The Tobacco Smoke Component, Acrolein, as a Major Culprit in Lung Diseases and Respiratory Cancers: Molecular Mechanisms of Acrolein Cytotoxic Activity

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

Ruthenium Dendrimers against Human Lymphoblastic Leukemia 1301 Cells

Ruthenium atoms located in the surfaces of carbosilane dendrimers markedly increase their anti-tumor properties. Carbosilane dendrimers have been widely studied as carriers of drugs and genes owing to such characteristic features as monodispersity, stability, and multivalence. The presence of ruthenium in the dendrimer structure enhances their successful use in anti-cancer therapy. In this paper, the activity of dendrimers of generation 1 and 2 against 1301 cells was evaluated using Transmission Electron Microscopy, comet assay and Real Time PCR techniques. Additionally, the level of reactive oxygen species (ROS) and changes of mitochondrial potential values were assessed. The results of the present study show that ruthenium dendrimers significantly decrease the viability of leukemia cells (1301) but show low toxicity to non-cancer cells (peripheral blood mononuclear cells—PBMCs). The in vitro test results indicate that the dendrimers injure the 1301 leukemia cells via the apoptosis pathway.Funding: This work was co-financed by the Project EUROPARTNER of Polish National Agency for Academic Exchange (NAWA) and Pl-SK 2019–2020 bilateral project -PPN/BIL/2018/1/00150; supported by the project “NanoTENDO” granted by National Science Centre, Poland under the M-ERA.NET 2 of Horizon 2020 programme, project No: 685451. This research was also supported by grants from CTQ2017-86224-P (MINECO), consortiums IMMUNOTHERCAN-CM B2017/BMD-3733, NANODENDMED II-CM ref B2017/BMD-3703 and Project SBPLY/17/180501/000358 Junta de Comunidades de Castilla-La Mancha (JCCM). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008–2011, IniciativaIngenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. Acknowledgments: N.S.d.O. wishes to thank JCCM for a predoctoral fellowship. This article is based upon work from COST Action CA17140 “Cancer Nanomedicine from the Bench to the Bedside” supported by COST(European Cooperation in Science and Technology)

Changes in fatty acid dietary profile affect the brain–gut axis functions of healthy young adult rats in a sex-dependent manner

This article belongs to the Special Issue Dietary Management of Gastrointestinal Diseases and Disorders.Dietary modifications, including those affecting dietary fat and its fatty acid (FA) composition, may be involved in the development of brain–gut axis disorders, with different manifestations in males and females. Our aim was to evaluate the impact of three purified diets with different FA composition on the brain–gut axis in rats of both sexes. Male and female Wistar rats fed a cereal-based standard diet from weaning were used. At young adult age (2–3 months old), animals were divided into three groups and treated each with a different refined diet for 6 weeks: a control group fed on AIN-93G diet containing 7% soy oil (SOY), and two groups fed on AIN-93G modified diets with 3.5% soy oil replaced by 3.5% coconut oil (COCO) or 3.5% evening primrose oil (EP). Different brain–gut axis parameters were evaluated during 4–6 weeks of dietary intervention. Compared with SOY diet (14% saturated FAs, and 58% polyunsaturated FAs), COCO diet (52.2% saturated FAs and 30% polyunsaturated FAs) produced no changes in brain functions and minor gastrointestinal modifications, whereas EP diet (11.1% saturated FAs and 70.56% polyunsaturated FAs) tended to decrease self-care behavior and colonic propulsion in males, and significantly increased exploratory behavior, accelerated gastrointestinal transit, and decreased cecum and fecal pellet density in females. Changes in FA composition, particularly an increase in ω-6 polyunsaturated FAs, seem to facilitate the development of brain–gut axis alterations in a sex-dependent manner, with a relatively higher risk in females.We thank Comunidad Autónoma de Madrid for the technician contract of Lorena Blanco (PEJ15/BIO/TL-0580) and the predoctoral contract of Yolanda López-Tofiño (PEJD-2017-PRE/BMD-3924), and URJC for the predoctoral contracts of Yolanda López-Tofiño and Carlos Gálvez-Robleño (both under PREDOC20-054 call). Damian Jacenik was a recipient of fellowship funded by Faculty of Biology and Environmental Protection, University of Lodz, Poland.Peer reviewe

Estrogen signaling in inflammatory bowel diseases

Wyniki wielu badań wskazują na immunomodulacyjną rolę estrogenów w patofizjologii licznych chorób, w tym chorób zapalnych jelit mogących prowadzić do transformacji nowotworowej. Niemniej do tej pory brak jest jednoznacznej odpowiedzi na pytanie czy za zaburzenia sygnalizacji estrogenowej w chorobach zapalnych jelit odpowiedzialne są estrogeny, których poziom zróżnicowany jest w zależności od płci i wieku pacjentów czy też ekspresja receptorów estrogenów odpowiedzialnych za efekt genomowy i niegenomowy działania estrogenów. Podobnie, znaczenie związanego z błonami komórkowymi receptora estrogenów oddziałującego z białkami G (GPER) odpowiedzialnego za szybką niegenomową odpowiedź komórki na estrogeny, jest słabo poznane. W pracy podjęto próbę odpowiedzi na pytanie o udział sygnalizacji estrogenowej w chorobach zapalnych jelit, tj. chorobie Leśniowskiego-Crohna i we wrzodziejącym zapaleniu jelita grubego. Celem przeprowadzonych badań była ocena poziomu zaburzeń sygnalizacji estrogenowej w chorobach zapalnych jelit w zależności od płci i wieku pacjentów oraz zidentyfikowanie mechanizmów molekularnych indukowanych z udziałem receptorów estrogenów, ze szczególnym uwzględnieniem GPER. Uzyskane wyniki wskazują na brak zmian w poziomie 17β-estradiolu i wybranych enzymów jego metabolizmu w chorobach zapalnych jelit. Stwierdzono natomiast istotne statystycznie różnice w poziomie ekspresji GPER oraz jądrowych receptorów estrogenów, tj. ERα i ERβ, a także produktów alternatywnego składania genu kodującego ERα, tj. ERα36 i ERα46. Obserwowane zmiany zależne były od płci i wieku pacjentów. W badaniach przeprowadzonych in vivo wykazano, że efektem aktywacji/inhibicji GPER jest modulowanie szlaku kinaz regulowanych sygnałem zewnątrzkomórkowym i ekspresja wielu genów, w tym zaangażowanych w sygnalizacje estrogenową oraz uczestniczących w odpowiedzi immunologicznej.Badania, których wyniki przedstawiono w niniejszej rozprawie, zostały sfinansowane ze środków przyznanych przez Narodowe Centrum Nauki na projekty: „Receptor estrogenów GPER jako modulator chorób zapalnych i czynnościowych układu pokarmowego oraz nowotworów jelita grubego” (2015/17/N/NZ5/00336), Preludium 9, 2016 – 2019, „Sygnalizacja estrogenowa w patofizjologii jelit” (2017/24/T/NZ5/00045), Etiuda 5, 2017 – 2018, we wsparciu finansowym Ministerstwa Nauki i Szkolnictwa Wyższego przyznanym przez Wydział Biologii i Ochrony Środowiska Uniwersytetu Łódzkiego w ramach dotacji na działalność polegającą na prowadzeniu badań naukowych lub prac rozwojowych oraz zadań z nimi związanych służących rozwojowi młodych naukowców oraz uczestników studiów doktoranckich na projekty: „Ekspresja cytokin immunomodulujących w chorobach zapalnych i czynnościowych układu pokarmowego oraz nowotworach jelita grubego” (5811/E-345/M/2016), 2016, „Ekspresja produktów alternatywnego składania genu kodującego ERα w chorobach czynnościowych i zapalnych układu pokarmowego oraz nowotworach jelita grubego” (5811/E-345/M/2017), 201

Diet as a Source of Acrolein: Molecular Basis of Aldehyde Biological Activity in Diabetes and Digestive System Diseases

Acrolein, a highly reactive α,β-unsaturated aldehyde, is a compound involved in the pathogenesis of many diseases, including neurodegenerative diseases, cardiovascular and respiratory diseases, diabetes mellitus, and the development of cancers of various origins. In addition to environmental pollution (e.g., from car exhaust fumes) and tobacco smoke, a serious source of acrolein is our daily diet and improper thermal processing of animal and vegetable fats, carbohydrates, and amino acids. Dietary intake is one of the main routes of human exposure to acrolein, which is a major public health concern. This review focuses on the molecular mechanisms of acrolein activity in the context of its involvement in the pathogenesis of diseases related to the digestive system, including diabetes, alcoholic liver disease, and intestinal cancer

Involvement of G-protein Coupled Estrogen Receptor in physiology and physiopathology

Estrogens, without doubt, play a pivotal role in the regulation of both physiological and pathological processes. A plethora of intercellular signaling pathways are regulated by estrogens on both genomic, and non–genomic pathways via canonical ERα and ERβ receptors. Studies published in recent years showed that not all biological effects of estrogens can be attributed to the classical model of estrogen signaling. Aside canonical ERα and ERβ receptors a G–protein coupled estrogen receptor plays its role in estrogen mediated regulation of various tissues and organs. Ubiquitous presence of G–protein coupled estrogen receptor in different tissues, as well as observed de–regulation of its expression in multiple pathologies suggest an important role of this receptor in functioning of cells, tissues and organisms. Activation/deactivation of GPER estrogen receptor takes place during the metabolism of carbohydrates, lipids and immunological response, it is involved in a number of events from reproductive, cardiovascular, neurological and skeletal systems.Estrogeny, bez wątpienia, odgrywają istotną rolę w regulacji procesów fizjologicznych i patofizjologicznych. Za pośrednictwem kanonicznych recepto– rów estrogenów ERα i ERβ hormony te modulują wiele ścieżek sygnałowych w komórce zarówno na drodze genomowej, jak i niegenomowej. Wyniki badań ostatnich lat ujawniają, że nie wszystkie biologiczne efekty estrogenów wynikają z ich klasycznego modelu działania. Obok kanonicznych receptorów ERα i ERβ w estrogenozależnej regulacji funkcjonowania wielu tkanek i narządów pośred– niczy receptor estrogenów oddziałujący z białkami G. Powszechne występowa– nie receptora estrogenów oddziałującego z białkami G w różnych tkankach, jak i obserwowana deregulacja jego ekspresji w określonych patologiach pozwala domniemywać o istotnej roli tego receptora w funkcjonowaniu komórek, tkanek i organizmów. Aktywacja/dezaktywacja receptora estrogenów GPER ma miejsce podczas metabolizmu węglowodanów i lipidów czy odpowiedzi immunologicznej, zaangażowana jest w wiele zdarzeń ze strony układu rozrodczego, sercowo– naczyniowego, nerwowego oraz kostnego

MK2 Promotes the Development and Progression of Pancreatic Neuroendocrine Tumors Mediated by Macrophages and Metabolomic Factors

Cases of pancreatic neuroendocrine tumors (PNETs) are growing in number, and new treatment options are needed in order to improve patient outcomes. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a crucial regulator of cytokine/chemokine production. The significance of MK2 expression and signaling pathway mediated by MK2 in PNETs has not been investigated. To characterize the impact of MK2 on PNET growth, we used the RipTag2 transgenic murine model of PNETs, and we developed a primary PNET cell line for both in vitro and in vivo studies. In the transgenic murine model of PNETs, we found that MK2 inhibition improves survival of mice and prevents PNET progression. MK2 blockade abolished cytokine/chemokine production, which was related to macrophage function. A role for MK2 in the regulation of metabolic factor secretion in PNETs was identified, making this the first study to identify a potential role for the MK2 pathway in regulation of tumor metabolism. Moreover, using an in vitro approach and allograft model of PNETs, we were able to show that macrophages with MK2 depletion exhibit increased cytotoxicity against PNET cells and substantially decreased production of pro-inflammatory cytokines and chemokines, as well as metabolic factors. Taken together, our work identifies MK2 as a potent driver of immune response and metabolic effectors in PNETs, suggesting it is a potential therapeutic target for patients with PNETs

The Expression Pattern of Adhesion G Protein-Coupled Receptor F5 Is Related to Cell Adhesion and Metastatic Pathways in Colorectal Cancer—Comprehensive Study Based on In Silico Analysis

Adhesion G protein-coupled receptor F5 (ADGRF5) is involved inthe neoplastic transformation of some cancer types. However, the significance of ADGRF5 expression signature and the impact of signaling pathways mediated by ADGRF5 during neoplastic transformation of the colon and colorectal cancer (CRC) progression has been poorly examined. Using Gene Expression Omnibus and The Cancer Genome Atlas datasets, we showed that ADGRF5 is overexpressed in the colons of patients with CRC. In line, combined analysis of ADGRF5 expression with clinical characterization revealed an increased expression of ADGRF5 in patients with more advanced stages of CRC compared to patients with early stages of CRC. The Spearman correlation analysis documented numerous genes positively and negatively correlated with the expression pattern of ADGRF5 in the colon of patients with CRC. In the colon of CRC patients, the expression signature of ADGRF5 was associated with genes participating in phosphatidylinositol 3-kinase/Akt, focal adhesion, cell adhesion molecules, and ribosome signaling pathways. Of note, ADGRF5 expression correlated with the levels of tumor-infiltrating immune cells in the colon of CRC patients. Moreover, we found that CRC patients with high expression of ADGRF5 had a significantly lower probability of overall survival and disease-free survival. In conclusion, our results support the prognostic value of ADGRF5 and its potent therapeutic implication in CRC