Nanovesicular Mediation of the Gut-Brain Axis by Probiotics: Insights into Irritable Bowel Syndrome.

BACKGROUND: Dysbiosis, influenced by poor diet or stress, is associated with various systemic diseases. Probiotic supplements are recognized for stabilizing gut microbiota and alleviating gastrointestinal issues, like irritable bowel syndrome (IBS). This study focused on the tryptophan pathways, which are important for the regulation of serotonin levels, and on host physiology and behavior regulation. METHODS: Nanovesicles were isolated from the plasma of subjects with chronic diarrhea, both before and after 60 days of consuming a probiotic mix (Acronelle®, Bromatech S.r.l., Milan, Italy). These nanovesicles were assessed for the presence of Tryptophan 2,3-dioxygenase 2 (TDO 2). Furthermore, the probiotics mix, in combination with H2O2, was used to treat HT29 cells to explore its cytoprotective and anti-stress effect. RESULTS: In vivo, levels of TDO 2 in nanovesicles were enhanced in the blood after probiotic treatment, suggesting a role in the gut-brain axis. In the in vitro model, a typical H2O2-induced stress effect occurred, which the probiotics mix was able to recover, showing a cytoprotective effect. The probiotics mix treatment significantly reduced the heat shock protein 60 kDa levels and was able to preserve intestinal integrity and barrier function by restoring the expression and redistribution of tight junction proteins. Moreover, the probiotics mix increased the expression of TDO 2 and serotonin receptors. CONCLUSIONS: This study provides evidence for the gut-brain axis mediation by nanovesicles, influencing central nervous system function.

Speeding up Glioblastoma Cancer Research: Highlighting the Zebrafish Xenograft Model.

Glioblastoma multiforme (GBM) is a very aggressive and lethal primary brain cancer in adults. The multifaceted nature of GBM pathogenesis, rising from complex interactions between cells and the tumor microenvironment (TME), has posed great treatment challenges. Despite significant scientific efforts, the prognosis for GBM remains very poor, even after intensive treatment with surgery, radiation, and chemotherapy. Efficient GBM management still requires the invention of innovative treatment strategies. There is a strong necessity to complete cancer in vitro studies and in vivo studies to properly evaluate the mechanisms of tumor progression within the complex TME. In recent years, the animal models used to study GBM tumors have evolved, achieving highly invasive GBM models able to provide key information on the molecular mechanisms of GBM onset. At present, the most commonly used animal models in GBM research are represented by mammalian models, such as mouse and canine ones. However, the latter present several limitations, such as high cost and time-consuming management, making them inappropriate for large-scale anticancer drug evaluation. In recent years, the zebrafish (Danio rerio) model has emerged as a valuable tool for studying GBM. It has shown great promise in preclinical studies due to numerous advantages, such as its small size, its ability to generate a large cohort of genetically identical offspring, and its rapid development, permitting more time- and cost-effective management and high-throughput drug screening when compared to mammalian models. Moreover, due to its transparent nature in early developmental stages and genetic and anatomical similarities with humans, it allows for translatable brain cancer research and related genetic screening and drug discovery. For this reason, the aim of the present review is to highlight the potential of relevant transgenic and xenograft zebrafish models and to compare them to the traditionally used animal models in GBM research.

Probiotics as Potential Therapeutic Agents: Safeguarding Skeletal Muscle against Alcohol-Induced Damage through the Gut-Liver-Muscle Axis.

Probiotics have shown the potential to counteract the loss of muscle mass, reduce physical fatigue, and mitigate inflammatory response following intense exercise, although the mechanisms by which they work are not very clear. The objective of this review is to describe the main harmful effects of alcohol on skeletal muscle and to provide important strategies based on the use of probiotics. The excessive consumption of alcohol is a worldwide problem and has been shown to be crucial in the progression of alcoholic liver disease (ALD), for which, to date, the only therapy available is lifestyle modification, including cessation of drinking. In ALD, alcohol contributes significantly to the loss of skeletal muscle, and also to changes in the intestinal microbiota, which are the basis for a series of problems related to the onset of sarcopenia. Some of the main effects of alcohol on the skeletal muscle are described in this review, with particular emphasis on the "gut-liver-muscle axis", which seems to be the primary cause of a series of muscle dysfunctions related to the onset of ALD. The modulation of the intestinal microbiota through probiotics utilization has appeared to be crucial in mitigating the muscle damage induced by the high amounts of alcohol consumed.

NF-kB Regulation and the Chaperone System Mediate Restorative Effects of the Probiotic Lactobacillus fermentum LF31 in the Small Intestine and Cerebellum of Mice with Ethanol-Induced Damage.

Probiotics are live microorganisms that yield health benefits when consumed, generally by improving or restoring the intestinal flora (microbiota) as part of the muco-microbiotic layer of the bowel. In this work, mice were fed with ethanol alone or in combination with the probiotic Lactobacillus fermentum (L. fermentum) for 12 weeks. The modulation of the NF-κB signaling pathway with the induction of Hsp60, Hsp90, and IkB-α by the probiotic occurred in the jejunum. L. fermentum inhibited IL-6 expression and downregulated TNF-α transcription. NF-κB inactivation concurred with the restoration of the intestinal barrier, which had been damaged by ethanol, via the production of tight junction proteins, ameliorating the ethanol-induced intestinal permeability. The beneficial effect of the probiotic on the intestine was repeated for the cerebellum, in which downregulation of glial inflammation-related markers was observed in the probiotic-fed mice. The data show that L. fermentum exerted anti-inflammatory and cytoprotective effects in both the small intestine and the cerebellum, by suppressing ethanol-induced increased intestinal permeability and curbing neuroinflammation. The results also suggest that L. fermentum could be advantageous, along with the other available means, for treating intestinal diseases caused by stressors associated with inflammation and dysbiosis.

Air Pollution: Role of Extracellular Vesicles-Derived Non-Coding RNAs in Environmental Stress Response.

Air pollution has increased over the years, causing a negative impact on society due to the many health-related problems it can contribute to. Although the type and extent of air pollutants are known, the molecular mechanisms underlying the induction of negative effects on the human body remain unclear. Emerging evidence suggests the crucial involvement of different molecular mediators in inflammation and oxidative stress in air pollution-induced disorders. Among these, non-coding RNAs (ncRNAs) carried by extracellular vesicles (EVs) may play an essential role in gene regulation of the cell stress response in pollutant-induced multiorgan disorders. This review highlights EV-transported ncRNAs' roles in physiological and pathological conditions, such as the development of cancer and respiratory, neurodegenerative, and cardiovascular diseases following exposure to various environmental stressors.

Oligomeric State and Holding Activity of Hsp60.

Similar to its bacterial homolog GroEL, Hsp60 in oligomeric conformation is known to work as a folding machine, with the assistance of co-chaperonin Hsp10 and ATP. However, recent results have evidenced that Hsp60 can stabilize aggregation-prone molecules in the absence of Hsp10 and ATP by a different, "holding-like" mechanism. Here, we investigated the relationship between the oligomeric conformation of Hsp60 and its ability to inhibit fibrillization of the Ab40 peptide. The monomeric or tetradecameric form of the protein was isolated, and its effect on beta-amyloid aggregation was separately tested. The structural stability of the two forms of Hsp60 was also investigated using differential scanning calorimetry (DSC), light scattering, and circular dichroism. The results showed that the protein in monomeric form is less stable, but more effective against amyloid fibrillization. This greater functionality is attributed to the disordered nature of the domains involved in subunit contacts.

Contribution of Extracellular Vesicles and Molecular Chaperones in Age-Related Neurodegenerative Disorders of the CNS.

Many neurodegenerative disorders are characterized by the abnormal aggregation of misfolded proteins that form amyloid deposits which possess prion-like behavior such as self-replication, intercellular transmission, and consequent induction of native forms of the same protein in surrounding cells. The distribution of the accumulated proteins and their correlated toxicity seem to be involved in the progression of nervous system degeneration. Molecular chaperones are known to maintain proteostasis, contribute to protein refolding to protect their function, and eliminate fatally misfolded proteins, prohibiting harmful effects. However, chaperone network efficiency declines during aging, prompting the onset and the development of neurological disorders. Extracellular vesicles (EVs) are tiny membranous structures produced by a wide range of cells under physiological and pathological conditions, suggesting their significant role in fundamental processes particularly in cellular communication. They modulate the behavior of nearby and distant cells through their biological cargo. In the pathological context, EVs transport disease-causing entities, including prions, α-syn, and tau, helping to spread damage to non-affected areas and accelerating the progression of neurodegeneration. However, EVs are considered effective for delivering therapeutic factors to the nervous system, since they are capable of crossing the blood-brain barrier (BBB) and are involved in the transportation of a variety of cellular entities. Here, we review the neurodegeneration process caused mainly by the inefficiency of chaperone systems as well as EV performance in neuropathies, their potential as diagnostic biomarkers and a promising EV-based therapeutic approach.

Muscle Histopathological Abnormalities in a Patient With a CCT5 Mutation Predicted to Affect the Apical Domain of the Chaperonin Subunit.

Recognition of diseases associated with mutations of the chaperone system genes, e.g., chaperonopathies, is on the rise. Hereditary and clinical aspects are established, but the impact of the mutation on the chaperone molecule and the mechanisms underpinning the tissue abnormalities are not. Here, histological features of skeletal muscle from a patient with a severe, early onset, distal motor neuropathy, carrying a mutation on the CCT5 subunit (MUT) were examined in comparison with normal muscle (CTR). The MUT muscle was considerably modified; atrophy of fibers and disruption of the tissue architecture were prominent, with many fibers in apoptosis. CCT5 was diversely present in the sarcolemma, cytoplasm, and nuclei in MUT and in CTR and was also in the extracellular space; it colocalized with CCT1. In MUT, the signal of myosin appeared slightly increased, and actin slightly decreased as compared with CTR. Desmin was considerably delocalized in MUT, appearing with abnormal patterns and in precipitates. Alpha-B-crystallin and Hsp90 occurred at lower signals in MUT than in CTR muscle, appearing also in precipitates with desmin. The abnormal features in MUT may be the consequence of inactivity, malnutrition, denervation, and failure of protein homeostasis. The latter could be at least in part caused by malfunction of the CCT complex with the mutant CCT5 subunit. This is suggested by the results of the in silico analyses of the mutant CCT5 molecule, which revealed various abnormalities when compared with the wild-type counterpart, mostly affecting the apical domain and potentially impairing chaperoning functions. Thus, analysis of mutated CCT5 in vitro and in vivo is anticipated to provide additional insights on subunit involvement in neuromuscular disorders.

Physiactisome: A New Nanovesicle Drug Containing Heat Shock Protein 60 for Treating Muscle Wasting and Cachexia.

Currently, no commercially available drugs have the ability to reverse cachexia or counteract muscle wasting and the loss of lean mass. Here, we report the methodology used to develop Physiactisome-a conditioned medium released by heat shock protein 60 (Hsp60)-overexpressing C2C12 cell lines enriched with small and large extracellular vesicles. We also present evidence supporting its use in the treatment of cachexia. Briefly, we obtain a nanovesicle-based secretion by genetically modifying C2C12 cell lines with an Hsp60-overexpressing plasmid. The secretion is used to treat naïve C2C12 cell lines. Physiactisome activates the expression of PGC-1α isoform 1, which is directly involved in mitochondrial biogenesis and muscle atrophy suppression, in naïve C2C12 cell lines. Proteomic analyses show Hsp60 localisation inside isolated nanovesicles and the localisation of several apocrine and merocrine molecules, with potential benefits for severe forms of muscle atrophy. Considering that Physiactisome can be easily obtained following tissue biopsy and can be applied to autologous muscle stem cells, we propose a potential nanovesicle-based anti-cachexia drug that could mimic the beneficial effects of exercise. Thus, Physiactisome may improve patient survival and quality of life. Furthermore, the method used to add Hsp60 into nanovesicles can be used to deliver other drugs or active proteins to vesicles.

5-Azacytidine Inhibits the Activation of Senescence Program and Promotes Cytotoxic Autophagy during Trdmt1-Mediated Oxidative Stress Response in Insulinoma ß-TC-6 Cells.

5-Azacytidine (5-azaC), a methyltransferase inhibitor and anticancer drug, can promote several cellular stress responses such as apoptosis, autophagy, and senescence. The action of 5-azaC is complex and can be modulated by dose, time of treatment, and co-administration with oxidants. Insulinoma is a rare pancreatic neuroendocrine tumor with limited chemotherapeutic options. In the present study, two cellular models of insulinoma were considered, namely NIT-1 and ß-TC-6 mouse cells, to evaluate the effects of 5-azaC post-treatment during hydrogen peroxide-induced oxidative stress. 5-azaC attenuated the development of oxidant-induced senescent phenotype in both cell lines. No pro-apoptotic action of 5-azaC was observed in cells treated with the oxidant. On the contrary, 5-azaC stimulated an autophagic response, as demonstrated by the increase in phosphorylated eIF2α and elevated pools of autophagic marker LC3B in oxidant-treated ß-TC-6 cells. Notably, autophagy resulted in increased necrotic cell death in ß-TC-6 cells with higher levels of nitric oxide compared to less affected NIT-1 cells. In addition, 5-azaC increased levels of RNA methyltransferase Trdmt1, but lowered 5-mC and m6A levels, suggesting Trdmt1 inhibition. We postulate that the 5-azaC anticancer action may be potentiated during oxidative stress conditions that can be used to sensitize cancer cells, at least insulinoma cells, with limited drug responsiveness.

Circulating Molecular Chaperones in Subjects with Amnestic Mild Cognitive Impairment and Alzheimer's Disease: Data from the Zabùt Aging Project.

Molecular chaperones play essential roles in many processes such as cell differentiation, tissue homeostasis, and organ remodeling. Recent data indicate that chaperones can act as cytoprotectants for brain cells during the progression of neurodegenerative diseases, including Alzheimer's disease (AD). However, very few data on the levels of chaperones in dementia, including its prodromal phases, have been reported. In this study, we used biological samples and epidemiological data collected during the Zabùt Aging Project (a prospective, community-based, cohort study of normal/pathological aging conducted in Sicily, Italy, with a follow-up of ten years) to determine if there is an association between plasma levels of the chaperones Hsp60, Hsp70, and Hsp90 with amnestic mild cognitive impairment (aMCI) and AD. Twenty-six aMCI individuals, 26 AD and 26 controls, matched for age and sex, were enrolled. After adjustment for education, subjects with AD showed significantly higher levels of Hsp60 than aMCI (OR = 1.16, 95% CI 1.04-1.30) and controls (OR = 1.12, 95% CI 1.03-1.22), while Hsp70 was significantly higher only in AD (OR = 1.84, 95% CI 1.09-3.10) than controls. In contrast, circulating levels of Hsp90 were significantly diminished in aMCI (OR = 0.69, 95% CI 0.52-0.91) and AD (OR = 0.51, 95% CI 0.35-0.75) compared to controls. However, these results were no longer significant after adjustment for multiple comparisons. Although the results lost significance after adjustment for multiple comparisons, they are encouraging despite the smallness of the sample and new studies should be carried out with larger populations to determine to what extent sequential measurement of serum chaperones in aMCI and AD can be trusted as indicators of disease status and progression.

Nicotine modulation of the lateral habenula/ventral tegmental area circuit dynamics: An electrophysiological study in rats.

Nicotine, the addictive component of tobacco, has bivalent rewarding and aversive properties. Recently, the lateral habenula (LHb), a structure that controls ventral tegmental area (VTA) dopamine (DA) function, has attracted attention as it is potentially involved in the aversive properties of drugs of abuse. Hitherto, the LHb-modulation of nicotine-induced VTA neuronal activity in vivo is unknown. Using standard single-extracellular recording in anesthetized rats, we observed that intravenous administration of nicotine hydrogen tartrate (25-800 µg/kg i.v.) caused a dose-dependent increase in the basal firing rate of the LHb neurons of nicotine-naïve rats. This effect underwent complete desensitization in chronic nicotine (6 mg/kg/day for 14 days)-treated animals. As previously reported, acute nicotine induced an increase in the VTA DA neuronal firing rate. Interestingly, only neurons located medially (mVTA) but not laterally (latVTA) within the VTA were responsive to acute nicotine. This pattern of activation was reversed by chronic nicotine exposure which produced the selective increase of latVTA neuronal activity. Acute lesion of the LHb, similarly to chronic nicotine treatment, reversed the pattern of DA cell activation induced by acute nicotine increasing latVTA but not mVTA neuronal activity. Our evidence indicates that LHb plays an important role in mediating the effects of acute and chronic nicotine within the VTA by activating distinct subregional responses of DA neurons. The LHb/VTA modulation might be part of the neural substrate of nicotine aversive properties. By silencing the LHb chronic nicotine could shift the balance of motivational states toward the reward.

Extracellular heat shock proteins in cancer: From early diagnosis to new therapeutic approach.

In cancer, human cells lose the ability to properly control the series of events that occur constantly during cell growth and division, including protein expression, stability, and dynamics. Heat shock proteins (Hsps) are key molecules in these events, constitutively expressed at high levels and could furthermore be induced by the response to cancer-induced stress. In tumor cells, Hsps have been shown to be implicated in the regulation of apoptosis, immune responses, angiogenesis and metastasis; in some cases, they can be overexpressed and dysregulated, representing important cancer hallmarks. In the past few years, it has been demonstrated that Hsps can be released by tumor cells through several secreting pathways, including the extracellular vesicles (EVs), thus modulating the tumor microenvironment as well as long-distance intercellular communication and metastatization. In this review, we discuss the role of extracellular Hsps in cancer, with a particular interest in Hsps in EVs. We would also like to highlight the importance of fully understanding of the role of extracellular Hsps released by EVs and encourage further research in this field the use of Hsps as early cancer biomarkers and therapeutic targets.

Morphological Alterations and Stress Protein Variations in Lung Biopsies Obtained from Autopsies of COVID-19 Subjects.

Molecular chaperones, many of which are heat shock proteins, play a role in cell stress response and regulate the immune system in various ways, such as in inflammatory/autoimmune reactions. It would be interesting to study the involvement of these molecules in the damage done to COVID-19-infected lungs. In our study, we performed a histological analysis and an immunomorphological evaluation on lung samples from subjects who succumbed to COVID-19 and subjects who died from other causes. We also assessed Hsp60 and Hsp90 distribution in lung samples to determine their location and post-translational modifications. We found histological alterations that could be considered pathognomonic for COVID-19-related lung disease. Hsp60 and Hsp90 immunopositivity was significantly higher in the COVID-19 group compared to the controls, and immunolocalization was in the plasma membrane of the endothelial cells in COVID-19 subjects. The colocalization ratios for Hsp60/3-nitrotyrosine and Hsp60/acetylate-lisine were significantly increased in the COVID-19 group compared to the control group, similar to the colocalization ratio for Hsp90/acetylate-lisine. The histological and immunohistochemical findings led us to hypothesize that Hsp60 and Hsp90 might have a role in the onset of the thromboembolic phenomena that lead to death in a limited number of subjects affected by COVID-19. Further studies on a larger number of samples obtained from autopsies would allow to confirm these data as well as discover new biomarkers useful in the battle against this disease.

Molecular Chaperones and miRNAs in Epilepsy: Pathogenic Implications and Therapeutic Prospects.

Epilepsy is a pathologic condition with high prevalence and devastating consequences for the patient and its entourage. Means for accurate diagnosis of type, patient monitoring for predicting seizures and follow up, and efficacious treatment are desperately needed. To improve this adverse outcome, miRNAs and the chaperone system (CS) are promising targets to understand pathogenic mechanisms and for developing theranostics applications. miRNAs implicated in conditions known or suspected to favor seizures such as neuroinflammation, to promote epileptic tolerance and neuronal survival, to regulate seizures, and others showing variations in expression levels related to seizures are promising candidates as useful biomarkers for diagnosis and patient monitoring, and as targets for developing novel therapies. Components of the CS are also promising as biomarkers and as therapeutic targets, since they participate in epileptogenic pathways and in cytoprotective mechanisms in various epileptogenic brain areas, even if what they do and how is not yet clear. The data in this review should help in the identification of molecular targets among the discussed miRNAs and CS components for research aiming at understanding epileptogenic mechanisms and, subsequently, develop means for predicting/preventing seizures and treating the disease.

Lateral Habenula 5-HT2C Receptor Function Is Altered by Acute and Chronic Nicotine Exposures.

Serotonin (5-HT) is important in some nicotine actions in the CNS. Among all the 5-HT receptors (5-HTRs), the 5-HT2CR has emerged as a promising drug target for smoking cessation. The 5-HT2CRs within the lateral habenula (LHb) may be crucial for nicotine addiction. Here we showed that after acute nicotine tartrate (2 mg/kg, i.p.) exposure, the 5-HT2CR agonist Ro 60-0175 (5-640 µg/kg, i.v.) increased the electrical activity of 42% of the LHb recorded neurons in vivo in rats. Conversely, after chronic nicotine treatment (6 mg/kg/day, i.p., for 14 days), Ro 60-0175 was incapable of affecting the LHb neuronal discharge. Moreover, acute nicotine exposure increased the 5-HT2CR-immunoreactive (IR) area while decreasing the number of 5-HT2CR-IR neurons in the LHb. On the other hand, chronic nicotine increased both the 5-HT2CR-IR area and 5-HT2CR-IR LHb neurons in the LHb. Western blot analysis confirmed these findings and further revealed an increase of 5-HT2CR expression in the medial prefrontal cortex after chronic nicotine exposure not detected by the immunohistochemistry. Altogether, these data show that acute and chronic nicotine exposure differentially affect the central 5-HT2CR function mainly in the LHb and this may be relevant in nicotine addiction and its treatment.

JNK pathway and heat shock response mediate the survival of C26 colon carcinoma bearing mice fed with the mushroom Pleurotus eryngii var. eryngii without affecting tumor growth or cachexia.

In the last few years, there has been emerging interest in developing treatments against human diseases using natural bioactive content. Here, the powder of the edible mushroom Pleurotus eryngii var. eryngii was mixed with the normal diet of mice bearing C26 colon carcinoma. Interestingly, it was evidenced by a significant increase in the survival rate of C26 tumor-bearing mice accompanied by a significant increase in Hsp90 and Hsp27 protein levels in the tumors. These data were paralleled by a decrease in Hsp60 levels. The mushroom introduced in the diet induced the inhibition of the transcription of the pro-inflammatory cytokines IL-6 and IL-1 exerting an anti-inflammatory action. The effects of the mushroom were mediated by the activation of c-Jun NH2-terminal kinases as a result of metabolic stress induced by the micronutrients introduced in the diet. In the tumors of C26 bearing mice fed with Pleurotus eryngii there was also a decreased expression of the mitotic regulator survivin and the anti-apoptotic factor Bcl-xL as well as an increase in the expression levels of Atg7, a protein that drives autophagy. In our hypothesis the interplay of these molecules favored the survival of the mice fed with the mushroom. These data are promising for the introduction of Pleurotus eryngii as a dietary supplement or as an adjuvant in anti-cancer therapy.

Sex-based differences after a single bout of exercise on PGC1α isoforms in skeletal muscle: A pilot study.

To date, there are limited and incomplete data on possible sex-based differences in fiber-types of skeletal muscle and their response to physical exercise. Adult healthy male and female mice completed a single bout of endurance exercise to examine the sex-based differences of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), heat shock protein 60 (Hsp60), interleukin 6 (IL-6) expression, as well as the Myosin Heavy Chain (MHC) fiber-type distribution in soleus and extensor digitorum longus (EDL) muscles. Our results showed for the first time that in male soleus, a muscle rich of type IIa fibers, endurance exercise activates specifically genes involved in mitochondrial biogenesis such as PGC1 α1 isoform, Hsp60 and IL-6, whereas the expression of PGC1 α2 and α3 was significantly upregulated in EDL muscle, a fast-twitch skeletal muscle, independently from the gender. Moreover, we found that the acute response of different PGC1α isoforms was muscle and gender dependent. These findings add a new piece to the huge puzzle of muscle response to physical exercise. Given the importance of these genes in the physiological response of the muscle to exercise, we strongly believe that our data could support future research studies to personalize a specific and sex-based exercise training protocol.

Plausible Role of Estrogens in Pathogenesis, Progression and Therapy of Lung Cancer.

Malignant neoplasms are among the most common diseases and are responsible for the majority of deaths in the developed world. In contrast to men, available data show a clear upward trend in the incidence of lung cancer in women, making it almost as prevalent as breast cancer. Women might be more susceptible to the carcinogenic effect of tobacco smoke than men. Furthermore, available data indicate a much more frequent mutation of the tumor suppressor gene-p53 in non-small cell lung cancer (NSCLC) female patients compared to males. Another important factor, however, might lie in the female sex hormones, whose mitogenic or carcinogenic effect is well known. Epidemiologic data show a correlation between hormone replacement therapy (HRT) or oral contraceptives (OCs), and increased mortality rates due to the increased incidence of malignant tumors, including lung cancer. Interestingly, two types of estrogen receptors have been detected in lung cancer cells: ERα and ERß. The presence of ERα has been detected in tissues and non-small-cell lung carcinoma (NSCLC) cell lines. In contrast, overexpression of ERß is a prognostic marker in NSCLC. Herein, we summarize the current knowledge on the role of estrogens in the etiopathogenesis of lung cancer, as well as biological, hormonal and genetic sex-related differences in this neoplasm.