Acute liver injury (ALI) has a clear requirement for novel therapies. One emerging option is the use of alternatively activated macrophages (AAMs); a distinct subtype of macrophage with a role in liver injury control and repair. In this comprehensive review, we provide an overview of the current limited options for ALI, and the potential advantages offered by AAMs. We describe the evidence supporting their use from in vitro studies, pre-clinical animal studies, and human clinical trials. We suggest why the first evidence for the clinical use of AAMs is likely to be found in acetaminophen toxicity, and discuss the specific evidence for AAM use in this population, as well as potential applications for AAMs in other patient populations. The key domains by which the performance of AAMs for the treatment of ALI will be assessed are identified, and remaining challenges to the successful delivery of AAMs to clinic are explored.

Indium compounds are used in manufacturing displays of mobile phones and televisions. These compounds cause interstitial pneumonia in workers and lung cancer in animals, but their precise mechanisms are unclear. In this study, we performed microarray analysis of gene expression in lung tissues of indium-exposed rats. Male Wistar rats (8-week-old) were exposed to indium oxide (InO, mean particle diameter 0.14 μm) and indium-tin oxide (ITO, mean particle diameter 0.95 μm) by intratracheal instillation (10 mg indium/kg body weight/instillation) twice a week and five times in total. These rats were sacrificed immediately, 3 weeks and 12 weeks after the last instillation. Hematoxylin and eosin and Masson's trichrome staining showed that indium compounds induced infiltration of neutrophils and macrophages into alveolar space, and fibrosis around bronchial epithelium and in alveolar wall. Microarray analysis revealed that InO and ITO significantly upregulated 233 and 676 genes at 12 weeks, respectively (> twofold, p < 0.05 by ANOVA + Tukey's test). InO and ITO largely upregulated Lcn2 (lipocalin-2) (49.4- and 91.8-fold), S100a9 (30.2- and 46.5-fold) and S100a8 (11.5- and 22.0-fold), respectively. Metascape database predicted that these genes participate in immunomodulatory and inflammatory responses. Real-time PCR confirmed that these genes were upregulated by indium compounds throughout the experiments. In Western blotting, S100A9 expression was significantly increased by indium exposure, whereas LCN2 expression was only slightly increased. Fluorescent immunohistochemistry revealed that S100A9 and S100A8 were expressed in alveolar epithelial cells and neutrophils in indium-exposed rats. These results suggest that S100 proteins contribute to indium-induced lung diseases via neutrophil-mediated inflammatory responses.

Polycyclic aromatic hydrocarbons (PAHs) represent one of the most extensive classes of known carcinogenic and genotoxic compounds widely distributed across the globe. Particularly relevant to ecotoxicological studies is the possible presence of PAHs with molecular weight (MW) 302 Da. Since the toxicity of 302 Da PAHs differs significantly from isomer to isomer, understanding their relative toxicity is essential for assessing their potential risks to human health. This study investigates the toxic effects of micromolar concentrations of four HMW-PAHs isomers of MW = 302 Da, namely dibenzo(b,l)fluoranthene (DB(b,l)F), dibenzo(a,j)fluoranthene (DB(a,j)F), dibenzo(a,l)fluoranthene (DB(a,l)F) and naphtho(1-2j)fluoranthene (N(1-2j)F), upon exposure and metabolic activation in HepG2 cells. Appropriate assays were selected to investigate their potential to disrupt cellular viability and to induce cytotoxicity, apoptosis/necrosis, genotoxicity, and oxidative stress with DNA damage. After 48 h of exposure time, DB(a,l)F was the only isomer to reduce cellular viability in a concentration-dependent manner. In all cases, apoptosis was the main mechanism of HepG2 cell death, which could be induced by the significant DNA damage and an increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG) adduct level formation. The highest concentrations of DB(a,l)F tested exhibited the greatest potential to induce HepG2 DNA damage and 8-OHdG formation. Altogether, these facts demonstrate that the distinct arrangements of the atoms in HMW-PAHs isomers can impact on their toxic potential and that DB(a,l)F was the most toxic isomer evaluated in this study. These results shed light on the importance to thoroughly characterize MW302 PAHs to substantiate their human and environmental risk assessments.

While antineoplastic therapies aim to specifically target cancer cells, they may also exert adverse effects on healthy tissues, like healthy hematopoietic stem and progenitor cells (HSPC), leading to hematotoxicity as a common side effect. Mesenchymal stromal cells (MSC) are a major component of the bone marrow (BM) microenvironment, regulating normal hematopoiesis, while their susceptibility to anticancer therapies and contribution to therapy-related hematotoxicity remains largely unexplored. To address this, we investigated the effects of etoposide, temozolomide, 5-azacitidine, and venetoclax on healthy BM-derived MSC functionality. Doses below therapeutic effects of etoposide (0.1-0.25 µM) inhibited cellular growth and induced cellular senescence in healthy MSC, accompanied by an increased mRNA expression of CDKN1A, decreased trilineage differentiation capacity, and insufficient hematopoietic support. Pharmacological doses of 5-azacitidine (2.5 µM) shifted MSC differentiation capacity by inhibiting osteogenic capacity but enhancing the chondrogenic lineage, as demonstrated by histochemical staining and on mRNA level. At the highest clinically relevant dose, neither venetoclax (40 nM) nor temozolomide (100 µM) exerted any effects on MSC but clearly inhibited cellular growth of cancer cell lines and primary healthy HSPC, pointing to damage to hematopoietic cells as a major driver of hematotoxicity of these two compounds. Our findings show that besides HSPC, also MSC are sensitive to certain antineoplastic agents, resulting in molecular and functional alterations that may contribute to therapy-related myelosuppression. Understanding these interactions could be helpful for the development of strategies to preserve BM MSC functionality during different kinds of anticancer therapies.

Polybrominated diphenyl ethers (PBDEs) are endocrine-disrupting persistent organic pollutants (POPs) used as flame retardants in a wide range of commercial applications. We have previously reported neurobehavioral and metabolic reprogramming produced by developmental PBDEs. PBDEs perturb the microbiome, an influencer of life-long health, while probiotic supplementation with Limosilactobacillus reuteri (LR) can avert neurobehavioral and endocrine disruption. We, therefore, tested the hypothesis that perinatal maternal LR supplementation would protect gut microbiome richness and diversity, developmental milestones, adult neurobehavior and metabolic homeostasis in PBDE-exposed offspring. C57BL/6N dams were orally exposed to a commercial penta-mixture of PBDEs, DE-71, at 0.1 mg/kg/day, or corn oil vehicle (VEH/CON) during gestation and lactation. Mice offspring received DE-71 or VEH/CON with or without co-administration of LR (ATCC-PTA-6475) indirectly via their mother from gestational day (GD) 0 until postnatal day (P)21 (Cohort 1), or continued to receive LR directly from P22 through adulthood (Cohort 2). Results of fecal 16S rRNA sequencing indicated age- and sex-dependent effects of DE-71 on gut microbial communities. Maternal LR treatment protected against DE-71-induced reduction in α-diversity in P22 females and against β-diversity alterations in P30 males. In females, DE-71 changed the relative abundance of specific bacterial taxa, such as Tenericutes and Cyanobacteria (elevated) and Deferribacterota (reduced). In males, several Firmicutes taxa were elevated, while Proteobacteria, Chlamydiae, and several Bacteroidota taxa were reduced. The number of disrupted taxa normalized by maternal LR supplementation was as follows: 100% in P22 females and 33% in males at P22 and 25% at P30. Maternal LR treatment protected against DE-71-induced delay of postnatal body weight gain in males and ameliorated the abnormal timing of incisor eruption in both sexes. Further, DE-71 produced exaggerated digging in both sexes as well as locomotor hyperactivity in females, effects that were mitigated by maternal LR only in females. Other benefits of LR therapy included normalization of glucose tolerance, insulin-to-glucose ratio and plasma leptin in adult DE-71 females (Cohort 2). This study provides evidence that probiotic supplementation can mitigate POP-induced reprogramming of neurodevelopment, adult neurobehavior, and glucose metabolism in association with modified gut microbial community structure in a sex-dependent manner.

Concentration-dependent cytotoxicity experiments are frequently used in toxicology. Although it has been reported that an adequate choice of concentrations improves the quality of the statistical inference substantially, a recent literature review of three major toxicological journals has shown that the corresponding methods are rarely used in toxicological practice. In this study the performance of different sets of concentrations, also called designs, are analyzed, while the overall goal is to promote the advantages of optimal design procedures and to present a user-friendly guideline for planning new cytotoxicity concentration-response experiments. We compare the frequently used log-equidistant design to a Bayesian design, which is constructed by methods of optimum design theory. Using both a dense data set of concentration-cytotoxicity data of valproic acid (VPA) and regular assay data of 104 substances, the performance of the different designs is analyzed in two scenarios, where detailed previous knowledge on VPA is available or not. The results show that it is critical to apply a specific design strategy to determine optimal concentrations for cytotoxicity testing. In particular, the Bayesian design technique with and without incorporating pre-existing knowledge of a specific test substance resulted in a more precise statistical inference than the other used designs. Finally, we present a guideline for upcoming experiments and an accessible user-friendly Shiny app (see http://shiny.statistik.tu-dortmund.de:8080/app/occe ).

Drug-induced cholestasis (DIC) is recognized as a major safety concern in drug development, as it represents one of the three types of drug-induced liver injury (DILI). Cholestasis is characterized by the disruption of bile flow, leading to intrahepatic accumulation of toxic bile acids. Bile acid regulation is a multifarious process, orchestrated by several hepatic mechanisms, namely sinusoidal uptake and efflux, canalicular secretion and intracellular metabolism. In the present study, we developed a prediction model of DIC using in vitro inhibition data for 47 marketed drugs on nine transporters and five enzymes known to regulate bile acid homeostasis. The resulting model was able to distinguish between drugs with or without DILI concern (p-value = 0.039) and demonstrated a satisfactory predictive performance, with the area under the precision-recall curve (PR AUC) measured at 0.91. Furthermore, we simplified the model considering only two processes, namely reversible inhibition of OATP1B1 and time-dependent inhibition of CYP3A4, which provided an enhanced performance (PR AUC = 0.95). Our study supports literature findings suggesting a contribution not only from a single process inhibition, but a rather synergistic effect of the key bile acid clearance processes in the development of cholestasis. The use of a quantitative model in the preclinical investigations of DIC is expected to reduce attrition rate in advanced development programs and guide the discovery and development of safe medicines.

Heavy metals are naturally occurring components of the Earth's crust and persistent environmental pollutants. Human exposure to heavy metals occurs via various pathways, including inhalation of air/dust particles, ingesting contaminated water or soil, or through the food chain. Their bioaccumulation may lead to diverse toxic effects affecting different body tissues and organ systems. The toxicity of heavy metals depends on the properties of the given metal, dose, route, duration of exposure (acute or chronic), and  extent of bioaccumulation. The detrimental impacts of heavy metals on human health are largely linked to their capacity to interfere with antioxidant defense mechanisms, primarily through their interaction with intracellular glutathione (GSH) or sulfhydryl groups (R-SH) of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and other enzyme systems. Although arsenic (As) is believed to bind directly to critical thiols, alternative hydrogen peroxide production processes have also been postulated. Heavy metals are known to interfere with signaling pathways and affect a variety of cellular processes, including cell growth, proliferation, survival, metabolism, and apoptosis. For example, cadmium can affect the BLC-2 family of proteins involved in mitochondrial death via the overexpression of antiapoptotic Bcl-2 and the suppression of proapoptotic (BAX, BAK) mechanisms, thus increasing the resistance of various cells to undergo malignant transformation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of antioxidant enzymes, the level of oxidative stress, and cellular resistance to oxidants and has been shown to act as a double-edged sword in response to arsenic-induced oxidative stress. Another mechanism of significant health threats and heavy metal (e.g., Pb) toxicity involves the substitution of essential metals (e.g., calcium (Ca), copper (Cu), and iron (Fe)) with structurally similar heavy metals (e.g., cadmium (Cd) and lead (Pb)) in the metal-binding sites of proteins. Displaced essential redox metals (copper, iron, manganese) from their natural metal-binding sites can catalyze the decomposition of hydrogen peroxide via the Fenton reaction and generate damaging ROS such as hydroxyl radicals, causing damage to lipids, proteins, and DNA. Conversely, some heavy metals, such as cadmium, can suppress the synthesis of nitric oxide radical (NO), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced oxidative stress has been shown to be indirectly responsible for the depletion of nitric oxide due to its interaction with superoxide radical (O), resulting in the formation of a potent biological oxidant, peroxynitrite (ONOO). This review comprehensively discusses the mechanisms of heavy metal toxicity and their health effects. Aluminum (Al), cadmium (Cd), arsenic (As), mercury (Hg), lead (Pb), and chromium (Cr) and their roles in the development of gastrointestinal, pulmonary, kidney, reproductive, neurodegenerative (Alzheimer's and Parkinson's diseases), cardiovascular, and cancer (e.g. renal, lung, skin, stomach) diseases are discussed. A short account is devoted to the detoxification of heavy metals by chelation via the use of ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propane sulfonic acid (DMPS), and penicillamine chelators.

Sepsis is a life-threatening form of organ dysfunction resulting from a dysregulated response to infection. The complex pathogenesis of sepsis poses challenges because of the lack of reliable biomarkers for early identification and effective treatments. As sepsis progresses to severe forms, cardiac dysfunction becomes a major concern, often manifesting as ventricular dilation, a reduced ejection fraction, and a diminished contractile capacity, known as sepsis-induced cardiomyopathy (SIC). The absence of standardized diagnostic and treatment protocols for SIC leads to varied criteria being used across medical institutions and studies, resulting in significant outcome disparities. Despite the high prevalence of SIC, accurate statistical data are lacking. To understand how SIC affects sepsis prognosis, a thorough exploration of its pathophysiological mechanisms, including systemic factors and complex signalling within myocardial and immune cells, is required. Identifying the factors influencing SIC occurrence and progression is crucial and must be conducted within specific clinical contexts. In this review, the clinical manifestations, pathophysiological mechanisms, and treatment strategies for SIC are discussed, along with the clinical background. We aim to connect current practices with future research challenges, providing clear guidance for clinicians and researchers.

Carbon black is a key component of air-borne particulate matter, linked to adverse health outcomes, such as increased susceptibility to respiratory infections and chronic pulmonary disease exacerbations. Fine and ultrafine particles can penetrate the lungs, enter the bloodstream, and induce pathogenetic events. Macrophages play a crucial role in responding to inhaled particles, including carbon black, by initiating an innate immune response and upregulating pro-inflammatory cytokines and anti-oxidative enzymes. This study investigates the effects of carbon black particles on human monocyte-derived macrophages in vitro at a concentration of 10 µg/ml, offering insights into their potential role in disease pathogenesis. We have compared two commercially available carbon black particle types using various physicochemical techniques and assessed their biological effects on monocyte-derived macrophages. We have evaluated changes in cell viability, morphology, and particle uptake/phagocytosis. Western blot, ELISA, and RT-qPCR measured inflammatory and oxidative stress biomarkers. Both types of carbon black particles induced similar responses in macrophages, including particle uptake, cytokine production, and oxidative stress-related protein expression. The observed changes suggest activation of the Nrf2-mediated antioxidant response, impaired autophagy, and decreased cellular defense against oxidative stress, indicating potential pathways for chronic inflammatory lung disease development.

Drug toxicity is an important cause of chronic liver damage, which in the long term can lead to impaired bone homeostasis through an imbalance in the liver-bone axis. For instance, non-steroidal anti-inflammatory drugs (e.g., diclofenac), which are commonly used to control pain during orthopaedic interventions, are known to reduce bone quality and are the most prevalent causes of drug-induced liver damage. Therefore, we used human cell lines to produce a stable, reproducible, and reliable in vitro liver-bone co-culture model, which mimics the impaired bone homeostasis seen after diclofenac intake in vivo. To provide the best cell culture conditions for the two systems, we tested the effects of supplements contained in liver and bone cell culture medium on liver and bone cell lines, respectively. Additionally, different ratios of culture medium combinations on bone cell scaffolds and liver spheroids' viability and function were also analysed. Then, liver spheroids and bone scaffolds were daily exposed to 3-6 µM diclofenac alone or in co-culture to compare and evaluate its effect on the liver and bone system. Our results demonstrated that a 50:50 liver:bone medium combination maintains the function of liver spheroids and bone scaffolds for up to 21 days. Osteoclast-like cell activity was significantly upregulated after chronic exposure to diclofenac only in bone scaffolds co-cultured with liver spheroids. Consequently, the mineral content and stiffness of bone scaffolds treated with diclofenac in co-culture with liver spheroids were significantly reduced. Interestingly, our results show that the increase in osteoclastic activity in the system is not related to the main product of diclofenac metabolism. However, osteoclast activation correlated with the increase in oxidative stress and inflammation associated with chronic diclofenac exposure. In summary, we established a long-term stable liver-bone system that represents the interaction between the two organs, meanwhile, it is also an outstanding model for studying the toxicity of drugs on bone homeostasis.

Zinc is an essential micronutrient that participates in a multitude of cellular and biochemical processes. It is indispensable for normal growth and the maintenance of physiological functions. As one of the most significant trace elements in the body, zinc fulfills three primary biological roles: catalytic, structural, and regulatory. It serves as a cofactor in over 300 enzymes, and more than 3000 proteins require zinc, underscoring its crucial role in numerous physiological processes such as cell division and growth, immune function, tissue maintenance, as well as synthesis protein and collagen synthesis. Zinc deficiency has been linked to increased oxidative stress and inflammation, which may contribute to the pathogenesis of a multitude of diseases, like neurological disorders and cancer. In addition, zinc is a key constituent of zinc-binding proteins, which play a pivotal role in maintaining cellular zinc homeostasis. This review aims to update and expand upon the understanding of zinc biology, highlighting the fundamental roles of zinc in biological processes and the health implications of zinc deficiency. This work also explores the diverse functions of zinc in immune regulation, cellular growth, and neurological health, emphasizing the need for further research to fully elucidate the therapeutic potential of zinc supplementation in disease prevention and management.

UV-P (2-(2H-Benzotriazol-2-yl)-p-cresol) is used as an ultraviolet (UV) light absorber in coating products, paints, adhesives, and sealants. Due to its widespread industrial and consumer uses, human exposure to UV-P is conceivable. In the study presented herein, initial data on its human in vivo metabolism were obtained for three study participants after single oral administration of 0.3 mg of UV-P/kg body weight. Urine and blood samples of two volunteers were collected up to 48 h after exposure. The third study participant donated urine and blood samples up to 72 h. Maximum levels of UV-P in blood of 184 ± 36 µg/l (85 ± 3% as conjugates) were reached 2.4 ± 1.2 h post-exposure. Maximum excretion rates of UV-P in urine of 2896 ± 884 µg/h (completely conjugated) were reached 3.5 ± 1.1 h post-exposure. 37.2 ± 5.4% of the orally administered dose of UV-P was recovered in urine within 48 h post-exposure. The present study provides insight into the complex absorption, distribution, metabolism, and elimination (ADME) processes of benzotriazole UV stabilizers (BUVS). The study also demonstrates differences in the ADME between sterically hindered BUVS, such as UV-327 and UV-328, and sterically unhindered BUVS, such as UV-P, in which the phenolic hydroxyl group is readily accessible for conjugation with glucuronic acid or sulfate.

In 2022, para-fluorofentanyl (pFF) rose to the 6th most reported drug and the most reported fentanyl analog in the United States according to the Drug Enforcement Administration (DEA). pFF differs from fentanyl by the addition of a single fluorine group. To date, pFF has not been extensively evaluated in vivo and is frequently seen in combination with fentanyl. In the present study, the pharmacodynamic (PD) and pharmacokinetic (PK) properties and brain region-specific concentrations of pFF were evaluated in male Sprague-Dawley rats and compared to fentanyl. A 300 μg/kg subcutaneous dose of fentanyl or pFF was administered to assess PD and PK parameters as well as brain region concentrations. PD parameters were evaluated via a tail flick test to evaluate analgesia and core body temperature to measure hypothermia, a surrogate marker of overall opioid toxicity. Fentanyl and pFF were found to be equally active at the tested dose in terms of tail flick response with both compounds producing an analgesic response that lasted up to 240 min post-drug treatment. pFF induced a significantly greater hypothermic effect compared to fentanyl with a maximum temperature decrease of -5.6 ℃. Plasma PK parameters (T, AUC, etc.) did not differ between fentanyl and pFF. However, pFF concentrations in the medulla, hippocampus, frontal cortex and striatum were more than two times the fentanyl concentrations. The increase in brain concentrations and greater hypothermic effect suggests that pFF is potentially more dangerous than fentanyl.

Multi-omics data integration has been repeatedly discussed as the way forward to more comprehensively cover the molecular responses of cells or organisms to chemical exposure in systems toxicology and regulatory risk assessment. In Canzler et al. (Arch Toxicol 94(2):371-388. https://doi.org/10.1007/s00204-020-02656-y ), we reviewed the state of the art in applying multi-omics approaches in toxicological research and chemical risk assessment. We developed best practices for the experimental design of multi-omics studies, omics data acquisition, and subsequent omics data integration. We found that multi-omics data sets for toxicological research questions were generally rare, with no data sets comprising more than two omics layers adhering to these best practices. Due to these limitations, we could not fully assess the benefits of different data integration approaches or quantitatively evaluate the contribution of various omics layers for toxicological research questions. Here, we report on a multi-omics study on thyroid toxicity that we conducted in compliance with these best practices. We induced direct and indirect thyroid toxicity through Propylthiouracil (PTU) and Phenytoin, respectively, in a 28-day plus 14-day recovery oral rat toxicity study. We collected clinical and histopathological data and six omics layers, including the long and short transcriptome, proteome, phosphoproteome, and metabolome from plasma, thyroid, and liver. We demonstrate that the multi-omics approach is superior to single-omics in detecting responses at the regulatory pathway level. We also show how combining omics data with clinical and histopathological parameters facilitates the interpretation of the data. Furthermore, we illustrate how multi-omics integration can hint at the involvement of non-coding RNAs in post-transcriptional regulation. Also, we show that multi-omics facilitates grouping, and we assess how much information individual and combinations of omics layers contribute to this approach.

The flow of potassium ions through cell membranes plays a crucial role in facilitating various cell processes such as hormone secretion, epithelial function, maintenance of electrochemical gradients, and electrical impulse formation. Potassium ion inhibitors are considered promising alternatives in treating cancer, muscle weakness, renal dysfunction, endocrine disorders, impaired cellular function, and cardiac arrhythmia. Thus, it becomes essential to identify and understand potassium ion inhibitors in order to regulate the ion flow across ion channels. In this study, we created a meta-model, POSSUM, for the identification of potassium ion inhibitors. Two distinct datasets were used for training, testing, and evaluation of the meta-model. We employed seven feature descriptors and five distinctive classifiers to construct 35 baseline models. We used the mean Gini index score to select the optimal base models and classifiers. The POSSUM method was trained on the optimal probabilistic feature vectors. The proposed optimal model, POSSUM, outperforms the baseline models and the existing methods on both datasets. We anticipate POSSUM will be a very useful tool and will be essential in the process of finding and screening possible potassium ion inhibitors.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

DNA damage is one of the primary mechanisms underlying cancer and other chronic degenerative diseases. Early evaluation of this damage in the affected cells and tissues is crucial for understanding pathogenesis and implementing effective prevention strategies. However, isolating target cells from affected organs, such as the lungs, can be challenging. Therefore, an alternative approach is to evaluate genotoxic damage in surrogate cells. Pulmonary alveolar macrophages are ideally suited for this purpose because they are in close contact with the target cells of the bronchial and alveolar epithelium, share the exact mechanisms and levels of exposure, and are easily recoverable in large numbers. This review comprehensively lists all studies using alveolar macrophages as surrogate cells to show genotoxic lung damage in humans or laboratory animals. These investigations provide fundamental information on the mechanisms of DNA damage in the lung and allow for better assessment and management of risk following exposure to inhalable genotoxic agents. Furthermore, they may be a valuable tool in cancer chemoprevention, helping the right choice of agents for clinical trials.

Methylmercury (MeHg) is an environmental neurotoxin that induces damage to the central nervous system and is the causative agent in Minamata disease. The mechanisms underlying MeHg neurotoxicity remain largely unknown, and there is a need for effective therapeutic agents, such as those that target MeHg-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which is activated as a defense mechanism. We investigated whether intraperitoneal administration of the chemical chaperone, 4-phenylbutyric acid (4-PBA), at 120 mg/kg/day can alleviate neurotoxicity in the brains of mice administered 50 ppm MeHg in drinking water for 5 weeks. 4-PBA significantly reduced MeHg-induced ER stress, neuronal apoptosis, and neurological symptoms. Furthermore, 4-PBA was effective even when administered 2 weeks after the initiation of exposure to 30 ppm MeHg in drinking water. Our results strongly indicate that ER stress and the UPR are key processes involved in MeHg toxicity, and that 4-PBA is a novel therapeutic candidate for MeHg-induced neurotoxicity.

Cyclophosphamide, daunorubicin, epirubicin, doxorubicin and paclitaxel are commonly used drugs in cancer treatment. However, there are no methods available enabling simultaneous measurement of these compounds and their metabolites in human plasma. Our aim was to develop and validate a sensitive method for simultaneous quantification of multiple antineoplastic drugs and their major metabolites in plasma. Solid phase extraction with Oasis PRiME HLB cartridges was used for sample clean-up. The samples were separated on an Acquity UPLC BEH C18 column, ionised by electrospray ionisation and detected with tandem mass spectrometry. The method was validated based on selectivity, extraction efficiency, matrix effect, process efficiency, linearity, sensitivity, precision and accuracy. The established LLOQs were 0.05 ng/mL (cyclophosphamide), 30 ng/mL (4-oxo-cyclophosphamide), 0.3 ng/mL (doxorubicin, daunorubicinol), 0.7 ng/mL (epirubicin, epirubicinol, doxorubicinol), 1 ng/mL (daunorubicin and paclitaxel) and 5 ng/mL (6-alpha-hydroxypaclitaxel). Afterwards, the method was tested in a real-life, unintentional exposure setting. Twenty-two plasma samples of matched maternal and cord blood pairs from pregnant cancer patients treated with chemotherapy were analysed. This resulted in two positive samples, with cyclophosphamide concentrations up to 0.37 ng/mL. The validated method is now ready to be applied in the field.

Telmisartan is an angiotensin receptor blocker (ARB) approved by the Food and Drug Administration of the US for the treatment of hypertension. It possesses unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a 24-h sustained reduction of blood pressure. Besides well-known antihypertensive and cardioprotective effects, there is also strong clinical evidence that telmisartan confers renoprotection. Aryl hydrocarbon receptor (AhR) belongs to the steroid receptor family. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous ligand of AhR. Cytochrome P450 (CYP) 1A1 is an AhR-target gene. In this article, we demonstrated that telmisartan (2.5-60 μM) enhanced CYP1A1 promoter activity and expressions of mRNA and protein. Telmisartan-induced CYP1A1 expression was blocked by the AhR antagonist CH-223191 in liver cell lines and was negligible in the AhR signaling-deficient mutant cells. In addition, telmisartan induced transcriptional activity mediated by aryl hydrocarbon response element in both human and mouse cells, and was able to induce AhR translocation into the nucleus. Accordingly, telmisartan is an AhR agonist. It also acted synergistically with ITE to further enhance the expression of CYP1A1 mRNA and protein. This synergistic effect was more pronounced in cells with AhR overexpression compared to those without. AhR activity has strong association with the progression of chronic renal disease. Our study demonstrated that telmisartan is an AhR agonist and has synergistic effect with ITE, an indole derivative, to potentiate the effect on AhR. This finding may provide additional clues about the mechanism of the protective effect of telmisartan on the kidney.