Publications by authors named "Yolanda I Chirino"

56 Publications

Differential response of immobile (pneumocytes) and mobile (monocytes) barriers against 2 types of metal oxide nanoparticles.

Chem Biol Interact 2021 Sep 28;347:109596. Epub 2021 Jul 28.

Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. de los Barrios No. 1, Tlalnepantla de Baz, CP, 54090, Estado de México, Mexico. Electronic address:

Background: Inhaled nanoparticles (NPs) challenges mobile and immobile barriers in the respiratory tract, which can be represented by type II pneumocytes (immobile) and monocytes (mobile) but what is more important for biological effects, the cell linage, or the type of nanoparticle? Here, we addressed these questions and we demonstrated that the type of NPs exerts a higher influence on biological effects, but cell linages also respond differently against similar type of NPs.

Design: Type II pneumocytes and monocytes were exposed to tin dioxide (SnO) NPs and titanium dioxide (TiO) NPs (1, 10 and 50 μg/cm) for 24 h and cell viability, ultrastructure, cell granularity, molecular spectra of lipids, proteins and nucleic acids and cytoskeleton architecture were evaluated.

Results: SnO NPs and TiO NPs are metal oxides with similar physicochemical properties. However, in the absence of cytotoxicity, SnO NPs uptake was low in monocytes and higher in type II pneumocytes, while TiO NPs were highly internalized by both types of cells. Monocytes exposed to both types of NPs displayed higher number of alterations in the molecular patterns of proteins and nuclei acids analyzed by Fourier-transform infrared spectroscopy (FTIR) than type II pneumocytes. In addition, cells exposed to TiO NPs showed more displacements in FTIR spectra of biomolecules than cells exposed to SnO NPs. Regarding cell architecture, microtubules were stable in type II pneumocytes exposed to both types of NPs but actin filaments displayed a higher number of alterations in type II pneumocytes and monocytes exposed to SnO NPs and TiO NPs. NPs exposure induced the formation of large vacuoles only in monocytes, which were not seen in type II pneumocytes.

Conclusions: Most of the cellular effects are influenced by the NPs exposure rather than by the cell type. However, mobile, and immobile barriers in the respiratory tract displayed differential response against SnO NPs and TiO NPs in absence of cytotoxicity, in which monocytes were more susceptible than type II pneumocytes to NPs exposure.
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http://dx.doi.org/10.1016/j.cbi.2021.109596DOI Listing
September 2021

STAT1 Is Required for Decreasing Accumulation of Granulocytic Cells via IL-17 during Initial Steps of Colitis-Associated Cancer.

Int J Mol Sci 2021 Jul 19;22(14). Epub 2021 Jul 19.

Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Edo. De México 54090, Mexico.

Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1 mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1 mice reduced the accumulation of CD11b+Ly6CLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.
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http://dx.doi.org/10.3390/ijms22147695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306338PMC
July 2021

Airborne particulate matter induces oxidative damage, DNA adduct formation and alterations in DNA repair pathways.

Environ Pollut 2021 Oct 5;287:117313. Epub 2021 May 5.

Subdirección de Investigación Básica, Instituto Nacional de Cancerología, San Fernando No. 22, Tlalpan, CP 14080, CDMX, Mexico. Electronic address:

Air pollution, which includes particulate matter (PM), is classified in group 1 as a carcinogen to humans by the International Agency for Research in Cancer. Specifically, PM exposure has been associated with lung cancer in patients living in highly polluted cities. The precise mechanism by which PM is linked to cancer has not been completely described, and the genotoxicity induced by PM exposure plays a relevant role in cell damage. In this review, we aimed to analyze the types of DNA damage and alterations in DNA repair pathways induced by PM exposure, from both epidemiological and toxicological studies, to comprehend the contribution of PM exposure to carcinogenesis. Scientific evidence supports that PM exposure mainly causes oxidative stress by reactive oxygen species (ROS) and the formation of DNA adducts, specifically by polycyclic aromatic hydrocarbons (PAH). PM exposure also induces double-strand breaks (DSBs) and deregulates the expression of some proteins in DNA repair pathways, precisely, base and nucleotide excision repairs and homologous repair. Furthermore, specific polymorphisms of DNA repair genes could lead to an adverse response in subjects exposed to PM. Nevertheless, information about the effects of PM on DNA repair pathways is still limited, and it has not been possible to conclude which pathways are the most affected by exposure to PM or if DNA damage is repaired properly. Therefore, deepening the study of genotoxic damage and alterations of DNA repair pathways is needed for a more precise understanding of the carcinogenic mechanism of PM.
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http://dx.doi.org/10.1016/j.envpol.2021.117313DOI Listing
October 2021

Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System.

Int J Mol Sci 2020 Dec 28;22(1). Epub 2020 Dec 28.

Netherlands Food and Consumer Product Safety Authority, P.O. Box 43006, 3540 AA Utrecht, The Netherlands.

Titanium dioxide (TiO) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO and nano-sized TiO in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO.
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http://dx.doi.org/10.3390/ijms22010207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795714PMC
December 2020

Long non-coding RNA NORAD upregulation induced by airborne particulate matter (PM) exposure leads to aneuploidy in A549 lung cells.

Chemosphere 2021 Mar 19;266:128994. Epub 2020 Nov 19.

Subdirección de Investigación Básica, Instituto Nacional de Cancerología, San Fernando No. 22, Tlalpan, CP 14080, Ciudad de México, Mexico. Electronic address:

Air pollution is a worldwide problem that affects human health predominantly in the largest cities. Particulate matter of 10 μm or less in diameter (PM) is considered a risk factor for multiple diseases, including lung cancer. The long non-coding RNA NORAD and the components of the spindle assembly checkpoint (SAC) ensure proper chromosomal segregation. Alterations in the SAC cause aneuploidy, a feature associated with carcinogenesis. In this study, we demonstrated that PM treatment increased the expression levels of NORAD as well as those of SAC components mitotic arrest deficient 1 (MAD1L1), mitotic arrest deficient 2 (MAD2L1), BubR1 (BUB1B), aurora B (AURKB), and survivin (BIRC5) in the lung A549 cell line. We also demonstrated that MAD1L1, MAD2L1, and BUB1B expression levels were reduced when cells were transfected with small interfering RNAs (siRNAs) against NORAD. Interestingly, the expression levels of AURKB and BIRC5 (survivin) were not affected by transfection with NORAD siRNAs. Cells treated with PM exhibited a decrease in mitotic arrest and an increase in micronuclei frequency in synchronized A549 cells. PM exposure induced aneuploidy events as a result of SAC deregulation. We also observed a reduction in the protein levels of Pumilio 1 after PM treatment. Our results provide novel clues regarding the effect of PM in the generation of chromosomal instability, a phenotype observed in lung cancer cells.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128994DOI Listing
March 2021

Food additives containing nanoparticles induce gastrotoxicity, hepatotoxicity and alterations in animal behavior: The unknown role of oxidative stress.

Food Chem Toxicol 2020 Dec 15;146:111814. Epub 2020 Oct 15.

Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México. Ciudad Universitaria, Coyoacán, CP 04510, Ciudad de México, Mexico.

Food additives such as titanium dioxide (E171), iron oxides and hydroxides (E172), silver (E174), and gold (E175) are highly used as colorants while silicon dioxide (E551) is generally used as anticaking in ultra-processed foodstuff highly used in the Western diets. These additives contain nanosized particles (1-100 nm) and there is a rising concern since these nanoparticles could exert major adverse effects due to they are not metabolized but are accumulated in several organs. Here, we analyze the evidence of gastrotoxicity, hepatotoxicity and the impact of microbiota on gut-brain and gut-liver axis induced by E171, E172, E174, E175 and E551 and their non-food grade nanosized counterparts after oral consumption. Although, no studies using these food additives have been performed to evaluate neurotoxicity or alterations in animal behavior, their non-food grade nanosized counterparts have been associated with stress, depression, cognitive and eating disorders as signs of animal behavior alterations. We identified that these food additives induce gastrotoxicity, hepatotoxicity and alterations in gut microbiota and most evidence points out oxidative stress as the main mechanism of toxicity, however, the role of oxidative stress as the main mechanism needs to be explored further.
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http://dx.doi.org/10.1016/j.fct.2020.111814DOI Listing
December 2020

Food-grade titanium dioxide (E171) induces anxiety, adenomas in colon and goblet cells hyperplasia in a regular diet model and microvesicular steatosis in a high fat diet model.

Food Chem Toxicol 2020 Dec 8;146:111786. Epub 2020 Oct 8.

Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México. Ciudad Universitaria, Coyoacán, CP 04510, Ciudad de México, Mexico.

Food-grade titanium dioxide (E171) is a white additive widely used in solid and liquid food products. There is still debate about E171 toxic effects after oral consumption since this additive is deposited in colon, liver, spleen, testis and brain. The consumption of E171 commonly occurs with Western diets that are characterized by a high fat content. Thus, E171 could worsen adverse effects associated with a high fat diet (HFD) such as anxiety, colon diseases and testicular damage. We aimed to evaluate the effects of E171 on anxiety-like behavior, colon, liver and testis and to analyze if the administration of a HFD could exacerbate adverse effects. E171 was administered at ~5 mg/kg by drinking water for 16 weeks and mice were fed with a Regular Diet or a HFD. E171 promoted anxiety, induced adenomas in colon, goblet cells hypertrophy and hyperplasia and mucins overexpression, but had no toxic effects on testicular tissue or spermatozoa in regular diet fed-mice. Additionally, E171 promoted microvesicular steatosis in liver in HFD fed-mice and the only HFD administration decreased the spermatozoa concentration and motility. In conclusion, E171 administration increases the number of adenomas in colon, induces hypertrophy and hyperplasia in goblet cells and microvesicular steatosis.
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http://dx.doi.org/10.1016/j.fct.2020.111786DOI Listing
December 2020

Toxicity of engineered nanomaterials with different physicochemical properties and the role of protein corona on cellular uptake and intrinsic ROS production.

Toxicology 2020 09 2;442:152545. Epub 2020 Aug 2.

Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México. Av. de los Barrios No. 1, Los Reyes Iztacala, Tlalnepantla de Baz, CP 54090, Estado de Mexico, Mexico. Electronic address:

The Organisation for Economic Co-operation and Development has listed thirteen engineered nanomaterials (ENM) in order to investigate their toxicity on human health. Silicon dioxide (SiO) and titanium dioxide (TiO) are included on that list and we added indium tin oxide (ITO) nanoparticles (NPs) to our study, which is not listed on OECD suggested ENM to be investigated, however ITO NPs has a high potential of industrial production. We evaluate the physicochemical properties of SiO NPs (10-20 nm), TiO nanofibers (NFs; 3 μm length) and ITO NPs (<50 nm) and the impact of protein-corona formation on cell internalization. Then, we evaluated the toxicity of uncoated ENM on human lung epithelial cells exposed to 10 and 50 μg/cm for 24 h. TiO NFs showed the highest capability to adsorb proteins onto the particle surface followed by SiO NPs and ITO NPs after acellular incubation with fetal bovine serum. The protein adsorption had no impact on Alizarin Red S conjugation, intrinsic properties for reactive oxygen (ROS) formation or cell uptake for all types of ENM. Moreover, TiO NFs induced highest cell alterations in human lung epithelial cells exposed to 10 and 50 μg/cm while ITO NPs induced moderated cytotoxicity and SiO NPs caused even lower cytotoxicity under the same conditions. DNA, proteins and lipids were mainly affected by TiO NFs followed by SiO NPs with toxic effects in protein and lipids while limited variations were detected after exposure to ITO NPs on spectra analyzed by Fourier Transform Infrared Spectroscopy.
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http://dx.doi.org/10.1016/j.tox.2020.152545DOI Listing
September 2020

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis.

Int J Mol Sci 2020 Mar 20;21(6). Epub 2020 Mar 20.

Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, Tlalnepantla 54090, Mexico.

Colorectal cancer (CRC) is one of the most widespread and deadly types of neoplasia around the world, where the inflammatory microenvironment has critical importance in the process of tumor growth, metastasis, and drug resistance. Despite its limited effectiveness, 5-fluorouracil (5-FU) is the main drug utilized for CRC treatment. The combination of 5-FU with other agents modestly increases its effectiveness in patients. Here, we evaluated the anti-inflammatory Trimethylglycine and the Signal transducer and activator of transcription (STAT6) inhibitor AS1517499, as possible adjuvants to 5-FU in already established cancers, using a model of colitis-associated colon cancer (CAC). We found that these adjuvant therapies induced a remarkable reduction of tumor growth when administrated together with 5-FU, correlating with a reduction in STAT6-phosphorylation. This reduction upgraded the effect of 5-FU by increasing both levels of apoptosis and markers of cell adhesion such as E-cadherin, whereas decreased epithelial-mesenchymal transition markers were associated with aggressive phenotypes and drug resistance, such as β-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, , and , critical pro-tumorigenic cytokines, were downmodulated in the colon by these adjuvant therapies. In vitro assays on human colon cancer cells showed that Trimethylglycine also reduced STAT6-phosphorylation. Our study is relatively unique in focusing on the effects of the combined administration of AS1517499 and Trimethylglycine together with 5-FU on already established CAC which synergizes to markedly reduce the colon tumor load. Together, these data point to STAT6 as a valuable target for adjuvant therapy in colon cancer.
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http://dx.doi.org/10.3390/ijms21062130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139326PMC
March 2020

Irreversible disruption of the cytoskeleton as induced by non-cytotoxic exposure to titanium dioxide nanoparticles in lung epithelial cells.

Chem Biol Interact 2020 May 26;323:109063. Epub 2020 Mar 26.

Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. de los Barrios No. 1, Los Reyes Iztacala, Tlalnepantla de Baz, CP 54090, Estado de México, Mexico. Electronic address:

Exposure to TiO NPs induces several cellular alterations after NPs uptake including disruption of cytoskeleton that is crucial for lung physiology but is not considered as a footprint of cell damage. We aimed to investigate cytoskeleton disturbances and the impact on cell migration induced by an acute TiO NPs exposure (24 h) and the recovery capability after 6 days of NPs-free treatment, which allowed investigating if cytoskeleton damage was reversible. Exposure to TiO NPs (10 μg/cm) for 24 h induced a decrease 20.2% and 25.1% in tubulin and actin polymerization. Exposure to TiO NPs (10 μg/cm) for 24 h followed by 6 days of NPs-free had a decrease of 26.6% and 21.3% in tubulin and actin polymerization, respectively. The sustained exposure for 7 days to 1 μg/cm and 10 μg/cm induced a decrease of 22.4% and 30.7% of tubulin polymerization respectively, and 28.7% and 46.2% in actin polymerization. In addition, 24 h followed 6 days of NPs-free exposure of TiO NPs (1 μg/cm and 10 μg/cm) decreased cell migration 40.7% and 59.2%, respectively. Cells exposed (10 μg/cm) for 7 days had a decrease of 65.5% in cell migration. Ki67, protein surfactant B (SFTPB) and matrix metalloprotease 2 (MMP2) were analyzed as genes related to lung epithelial function. The results showed a 20% of Ki67 upregulation in cells exposed for 24 h to 10 μg/cm TiO NPs while a downregulation of 20% and 25.8% in cells exposed to 1 μg/cm and 10 μg/cm for 24 h followed by 6 days of NPs-free exposure. Exposure to 1 μg/cm and 10 μg/cm for 24 h and 7 days upregulates SFTPB expression in 53% and 59% respectively, MMP2 expression remain unchanged. In conclusion, exposure of TiO NPs affected cytoskeleton of lung epithelial cells irreversibly but this damage was not cumulative.
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http://dx.doi.org/10.1016/j.cbi.2020.109063DOI Listing
May 2020

Differences in cytotoxicity of lung epithelial cells exposed to titanium dioxide nanofibers and nanoparticles: Comparison of air-liquid interface and submerged cell cultures.

Toxicol In Vitro 2020 Jun 19;65:104798. Epub 2020 Feb 19.

Laboratorio de Carcinogénesis y Toxicología, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, Mexico.

Air Liquid Interface (ALI) system has emerged as a useful tool for toxicity evaluation of nanomaterials related to inhalation since the system mimics the aerosol exposure. We compared the biological responses of lung epithelial cells exposed to titanium dioxide (TiO) nanofibers and nanoparticles in ALI and submerged cell cultures systems. Cells were exposed to 2 and 10 μg/cm for 24 h, 48 h and 72 h and LDH release, TiO internalization, DNA-double strand breaks (DSBs) and ROS production were assessed. LDH release was similar in both systems and particles had higher cytoplasmic uptake in submerged systems. Both TiO types were located in the cytoplasm but nanofibers had nuclear uptake regardless to the system tested. Cells exposed to TiO nanofibers had higher DSBs in the ALI system than in submerged cell cultures but cells exposed to TiO nanoparticles had similar DSBs in both systems. ROS production was higher in cells exposed to TiO nanofibers compared to cells exposed to TiO nanoparticles. In conclusion, cytotoxicity of lung epithelial cells was similar in ALI or submerged cell cultures, however cells exposed to TiO nanofibers displayed higher toxicity than cells exposed to TiO nanoparticles.
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http://dx.doi.org/10.1016/j.tiv.2020.104798DOI Listing
June 2020

International landscape of limits and recommendations for occupational exposure to engineered nanomaterials.

Toxicol Lett 2020 Apr 22;322:111-119. Epub 2020 Jan 22.

Laboratorio de Carcinogénesis y Toxicología, Unidad de Biomedicina, Facultad de Estudios Superiores, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Col. Los Reyes Iztacala, Tlalnepantla, CP 54059, Estado de México, Mexico. Electronic address:

The increasing concern of possible adverse effects on human health derived from occupational engineered nanomaterials (ENMs) exposure is an issue addressed by entities related to provide guidelines and/or protocols for ENMs regulation. Here we analysed 17 entities from America, Europe and Asia, and some of these entities provide limits of exposure extrapolated from the non-nanosized counterparts of ENMs. The international landscape shows that recommendations are mostly made for metal oxide based ENMs and tonnage is one of the main criteria for ENMs registration, however, sub-nanometric ENMs are emerging and perhaps a novel category of ENMs will appear soon. We identify that besides the lack of epidemiological evidence of ENMs toxicity in humans and difficulties in analysing the toxicological data derived from experimental models, the lack of information on airborne concentrations of ENMs in occupational settings is an important limitation to improve the experimental designs. The development of regulations related to ENMs exposure would lead to provide safer work places for ENMs production without delaying the nanotechnology progress but will also help to protect the environment by taking opportune and correct measures for nanowaste, considering that this could be a great environmental problem in the coming future.
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http://dx.doi.org/10.1016/j.toxlet.2020.01.016DOI Listing
April 2020

Airborne Particulate Matter (PM) Inhibits Apoptosis through PI3K/AKT/FoxO3a Pathway in Lung Epithelial Cells: The Role of a Second Oxidant Stimulus.

Int J Mol Sci 2020 Jan 11;21(2). Epub 2020 Jan 11.

Instituto Nacional de Cancerología (INCan), Subdirección de Investigación Básica, San Fernando No. 22, Tlalpan, CDMX 14080, Mexico.

Outdoor particulate matter (PM) exposure is carcinogenic to humans. The cellular mechanism by which PM is associated specifically with lung cancer includes oxidative stress and damage to proteins, lipids, and DNA in the absence of apoptosis, suggesting that PM induces cellular survival. We aimed to evaluate the PI3K/AKT/FoxO3a pathway as a mechanism of cell survival in lung epithelial A549 cells exposed to PM that were subsequently challenged with hydrogen peroxide (HO). Our results showed that pre-exposure to PM followed by HO, as a second oxidant stimulus increased the phosphorylation rate of pAKT, pAKT, and pFoxO3a 2.5-fold, 1.8-fold, and 1.2-fold, respectively. Levels of catalase and p27, which are targets of the PIK3/AKT/FoxO3a pathway, decreased 38.1% and 62.7%, respectively. None of these changes had an influence on apoptosis; however, the inhibition of PI3K using the LY294002 compound revealed that the PI3K/AKT/FoxO3a pathway was involved in apoptosis evasion. We conclude that nontoxic PM exposure predisposes lung epithelial cell cultures to evade apoptosis through the PI3K/AKT/FoxO3a pathway when cells are treated with a second oxidant stimulus.
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http://dx.doi.org/10.3390/ijms21020473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014458PMC
January 2020

Deciphering the Code between Air Pollution and Disease: The Effect of Particulate Matter on Cancer Hallmarks.

Int J Mol Sci 2019 Dec 24;21(1). Epub 2019 Dec 24.

Subdirección de Investigación Básica, Instituto Nacional de Cancerología, San Fernando No. 22, Tlalpan, México CP 14080, DF, Mexico.

Air pollution has been recognized as a global health problem, causing around 7 million deaths worldwide and representing one of the highest environmental crises that we are now facing. Close to 30% of new lung cancer cases are associated with air pollution, and the impact is more evident in major cities. In this review, we summarize and discuss the evidence regarding the effect of particulate matter (PM) and its impact in carcinogenesis, considering the "hallmarks of cancer" described by Hanahan and Weinberg in 2000 and 2011 as a guide to describing the findings that support the impact of particulate matter during the cancer continuum.
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http://dx.doi.org/10.3390/ijms21010136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982149PMC
December 2019

Food-grade titanium dioxide (E171) by solid or liquid matrix administration induces inflammation, germ cells sloughing in seminiferous tubules and blood-testis barrier disruption in mice.

J Appl Toxicol 2019 11 15;39(11):1586-1605. Epub 2019 Aug 15.

Unidad de Biomedicina. Facultad de Estudios Superiores, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, México.

Food-grade titanium dioxide labeled as E171 has been approved for human consumption by the Food and Drug Administration (USA) and by the European Union for five decades. However, titanium dioxide has been classified as a possible carcinogen for humans by the International Agency of Research in Cancer raising concerns of its oral intake and the translocation to bloodstream, which could disturb barriers such as the blood-testis barrier. There is evidence that titanium dioxide by intragastric/intraperitoneal/intravenous administration induced alterations on testosterone levels, testicular function and architecture, but studies of the E171 effects on the testicle structure and blood-testis barrier are limited. E171 is contained not only in foods in liquid matrix but also in solid ones, which can exert different biological effects. We aimed to compare the effects of E171 consumption in a solid matrix (0.1%, 0.5% and 1% in pellets) and liquid suspension (5 mg/kg body weight) on testis structure, inflammation infiltrate and blood-testis barrier disruption of male BALB/c mice. Results showed that none of the administration routes had influence on body weight but an increase in germ cell sloughing and the infiltrate of inflammatory cells in seminiferous tubules, together with disruption of the blood-testis barrier were similar in testis of both groups even if the dose received in mice in liquid matrix was 136 or 260 times lower than the dose reached by oral intake in solid E171 pellets in 0.5% E171 and 1% E171, respectively. This study highlights the attention on matrix food containing E171 and possible adverse effects on testis when E171 is consumed in a liquid matrix.
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http://dx.doi.org/10.1002/jat.3842DOI Listing
November 2019

Helminth-derived molecules inhibit colitis-associated colon cancer development through NF-κB and STAT3 regulation.

Int J Cancer 2019 12 30;145(11):3126-3139. Epub 2019 Aug 30.

Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico.

Inflammation is currently considered a hallmark of cancer and plays a decisive role in different stages of tumorigenesis, including initiation, promotion, progression, metastasis and resistance to antitumor therapies. Colorectal cancer is a disease widely associated with local chronic inflammation. Additionally, extrinsic factors such as infection may beneficially or detrimentally alter cancer progression. Several reports have noted the ability of various parasitic infections to modulate cancer development, favoring tumor progression in many cases and inhibiting tumorigenesis in others. The aim of our study was to determine the effects of excreted/secreted products of the helminth Taenia crassiceps (TcES) as a treatment in a murine model of colitis-associated colon cancer (CAC). Here, we found that after inducing CAC, treatment with TcES was able to reduce inflammatory cytokines such as IL-1β, TNF-α, IL-33 and IL-17 and significantly attenuate colon tumorigenesis. This effect was associated with the inhibition of signal transducer and activator of transcription 3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation. Furthermore, we determined that TcES interfered with LPS-induced NF-κB p65 activation in human colonic epithelial cell lines in a Raf-1 proto-oncogene-dependent manner. Moreover, in three-dimensional cultures, TcES promoted reorganization of the actin cytoskeleton, altering cell morphology and forming colonospheres, features associated with a low grade of aggressiveness. Our study demonstrates a remarkable effect of helminth-derived molecules on suppressing ongoing colorectal cancer by downregulating proinflammatory and protumorigenic signaling pathways.
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http://dx.doi.org/10.1002/ijc.32626DOI Listing
December 2019

Macrophage Migration Inhibitory Factor Promotes the Interaction between the Tumor, Macrophages, and T Cells to Regulate the Progression of Chemically Induced Colitis-Associated Colorectal Cancer.

Mediators Inflamm 2019 10;2019:2056085. Epub 2019 Jul 10.

Biomedicine Unit, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Tlalnepantla C.P. 54090, Mexico.

Colitis-associated colorectal cancer (CRC) development has been shown to be related to chronically enhanced inflammation. Macrophage migration inhibitory factor (MIF) is an inflammatory mediator that favors inflammatory cytokine production and has chemotactic properties for the recruitment of macrophages (Møs) and T cells. Here, we investigated the role of MIF in the inflammatory response and recruitment of immune cells in a murine model of chemical carcinogenesis to establish the impact of MIF on CRC genesis and malignancy. We used BALB/c MIF-knockout (MIF) and wild-type (WT) mice to develop CRC by administering intraperitoneal (i.p.) azoxymethane and dextran sodium sulfate in drinking water. Greater tumor burdens were observed in MIF mice than in WT mice. Tumors from MIF mice were histologically identified to be more aggressive than tumors from WT mice. The localization of MIF suggests that it is also involved in cell differentiation. The relative gene expression of , measured by real-time PCR, was higher in MIF CRC mice, compared to the WT CRC and healthy MIF mice. Importantly, compared to the WT intestinal epithelium, lower percentages of tumor-associated Møs were found in the MIF intestinal epithelium. These results suggest that MIF plays a role in controlling the initial development of CRC by attracting Møs to the tumor, which is a condition that favors the initial antitumor responses.
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http://dx.doi.org/10.1155/2019/2056085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652048PMC
January 2020

Airborne particulate matter induces mitotic slippage and chromosomal missegregation through disruption of the spindle assembly checkpoint (SAC).

Chemosphere 2019 Nov 1;235:794-804. Epub 2019 Jul 1.

Subdirección de Investigación Básica, Instituto Nacional de Cancerología, San Fernando No. 22, Tlalpan, CP 14080 México, DF, Mexico. Electronic address:

Particulate matter (PM) is a risk factor for lung cancer development and chromosomal missegregation and cell cycle disruptions are key cellular events that trigger tumorigenesis. We aimed to study the effect of PM (PM with an aerodynamic diameter ≤10 μm) on mitotic arrest and chromosomal segregation, evaluating the spindle assembly checkpoint (SAC) protein dynamics in the human lung A549 adenocarcinoma cell line. For this purpose, synchronized cells were exposed to PM for 24 h to obtain the frequency of micronucleated (MN) and trinucleated (TN) cells. Then, the efficiency of the mitotic arrest after PM exposure was analyzed. To elucidate the effect of PM in chromosomal segregation, the levels and subcellular localization of essential SAC proteins were evaluated. Results indicated that A549 cells exposed to PM exhibited an increase in MN and TN cells and a decrease in mitotic indexes and G2/M phase. A549 cells treated with PM showed reduced protein levels of MDC1 and NEK2 (38% and 35% respectively), which is required for MAD2 recruitment to kinetochores, MAD2 and BUBR1, effectors of the SAC (25% and 18% respectively), and CYCLIN B1, required during G2/M phase (35%). Besides, PM exposure increase the levels of AURORA B and SURVIVIN, required for SAC activation through chromosome-microtubule attachment errors (85% and 74% respectively). We suggest that PM causes mitotic slippage due to alterations in MAD2 localization. Thus, PM causes inadequate chromosomal segregation and deficient mitotic arrest by altering SAC protein levels, predisposing A549 cells to chromosomal instability, a common feature observed in cancer.
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http://dx.doi.org/10.1016/j.chemosphere.2019.06.232DOI Listing
November 2019

Deficiency in STAT1 Signaling Predisposes Gut Inflammation and Prompts Colorectal Cancer Development.

Cancers (Basel) 2018 Sep 19;10(9). Epub 2018 Sep 19.

Unidad de Biomedicina. Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México (UNAM), Av. De los Barrios 1, Los Reyes Iztacala, Tlalnepantla, Edo. De México 54090, Mexico.

Signal transducer and activator of transcription 1 (STAT1) is part of the Janus kinase (JAK/STAT) signaling pathway that controls critical events in intestinal immune function related to innate and adaptive immunity. Recent studies have implicated STAT1 in tumor⁻stroma interactions, and its expression and activity are perturbed during colon cancer. However, the role of STAT1 during the initiation of inflammation-associated cancer is not clearly understood. To determine the role of STAT1 in colitis-associated colorectal cancer (CAC), we analyzed the tumor development and kinetics of cell recruitment in wild-type WT or STAT1 mice treated with azoxymethane (AOM) and dextran sodium sulfate (DSS). Following CAC induction, STAT1 mice displayed an accelerated appearance of inflammation and tumor formation, and increased damage and scores on the disease activity index (DAI) as early as 20 days after AOM-DSS exposure compared to their WT counterparts. STAT1 mice showed elevated colonic epithelial cell proliferation in early stages of injury-induced tumor formation and decreased apoptosis in advanced tumors with over-expression of the anti-apoptotic protein Bcl2 at the colon. STAT1 mice showed increased accumulation of Ly6G⁺Ly6CCD11b⁺ cells in the spleen at 20 days of CAC development with concomitant increases in the production of IL-17A, IL-17F, and IL-22 cytokines compared to WT mice. Our findings suggest that STAT1 plays a role as a tumor suppressor molecule in inflammation-associated carcinogenesis, particularly during the very early stages of CAC initiation, modulating immune responses as well as controlling mechanisms such as apoptosis and cell proliferation.
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http://dx.doi.org/10.3390/cancers10090341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162416PMC
September 2018

Transcriptomics analysis reveals new insights in E171-induced molecular alterations in a mouse model of colon cancer.

Sci Rep 2018 06 27;8(1):9738. Epub 2018 Jun 27.

Laboratorio de Carcinogénesis y Toxicología, Unidad de Biomedicina, FES-Iztacala, UNAM, Estado de México, Mexico.

Titanium dioxide as a food additive (E171) has been demonstrated to facilitate growth of chemically induced colorectal tumours in vivo and induce transcriptomic changes suggestive of an immune system impairment and cancer development. The present study aimed to investigate the molecular mechanisms behind the tumour stimulatory effects of E171 in combination with azoxymethane (AOM)/dextran sodium sulphate (DSS) and compare these results to a recent study performed under the same conditions with E171 only. BALB/c mice underwent exposure to 5 mg/kg/day of E171 by gavage for 2, 7, 14, and 21 days. Whole genome mRNA microarray analyses on the distal colon were performed. The results show that E171 induced a downregulation of genes involved in the innate and adaptive immune system, suggesting impairment of this system. In addition, over time, signalling genes involved in colorectal cancer and other types of cancers were modulated. In relation to cancer development, effects potentially associated with oxidative stress were observed through modulation of genes related to antioxidant production. E171 affected genes involved in biotransformation of xenobiotics which can form reactive intermediates resulting in toxicological effects. These transcriptomics data reflect the early biological responses induced by E171 which precede tumour formation in an AOM/DSS mouse model.
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http://dx.doi.org/10.1038/s41598-018-28063-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021444PMC
June 2018

miRNAs deregulation in lung cells exposed to airborne particulate matter (PM) is associated with pathways deregulated in lung tumors.

Environ Pollut 2018 Oct 22;241:351-358. Epub 2018 May 22.

Subdirección de Investigación Básica, Instituto Nacional de Cancerología, San Fernando No. 22, Tlalpan, CP, 14080, Ciudad de México, Mexico. Electronic address:

Particulate matter (PM) is an environmental pollutant that has been associated with an increased risk for lung cancer. PM exposure induces cellular alterations and the deregulation of cell signaling pathways. However other mechanisms such as microRNAs deregulation, might be involved in the development and progression of some types of epithelial cancer. The aim of this work was to evaluate miRNA expression in epithelial lung cells after exposure to PM and to identify the possible gene targets of deregulated miRNAs. We measured the expression of 2538 miRNAs using a microarray platform after 72 h of PM exposure; the potential biological function was inferred with bioinformatics analysis and we validated the relative expression of 10 selected miRNAs with real-time PCR. We found that the expression of 74 miRNAs was significantly changed: 45 miRNAs were downregulated and were involved in proliferation, cell cycle, cytoskeleton modification and autophagy; meanwhile, 29 miRNAs related to apoptosis, DNA damage repair and xenobiotic metabolism were upregulated.
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http://dx.doi.org/10.1016/j.envpol.2018.05.073DOI Listing
October 2018

Early and Partial Reduction in CD4Foxp3 Regulatory T Cells during Colitis-Associated Colon Cancer Induces CD4 and CD8 T Cell Activation Inhibiting Tumorigenesis.

J Cancer 2018 1;9(2):239-249. Epub 2018 Jan 1.

Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM).

Colorectal cancer (CRC) is the second most commonly diagnosed cancer in women and the third in men in North America and Europe. CRC is associated with inflammatory responses in which intestinal pathology is caused by different cell populations including a T cell dysregulation that concludes in an imbalance between activated T (Tact) and regulatory T (Treg) cells. Treg cells are CD4Foxp3 cells that actively suppress pathological and physiological immune responses, contributing to the maintenance of immune homeostasis. A tumor-promoting function for Treg cells has been suggested in CRC, but the kinetics of Treg cells during CRC development are poorly known. Therefore, using a mouse model of colitis-associated colon cancer (CAC) induced by azoxymethane and dextran sodium sulfate, we observed the dynamic and differential kinetics of Treg cells in blood, spleen and mesenteric lymph nodes (MLNs) as CAC progresses, highlighting a significant reduction in Treg cells in blood and spleen during early CAC development, whereas increasing percentages of Treg cells were detected in late stages in MLNs. Interestingly, when Treg cells were decreased, Tact cells were increased and vice versa. Treg cells from late stages of CAC displayed an activated phenotype by expressing PD1, CD127 and Tim-3, suggesting an increased suppressive capacity. Suppression assays showed that T-CD4 and T-CD8 cells were suppressed more efficiently by MLN Treg cells from CAC animals. Finally, an antibody-mediated reduction in Treg cells during early CAC development resulted in a better prognostic value, because animals showed a reduction in tumor progression associated with an increased percentage of activated CD4CD25Foxp3 and CD8CD25 T cells in MLNs, suggesting that Treg cells suppress T cell activation at early steps during CAC development.
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http://dx.doi.org/10.7150/jca.21336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771330PMC
January 2018

Time course gene expression data in colon of mice after exposure to food-grade E171.

Data Brief 2018 Feb 22;16:531-600. Epub 2017 Nov 22.

Department of Toxicogenomics, GROW Institute of Oncology and Developmental Biology, Maastricht University, The Netherlands.

We investigated gene expression responses in BALB/c mice exposed by gavage to 5 mg/kg bw/day of E171 for 2, 7, 14 and 21 days. Food additive E171 (titanium dioxide) has been shown to induce oxidative stress and DNA damage as well as facilitating growth of colorectal tumours . Full genome expression changes of the colon of mice were investigated by using Agilent SurePrint G3 mouse Gene exp 60kv2 microarrays slides. The data presented in this DiB include all differentially expressed for each time point with EntrezGeneID, gene symbols, gene names and Log2FC as well as genes included in pathways after over-representation analysis in ConsensusPathDataBase. The functions of these genes in relation to the colon were described in our associated article (Proquin et al., 2017 in press) [1]. Raw and normalized gene expression data are available through NCBI GEO (GEO accession: GSE92563).
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http://dx.doi.org/10.1016/j.dib.2017.11.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726758PMC
February 2018

Influence of shape and dispersion media of titanium dioxide nanostructures on microvessel network and ossification.

Colloids Surf B Biointerfaces 2018 Feb 23;162:193-201. Epub 2017 Nov 23.

Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Av. De los Barrios 1, Col. Los Reyes Iztacala, CP 54090, Tlalnepantla, Estado de México, Mexico. Electronic address:

Titanium dioxide nanoparticles (TiO NPs) production has been used for pigment, food and cosmetic industry and more recently, shaped as belts for treatment of contaminated water, self-cleaning windows and biomedical applications. However, the toxicological data have demonstrated that TiO NPs inhalation induce inflammation in in vivo models and in vitro exposure leads to cytotoxicity and DNA damage. Dermal exposure has limited adverse effects and the possible risks for implants used for tissue regeneration is still under research. Then, it has been difficult to establish a straight statement about TiO NPs toxicity since route of exposure and shapes of nanoparticles play an important role in the effects. In this study we aimed to investigate the effect of three different types of TiO NPs (industrial, food-grade and belts) dispersed in fetal bovine serum (FBS) and saline solution (SS) on microvessel network, angiogenesis gene expression and femur ossification using a chick embryo model after an acute exposure of NPs on the day 7 after eggs fertilization. Microvascular density of chorioallantoic membrane (CAM) was analyzed after 7days of NPs injection and vehicles induced biological effects per se. NPs dispersed in FBS or SS have slight differences in microvascular density, mainly opposite effect on angiogenesis gene expression and no effects on femur ossification for NPs dispersed in SS. Interestingly, NPs shaped as belts dramatically prevented the alterations in ossification induced by FBS used as vehicle.
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http://dx.doi.org/10.1016/j.colsurfb.2017.11.049DOI Listing
February 2018

Gene expression profiling in colon of mice exposed to food additive titanium dioxide (E171).

Food Chem Toxicol 2018 Jan 8;111:153-165. Epub 2017 Nov 8.

Department of Toxicogenomics, GROW Institute of Oncology and Developmental Biology, Maastricht University, The Netherlands.

Dietary factors that may influence the risks of colorectal cancer, including specific supplements, are under investigation. Previous studies showed the capacity of food additive titanium dioxide (E171) to induce DNA damage in vitro and facilitate growth of colorectal tumours in vivo. This study aimed to investigate the molecular mechanisms behind these effects after E171 exposure. BALB/c mice were exposed by gavage to 5 mg/kg/day of E171 for 2, 7, 14, and 21 days. Transcriptome changes were studied by whole genome mRNA microarray analysis on the mice's distal colons. In addition, histopathological changes as well as a proliferation marker were analysed. The results showed significant gene expression changes in the olfactory/GPCR receptor family, oxidative stress, the immune system and of cancer related genes. Transcriptome analysis also identified genes that thus far have not been included in known biological pathways and can induce functional changes by interacting with other genes involved in different biological pathways. Histopathological analysis showed alteration and disruption in the normal structure of crypts inducing a hyperplastic epithelium. At cell proliferation level, no consistent increase over time was observed. These results may offer a mechanistic framework for the enhanced tumour growth after ingestion of E171 in BALB/c mice.
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http://dx.doi.org/10.1016/j.fct.2017.11.011DOI Listing
January 2018

Lack of STAT6 Attenuates Inflammation and Drives Protection against Early Steps of Colitis-Associated Colon Cancer.

Cancer Immunol Res 2017 05 6;5(5):385-396. Epub 2017 Apr 6.

Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de México, Edo. De México, Mexico.

Colitis-associated colon cancer (CAC) is one of the most common malignant neoplasms and a leading cause of death. The immunologic factors associated with CAC development are not completely understood. Signal transducer and activator of transcription 6 (STAT6) is part of an important signaling pathway for modulating intestinal immune function and homeostasis. However, the role of STAT6 in colon cancer progression is unclear. Following CAC induction in wild-type (WT) and STAT6-deficient mice (STAT6), we found that 70% of STAT6 mice were tumor-free after 8 weeks, whereas 100% of WT mice developed tumors. STAT6 mice displayed fewer and smaller colorectal tumors than WT mice; this reduced tumorigenicity was associated with decreased proliferation and increased apoptosis in the colonic mucosa in the early steps of tumor progression. STAT6 mice also exhibited reduced inflammation, diminished concentrations COX2 and nuclear β-catenin protein in the colon, and decreased mRNA expression of IL17A and TNFα, but increased IL10 expression when compared with WT mice. Impaired mucosal expression of CCL9, CCL25, and CXCR2 was also observed. In addition, the number of circulating CD11bLy6CCCR2 monocytes and CD11bLy6CLy6G granulocytes was both decreased in a STAT6-dependent manner. Finally, WT mice receiving a STAT6 inhibitor confirmed a significant reduction in tumor load as well as less intense signs of CAC. Our results demonstrate that STAT6 is critical in the early steps of CAC development for modulating inflammatory responses and controlling cell recruitment and proliferation. Thus, STAT6 may represent a promising target for CAC treatment. .
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http://dx.doi.org/10.1158/2326-6066.CIR-16-0168DOI Listing
May 2017

Current FDA-approved treatments for non-small cell lung cancer and potential biomarkers for its detection.

Biomed Pharmacother 2017 Jun 21;90:24-37. Epub 2017 Mar 21.

Laboratorio de Carcinogénesis y Toxicología, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, CP 54059, Estado de México, Mexico. Electronic address:

Background: Lung cancer is the leading worldwide cancer with almost 1.5 million deaths every year. Some drugs for lung cancer treatment have been available on the market for decades, but novel drugs have emerged promising better outcomes, especially for Non-Small Cell Lung Cancer (NSCLC), which represents 75% of lung cancer cases. However, how much do drugs have evolved for NSCLC treatment? Are they sharing the same mechanism of action?

Aim: In this review we analyzed how the approved drugs by Federal Drug Agency for NSCLC have advanced in the last four decades identifying shared mechanism of action of medicines against NSCLC treatment and some of the potential biomarkers for early detection.

Results: Cisplatin and its derivatives are still the most used therapy in combination with some other more specific drugs. However, increasing the survival rates seems to be a great challenge and research is moving into early detection through biomarkers but also trying to identify molecules such as those derived from the immune system, cell-free DNA, non-coding RNAs, but also polymorphisms to detect early tumor formation.

Conclusions: Cisplatin and derivatives have been one of the most successful therapies in spite of their side effects and low specificity. Some of the drugs developed after cisplatin discovery, have been targeted the epidermal growth factor receptor, anaplastic lymphoma kinase, programmed cell death 1 ligand and vascular endothelial growth factor. Since none of the pharmacological treatments in combination with radiation/surgery have extended dramatically the survival rate, research is now focused in early cancer detection in combination with precision medicine, which attempts to treat patients individually according to their stage and tumor characteristics.
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http://dx.doi.org/10.1016/j.biopha.2017.03.018DOI Listing
June 2017

Airborne particulate matter in vitro exposure induces cytoskeleton remodeling through activation of the ROCK-MYPT1-MLC pathway in A549 epithelial lung cells.

Toxicol Lett 2017 Apr 6;272:29-37. Epub 2017 Mar 6.

Instituto Nacional de Cancerología (INCan), Subdirección de Investigación Básica, San Fernando No. 22, Tlalpan, 14080 CDMX, Mexico. Electronic address:

Airborne particulate matter with an aerodynamic diameter ≤10μm (PM) is considered a risk factor for the development of lung cancer. Little is known about the cellular mechanisms by which PM is associated with cancer, but there is evidence that its exposure can lead to an acquired invasive phenotype, apoptosis evasion, inflammasome activation, and cytoskeleton remodeling in lung epithelial cells. Cytoskeleton remodeling occurs through actin stress fiber formation, which is partially regulated through ROCK kinase activation, we aimed to investigate if this protein was activated in response to PM exposure in A549 lung epithelial cells. Results showed that 10μg/cm of PM had no influence on cell viability but increased actin stress fibers, cytoplasmic ROCK expression, and phosphorylation of myosin phosphatase-targeting 1 (MYPT1) and myosin light chain (MLC) proteins, which are targeted by ROCK. The inhibition of ROCK prevented actin stress fiber formation and the phosphorylation of MYPT1 and MLC, suggesting that PM activated the ROCK-MYPT1-MLC pathway in lung epithelial cells. The activation of ROCK1 has been involved in the acquisition of malignant phenotypes, and its induction by PM exposure could contribute to the understanding of PM as a risk factor for cancer development through the mechanisms associated with invasive phenotype.
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http://dx.doi.org/10.1016/j.toxlet.2017.03.002DOI Listing
April 2017

Titanium dioxide food additive (E171) induces ROS formation and genotoxicity: contribution of micro and nano-sized fractions.

Mutagenesis 2017 01 27;32(1):139-149. Epub 2016 Oct 27.

Unidad de Biomedicina, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autonoma de Mexico (UNAM), Estado de Mexico, Mexico and.

Since 1969, the European Union approves food-grade titanium dioxide (TiO), also known as E171 colouring food additive. E171 is a mixture of micro-sized particles (MPs) and nano-sized particles (NPs). Previous studies have indicated adverse effects of oral exposure to E171, i.e. facilitation of colon tumour growth. This could potentially be partially mediated by the capacity to induce reactive oxygen species (ROS). The aim of the present study is to determine whether E171 exposure induces ROS formation and DNA damage in an in vitro model using human Caco-2 and HCT116 cells and to investigate the contribution of the separate MPs and NPs TiO fractions to these effects. After suspension of the particles in Hanks' balanced salt solution buffer and cell culture medium with either bovine serum albumin (BSA) or foetal bovine serum, characterization of the particles was performed by dynamic light scattering, ROS formation was determined by electron spin/paramagnetic resonance spectroscopy and DNA damage was determined by the comet and micronucleus assays. The results showed that E171, MPs and NPs are stable in cell culture medium with 0.05% BSA. The capacity for ROS generation in a cell-free environment was highest for E171, followed by NPs and MPs. Only MPs were capable to induce ROS formation in exposed Caco-2 cells. E171, MPs and NPs all induced single-strand DNA breaks. Chromosome damage was shown to be induced by E171, as tested with the micronucleus assay in HCT116 cells. In conclusion, E171 has the capability to induce ROS formation in a cell-free environment and E171, MPs and NPs have genotoxic potential. The capacity of E171 to induce ROS formation and DNA damage raises concerns about potential adverse effects associated with E171 (TiO) in food.
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http://dx.doi.org/10.1093/mutage/gew051DOI Listing
January 2017
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