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Asbestos minerals have been widely exploited due to their physical-chemical properties, and chrysotile asbestos has accounted for about 95% of all asbestos commercially employed worldwide. The exposure to chrysotile, classified like other five amphibole asbestos species as carcinogenic to humans, represents a serious occupational and environmental hazard. Nevertheless, this mineral is still largely employed in about 65% of the countries worldwide, which still allow its "safe use". The complex mechanisms through which the mineral fibres induce toxicity are not yet completely understood. In this regard, the morphometric parameters of asbestos fibres (e.g., length, width, aspect ratio) are known for their fundamental role in determining the degree of pathogenicity. In this context, the potential toxicity of short chrysotile fibres remains widely debated due to the contradictory results from countless studies. Thus, the present study investigated the different toxicity mechanisms of two representative batches of short (length ≤5µm) and long (length >5µm) chrysotile fibres obtained by cryogenic milling. The doses were based upon equal mass of each fiber type and size used without considering the differences in the number of fibers applied per cell among the different minerals. The cytotoxic, genotoxic, and pro-inflammatory potential of the two size-separated chrysotile fractions was investigated on human THP-1-derived macrophages and HECV endothelial cells, both separately and in a co-culture setup, mimicking the alveolar pro-inflammatory microenvironment, in time course experiments up to 1 week. Both chrysotile fractions displayed cytotoxic, genotoxic, and pro-inflammatory effects, with results comparable to the well-known damaging effects of crocidolite asbestos, or higher, as in the case of the longer chrysotile fraction. Furthermore, in presence of HECV, fibre-treated macrophages showed prolonged inflammation, indicating an interesting crosstalk between these cells able to sustain a low-grade chronic inflammation in the lung. In conclusion, these results help to shed light on some important open questions on the mechanisms of toxicity of chrysotile asbestos fibres., 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.)

Background: Today, many research groups in the world are struggling to fully understand the mechanisms leading to the carcinogenesis of hazardous mineral fibres, like asbestos, in view of devising effective cancer prevention strategies and therapies. Along this research line, our work attempts the completion of a model aimed at evaluating how, and to what extent, physical-crystal-chemical and morphological parameters of mineral fibres prompt adverse effects in vivo leading to carcinogenesis., Methods: In vitro toxicology tests that deliver information on the 10 key characteristics of carcinogens adopted by the International Association for Research on Cancer (IARC) have been systematically collected for a commercial chrysotile, standard UICC crocidolite and wollastonite. The analysis of the in vitro data allowed us to assess the major fibre parameters responsible for alterations in the key characteristics of carcinogens for each investigated fibre and the intensity of their effect., Results: Crystal habit and density of the fibres affect exposure but are not major parameters contributing to the KCs. For chrysotile, besides length, we found that fibre parameters that greatly contribute to the KCs are the surface area and the dissolution rate with the related velocity of release of metals (namely iron). For crocidolite, they are the fibre length, iron content and related parameters like the ferrous iron content, iron nuclearity, transition metals content and zeta potential., Conclusions: The results of our study can be a starting point for developing personalized cancer screening and prevention strategies as long as the nature of the fibre of the exposed patient is known. We can speculate on a future personalized prevention therapy targeting the fibres with surface-engineered nanocarriers with active complexes that are selective for the surface charge of the fibres. For chrysotile, a complex with deferasirox that can chelate Fe 2+ and deferoxamine that preferentially chelates Fe 3+ is proposed with the anchorage to the silica chrysotile surface driven by aspartic acid. For crocidolite, deferiprone chelating both Fe 3+ and Fe 2+ combined with lysine to attract the silica crocidolite surface is proposed., Competing Interests: 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., (© 2024 The Author(s).)

This work is an in vitro toxicity study of two asbestiform erionites from Kaipara and Gawler Downs in New Zealand. This study is the first, to the knowledge of the authors, to investigate the mechanisms that trigger adverse effects leading to carcinogenicity from New Zealand erionites. The effects induced by the erionite fibres from New Zealand were compared with those produced by positive (crocidolite) and negative (wollastonite) standards, and other erionite fibres described in the literature. The cytotoxicity/genotoxicity/inflammatory potential was determined by: (i) analysis of the cytotoxic potential by MTT tests on human cell lines mimicking primary cells making direct contact with fibres in the lungs, combined with apoptosis tests and cell membrane damage by fluorescence microscopy analyses; (ii) analysis of the genotoxic potential by quantification of DNA damage measuring double strand break foci by γ-H2AX nuclear staining in confocal microscopy analyses; (iii) analyses of the acute (24-72h) and early-chronic (7d) inflammatory effect by gene expression analyses of several cytokines, as well as of fibrotic and Epithelial to Mesenchymal transition (EMT) markers. The intensity of cell responses to these erionites are comparable to that of standard carcinogenic crocidolite, indicating that the two erionite fibres exhibit a significant acute toxic potential, with a particular alarming effect from the Gawler Downs sample from South Island. Our results confirm that the investigated erionites from New Zealand may represent an environmental hazard. However, further investigation is required to determine potential environmental exposure pathways by which erionite may become airborne and assess any environmental risks that may arise., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Martin Brook reports financial support was provided by New Zealand Ministry of Business Innovation and Employment. If there are other authors, they 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.)

Asbestos fibres have been considered an environmental hazard for decades. However, little is known about the attempts of circulating immune cells to counteract their toxicity. We addressed the early effects of fibre-released soluble factors (i.e. heavy metals) in naïve immune cells, circulating immediately below the alveolar/endothelial cell layer. By comparison, the direct fibre effects on endotheliocytes were also studied since these cells are known to sustain inflammatory processes. The three mineral fibres analysed showed that mainly chrysotile (CHR) and erionite (ERI) were able to release toxic metals in extracellular media respect to crocidolite (CRO), during the first 24 h. Nevertheless, all three fibres were able to induce oxidative stress and genotoxic damage in indirectly challenged naïve THP-1 monocytes (separated by a membrane). Conversely, only CHR-released metal ions induced apoptosis, NF-κB activation, cytokines and CD163 gene overexpression, indicating a differentiation towards the M0 macrophage phenotype. On the other hand, all three mineral fibres in direct contact with HECV endothelial cells showed cytotoxic, genotoxic and apoptotic effects, cytokines and ICAM-I overexpression, indicating the ability of these cells to promote an inflammatory environment in the lung independently from the type of inhaled fibre. Our study highlights the different cellular responses to mineral fibres resulting from both the nature of the cells and their function, but also from the chemical-physical characteristics of the fibres. In conclusion, CHR represented the main pro-inflammatory trigger, able to recruit and activate circulating naïve monocytes, through its released metals, already in the first 24 h after inhalation., (© 2024 John Wiley & Sons Ltd.)

Introduction: The latest GLOBOCAN 2021 reports that colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Most CRC cases are sporadic and associated with several risk factors, including lifestyle habits, gut dysbiosis, chronic inflammation, and oxidative stress., Aim: To summarize the biology of CRC and discuss current therapeutic interventions designed to counteract CRC development and to overcome chemoresistance., Methods: Literature searches were conducted using PubMed and focusing the attention on the keywords such as "Current treatment of CRC" or "chemoresistance and CRC" or "oxidative stress and CRC" or "novel drug delivery approaches in cancer" or "immunotherapy in CRC" or "gut microbiota in CRC" or "systematic review and meta-analysis of randomized controlled trials" or "CSCs and CRC". The citations included in the search ranged from September 1988 to December 2022. An additional search was carried out using the clinical trial database., Results: Rounds of adjuvant therapies, including radiotherapy, chemotherapy, and immunotherapy are commonly planned to reduce cancer recurrence after surgery (stage II and stage III CRC patients) and to improve overall survival (stage IV). 5-fluorouracil-based chemotherapy in combination with other cytotoxic drugs, is the mainstay to treat CRC. However, the onset of the inherent or acquired resistance and the presence of chemoresistant cancer stem cells drastically reduce the efficacy. On the other hand, the genetic-molecular heterogeneity of CRC often precludes also the efficacy of new therapeutic approaches such as immunotherapies. Therefore, the CRC complexity made of natural or acquired multidrug resistance has made it necessary the search for new druggable targets and new delivery systems., Conclusion: Further knowledge of the underlying CRC mechanisms and a comprehensive overview of current therapeutic opportunities can provide the basis for identifying pharmacological and biological barriers that render therapies ineffective and for identifying new potential biomarkers and therapeutic targets for advanced and aggressive CRC., Competing Interests: The authors declare that the review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tirendi, Marengo, Domenicotti, Bassi, Almonti and Vernazza.)

Alveolar macrophages are the first line of defence against detrimental inhaled stimuli. To date, no comparative data have been obtained on the inflammatory response induced by different carcinogenic mineral fibres in the three main macrophage phenotypes: M0 (non-activated), M1 (pro-inflammatory) and M2 (alternatively activated). To gain new insights into the different toxicity mechanisms of carcinogenic mineral fibres, the acute effects of fibrous erionite, crocidolite and chrysotile in the three phenotypes obtained by THP-1 monocyte differentiation were investigated. The three mineral fibres apparently act by different toxicity mechanisms. Crocidolite seems to exert its toxic effects mostly as a result of its biodurability, ROS and cytokine production and DNA damage. Chrysotile, due to its low biodurability, displays toxic effects related to the release of toxic metals and the production of ROS and cytokines. Other mechanisms are involved in explaining the toxicity of biodurable fibrous erionite, which induces lower ROS and toxic metal release but exhibits a cation-exchange capacity able to alter the intracellular homeostasis of important cations. Concerning the differences among the three macrophage phenotypes, similar behaviour in the production of pro-inflammatory mediators was observed. The M2 phenotype, although known as a cell type recruited to mitigate the inflammatory state, in the case of asbestos fibres and erionite, serves to support the process by supplying pro-inflammatory mediators.

Inhalation of mineral fibres is associated with the onset of an inflammatory activity in the lungs and the pleura responsible for the development of fatal malignancies. It is known that cell damage is a necessary step for triggering the inflammatory response. However, the mechanisms by which mineral fibres exert cytotoxic activity are not fully understood. In this work, the kinetics of the early cytotoxicity mechanisms of three mineral fibres (i.e., chrysotile, crocidolite and fibrous erionite) classified as carcinogenic by the International Agency for Research on Cancer, was determined for the first time in a comparative manner using time-lapse video microscopy coupled with in vitro assays. All tests were performed using the THP-1 cell line, differentiated into M0 macrophages (M0-THP-1) and exposed for short times (8 h) to 25 μg/mL aliquots of chrysotile, crocidolite and fibrous erionite. The toxic action of fibrous erionite on M0-THP-1 cells is manifested since the early steps (2 h) of the experiment while the cytotoxicity of crocidolite and chrysotile gradually increases during the time span of the experiment. Chrysotile and crocidolite prompt cell death mainly via apoptosis, while erionite exposure is also probably associated to a necrotic-like effect. The potential mechanisms underlying these different toxicity behaviours are discussed in the light of the different morphological, and chemical-physical properties of the three fibres., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Multidrug resistance is still an obstacle for chemotherapeutic treatments. One of the proteins involved in this phenomenon is the P-glycoprotein, P-gp, which is known to be responsible for the efflux of therapeutic substances from the cell cytoplasm. To date, the identification of a drug that can efficiently inhibit P-gp activity remains a challenge, nevertheless some studies have identified natural compounds suitable for that purpose. Amongst them, curcumin has shown an inhibitory effect on the protein in in vitro studies using Caco-2 cells. To understand if flow can modulate the influence of curcumin on the protein's activity, we studied the uptake of a P-gp substrate under static and dynamic conditions. Caco-2 cells were cultured in bioreactors and in Transwells and the basolateral transport of rhodamine-123 was assessed in the two systems as a function of the P-gp activity. Experiments were performed with and without pre-treatment of the cells with an extract of curcumin or an arylmethyloxy-phenyl derivative to evaluate the inhibitory effect of the natural substance with respect to a synthetic compound. The results indicated that the P-gp activity of the cells cultured in the bioreactors was intrinsically lower, and that the effect of both natural and synthetic inhibitors was up modulated by the presence of flow. Our study underlies the fact that the use of more sophisticated and physiologically relevant in vitro models can bring new insights on the therapeutic effects of natural substances such as curcumin.