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Plastic material versatility has resulted in a substantial increase in its use in several sectors of our everyday lives. Consequently, concern regarding human exposure to nano-plastics (NPs) and micro-plastics (MPs) has recently increased. It has been shown that plastic particles entering the bloodstream may adhere to the erythrocyte surface and exert adverse effects following erythrocyte aggregation and adhesion to blood vessels. Here, we explored the effects of polystyrene nano-plastics (PS-NPs) and micro-plastics (PS-MPs) on human erythrocytes. Cellular morphology, binding/internalization of PS-NPs and PS-MPs, oxidative stress parameters, as well as the distribution and anion exchange capability of band 3 (anion exchanger 1; SLC4A1) have been analyzed in human erythrocytes exposed to 1 µg/mL PS-NPs or PS-MPs for 3 and 24 h, respectively. The data obtained showed significant modifications of the cellular shape after exposure to PS-NPs or PS-MPs. In particular, a significantly increased number of acanthocytes, echinocytes and leptocytes were detected. However, the percentage of eryptotic cells (<1 %) was comparable to physiological conditions. Analytical cytology and confocal microscopy showed that PS-NPs and PS-MPs bound to the erythrocyte plasma membrane, co-localized with estrogen receptors (Erα/ERß), and were internalized. An increased trafficking from the cytosol to the erythrocyte plasma membrane and abnormal distribution of ERs were also observed, consistent with ERα-mediated binding and internalization of PS-NPs. An increased phosphorylation of ERK1/2 and AKT kinases indicated that an activation of the ER-modulated non-genomic pathway occurred following exposure to PS-NPs and PS-MPs. Interestingly, PS-NPs or PS-MPs caused a significant production of reactive oxygen species, resulting in an increased lipid peroxidation and protein sulfhydryl group oxidation. Oxidative stress was also associated with an altered band 3 ion transport activity and increased oxidized haemoglobin, which led to abnormal clustering of band 3 on the plasma membrane. Taken together, these findings identify cellular events following the internalization of PS-NPs or PS-MPs in human erythrocytes and contribute to elucidating potential oxidative stress-related harmful effects, which may affect erythrocyte and systemic homeostasis.
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BACKGROUND: The natural history and pathophysiology of diverticular disease (DD) are still uncertain. An ex-vivo human complicated DD (cDD) model has recently shown a predominant transmural oxidative imbalance. The present study aims to evaluate whether the previously described alterations may precede the symptomatic form of the disease. METHODS: Colonic surgical samples obtained from patients with asymptomatic diverticulosis (DIV), complicated DD, and controls were systematically and detailed morphologically and molecularly analyzed. Therefore, histologic, histomorphometric, immunohistochemical evaluation, and gene and protein expression analysis were performed to characterize colonic muscle changes and evaluate chronic inflammation, oxidative imbalance, and hypoxia. Functional muscle activity was tested on strips and isolated cells in response to contractile and relaxant agents. KEY RESULTS: Compared with controls, DD showed a marketed increase in muscle layer thickness, smooth muscle cell syncytium disarray, and increased interstitial fibrosis; moreover, the observed features were more evident in the cDD group. These changes mainly affected longitudinal muscle and were associated with altered contraction-relaxation dynamics and fibrogenic switch of smooth muscle cells. Chronic lymphoplasmacytic inflammation was primarily evident in the mucosa and spared the muscle. A transmural increase in carbonylated and nitrated proteins, with loss of antioxidant molecules, characterized both stages of DD, suggesting early oxidative stress probably triggered by recurrent ischemic events, more pronounced in cDD, where HIF-1 was detected in both muscle and mucosa. CONCLUSION & INFERENCES: The different DD clinical scenarios are part of a progressive process, with oxidative imbalance representing a new target in the management of DD.
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Progresión de la Enfermedad , Músculo Liso , Estrés Oxidativo , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estrés Oxidativo/fisiología , Músculo Liso/metabolismo , Músculo Liso/patología , Enfermedades Diverticulares/metabolismo , Diverticulosis del Colon/metabolismo , Diverticulosis del Colon/patología , Colon/patología , Colon/metabolismo , Contracción Muscular/fisiologíaRESUMEN
Diverticular disease (DD) management is impaired by its pathogenesis, which is still not completely defined, with an unmet clinical need for improved therapies. Ex vivo DD human models demonstrated the presence of a transmural oxidative imbalance that supports an ischemic pathogenesis. This study aimed to assess, with the use of circulating biomarkers, insights into DD pathogenesis and possible therapeutic targets. Nox2-derived peptide, H2O2, antioxidant capacity, isoprostanes, thromboxanes, TNF-α, LPS and zonulin were evaluated by ELISA in healthy subjects (HS) and asymptomatic and symptomatic DD patients. Compared to HS, DD patients presented low antioxidant capacity and increase in sNox2-dp, H2O2 and isoprostanes paralleled to a TNFα increase, lower than that of oxidative markers. TxB2 production correlated to Nox2 and isoprostanes, suggesting platelet activation. An increase in zonulin and LPS highlighted the role of gut permeability and LPS translocation in DD pathogenesis. The increase of all the markers statistically correlated with DD severity. The present study confirmed the presence of a main oxidative imbalance in DD and provides evidence of platelet activation driven by LPS translocation. The use of circulating biomarkers could represent a new clinical tool for monitoring disease progression and validate therapeutic strategies never tested in DD as antioxidant supplementation.
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Dynamic reciprocity between cellular components of the tumor microenvironment and tumor cells occurs primarily through the interaction of soluble signals, i.e., cytokines produced by stromal cells to support cancer initiation and progression by regulating cell survival, differentiation and immune cell functionality, as well as cell migration and death. In the present study, we focused on the analysis of the functional response of non-small cell lung cancer cell lines elicited by the treatment with some crucial stromal factors which, at least in part, mimic the stimulus exerted in vivo on tumor cells by microenvironmental components. Our molecular and functional results highlight the role played by the autophagic machinery in the cellular response in terms of the invasive capacity, stemness and drug resistance of two non-small lung cancer cell lines treated with stromal cytokines, also highlighting the emerging role of the YAP pathway in the mutual and dynamic crosstalk between tumor cells and tumor microenvironment elements. The results of this study provide new insights into the YAP-mediated autophagic mechanism elicited by microenvironmental cytokines on non-small cell lung cancer cell lines and may suggest new potential strategies for future cancer therapeutic interventions.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Microambiente Tumoral , Citocinas , Línea Celular Tumoral , Autofagia , Resistencia a MedicamentosRESUMEN
BACKGROUND: Social distancing and quarantine imposed by the authority during the COVID-19 pandemic caused restrictions, which had a negative impact on eating behavior, especially among adolescents. We proposed a retrospective study aimed to evaluate the effect of the COVID-19 pandemic on eating disorders risk and symptoms. METHODS: In this study, a group of 127 pediatric patients (117 females and 10 males) with eating disorders admitted to the Bambino Gesù Children's Hospital of Rome (Italy), in the period between August 2019 and April 2021, was analyzed. All patient data were collected from patients' electronic medical records. RESULTS: We found that 80.3% of patients were at the onset of eating disorders and that 26% of patients had familiarity for psychotic disorders. Often these patients had comorbidities and alterations in blood parameters such as leukocytopenia, neutropenia, hypovitaminosis and hormonal problems that could affect their future. CONCLUSIONS: Our findings could provide a framework for developing clinical and educational interventions to mitigate the short- and long-term negative impact of the pandemic on adolescent future health.
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COVID-19 , Trastornos de Alimentación y de la Ingestión de Alimentos , Adolescente , Femenino , Masculino , Humanos , Niño , COVID-19/epidemiología , Estudios Retrospectivos , Pandemias , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Salud del AdolescenteRESUMEN
Downregulation of cell surface ß-adrenergic receptors (ß-AR) is an important adaptive response that prevents deleterious effects of receptor overstimulation. Various factors including reactive oxygen species cause ß-AR downregulation. In this study, we evaluated the effects of ligands of the peripheral benzodiazepine receptor (PBR), a key protein in regulating oxidative stress, on surface density of endogenous ß1-and ß2-ARs in highly differentiated cells such as human monocytes, which express both ß-AR subtypes. ß-AR expression in human monocytes was evaluated by flow cytometry, qPCR and western blotting. Monocyte treatment with ß-AR agonist isoproterenol did not change surface ß1-AR density while downregulating surface ß2-AR density. This effect was antagonized by the ß-blocker propranolol. An opposite response was observed with benzodiazepine diazepam that led to a time-dependent reduction in ß1-AR density. In particular, while no significant downregulation was observed after 3 h of treatment, only 63% of ß1-ARs were still present on the cell surface after 48 h of treatment with diazepam at 1 µM. Treatment with the PBR antagonist PK11195, but not with propranolol, antagonized the effects of diazepam. No change in ß1-AR-mRNA or protein levels was observed at any time after diazepam treatment. We also found that diazepam did not affect Gs-protein or ß-arrestin-2 recruitment for both ß-ARs in engineered fibroblasts, further suggesting that diazepam activity on ß1-AR density is mediated by PBR. Finally, no sex-related differences were found. Collectively, these results indicate that monocyte ß1-ARs are resistant to catecholamine-mediated downregulation and suggest that PBR plays an important role in regulating ß1-AR density.
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Monocitos , Propranolol , Humanos , Monocitos/metabolismo , Propranolol/farmacología , Benzodiazepinas , Diazepam/farmacología , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismoRESUMEN
Red blood cells (RBCs) are recognized to be important pathogenetic determinants in several human cardiovascular diseases (CVD). Undergoing to functional alterations when submitted to risk factors, RBCs modify their own intracellular signaling and the redox balance, shift their status from antioxidant defense to pro-oxidant agents, become a potent atherogenic stimulus playing a key role in the dysregulation of the vascular homeostasis favoring the developing and progression of CVD. Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a significantly increased risk of cardiovascular mortality with a prevalence from two to five more likely in woman, mainly attributed to accelerated atherosclerosis. The purpose of this study was to correlate the RA disease activity and the RBCs functional characteristics. Thirty-two women (aged more than 18 years) with RA, and 25 age-matched healthy women were included in this study. The disease activity, measured as the number of swollen and painful joints (DAS-28), was correlated with 1) the expression of RBCs estrogen receptors, which modulate the RBC intracellular signaling, 2) the activation of the estrogen-linked kinase ERK½, which is a key regulator of RBC adhesion and survival, and 3) the levels of inflammatory- and oxidative stress-related biomarkers, such as the acute-phase reactants, the antioxidant capacity of plasma, the reactive oxidizing species formation and 3-nitrotyrosine. All the biomarkers were evaluated in RA patients at baseline and 6 months after treatment with disease-modifying anti-rheumatic drugs (DMARDs). We found, for the first times, that in RA patients 1) the DAS-28 correlated with RBC ER-α expression, and did not correlate with total antioxidant capacity of plasma; 2) the RBC ER-α expression correlated with systemic inflammatory biomarkers and oxidative stress parameters, as well as ERK½ phosphorylation; and 3) the DMARDs treatments improved the clinical condition measured by DAS-28 score decrease, although the RBCs appeared to be more prone to pro-oxidant status associated to the expression of survival molecules. These findings represent an important advance in the study of RA determinants favoring the developing of CVD, because strongly suggest that RBCs could also participate in the vascular homeostasis through fine modulation of an intracellular signal linked to the ER-α.
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Autophagy is a lysosomal degradation and recycling process involved in tumor progression and drug resistance. The aim of this work was to inhibit autophagy and increase apoptosis in a 3D model of human colorectal cancer by combined treatment with our patented natural product Prunus spinosa + nutraceutical activator complex (PsT + NAC®) and 5-fluorouracil (5-FU). By means of cytotoxic evaluation (MTT assay), cytofluorimetric analysis, light and fluorescence microscopy investigation and Western blotting evaluation of the molecular pathway PI3/AKT/mTOR, Caspase-9, Caspase-3, Beclin1, p62 and LC3, we demonstrated that the combination PsT + NAC® and 5-FU significantly reduces autophagy by increasing the apoptotic phenomenon. These results demonstrate the importance of using non-toxic natural compounds to improve the therapeutic efficacy and reduce the side effects induced by conventional drugs in human colon cancer.
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Antineoplásicos , Neoplasias del Colon , Prunus , Humanos , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Antineoplásicos/farmacología , Neoplasias del Colon/patología , Apoptosis , Autofagia , Línea Celular TumoralRESUMEN
Adrenergic receptors (AR) belong to the G protein-coupled receptor superfamily and regulate migration and proliferation in various cell types. The objective of this study was to evaluate whether ß-AR stimulation affects the antiproliferative action of α2-AR agonists on B16F10 cells and, if so, to determine the relative contribution of ß-AR subtypes. Using pharmacological approaches, evaluation of Ki-67 expression by flow cytometry and luciferase-based cAMP assay, we found that treatment with isoproterenol, a ß-AR agonist, increased cAMP levels in B16F10 melanoma cells without affecting cell proliferation. Propranolol inhibited the cAMP response to isoproterenol. In addition, stimulation of α2-ARs with agonists such as clonidine, a well-known antihypertensive drug, decreased cancer cell proliferation. This effect on cell proliferation was suppressed by treatment with isoproterenol. In turn, the suppressive effects of isoproterenol were abolished by the treatment with either ICI 118,551, a ß2-AR antagonist, or propranolol, suggesting that isoproterenol effects are mainly mediated by the ß2-AR stimulation. We conclude that the crosstalk between the ß2-AR and α2-AR signaling pathways regulates the proliferative activity of B16F10 cells and may therefore represent a therapeutic target for melanoma therapy.
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Melanoma , Receptores Adrenérgicos alfa 2 , Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacología , Línea Celular Tumoral , Proliferación Celular , Humanos , Isoproterenol/farmacología , Isoproterenol/uso terapéutico , Melanoma/metabolismo , Propranolol/farmacología , Propranolol/uso terapéutico , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 1 , Receptores Adrenérgicos beta 2/metabolismoRESUMEN
BACKGROUND: It is still a matter of debate if neuromuscular alterations reflect a primary event in diverticular disease (DD). AIMS: This study aimed to assess colonic wall layers from both stenotic and non-stenotic complicated DD, bio-phenotypic alterations, inflammatory and oxidative status. METHODS: A systematic analysis of colonic specimens obtained from stenotic and non-stenotic DD specimens was conducted and compared with controls. Biological activity and qPCR analysis were performed on longitudinal and circular muscles. Western blot analysis was performed throughout colonic wall layers to quantify oxidative and inflammatory markers. RESULTS: A homogenous increase in oxidative stress was observed through all the layers, which were more sharpened in the longitudinal muscle for a loss in antioxidant defenses. In both stenotic and non-stenotic colon, the longitudinal muscle presented an impaired relaxation and a cellular phenotypic switch driven by transforming growth factor-ß with an increase in mRNA expression of collagen Iα and a decrease in myosin heavy chain. The circular muscle, as the mucosa, was less affected by molecular alterations. No peculiar increase in inflammatory markers was observed. CONCLUSION: A longitudinal colonic myopathy is present in DD, independently from the disease stage associated with an oxidative imbalance that could suggest new therapeutic strategies.
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Enfermedades Diverticulares , Diverticulitis del Colon , Colon , Humanos , Músculo Liso , Estrés OxidativoRESUMEN
In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by both unfavorable environmental conditions and therapeutic drugs. Many oncogenes and tumor suppressor genes have a significant effect on cellular metabolism, as there is a close relationship between the pathways activated by these genes and the various metabolic options. The metabolic adaptations observed in cancer cells not only promote their proliferation and invasion, but also their survival by inducing intrinsic and acquired resistance to various anticancer agents and to various forms of cell death, such as apoptosis, necroptosis, autophagy, and ferroptosis. In this review we analyze the main metabolic differences between cancer and non-cancer cells and how these can affect the various cell death pathways, effectively determining the susceptibility of cancer cells to therapy-induced death. Targeting the metabolic peculiarities of cancer could represent in the near future an innovative therapeutic strategy for the treatment of those tumors whose metabolic characteristics are known.
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Mitochondria constitute an ever-reorganizing dynamic network that plays a key role in several fundamental cellular functions, including the regulation of metabolism, energy production, calcium homeostasis, production of reactive oxygen species, and programmed cell death. Each of these activities can be found to be impaired in cancer cells. It has been reported that mitochondrial dynamics are actively involved in both tumorigenesis and metabolic plasticity, allowing cancer cells to adapt to unfavorable environmental conditions and, thus, contributing to tumor progression. The mitochondrial dynamics include fusion, fragmentation, intracellular trafficking responsible for redistributing the organelle within the cell, biogenesis, and mitophagy. Although the mitochondrial dynamics are driven by the cytoskeleton-particularly by the microtubules and the microtubule-associated motor proteins dynein and kinesin-the molecular mechanisms regulating these complex processes are not yet fully understood. More recently, an exchange of mitochondria between stromal and cancer cells has also been described. The advantage of mitochondrial transfer in tumor cells results in benefits to cell survival, proliferation, and spreading. Therefore, understanding the molecular mechanisms that regulate mitochondrial trafficking can potentially be important for identifying new molecular targets in cancer therapy to interfere specifically with tumor dissemination processes.
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Acute myocardial infarction (MI) is associated with an intense inflammatory response that is critical for cardiac repair but is also involved in the pathogenesis of adverse cardiac remodeling, i.e., the set of size, geometry, and structure changes that represent the structural substrate for the development of post-MI heart failure. Deciphering the pathophysiological mechanisms underlying cardiac repair after MI is, therefore, critical to favorably regulate cardiac wound repair and to prevent development of heart failure. Catecholamines and estrogen play an active role in regulating the inflammatory response in the infarcted area. For example, stress-induced catecholamines alter recruitment and trafficking of leukocytes to the heart. Additionally, estrogen affects rate of cardiac rupture during the acute phase of MI, as well as infarct size and survival in animal models of MI. In this review, we will summarize the role of ß-adrenergic receptors and estrogen in cardiac repair after infarction in preclinical studies.
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Estrógenos/metabolismo , Insuficiencia Cardíaca/prevención & control , Infarto del Miocardio/complicaciones , Receptores Adrenérgicos beta/metabolismo , Remodelación Ventricular , Animales , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , HumanosRESUMEN
We investigated the chemosensitizing effect of electroporation (EP), which, using electrical pulses, permeabilizes cancer cells to drugs. The study involved two human hypopharyngeal and tongue carcinoma cell lines. The surface and intracytoplasmic expression of P-gp were evaluated by flow cytometry, demonstrating that both lines were intrinsically resistant. After establishing the optimal dose of mitomycin C (MMC) to be used, in combination with EP, we showed, by both MTT assay and optical and electron scanning microscopy, the potentiating cytotoxic effect of EP with MMC compared to single treatments. Flow cytometry showed that the cytotoxicity of EP + MMC was due to the induction of apoptosis. In addition to verifying the release of cytochrome C in EP + MMC samples, we performed an expression analysis of caspase-3, caspase-9, Akt, pAkt, HMGB1, LC3I, LC3II, p62, Beclin1, and associated proteins with both apoptotic and autophagic phenomena. Our results were confirmed by two veterinary patients in whom the EP + MMC combination was used to control margins after the resection of corneal squamous carcinoma. In conclusion, we affirmed that the effect for which EP enhances MMC treatment is due to the inhibition of the autophagic process induced by the drug in favor of apoptosis.
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BACKGROUND: Since December 2019 coronavirus disease (COVID-19) emerged in Wuhan and spread rapidly worldwide. Despite the high number of people affected, data on clinical features and prognostic factors in children and adolescents are limited. We propose a retrospective study aimed to evaluate clinical characteristics of children infected with SARS-CoV-2 in Italy. METHODS: A pediatric population admitted with COVID-19 to Bambino Gesù Children's Hospital of Rome (Italy) in the period from the end of February to July 2020 has been studied. Medical history, comorbidities, symptoms and laboratory findings were obtained from patients' electronic medical records. RESULTS: In 66 patients (35 males and 31 females) we found that: i) fever and cough were the dominant symptoms, while vomit and convulsions were rare symptoms; and ii) all ages of childhood were susceptible to COVID-19. Furthermore, we found that, compared to females, males with COVID-19, although not significantly, had higher values of inflammatory markers such as C-reactive protein (CRP) and ESR. Conversely, we found that COVID-19 positive females were older than males and required more days of hospitalization. Both males and females COVID-19 positives had procalcitonin values within the normal range and D-Dimer values slightly higher than the normal range. With regard to this latter marker, the value measured in females, although not significant, was higher than that measured in males. Interestingly, the presence of leukopenia was found in both sexes. CONCLUSIONS: Compared to the adults we found that COVID-19 infection in children is a non-severe inflammatory disease in both males and females. In any case, many detailed studies should be conducted.
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COVID-19/epidemiología , Neumonía Viral/epidemiología , Índice de Severidad de la Enfermedad , Adolescente , Niño , Preescolar , Comorbilidad , Femenino , Humanos , Lactante , Italia/epidemiología , Masculino , Pandemias , Neumonía Viral/virología , Pronóstico , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the major lipid component of lipid rafts, a sort of lipid-based structures that regulate the assembly and functioning of numerous cell signaling pathways, including those related to cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every stage: import, synthesis, export, metabolism, and storage. The alterations of this homeostatic balance are known to be associated with cardiovascular diseases and atherosclerosis, but mounting evidence also connects these behaviors to increased cancer risks. Although there is conflicting evidence on the role of cholesterol in cancer development, most of the studies consistently suggest that a dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of major players in cholesterol regulation and the organization of lipid rafts, which could represent promising therapeutic targets.
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Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the ß-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.
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Accumulating evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of many diseases. The imbalance between the production of reactive oxygen species (ROS) and the antioxidant systems has been extensively studied in pulmonary, neurodegenerative cardiovascular disorders; however, its contribution is still debated in gastrointestinal disorders. Evidence suggests that oxidative stress affects gastrointestinal motility in obesity, and post-infectious disorders by favoring the smooth muscle phenotypic switch toward a synthetic phenotype. The aim of this review is to gain insight into the role played by oxidative stress in gastrointestinal pathologies (GIT), and the involvement of ROS in the signaling underlying the muscular alterations of the gastrointestinal tract (GIT). In addition, potential therapeutic strategies based on the use of antioxidants for the treatment of inflammatory gastrointestinal diseases are reviewed and discussed. Although substantial progress has been made in identifying new techniques capable of assessing the presence of oxidative stress in humans, the biochemical-molecular mechanisms underlying GIT mucosal disorders are not yet well defined. Therefore, further studies are needed to clarify the mechanisms through which oxidative stress-related signaling can contribute to the alteration of the GIT mucosa in order to devise effective preventive and curative therapeutic strategies.
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Human papillomavirus 16 (HPV16) exhibits a strong oncogenic potential mainly in cervical, anogenital and oropharyngeal cancers. The E6 and E7 viral oncoproteins, acting via specific interactions with host cellular targets, are required for cell transformation and maintenance of the transformed phenotype as well. We previously demonstrated that HPV16E7 interacts with the actin-binding protein gelsolin, involved in cytoskeletal F-actin dynamics. Herein, we provide evidence that the E7/gelsolin interaction promotes the cytoskeleton rearrangement leading to epithelial-mesenchymal transition-linked morphological and transcriptional changes. E7-mediated cytoskeletal actin remodeling induces the HIPPO pathway by promoting the cytoplasmic retention of inactive P-YAP. These results suggest that YAP could play a role in the "de-differentiation" process underlying the acquisition of a more aggressive phenotype in HPV16-transformed cells. A deeper comprehension of the multifaceted mechanisms elicited by the HPV infection is vital for providing novel strategies to block the biological and clinical features of virus-related cancers.
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Several chronic neuroinflammatory diseases, including Parkinson's disease (PD), have the so-called 'redox imbalance' in common, a dynamic system modulated by various factors. Among them, alteration of the mitochondrial functionality can cause overproduction of reactive oxygen species (ROS) with the consequent induction of oxidative DNA damage and apoptosis. Considering the failure of clinical trials with drugs that eliminate ROS directly, research currently focuses on approaches that counteract redox imbalance, thus restoring normal physiology in a neuroinflammatory condition. Herein, we used SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA), a neurotoxin broadly employed to generate experimental models of PD. Cells were pre-treated with the Rho-modulating Escherichia coli cytotoxic necrotizing factor 1 (CNF1), before the addition of 6-OHDA. Then, cell viability, mitochondrial morphology and dynamics, redox profile as well as autophagic markers expression were assessed. We found that CNF1 preserves cell viability and counteracts oxidative stress induced by 6-OHDA. These effects are accompanied by modulation of the mitochondrial network and an increase in macroautophagic markers. Our results confirm the Rho GTPases as suitable pharmacological targets to counteract neuroinflammatory diseases and evidence the potentiality of CNF1, whose beneficial effects on pathological animal models have been already proven to act against oxidative stress through an autophagic strategy.