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Mechanistic insight of neurodegeneration due to micro/nano-plastic-induced gut dysbiosis.

Despite offering significant conveniences, plastic materials contribute substantially in developing environmental hazards and pollutants. Plastic trash that has not been adequately managed may eventually break down into fragments caused by human or ecological factors. Arguably, the crucial element for determining the biological toxicities of plastics are micro/nano-forms ofplastics (MPs/NPs), which infiltrate the mammalian tissue through different mediaand routes. Infiltration of MPs/NPs across the intestinal barrier leads to microbial architectural dysfunction, which further modulates the population of gastrointestinal microbes. Thereby, it triggers inflammatory mediators (e.g., IL-1α/β, TNF-α, and IFN-γ) by activating specific receptors located in the gut barrier. Mounting evidence indicates that MPs/NPs disrupt host pathophysiological function through modification of junctional proteins and effector cells. Moreover, the alteration of microbial diversity by MPs/NPs causes the breakdown of the blood-brain barrier and translocation of metabolites (e.g., SCFAs, LPS) through the vagus nerve. Potent penetration affects the neuronal networks, neuronal protein accumulation, acceleration of oxidative stress, and alteration of neurofibrillary tangles, and hinders distinctive communicatingpathways. Conclusively, alterations of these neurotoxic factors are possibly responsible forthe associated neurodegenerative disordersdue to the exposure of MPs/NPs. In this review, the hypothesis on MPs/NPs associated with gut microbial dysbiosis has been interlinked to the distinct neurological impairment through the gut-brain axis.

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Arylacetamide deacetylase regulates hepatic iron homeostasis to protect against carbon tetrachloride-induced ferroptosis.

Arylacetamide deacetylase (AADAC) catalyzes the hydrolysis of small molecules containing ester and amide bonds. Recently, it has been reported that AADAC can suppress reactive oxygen species production in cancer cells. This study aimed to elucidate the possibility that AADAC protects against drug-induced liver injury accompanied by oxidative stress and to explore its molecular mechanisms. Intraperitoneal administration of carbon tetrachloride induced significantly more severe liver injury in Aadac knockout (KO) mice (plasma alanine aminotransferase level: 19,381 ± 10,578 U/L) than in wild-type (WT) mice (7219 ± 4729 U/L). More severe liver injury in Aadac KO mice was accompanied by higher hepatic malondialdehyde and antioxidant gene mRNA levels than those in WT mice. The increase in plasma alanine aminotransferase levels in Aadac KO mice was substantially suppressed by pretreatment with the ferroptosis inhibitors deferoxamine or ferrostatin-1, suggesting that Aadac deficiency increases susceptibility to ferroptosis. Immunoprecipitation followed by proteomic analysis revealed that AADAC interacts with ceruloplasmin (CP), which oxidizes ferrous iron to ferric iron. Hepatic CP activity was significantly lower in Aadac KO mice than that in WT mice, resulting in elevated hepatic ferrous iron levels in Aadac KO mice. Overexpression of human AADAC in Huh-7 cells significantly attenuated carbon tetrachloride-induced cytotoxicity by suppressing ferrous iron accumulation, suggesting that AADAC interacts with CP to suppress hepatic ferrous iron accumulation. The hepatoprotective role of Aadac in ferroptosis was also observed in mice with acetaminophen-induced liver injury. This study demonstrates a novel function of AADAC in protecting against ferroptosis induced by hepatotoxicants, carbon tetrachlorideand acetaminophen.

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Minimum information for reporting on the TEER (trans-epithelial/endothelial electrical resistance) assay (MIRTA).

Standard information reporting helps to ensure that assay conditions and data are consistently reported and to facilitate inter-laboratory comparisons. Here, we present recommendations on minimum information for reporting on the TEER (trans-epithelial/endothelial electrical resistance) assay (MIRTA). The TEER assay is extensively used to evaluate the health of an epithelial/endothelial cell culture model and as an indicator of the potential toxicity of a test substance. This publication is the result of an international collaboration─called the RespTox (Respiratory Toxicity) Collaborative─through which twelve laboratories shared their protocols for assessing the barrier function of respiratory epithelial cells using the TEER assay following exposure to substances. The protocols from each laboratory were reviewed to identify general steps for performing the TEER assay, interlaboratory differences between steps, the rationale for differences, whether these differences impact results or cross-laboratory comparisons between TEER measurements. While the MIRTA recommendations are focused on respiratory epithelial cell systems, these recommendations can be adapted for other cell systems that form barriers. The use of these recommendations will support data transparency and reproducibility, reduce challenges in data interpretation, enable cross-laboratory comparisons, help assess study quality, and facilitate the incorporation of the TEER assay into national and international testing guidance.

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Animal-free safety assessment of chemicals: an innovation system perspective.

This perspective paper, which is the result of a collaborative effort between toxicologists and scholars in innovation and transition studies, presents a heuristic framework based on innovation system literature for understanding and appraising mission achievement to animal-free chemical safety assessment using New Approach Methodologies (NAMs). While scientific and technical challenges in this area are relatively well known, the recent establishment of missions and roadmaps to accelerate the acceptance and effective use of NAMs for chemical safety assessment raises new questions about how we can grasp the systemic nature of all changes needed in this transition. This includes recognising broader societal, institutional, and regulatory shifts necessary for NAM acceptance and uptake. Our paper discusses how the innovation system approach offers insights into key processes and associated activities that include as well as transcend the technical and scientific realm, and can help to accelerate acceptance and uptake of NAMs. Based on these insights, we present a comprehensive framework that, next to scientific and technological developments, recognises the need for coordinated efforts in areas like education, training, funding, policy-making, and public engagement to promote the acceptance and uptake of NAMs. Our framework can be used to perform structural and functional analyses of the innovation system of NAMs and animal-free safety assessment and as such provides handholds to track progress and organise collective efforts of actors to make sure we are moving in the right direction.

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Standardization and optimization of the hiPSC-based PluriLum assay for detection of embryonic and developmental toxicants.

New approach methodologies (NAMs) for predicting embryotoxicity and developmental toxicity are urgently needed for generating human relevant data, while reducing turnover time and costs, and alleviating ethical concerns related to the use of animal models. We have previously developed the PluriLum assay, a NKX2.5-reporter gene 3D model using human-induced pluripotent stem cells (hiPSCs) that are genetically modified to enable the assessment of adverse effects of chemicals on the early-stage embryo. Aiming at improving the predictive value of the PluriLum assay for future screening purposes, we sought to introduce standardization steps to the protocol, improving the overall robustness of the PluriLum assay, as well as a shortening of the assay protocol. First, we showed that the initial size of embryoid bodies (EBs) is crucial for a proper differentiation into cardiomyocytes and overall reproducibility of the assay. When the starting diameter of the EBs exceeds 500 µm, robust differentiation can be anticipated. In terms of reproducibility, exposure to the fungicide epoxiconazole at smaller initial diameters resulted in a larger variation of the derived data, compared to more reliable concentration-response curves obtained using spheroids with larger initialdiameters. We further investigated the ideal length of the differentiation protocol, resulting in a shortening of the PluriLum assay by 24 h to 7 days. Following exposure to the teratogens all-trans and 13-cis retinoic acid, both cardiomyocyte contraction and measurement of NKX2.5-derived luminescence were recorded with a similar or increased sensitivity after 6 days of differentiation when compared to the original 7 days. Finally, we have introduced an efficient step for enzymatic dissociation of the EBs at assay termination. This allows for an even splitting of the individual EBs and testing of additional endpoints other than the NKX2.5-luciferase reporter, which was demonstrated in this work by the simultaneous assessment of ATP levels. In conclusion, we have introduced standardizations and streamlined the PluriLum assay protocol to improve its suitability as a NAM for screening of a large number of chemicals for developmental toxicity testing.

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Thallium reabsorption via NKCC2 causes severe acute kidney injury with outer medulla-specific calcium crystal casts in rats.

Thallium (Tl) is one of the most toxic heavy metals, associated with accidental poisoning and homicide. It causes acute and chronic systemic diseases, including gastrointestinal and cardiovascular diseases and kidney failure. However, few studies have investigated the mechanism by which Tl induces acute kidney injury (AKI). This study investigated the toxic effects of Tl on the histology and function of rat kidneys using biochemical and histopathological assays after intraperitoneal thallium sulfate administration (30mg/kg). Five days post-administration, rats exhibited severely compromised kidney function. Low-vacuum scanning electron microscopy revealed excessive calcium (Ca) deposition in the outer medulla of Tl-loaded rats, particularly in the medullary thick ascending limb (mTAL) of the loop of Henle. Tl accumulated in the mTAL, accompanied by mitochondrial dysfunction in this segment. Tl-loaded rats showed reduced expression of kidney transporters and channels responsible for Ca2+ reabsorption in the mTAL. Pre-administration of the Na-K-Cl cotransporter 2 (NKCC2) inhibitor furosemide alleviated Tl accumulation and mitochondrial abnormalities in the mTAL. These findings suggest that Tl nephrotoxicity is associated with preferential Tl reabsorption in the mTAL via NKCC2, leading to mTAL mitochondrial dysfunction and disrupted Ca2+ reabsorption, culminating in mTAL-predominant Ca crystal deposition and AKI. These findings on the mechanism of Tl nephrotoxicity may contribute to the development of novel therapeutic approaches to counter Tl poisoning. Moreover, the observation of characteristic Ca crystal deposition in the outer medulla provides new insights into diagnostic challenges in Tl intoxication.

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Discovery of the Alternaria mycotoxins alterperylenol and altertoxin I as novel immunosuppressive and antiestrogenic compounds in vitro.

Alternaria mycotoxins may pose significant challenges to food safety and public health due to the wide spectrum of reported adverse effects. Despite this, critical information on the immunomodulatory and antiestrogenic properties of most of these contaminants is still lacking. The present study aimed to identify the mycotoxins responsible for the immunosuppressive and antiestrogenic effects of a complex extract of Alternaria mycotoxins (CE) obtained by growing an Alternaria alternata strain on rice. Through a toxicity-guided fractionation procedure involving the production of CE-fractions by supercritical fluid chromatography and mycotoxin quantification by LC-MS/MS, the mycotoxins alternariol (AOH), tenuazonic acid (TeA), altertoxin I (ATX-I), and alterperylenol (ALTP) were identified as potential toxicologically relevant constituents contributing to the in vitro effects exerted by the extract. The assessment of the immunomodulatory effects, performed by applying the NF-κB reporter gene assay in THP1-Lucia™ monocytes, revealed the scarce contribution of AOH to the effects exerted by the CE. TeA showed no effect on the NF-κB pathway up to 250µM, whereas ATX-I and ALTP suppressed the LPS-mediated pathway activation at concentrations ≥ 1µM. The evaluation of antiestrogenic effects, performed in Ishikawa cells by applying the alkaline phosphatase assay, revealed the ability of ALTP (≥ 0.4µM) and ATX-I (≥ 2µM) to suppress the estrogen-dependent expression of enzyme activity. Given the risk of detrimental impacts stemming from alterations in endocrine and systemic immune responses by the investigated mycotoxins, further studies are needed to elucidate their underlying mechanisms of action and comprehensively evaluate the health risks posed by these toxins.

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Hypertension toxicity of VEGFR-TKIs in cancer treatment: incidence, mechanisms, and management strategies.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are a class of targeted anticancer agents that include pazopanib, sunitinib, axitinib, and others. Currently, VEGFR-TKIs are widely used in the clinical treatment of various tumors, which can prolong patients' survival and even cure tumors. However, the use of VEGFR-TKIs is frequently associated with the occurrence of cardiovascular adverse events, with hypertension being the most prevalent. Hypertension and its complications can significantly impact the prognosis of patients, potentially jeopardizing their lives and resulting in the reduction or even cessation of treatment in severe cases. This review addresses the incidence of hypertension due to VEGFR-TKIs, mechanisms of toxicity, management strategies, and future research directions. In addition, hypertension due to VEGFR-TKIs may be associated with salt sensitivity, and possible mechanisms of hypertensive side effects are vasodilator imbalance, decreased capillary density, renal injury, impaired endothelial function due to oxidative stress, decreased lymphatic vascular density, and "off-target effect". A comprehensive understanding of hypertension toxicity due to cancer treatment with VEGFR-TKIs, can enhance clinical practice, thereby improving the prognostic outcomes of VEGFR-TKIs in oncology patients.

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