. fischeri since the inhibition caused by W-Ib or W-Sz complexes was near 39%. The W-Sz complex significantly reduced leaf development in L. sativa, and a reduction of 30% in seed germination was detected when the complex FB-Sz was tested. This study reveals the importance of designing a complete set of analyses with organisms from different trophic levels, considering the great variability in the effects of MPs and the high number of relevant factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Nowadays the presence of pharmaceuticals in the environment is a real problem. Ending up in aquatic environments they negatively affect non-target organisms. Considering the limited studies on the negative effects of pharmaceuticals in amphibians, a better understanding of the mechanisms underlying the sub-lethal effects of drug mixtures in wildlife is an urgent call. Representing particularly vulnerable organisms currently at risk of extinction, amphibians are perfect non-target organisms to explore the consequences of pharmaceuticals during sensitive life-stages. To address this existing research gap, the effects of two drugs, the antidepressant fluoxetine and the anti-inflammatory ibuprofen, as well as their combination has been studied. Tadpoles of Bufo bufo were exposed for seven days to two environmentally realistic concentrations of fluoxetine, ibuprofen and their mixture. The development, behavior and erythron profile were then evaluated as endpoints of exposure response. Both drugs negatively affected tadpoles' growth and development by significantly delayed their time to metamorphosis and reduced body weight. Behaviors were also impaired with a significant increase of unresponsiveness to different stimuli. Mutagenic analysis of blood revealed a significant increase in the frequency of cellular and nuclear abnormalities. Given the complexity of systems and functions affected, our work confirms the toxicological potential of fluoxetine and ibuprofen in B. bufo tadpoles by emphasizing their role as tadpole development delayers and erythrocyte apoptosis-inducers. To our knowledge, this is the first study trying to elucidate the potentially toxic effects of a mixture of an antidepressant with a non-steroidal anti-inflammatory drug using bullfrog tadpole as model organism. Both drugs interacted in impairing development and fitness in tadpoles, which might affect long-term species perpetuation and population dynamic. More in-depth research is needed to elucidate the nature of interaction and molecular mechanisms of mixed pharmaceutical compounds on non-targeted organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The environmental-friendly photocatalytic process with a magnetic catalyst CoFe 2 O 4 /TiO 2 mediated by solar light for ibuprofen (IBP) degradation in pure water, wastewater effluent and artificial seawater was investigated systematically. The study aims to reveal the efficiency, the mechanism and toxicity evolution during IBP degradation. Hydroxyl radicals and photo-hole (h + ) were found to contribute to the IBP decay. The presence of SO 4 2- showed no significant effect, while NO 3 - accelerated the photodegradation, and other anions including HCO 3 - , Cl - , F - , and Br - showed significant inhibition. The removal efficiency was significantly elevated with the addition of peroxymonosulfate (PMS) or persulfate (PS) ([Oxidant] 0 :[IBP] 0  = 0.4-4), with reaction rate of 5.3-13.1 and 1.3-2.9 times as high as the control group, respectively. However, the reaction was slowed down with the introduction of H 2 O 2 . A mathematic model was employed to describe the effect of ferrate, high concentration or stepwise addition of ferrate was suggested to play a positive role in IBP photodegradation. Thirteen transformation products were identified and five of them were newly reported. The degradation pathways including hydroxylation, the benzene ring opening and the oxidation of carbon were proposed. IBP can be efficiently removed when spiked in wastewater and seawater despite the decreased degradation rate by 41% and 56%, respectively. Compared to the IBP removal, mineralization was relatively lower. The adverse effect of the parent compound IBP to the green algae Chlorella vulgaris was gradually eliminated with the decomposition of IBP. The transformation product C178a which possibly posed toxicity to rotifers Brachionus calyciflorus can also be efficiently removed, indicating that the photocatalysis process is effective in IBP removal, mineralization and toxicity elimination., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Numerous active pharmaceutical ingredients (APIs) have been detected in various environmental matrices. Thus, their potential to elicit their toxic effect on non-target organisms is a growing concern, especially in the aquatic environment. This study aimed to investigate the potential toxicity of ibuprofen (IBU) at environmentally relevant concentration on the haematology and histology of the gill, liver, and kidney over 30 days. The 96-h acute toxicity data showed that IBU was moderately toxic to C. gariepinus with an LC50 value of 3.78 mg/L. After 15 and 30 days of exposure, there was a significant alteration in haematological indices in the treated fishes when compared to the control group. Throughout the experimental duration, the level of the mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) were consistently lower significantly, in contrast to the control group. IBU induced histopathological deformities in the gills, liver, and kidney of the exposed fishes, with alterations such as showing severe secondary lamella necrosis (SLN), epithelial lifting (EL), mild deformity of the secondary lamella (DSL), mild secondary lamella necrosis (MLN), and mild vascular congestion in the liver and kidney, respectively. This study has demonstrated that IBU at environmentally relevant concentrations can significantly impact the haematology, gills, liver, and kidney of C. gariepinus. This study's results can provide baseline info for regulatory agencies to set safe limits for NSAIDs as a safeguard for the aquatic environment.

Residues of antiseptics and drugs have been ubiquitously detected in aquatic water-sediment systems, and are thus considered emerging contaminants that threaten our global environment. To investigate the potential risk of ibuprofen and triclocarban in sediment, effects of enzyme activity on the enantioselective degradation in sediment were investigated. Enantioselective fate of rac-ibuprofen was observed in sediment with R-enantiomer exhibiting preferential degradation. Enzyme evidence showed that high levels of triclocarban could significantly inhibit activities of catalase and urease activities in sediment, as well as increase the half-life of ibuprofen (from 5.8 d to 10.1 d). Cytotoxicity data suggested that cell growth processes were significantly affected by ibuprofen and triclocarban co-exposure, which was consistent with apoptosis results. Additionally, the expression of several proteins (Cyto-c, Nrf2, p62, Keap1, NQO1, and Pink1) were markedly induced upon exposure to ibuprofen in the presence of triclocarban. In conclusion, these findings illustrated that co-occurrence of ibuprofen and triclocarban residues have synergistic adverse effects to the environment and synergistically threaten human health., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: The low solubility and consequent poor bioavailability of ibuprofen (IBU) is a major drawback that can be overcome by anchoring IBU on ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) as effective multifunctional carriers for drug delivery. Methods: USPIONs were conjugated with glycerol phosphate (USPION-GP) and also co-conjugated with IBU (USPION-GP/IBU), and their in vivo toxicity and anti-inflammatory effects investigated. Phosphate buffer saline (control), IBU, USPION-GP and USPION-GP/IBU were intravenously administered 15 min before lipopolysaccharide-induced peritonitis in male Balb/c mice. Results: 4 h later, USPION bioconjugates did not appear to have caused toxicity to blood leukocytes or caused alterations in the spleen, liver or kidneys. Also, they inhibited lipopolysaccharide-induced neutrophil mobilization into the peritoneum. Conclusion: The absence of systemic toxicity and the unexpected anti-inflammatory action of USPION bioconjugates indicates that they could be a novel and effective approach to administer IBU and warrant further investigation.

Background: Aryl-propionic acid derivatives with ibuprofen as representative drug are very important for therapy, being recommended especially for anti-inflammatory and analgesic effects. On other hand 1,3-thiazolidine-4-one scaffold is an important heterocycle, which is associated with different biological effects such as anti-inflammatory and analgesic, antioxidant, antiviral, antiproliferative, antimicrobial etc. The present study aimed to evaluated the toxicity degree and the anti-inflammatory and analgesic effects of new 1,3-thiazolidine-4-one derivatives of ibuprofen., Methods: For evaluation the toxicity degree, cell viability assay using MTT method and acute toxicity assay on rats were applied. The carrageenan-induced paw-edema in rat was used for evaluation of the anti-inflammatory effect while for analgesic effect the tail-flick test, as thermal nociception in rats and the writhing assay, as visceral pain in mice, were used., Results: The toxicological screening, in terms of cytotoxicity and toxicity degree on mice, revealed that the ibuprofen derivatives (4a-n) are non-cytotoxic at 2 μg/ml. In addition, ibuprofen derivatives reduced carrageenan-induced paw edema in rats, for most of them the maximum effect was recorded at 4 h after administration which means they have medium action latency, similar to that of ibuprofen. Moreover, for compound 4d the effect was higher than that of ibuprofen, even after 24 h of administration. The analgesic effect evaluation highlighted that 4 h showed increased pain inhibition in reference to ibuprofen in thermal (tail-flick assay) and visceral (writhing assay) nociception models., Conclusions: The study revealed for ibuprofen derivatives, noted as 4 m, 4 k, 4e, 4d, a good anti-inflammatory and analgesic effect and also a safer profile compared with ibuprofen. These findings could suggest the promising potential use of them in the treatment of inflammatory pain conditions.