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The persistent challenge of water pollution, exacerbated by slow progress in ecofriendly technologies and accumulating pollutants, underscores the need for innovative solutions. Constructed Wetland Microbial Fuel Cell (CW-MFC) emerges as an intriguing environmental technology capable of adressing this issue by eliminating contaminants from wastewater while simultaneously producing green energy as an additional bonus. In recent years, CW-MFC technology has gained attention due to its sustainability and promising prospects for a circular waste-free industry. However, due to various technological and biological challenges, it has not yet achieved wide-scale application. This review examines the current state of CW-MFC technology and identifies both biotic and abiotic strategies for optimization through operational and structural improvements affecting biocomponents. Our review highlights several key findings: (1) Plants play an important role in reducing the system's inner resistance through mechanisms such as radial oxygen loss, evapotranspiration, and high photosynthetic flow, which facilitate electroactive bacteria and affect redox potential. (2) Plant characteristics such as root porosity, phloem and aerenchyma development, chlorophyll content, and plant biomass are key indicators of CW-MFC performance and significantly impact both pollutant removal and energy harvesting. (3) We expand the criteria for selecting suitable plants to include mesophytes and C3 pollutant-tolerant species, in addition to traditional aquatic and C4 plants. Additionally, the review presents several technical approaches that enhance CW-MFC efficiency: (1) design optimization, (2) use of novel materials, and (3) application of external electrical fields, aeration, light, and temperature adjustments. CW-MFCs are capable of nearly complete elimination of a wide range of contaminants, including organic matter (84 % ± 10), total nitrogen (80 % ± 7) and phosphorus (79 % ± 18) compounds, metals (86 % ± 10), pharmaceuticals (87 % ± 7), dyes (90 % ± 8), and other complex pollutants, while generating green energy. We hope our findings will be useful in optimizing CW-MFC design and providing insights for researchers aiming to advance the technology and facilitate its future scaling., 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.)

Deoxynivalenol (DON) is a mycotoxin frequently observed in cereals and cereal-based foods, with reported toxicological effects including reduced body weight, immunotoxicity and reproductive defects. The European Food Safety Authority used traditional risk assessment approaches to derive a deterministic Tolerable Daily Intake (TDI) of 1 μg/kg-day, however data from human biomarkers studies indicate widespread and variable exposure worldwide, necessitating more sophisticated and advanced methods to quantify population risk. The World Health Organization/International Programme on Chemical Safety (WHO/IPCS) has previously used DON as a case example in replacing the TDI with a probabilistic toxicity value, using default uncertainty and variability distributions to derive the Human Dose corresponding to an effect size M in the I th percentile of the population (HD M ) for M = 5 % decrease in body weight and I = 1 %. In this study, we extend this case study by incorporating (1) Bayesian modeling approaches, (2) using both in vivo data and in vitro population new approach methods to replace default distributions for interspecies toxicokinetic (TK) differences and intraspecies TK and toxicodynamic (TD) variability, and (3) integrating biomonitoring data and probabilistic dose-response functions to characterize population risk distributions. We first derive an HD I ) for M = 5 % decrease in body weight and I = 1 %. In this study, we extend this case study by incorporating (1) Bayesian modeling approaches, (2) using both in vivo data and in vitro population new approach methods to replace default distributions for interspecies toxicokinetic (TK) differences and intraspecies TK and toxicodynamic (TD) variability, and (3) integrating biomonitoring data and probabilistic dose-response functions to characterize population risk distributions. We first derive an HD M I of 5.5 [1.4-24] μg/kg-day, also using TK modeling to converted the HD M I to Biomonitoring Equivalents, BE M I for comparison with biomonitoring data, with a blood BE M I of 0.53 [0.17-1.6] μg/L and a urinary excretion BE M I of 3.9 [1.0-16] μg/kg-day. We then illustrate how this integrative approach can advance quantitative risk characterization using two human biomonitoring datasets, estimating both the fraction of population with an effect size M ≥ 5 % as well as the distribution of effect sizes. Overall, we demonstrate that integration of Bayesian modeling, human biomonitoring data, and in vitro population-based TD data within the WHO/IPCS probabilistic framework yields more accurate, precise, and comprehensive risk characterization., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Weihsueh Chiu reports financial support was provided by National Institute of Environmental Health Sciences. Ivan Rusyn reports financial support was provided by National Institute of Environmental Health Sciences. Weihsueh Chiu reports financial support was provided by United States Environmental Protection Agency. Ivan Rusyn reports financial support was provided by United States Environmental Protection Agency. Marthe De Boevre reports financial support was provided by European Union. Weihsueh Chiu reports a relationship with Dreamtech Co Ltd that includes: consulting or advisory. The NIH Awards R41TR002567 and R42ES032642 were granted to DREAM Tech, LLC to develop and commercialize the BBMD modeling system. W.A.C. is affiliated with DREAM Tech, LLC, and may benefit from the success of the BBMD system. Other 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 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is characterized by the excessive accumulation of lipid species in hepatocytes. Recent studies have indicated that in addition to the total lipid quantities, changes in lipid composition are a determining factor in hepatic lipotoxicity. Using ultra-high performance liquid chromatography coupled with electrospray tandem mass spectrometry, we analyzed the esterified fatty acid composition in 24 strains of male and female Collaborative Cross (CC) mice fed a high fat/high sucrose (HF/HS) diet for 12 weeks. Changes in lipid composition were found in all strains after the HF/HS diet, most notably characterized by increases in monounsaturated fatty acids (MUFA) and decreases in polyunsaturated fatty acids (PUFA). Similar changes in MUFA and PUFA were observed in a choline- and folate-deficient (CFD) mouse model of NAFLD, as well as in hepatocytes treated in vitro with free fatty acids. Analysis of fatty acid composition revealed that alterations were accompanied by an increase in the estimated activity of MUFA generating SCD1 enzyme and an estimated decrease in the activity of PUFA generating FADS1 and FADS2 enzymes. PUFA/MUFA ratios were inversely correlated with lipid accumulation in male and female CC mice fed the HF/HS diet and with morphological markers of hepatic injury in CFD diet-fed mouse model of NAFLD. These results demonstrate that different models of NAFLD are characterized by similar changes in the esterified fatty acid composition and that alterations in PUFA/MUFA ratios may serve as a diagnostic marker for NAFLD severity., (Copyright © 2022. Published by Elsevier Inc.)

Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers. The rising incidence of HCC worldwide and its resistance to pharmacotherapy indicate that the prevention of HCC development may be the most impactful strategy to improve HCC-related morbidity and mortality. Among the broad range of chemopreventive agents, the use of dietary and nutritional agents is an attractive and promising approach; however, a better understanding of the mechanisms of their potential cancer suppressive action is needed to justify their use. In the present study, we investigated the underlying molecular pathways associated with the previously observed suppressive effect of butyrate-containing structured lipids (STLs) against liver carcinogenesis using a rat "resistant hepatocyte" model of hepatocarcinogenesis that resembles the development of HCC in humans. Using whole transcriptome analysis, we demonstrate that the HCC suppressive effect of butyrate-containing STLs is associated with the inhibition of the cell migration, cytoskeleton organization, and epithelial-to-mesenchymal transition (EMT), mediated by the reduced levels of RACGAP1 and RAC1 proteins. Mechanistically, the inhibition of the Racgap1 and Rac1 oncogenes is associated with cytosine DNA and histone H3K27 promoter methylation. Inhibition of the RACGAP1/RAC1 oncogenic signaling pathways and EMT may be a valuable approach for liver cancer prevention., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In the United States, onshore oil and gas extraction operations generate an estimated 900 billion gallons of produced water annually, making it the largest waste stream associated with upstream development of petroleum hydrocarbons. Management and disposal practices of produced water vary from deep well injection to reuse of produced water in agricultural settings. However, there is relatively little information with regard to the chemical or toxicological characteristics of produced water. A comprehensive literature review was performed, screening nearly 16,000 published articles, and identifying 129 papers that included data on chemicals detected in produced water. Searches for information on the potential ecotoxicological or mammalian toxicity of these chemicals revealed that the majority (56%) of these compounds have not been a subject of safety evaluation or mechanistic toxicology studies and 86% lack data to be used to complete a risk assessment, which underscores the lack of toxicological information for the majority of chemical constituents in produced water. The objective of this study was to develop a framework to identify potential constituents of concern in produced water, based on available and predicted toxicological hazard data, to prioritize these chemicals for monitoring, treatment, and research. In order to integrate available evidence to address gaps in toxicological hazard on the chemicals in produced water, we have catalogued available information from ecological toxicity studies, toxicity screening databases, and predicted toxicity values. A Toxicological Priority Index (ToxPi) approach was applied to integrate these various data sources. This research will inform stakeholders and decision-makers on the potential hazards in produced water. In addition, this work presents a method to prioritize compounds that, based on hazard and potential exposure, may be considered during various produced water reuse strategies to reduce possible human health risks and environmental impacts., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Population-based human in vitro models offer exceptional opportunities for evaluating the potential hazard and mode of action of chemicals, as well as variability in responses to toxic insults among individuals. This study was designed to test the hypothesis that comparative population genomics with efficient in vitro experimental design can be used for evaluation of the potential for hazard, mode of action, and the extent of population variability in responses to chemical mixtures. We selected 146 lymphoblast cell lines from 4 ancestrally and geographically diverse human populations based on the availability of genome sequence and basal RNA-seq data. Cells were exposed to two pesticide mixtures - an environmental surface water sample comprised primarily of organochlorine pesticides and a laboratory-prepared mixture of 36 currently used pesticides - in concentration response and evaluated for cytotoxicity. On average, the two mixtures exhibited a similar range of in vitro cytotoxicity and showed considerable inter-individual variability across screened cell lines. However, when in vitro-to-in vivo extrapolation (IVIVE) coupled with reverse dosimetry was employed to convert the in vitro cytotoxic concentrations to oral equivalent doses and compared to the upper bound of predicted human exposure, we found that a nominally more cytotoxic chlorinated pesticide mixture is expected to have greater margin of safety (more than 5 orders of magnitude) as compared to the current use pesticide mixture (less than 2 orders of magnitude) due primarily to differences in exposure predictions. Multivariate genome-wide association mapping revealed an association between the toxicity of current use pesticide mixture and a polymorphism in rs1947825 in C17orf54. We conclude that a combination of in vitro human population-based cytotoxicity screening followed by dosimetric adjustment and comparative population genomics analyses enables quantitative evaluation of human health hazard from complex environmental mixtures. Additionally, such an approach yields testable hypotheses regarding potential toxicity mechanisms., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Reactive oxygen species are thought to be crucial for peroxisome proliferator-induced liver carcinogenesis. Free radicals have been shown to mediate the production of mitogenic cytokines by Kupffer cells and cause DNA damage in rodent liver. Previous in vivo experiments demonstrated that acute administration of the peroxisome proliferator di(2-ethylhexyl) phthalate (DEHP) led to an increase in production of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts in liver, an event that was dependent on Kupffer cell NADPH oxidase, but not peroxisome proliferator-activated receptor (PPAR)alpha. Here, we hypothesized that continuous treatment with peroxisome proliferators will cause a sustained formation in POBN radical adducts in liver. Mice were fed diets containing either 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14,643, 0.05% w/w) or DEHP (0.6% w/w) for up to 3 weeks. Liver-derived radical production was assessed in bile samples by measuring POBN radical adducts using electron spin resonance. Our data indicate that WY-14,643 causes a sustained increase in POBN radical adducts in mouse liver and that this effect is greater than that of DEHP. To understand the molecular source of these radical species, NADPH oxidase-deficient (p47phox-null) and PPARalpha-null mice were examined after treatment with WY-14,643. No increase in radicals was observed in PPARalpha-null mice that were treated with WY-14,643 for 3 weeks, while the response in p47phox-nulls was similar to that of wild-type mice. These results show that PPARalpha, not NADPH oxidase, is critical for a sustained increase in POBN radical production caused by peroxisome proliferators in rodent liver. Therefore, peroxisome proliferator-induced POBN radical production in Kupffer cells may be limited to an acute response to these compounds in mouse liver.

The swift increase in alcohol metabolism (SIAM) is a phenomenon defined as a rapid increase in hepatic respiration and alcohol metabolism after administration of a bolus dose of alcohol. Continuous exposure to alcohol is known to produce adaptive changes in liver alcohol and oxygen metabolism. A considerable burst of hepatic respiration can also occur after administration of a single large dose of alcohol and results in a near doubling of alcohol metabolism, a high demand for oxygen, and downstream or pericentral hypoxia. These dramatic changes in rates of alcohol metabolism and tissue concentrations of oxygen are not due to induced enzyme activity in liver. This phenomenon depends on activation of mitochondrial function, an increase in co-factor supply for nicotinamide adenine dinucleotide-dependent alcohol metabolism, depletion of glycogen reserves, liberation of fatty acids through activation of an adrenergic response to alcohol providing substrate for catalase, and activation of Kupffer cells, the hepatic resident macrophages responsible for production of cytokines and prostaglandins. An understanding of the mechanisms of hypermetabolism in liver can have vital ramifications for knowledge of both alcohol-related and alcohol-unrelated liver injury because hypoxia that is a result of hypermetabolism can compound effects of pharmaceuticals and environmental agents on the liver. Swift increase in alcohol metabolism is an excellent example of the complexity of cell-cell interactions in liver and extrahepatic regulation of biochemical and molecular events in this organ, and this important phenomenon shall be considered in studies of liver disease and biochemistry.

Considerable evidence for a role of Kupffer cells in alcoholic liver disease has accumulated and they have recently been shown to be a predominant source of free radicals. Several approaches including pharmacological agents, knockout mice, and viral gene transfer have been used to fill critical gaps in understanding key mechanisms by which Kupffer cell activation, oxidant formation, and cytokine production lead to liver damage and subsequent pathogenesis. This review highlights new data in support of the hypothesis that Kupffer cells play a pivotal role in hepatotoxicity due to ethanol by producing oxidants via NADPH oxidase.

Oxidants have been shown to be involved in alcohol-induced liver injury. Moreover, 2-phenyl-1,2-benzisoselenazole-3(2H)-one (ebselen), an organoselenium compound and glutathione peroxidase mimic, decreases oxidative stress and protects against stroke clinically. This study was designed to test the hypothesis that ebselen protects against early alcohol-induced liver injury in rats. Male Wistar rats were fed high-fat liquid diets with or without ethanol (10-16 g/kg/d) continuously for up to 4 weeks using the intragastric enteral feeding protocol developed by Tsukamoto and French. Ebselen (50 mg/kg twice daily, intragastrically) or vehicle (1% tylose) was administered throughout the experiment. Mean urine ethanol concentrations were not significantly different between treatment groups, and ebselen did not affect body weight gains or cyclic patterns of ethanol concentrations in urine. After 4 weeks, serum ALT levels were increased significantly about 4-fold over control values (37 +/- 5 IU/l) by enteral ethanol (112 +/- 7 IU/l); ebselen blunted this increase significantly (61 +/- 8 IU/l). Enteral ethanol also caused severe fatty accumulation, mild inflammation, and necrosis in the liver (pathology score: 4.3 +/- 0.3). In contrast, these pathological changes were blunted significantly by ebselen (pathology score: 2.5 +/- 0.4). While there were no significant effects of either ethanol or ebselen on glutathione peroxidase activity in serum or liver tissue, ebselen blocked the increase in serum nitrate/nitrite caused by ethanol. Furthermore, ethanol increased the activity of NF-kappaB over 5-fold, the number of infiltrating neutrophils 4-fold, and the accumulation of 4-hydroxynonenal over 5-fold. Ebselen blunted all of these effects significantly. These results indicate that ebselen prevents early alcohol-induced liver injury, most likely by preventing oxidative stress, which decreases inflammation.