Although microRNAs have been investigated extensively in cancer research, little is known regarding their response to noxious agents in apparently healthy tissues. We analyzed the expression of 484 miRNAs in the lungs of rats exposed to environmental cigarette smoke (ECS) for 28 days. ECS down‐regulated 126 miRNAs (26.0%) at least 2‐fold and 24 miRNAs more than 3‐fold. We previously demonstrated that 107 of 4858 genes (2.9%) and 50 of 518 proteins (9.7%) were up‐regulated by ECS in the same tissue, which is consistent with the role of microRNAs as negative regulators of gene expression. The most remarkably down‐regulated microRNAs belonged to the families of let‐7, miR‐10, miR‐26, miR‐30, miR‐34, miR‐99, miR‐122, miR‐123, miR‐124, miR‐125, miR‐140, miR‐145, miR‐146, miR‐191, miR‐192, miR‐219, miR‐222 , and miR‐223 , which regulate stress response, apoptosis, proliferation, an‐giogenesis, and expression of genes. In contrast, miR‐294 , an inhibitor of transcriptional repressor genes, was up‐regulated by ECS. There was a strong parallelism in dysregulation of rodent microRNAs and their human homologues, which are often transcribed from genes localized in fragile sites deleted in lung cancer. Five ECS‐down‐regulated microRNAs are known to be affected by single nucleotide polymorphisms. Thus, changes in microRNA expression are an early event following exposure to cigarette smoke.— Izzotti, A., Calin, G. A., Arrigo, P., Steele, V. E., Croce, C. M., De Flora, S. Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke. FASEB J. 23, 806–812 (2009)

Although smoking cessation is the primary goal for the control of cancer and other smoking-related diseases, chemoprevention provides a complementary approach applicable to high risk individuals such as current smokers and ex-smokers. The thiol N-acetylcysteine (NAC) works per se in the extracellular environment, and is a precursor of intracellular cysteine and glutathione (GSH). Almost 40 years of experience in the prophylaxis and therapy of a variety of clinical conditions, mostly involving GSH depletion and alterations of the redox status, have established the safety of this drug, even at very high doses and for long-term treatments. A number of studies performed since 1984 have indicated that NAC has the potential to prevent cancer and other mutation-related diseases. N-Acetylcysteine has an impressive array of mechanisms and protective effects towards DNA damage and carcinogenesis, which are related to its nucleophilicity, antioxidant activity, modulation of metabolism, effects in mitochondria, decrease of the biologically effective dose of carcinogens, modulation of DNA repair, inhibition of genotoxicity and cell transformation, modulation of gene expression and signal transduction pathways, regulation of cell survival and apoptosis, anti-inflammatory activity, anti-angiogenetic activity, immunological effects, inhibition of progression to malignancy, influence on cell cycle progression, inhibition of pre-neoplastic and neoplastic lesions, inhibition of invasion and metastasis, and protection towards adverse effects of other chemopreventive agents or chemotherapeutical agents. These mechanisms are herein reviewed and commented on with special reference to smoking-related end-points, as evaluated in in vitro test systems, experimental animals and clinical trials. It is important that all protective effects of NAC were observed under a range of conditions produced by a variety of treatments or imbalances of homeostasis. However, our recent data show that, at least in mouse lung, under physiological conditions NAC does not alter per se the expression of multiple genes detected by cDNA array technology. On the whole, there is overwhelming evidence that NAC has the ability to modulate a variety of DNA damage- and cancer-related end-points.

Ten years have elapsed since the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of chromium and chromium compounds. Further studies performed during the last decade have provided further epidemiological, experimental and mechanistic data which support the IARC conclusions. A wealth of results indicate that, at variance with chromium(0) and chromium(III), chromium(VI) can induce a variety of genetic and related effects in vitro. The lack of carcinogenicity of chromium(0) and chromium(III) compounds in experimental animals is well established, and only a minority of animal carcinogenicity data with chromium(VI) compounds were positive (30 out of 70, i.e. 42.9%). Moreover, most positive studies used administration routes which do not mimic any human exposure and by-pass physiological defense mechanisms. Typically, positive results were only obtained at implantation sites and at the highest dose tested. Exposure to chromium(VI) has been known for more than a century to be associated with induction of cancer in humans. Carcinogenicity requires massive exposures, as is only encountered in well defined occupational settings, and is site specific, being specifically targeted to the lung and, in some cases, to the sinonasal cavity. Increased death rates for cancers at other sites, which were occasionally reported in some epidemiological studies, were almost invariably not statistically significant, and inconsistent (being counterbalanced by other studies which apparently showed decreased rates for the same cancers). As we recently quantified in human body compartments, chromium(VI) can be reduced in body fluids and non-target cells, which results in its detoxification, due to the poor ability of chromium(III) to cross cell membranes. In target cells, chromium(VI) tends to be metabolized by a network of mechanisms leading to generation of reduced chromium species and reactive oxygen species, which will result either in activation or in detoxification depending on the site of the intracellular reduction and its proximity to DNA. When introduced by the oral route, chromium(VI) is efficiently detoxified upon reduction by saliva and gastric juice, and sequestration by intestinal bacteria. If some chromium(VI) is absorbed by the intestine, it is massively reduced in the blood of the portal system and then in the liver. These mechanisms explain the lack of genotoxicity, carcinogenicity, and induction of other long-term health effects of chromium (VI) by the oral route. Within the respiratory tract, chromium(VI) is reduced in the epithelial-lining fluid, pulmonary alveolar macrophages, bronchial tree and peripheral lung parenchyma cells. Hence, lung cancer can only be induced when chromium(VI) doses overwhelm these defense mechanisms. The efficient uptake and reduction of chromium(VI) in red blood cells explains its lack of carcinogenicity at a distance from the portal of entry into the body. All experimental and epidemiological data, and the underlying mechanisms, point to the occurrence of thresholds in chromium(VI) carcinogenesis.

COVID‐19 may cause pneumonia, acute respiratory distress syndrome, cardiovascular alterations, and multiple organ failure, which have been ascribed to a cytokine storm, a systemic inflammatory response, and an attack by the immune system. Moreover, an oxidative stress imbalance has been demonstrated to occur in COVID‐19 patients. N ‐ Acetyl‐L‐cysteine (NAC) is a precursor of reduced glutathione (GSH). Due to its tolerability, this pleiotropic drug has been proposed not only as a mucolytic agent, but also as a preventive/therapeutic agent in a variety of disorders involving GSH depletion and oxidative stress. At very high doses, NAC is also used as an antidote against paracetamol intoxication. Thiols block the angiotensin‐converting enzyme 2 thereby hampering penetration of SARS‐CoV‐2 into cells. Based on a broad range of antioxidant and anti‐inflammatory mechanisms, which are herein reviewed, the oral administration of NAC is likely to attenuate the risk of developing COVID‐19, as it was previously demonstrated for influenza and influenza‐like illnesses. Moreover, high‐dose intravenous NAC may be expected to play an adjuvant role in the treatment of severe COVID‐19 cases and in the control of its lethal complications, also including pulmonary and cardiovascular adverse events.