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)

MiRNAs, the smallest nucleotide molecules able to regulate gene expression at post transcriptional level, are found in both animals and plants being involved in fundamental processes for growth and development of living organisms. The number of miRNAs has been hypothesized to increase when some organisms specialized the process of mastication and grinding of food. Further to the vertical transmission, miRNAs can undergo horizontal transmission among different species, in particular between plants and animals. In the last years, an increasing number of studies reported that miRNA passage occurs through feeding, and that in animals, plant miRNAs can survive the gastro intestinal digestion and transferred by blood into host cells, where they can exert their functions modulating gene expression. The present review reports studies on miRNAs during evolution, with particular focus on biogenesis and mechanisms regulating their stability in plants and animals. The different biogenesis and post biogenesis modifications allow to discriminate miRNAs of plant origin from those of animal origin, and make it possible to better clarify the controversial question on whether a possible cross-kingdom miRNA transfer through food does exist. The majority of human medicines and supplements derive from plants and a regular consumption of plant food is suggested for their beneficial effects in the prevention of metabolic diseases, cancers, and dietary related disorders. So far, these beneficial effects have been generally attributed to the content of secondary metabolites, whereas mechanisms regarding other components remain unclear. Therefore, in light of the above reported studies miRNAs could result another component for the medical properties of plants. miRNAs have been mainly studied in mammals characterizing their sequences and molecular targets as available in public databases. The herein presented studies provide evidences that miRNA situation is much more complex than the static situation reported in databases. Indeed, miRNAs may have redundant activities, variable sequences, different methods of biogenesis, and may be differently influenced by external and environmental factors. In-depth knowledge of mechanisms of synthesis, regulation and transfer of plant miRNAs to other species can open new frontiers in the therapy of many human diseases, including cancer.

The trabecular meshwork represents the “key” region in glaucoma pathogenesis, its alterations resulting in increased resistance of the outflow system.¹ In the primate eye, approximately 75% of the resistance to aqueous humor outflow resides in the tissues between the anterior chamber and the lumen of the Schlemm canal.¹ In particular, the human trabecular meshwork (HTM) is a specialized eye tissue that regulates the aqueous humor outflow and controls intraocular pressure (IOP). The HTM has been interpreted as a biological filter to be transited by the aqueous humor to reach the Schlemm canal.² More recently, it has been established that HTM cells are essential for maintenance of the whole outflow system homeostasis,³ thus recognizing the possible importance of HTM cell damage in the pathogenesis of glaucoma. Although many researchers suggest that glaucoma is the consequence of an ischemic injury,⁴ it is recognized that IOP has a pathogenetic role toward glaucomatous neuropathy, possibly by inducing the formation of oxidative free radicals.⁵ A previous study⁶ in patients with open-angle glaucoma provided evidence of the increased oxidative DNA damage in patients with glaucoma and its relationship to the lack of the GSTM1 gene, which catalyzes the neutralization of free radicals by their conjugation with glutathione.

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.