Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant that seriously threatens human health and life. Due to its high reactivity, cytotoxicity and genotoxicity, acrolein is involved in the development of several diseases, including multiple sclerosis, neurodegenerative diseases such as Alzheimer’s disease, cardiovascular and respiratory diseases, diabetes mellitus and even the development of cancer. Traditional tobacco smokers and e-cigarette users are particularly exposed to the harmful effects of acrolein. High concentrations of acrolein have been found in both mainstream and side-stream tobacco smoke. Acrolein is considered one of cigarette smoke’s most toxic and harmful components. Chronic exposure to acrolein through cigarette smoke has been linked to the development of asthma, acute lung injury, chronic obstructive pulmonary disease (COPD) and even respiratory cancers. This review addresses the current state of knowledge on the pathological molecular mechanisms of acrolein in the induction, course and development of lung diseases and cancers in smokers.

Estrogens play important roles in the development and progression of multiple tumor types. Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast, endometrium and ovary, but also in the development of colorectal cancer (CRC). The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptors α and β, as well as the membrane-bound G protein-coupled estrogen receptor (GPER). The roles of GPER in CRC development and progression, however, remain poorly understood. Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases, such as Crohn's disease and ulcerative colitis. GPER is also involved in cell cycle regulation, endoplasmic reticulum stress, proliferation, apoptosis, vascularization, cell migration, and the regulation of fatty acid and estrogen metabolism in CRC cells. Thus, multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis. In this review, we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.

Background: Immunotherapy of gastrointestinal cancers is challenging; however, several lines of evidence suggest that adoptive transfer of stimulated or modified immune cells support not only protective role of immune cells in tumor microenvironment, but actively participate in the elimination of cancer cells. Methods: In vivo studies employing cancer cell-derived allograft murine models of gastrointestinal cancers were performed. The effects of T helper (Th) 2 cells on gastrointestinal cancers growth and tumor microenvironment composition using adoptive transfer of Th2 cells, interleukin (IL)-5 treatment, and immunofluorescence, multiplex and real-time PCR were explored. Results: Here, we show that Th2 cells play an essential role in the inhibition of colon and pancreas cancers progression. In murine models of gastrointestinal tumors using adoptive transfer of Th2 cells, we identify that Th2 cells are responsible for generation of apoptotic factors and affect macrophage as well as eosinophil recruitment into tumors where they produce cytotoxic factors. Moreover, we found that Th2 cells lead to IL-5 hypersecretion, which links the anti-tumorigenic function of Th2 cells and eosinophils. Importantly, we noted that recombinant IL-5 administration is also related with inhibition of gastrointestinal tumor growth. Finally, using an in vitro approach, we documented that both Th2 cells and eosinophils are directly responsible for gastrointestinal cancer cell killing. Conclusions: These data demonstrate the significance of Th2 cells, eosinophils and IL-5 in the inhibition of gastrointestinal tumor growth, and pointed toward tumor microenvironment reprogramming as a Th2 cell-mediated anti-tumorigenic mechanism of action.

The pathogenesis of inflammatory bowel diseases (IBD) seems to be associated with alterations of immunoregulation. Several lines of evidence suggest that estrogens play a role in the modulation of immune responses and may be related to the etiology of IBD. The purpose of this work was to examine the involvement of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα), estrogen receptor β (ERβ) and ERα spliced variants ERα36 and ERα46 in Crohn’s disease (CD) and ulcerative colitis (UC). The studied group included 73 patients with IBD and 31 sex and age-related controls. No differences in serum levels of 17β-estradiol nor of CYP1A1 and SULT1E1 enzymes involved in estrogen catabolism were stated. The expression pattern of estrogen receptors in tissue samples was quantified using real-time PCR and Western blotting. Statistically significant up-regulation of GPER and ERα in both CD and UC as well as down-regulation of ERβ in CD patients was found. However, differences in the expression of estrogen receptors in CD and UC have been identified, depending on the sex and age of patients. In men, up-regulation of GPER, ERα and ERα46 expression was shown in CD and UC patients. In women under 50 years of age, GPER protein level increased in UC whereas ERβ expression tended to decrease in CD and UC patients. In turn, in women over 50 the protein level of ERα increased in UC while ERβ expression decreased in CD patients. Dysregulation of estrogen receptors in the intestinal mucosa of patients with CD and UC indicates that estrogen signaling may play a role in the local immune response and maintain epithelial homeostasis in a gender- and age-dependent manner.

Estrogens exert immunomodulatory action in many autoimmune diseases. Accumulating evidence highlights the meaningful impact of estrogen receptors in physiology and pathophysiology of the colon. However, the significance of G protein-coupled estrogen receptor (GPER) on Crohn’s disease (CD), one of the inflammatory bowel disease (IBD) types, is still elusive. Our study revealed GPER overexpression at the mRNA and protein levels in patients with CD. To evaluate the effects of GPER activation/inhibition on colitis development, a murine 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced model of CD was used. We showed that activation of GPER reduces mortality, improves macroscopic and microscopic scores and lowers C-reactive protein (CRP) level. The impact of estrogen signaling on the suppression of the intestinal inflammation was proved by immunohistochemistry. It was demonstrated that GPER activation is accompanied by modulation of extracellular-signal regulated kinase (ERK) signaling pathway and expression level of genes involved in signal transmission and immune response as well as the expression of some microRNAs (miR-145, miR-148-5p and miR-592). Our study revealed that the membrane-bound estrogen receptor GPER mediates anti-inflammatory action and seems to be a potent therapeutic target in maintaining remission in CD.