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Intestinal fibrosis, the most common complication of inflammatory bowel disease (IBD), is characterized by an uncontrolled deposition of extracellular matrix proteins leading to complications resolvable only with surgery. Transforming growth factor is the key player in the epithelial-mesenchymal transition (EMT) and fibrogenesis process, and some molecules modulating its activity, including peroxisome proliferator-activated receptor (PPAR)-γ and its agonists, exert a promising antifibrotic action. The purpose of this study is to evaluate the contribution of signaling other than EMT, such as the AGE/RAGE (advanced glycation end products/receptor of AGEs) and the senescence pathways, in the etiopathogenesis of IBD. We used human biopsies from control and IBD patients, and we used a mouse model of colitis induced by dextran-sodium-sulfate (DSS), without/with treatments with GED (PPAR-gamma-agonist), or 5-aminosalicylic acid (5-ASA), a reference drug for IBD treatment. In patients, we found an increase in EMT markers, AGE/RAGE, and senescence signaling activation compared to controls. Consistently, we found the overexpression of the same pathways in DSS-treated mice. Surprisingly, the GED reduced all the pro-fibrotic pathways, in some circumstances more efficiently than 5-ASA. Results suggest that IBD patients could benefit from a combined pharmacological treatment targeting simultaneously different pathways involved in pro-fibrotic signals. In this scenario, PPAR-gamma activation could be a suitable strategy to alleviate the signs and symptoms of IBD and also its progression.
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Colite , Doenças Inflamatórias Intestinais , Humanos , Camundongos , Animais , PPAR gama/metabolismo , Transição Epitelial-Mesenquimal , Colo/patologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Epitélio/metabolismo , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BLRESUMO
(1) The high-fat diet (HFD) of western countries has dramatic effect on the health of several organs, including the digestive tract, leading to the accumulation of fats that can also trigger a chronic inflammatory process, such as that which occurs in non-alcohol steatohepatitis. The effects of a HFD on the small intestine, the organ involved in the absorption of this class of nutrients, are still poorly investigated. (2) To address this aspect, we administered a combined HFD with sucrose (HFD w/Suc, fat: 58% Kcal) regimen (18 months) to mice and investigated the morphological and molecular changes that occurred in the wall of proximal tract of the small intestine compared to the intestine of mice fed with a standard diet (SD) (fat: 18% Kcal). (3) We found an accumulation of lipid droplets in the mucosa of HFD w/Suc-fed mice that led to a disarrangement of mucosa architecture. Furthermore, we assessed the expression of several key players involved in lipid metabolism and inflammation, such as perilipin, leptin, leptin receptor, PI3K, p-mTOR, p-Akt, and TNF-α. All these molecules were increased in HFD mice compared to the SD group. We also evaluated anti-inflammatory molecules like adiponectin, adiponectin receptor, and PPAR-γ, and observed their significant reduction in the HFD w/Suc group compared to the control. Our data are in line with the knowledge that improper eating habits present a primary harmful assault on the bowel and the entire body's health. (4) These results represent a promising starting point for future studies, helping to better understand the complex and not fully elucidated spectrum of intestinal alterations induced by the overconsumption of fat.
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Dieta Hiperlipídica/efeitos adversos , Sacarose Alimentar/administração & dosagem , Sacarose Alimentar/efeitos adversos , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Adiponectina/metabolismo , Animais , Comportamento Alimentar/fisiologia , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/metabolismo , Receptores para Leptina/metabolismoRESUMO
PURPOSE: The characterization of atherosclerotic carotid plaque plays a key role in the identification of patients at risk. The aim of our work was to evaluate the potentialities of carotid computed tomography angiography (CCTA) in assessing composition of atherosclerotic plaque. MATERIALS AND METHODS: We retrospectively evaluated 29 patients (7 women and 22 men, age range 54-81; mean age 69) who underwent carotid endarterectomy. All patients underwent pre-surgical CCTA using a 320-slice scanner. Post-processing reconstructions and analysis were performed using a specific software. Percentage of three different components of the atherosclerotic plaque (adipose, fibrotic and calcific) were classified based on Hounsfield unit values. Post-processing results were compared with histological analysis. Vessel and plaque parameters were compared using the Pearson correlation coefficient (r). Bland-Altman plots with 95% confidence intervals were calculated for correlation. McNemar's test was used for comparison of dichotomous variables. RESULTS: A significant correlation between histology and CCTA was found with respect to the areas corresponding to adipose, fibrotic and calcified plaques. The existence of proportional bias was observed between the two quantifying methods with lower discrepancies found for the adipose and fibrotic plaque areas. The Bland-Altman analyses showed a mean bias of 3.2%, 2.5% and 0.6% between histology and CCTA, for adipose, fibrotic and calcified plaque areas, respectively. CONCLUSIONS: Multi-detector CT angiography represents a valuable technique to assess quantitatively the composition of atherosclerotic plaques, with particular reference to the prevalence of fibrotic tissue, and is a useful diagnostic tool to improve risk stratification of patients for cerebral stroke.
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Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/patologia , Imageamento Tridimensional , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
One of the main mechanisms carried out by the cells to counteract several forms of stress is the activation of the nuclear factor erythroid 2-related factor (Nrf2) signaling. Nrf2 signaling controls the expression of many genes through the binding of a specific cis-acting element known as the antioxidant response element (ARE). Activation of Nrf2/ARE signaling can mitigate several pathologic mechanisms associated with an autoimmune response, digestive and metabolic disorders, as well as respiratory, cardiovascular, and neurodegenerative diseases. Indeed, several studies have demonstrated that Nrf2 pathway plays a key role in inflammation and in cancer development in many organs, including the intestine. Nrf2 appears to be involved in inflammatory bowel disease (IBD), an immune-mediated chronic and disabling disease, with a high risk of developing intestinal fibrotic strictures and cancer. Currently, drugs able to increase cytoprotective Nrf2 function are in clinical trials or already being used in clinical practice to reduce the progression of some degenerative conditions. The role of Nrf2 in cancer development and progression is controversial, and drugs able to inhibit abnormal levels of Nrf2 are also under investigation. The goal of this review is to analyze and discuss Nrf2-dependent signals in the initiation and progression of intestinal fibrosis and cancers occurring in IBD.
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Neoplasias Colorretais/metabolismo , Inflamação/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Fibrose/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Morbidity in advanced prostate cancer patients is largely associated with bone metastatic events. The development of novel therapeutic strategies is imperative in order to effectively treat this incurable stage of the malignancy. In this context, Akt signaling pathway represents a promising therapeutic target able to counteract biochemical recurrence and metastatic progression in prostate cancer. We explored the therapeutic potential of a novel dual PI3 K/mTOR inhibitor, X480, to inhibit tumor growth and bone colonization using different in vivo prostate cancer models including the subcutaneous injection of aggressive and bone metastatic (PC3) and non-bone metastatic (22rv1) cell lines and preclinical models known to generate bone lesions. We observed that X480 both inhibited the primary growth of subcutaneous tumors generated by PC3 and 22rv1 cells and reduced bone spreading of PCb2, a high osteotropic PC3 cell derivative. In metastatic bone, X480 inhibited significantly the growth and osteolytic activity of PC3 cells as observed by intratibial injection model. X480 also increased the bone disease-free survival compared to untreated animals. In vitro experiments demonstrated that X480 was effective in counteracting osteoclastogenesis whereas it stimulated osteoblast activity. Our report provides novel information on the potential activity of PI3 K/Akt inhibitors on the formation and progression of prostate cancer bone metastases and supports a biological rationale for the use of these inhibitors in castrate-resistant prostate cancer patients at high risk of developing clinically evident bone lesions.
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Antineoplásicos/uso terapêutico , Neoplasias Ósseas , Compostos Orgânicos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Remodelação Óssea/fisiologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/biossíntese , Células RAW 264.7 , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioblastoma is the most frequent and the most lethal primary brain tumor among adults. Standard of care is the association of radiotherapy with concomitant or adjuvant temozolomide. However, to date, recurrence is inevitable. The CXCL12/CXCR4 pathway is upregulated in the glioblastoma tumor microenvironment regulating tumor cell proliferation, local invasion, angiogenesis, and the efficacy of radio-chemotherapy. In this study, we evaluated the effects of the novel CXCR4 antagonist, PRX177561, in preclinical models of glioblastoma. CXCR4 expression and PRX177561 effects were assessed on a panel of 12 human glioblastoma cells lines and 5 patient-derived glioblastoma stem cell cultures. Next, the effect of PRX177561 was tested in vivo, using subcutaneous injection of U87MG, U251, and T98G cells as well as orthotopic intrabrain inoculation of luciferase-transfected U87MG cells. Here we found that PRX177561 impairs the proliferation of human glioblastoma cell lines, increases apoptosis, and reduces CXCR4 expression and cell migration in response to stromal cell-derived factor 1alpha in vitro. PRX177561 reduced the expression of stem cell markers and increased that of E-cadherin and glial fibrillary acidic protein in U87MG cells consistent with a reduction in cancer stem cells. In vivo, PRX177561 reduced the weight and increased the time to progression of glioblastoma subcutaneous tumors while increasing disease-free survival and overall survival of mice bearing orthotopic tumors. Our findings suggest that targeting stromal cell-derived factor 1 alpha/CXCR4 axis by PRX177561 might represent a novel therapeutic approach against glioblastoma and support further investigation of this compound in more complex preclinical settings in order to determine its therapeutic potential.
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Quimiocina CXCL12/genética , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Receptores CXCR4/genética , Adulto , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Glioblastoma/genética , Humanos , Camundongos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: The majority of prostate cancer (Pca) patient morbidity can be attributed to bone metastatic events, which poses a significant clinical obstacle. Therefore, a better understanding of this phenomenon is imperative and might help to develop novel therapeutic strategies. Stromal cell-derived factor 1α (SDF-1α) and its receptor CXCR4 have been implicated as regulators of bone resorption and bone metastatic development, suggesting that agents able to suppress this signaling pathway may be used as pharmacological treatments. In this study we studied if two CXCR4 receptor antagonists, Plerixafor and CTE9908, may affect bone metastatic disease induced by Pca in preclinical experimental models METHODS: To verify the hypothesis that CXCR4 inhibition affects Pca metastatic disease, selective CXCR4 compounds, Plerixafor, and CTE9908, were tested in preclinical models known to generate bone lesions. Additionally, the expression levels of CXCR4 and SDF-1α were analyzed in a number of human tissues derived from primary tumors, lymph-nodes and osseous metastases of Pca as well as in a wide panel of human Pca cell lines to non-tumorigenic and tumorigenic phenotype. RESULTS: Bone-derived Pca cells express higher CXCR4 levels than other Pca cell lines. This differential expression was also observed in human Pca samples. In vitro evidence supports the hypothesis that factors produced by bone microenvironment differentially sustain CXCR4 and SDF1-α expression with respect to prostate microenvironment determining increased efficacy toward Plerixafor. The use of SDF1-α neutralizing antibodies greatly reduced the increase of CXCR4 expression in cells co-cultured with bone stromal cells (BMSc) and to a lesser extent in cells co-cultured with prostate stromal cells (HPSc) and partially reduced SDF1-α Plerixafor efficacy. SDF-1α induced tumor cell migration and invasion, as well as MMP-9, MMP-2, and uPA expression, which were reduced by Plerixafor. The incidence of X-ray detectable bone lesions was significantly reduced following Plerixafor and CTE9908 treatment Kaplan-Meier probability plots showed a significant improvement in the overall survival of mice treated with Plerixafor and CTE9908. The reduced intra-osseous growth of PC3 and PCb2 tumor cells after intratibial injection, as a result of Plerixafor and CTE9908 treatment, correlated with decreased osteolysis and serum levels of both mTRAP and type I collagen fragments (CTX), which were significantly lower with respect to controls. CONCLUSIONS: Our report provides novel information on the potential activity of CXCR4 inhibitors on the formation and progression of Pca bone and soft tissue metastases and supports a biological rationale for the use of these inhibitors in men at high risk to develop clinically evident bone lesions.
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Neoplasias Ósseas/secundário , Compostos Heterocíclicos/farmacologia , Peptídeos/farmacologia , Neoplasias da Próstata/patologia , Receptores CXCR4/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Antivirais/farmacologia , Benzilaminas , Western Blotting , Adesão Celular , Movimento Celular , Quimiocina CXCL12/metabolismo , Técnicas de Cocultura , Ciclamos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Xenoenxertos , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/metabolismo , Receptores CXCR4/metabolismo , Tomografia Computadorizada por Raios X , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Nonalcoholic fatty liver disease (NALFD) represents a complex condition ranging from simple steatosis (nonalcoholic fatty liver, NAFL) to inflammation, and fibrosis is one of the main features of nonalcoholic steatohepatitis (NASH). The pathogenesis of NAFLD is not well established but involves several factors (i.e., predisposition of genetic variants, obesity, and unhealthy lifestyle as unbalanced diets) that lead to an alteration of lipid homeostasis and consequently to an abnormal accumulation of triglycerides and other lipids in the liver parenchyma. Currently, no resolutive pharmacological treatment for NAFLD is available, and the only therapeutic approach is a healthy diet and physical exercise. In this study, we investigated the potential beneficial effect of GprA, a new synthetic agonist of G-protein-coupled receptor 120/free fatty acid receptor 4 (GPR120/FFAR4), in the progression of NAFL/NASH in mice fed for different periods (26 weeks and 30 weeks), with a high-fat (40% kcal) and high-carbohydrate diet, also called a Western-style diet (WSD). In our experimental model, the histological, protein, and transcriptomic analyses highlighted that the GprA can reduce signs of steatosis in WSD-fed mice. Furthermore, in 30 week-treated mice, GprA is also effective in the reduction of collagen deposition and fibrosis development. Altogether, our data validate the central role of FFAR4 in the context of NAFL/NASH onset and progression and reveal that GprA could represent an interesting candidate for the development of a new therapeutic approach in NAFLD treatment.
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Although surgical procedures and clinical care allow reaching high success in fighting most tumors, cancer is still a formidable foe. Recurrence and metastatization dampen the patients' overall survival after the first diagnosis; nevertheless, the large knowledge of the molecular bases drives these aspects. Chemoresistance is tightly linked to these features and is mainly responsible for the failure of cancer eradication, leaving patients without a crucial medical strategy. Many pathways have been elucidated to trigger insensitiveness to drugs, generally associated with the promotion of tumor growth, aggressiveness, and metastatisation. The main mechanisms reported are the expression of transporter proteins, the induction or mutations of oncogenes and transcription factors, the alteration in genomic or mitochondrial DNA, the triggering of autophagy or epithelial-to-mesenchymal transition, the acquisition of a stem phenotype, and the activation of tumor microenvironment cells. Extracellular vesicles (EVs) can directly transfer or epigenetically induce to a target cell the molecular machinery responsible for the acquisition of resistance to drugs. In this review, we resume the main body of knowledge supporting the crucial role of EVs in the context of chemoresistance, with a particular emphasis on the mechanisms related to some of the main drugs used to fight cancer.
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Cellular senescence and ferroptosis are the two main, fine-tuned processes in tissue damage restraint; however, they can be overactivated in pathologies such as nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), becoming dangerous stimuli. Senescence is characterized by a decline in cell division and an abnormal release of reactive oxygen species (ROS), and ferroptosis is represented by iron deposition associated with an excessive accumulation of ROS. ROS and cellular stress pathways are also drivers of NAFLD/NASH development. The etiology of NAFLD/NASH lies in poor diets enriched in fat and sugar. This food regimen leads to liver steatosis, resulting in progressive degeneration of the organ, with a late onset of irreversible fibrosis and cirrhosis. Few studies have investigated the possible connection between senescence and ferroptosis in NAFLD/NASH progression, despite the two events sharing some molecular players. We hypothesized a possible link between senescence and ferroptosis in a NAFLD background. To thoroughly investigate this in the context of "Western-style" diet (WSD) abuse, we used an amylin-modified liver NASH mouse model. The main NASH hallmarks have been confirmed in this model, as well as an increase in apoptosis, and Ki67 and p53 expression in the liver. Senescent beta-galactosidase-positive cells were elevated, as well as the expression of the related secretory molecules Il-6 and MMP-1. Features of DNA damage and iron-overload were found in the livers of NASH mice. Gpx4 (glutathione peroxidase 4) expression, counteracting ferroptotic cell death, was increased. Notably, an increased number of senescent cells showing overexpression of gpx4 was also found. Our data seem to suggest that senescent cells acquire a gpx4-mediated mechanism of ferroptosis resistance and thus remain in the liver, fostering the deterioration of liver fitness.
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Ferroptose , Hepatopatia Gordurosa não Alcoólica , Animais , Senescência Celular , Modelos Animais de Doenças , Ferro/metabolismo , Fígado/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
OBJECTIVES: After a chronic intestinal injury, several intestinal cells switch their phenotype to activated myofibroblasts, which in turn release an abnormal amount of extracellular matrix proteins, leading to the onset of the fibrotic process. To date, no resolutive pharmacological treatments are available, and the identification of new therapeutic approaches represents a crucial goal to achieve. The onset, maintenance, and progression of inflammatory bowel disease are related to abnormal intestinal immune responses to environmental factors, including diet and intestinal microflora components. This study aimed to evaluate the potential antiinflammatory and antifibrotic effect of a biologically debittered olive cream and its probiotic oral administration in an experimental model of dextran sodium sulfate (DSS)-induced chronic colitis. METHODS: Chronic colitis was induced in mice by three cycles of oral administration of 2.5% DSS (5 d of DSS followed by 7 d of tap water). Mice were randomly divided into five groups: 10 control mice fed with standard diet (SD), 20 mice receiving SD and DSS (SD+DSS), 20 mice receiving an enriched diet (ED) with olive cream and DSS (ED+DSS), 20 mice receiving SD plus probiotics (PB; Lactiplantibacillus plantarum IMC513) and DSS (SD+PB+DSS), and 20 mice receiving ED plus PB and DSS (ED+ PB+DSS). Clinical features and large bowel macroscopic, histologic, and immunohistochemical findings were evaluated. RESULTS: The simultaneous administration of ED and PB induced a significant reduction in macroscopic and microscopic colitis scores compared with the other DSS-treated groups. In addition, ED and PB led to a significant decrease in the expression of inflammatory cytokines and profibrotic molecules. CONCLUSIONS: The concomitant oral administration of a diet enriched with biologically debittered olive cream and a specific probiotic strain (Lactiplantibacillus plantarum IMC513) can exert synergistic antiinflammatory and antifibrotic action in DSS-induced chronic colitis. Further studies are needed to define the cellular and molecular mechanisms modulated by olive cream compounds and by Lactiplantibacillus plantarum IMC513.
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Colite , Olea , Probióticos , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colo , Citocinas/metabolismo , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Fenóis , Probióticos/uso terapêutico , SulfatosRESUMO
The number of intestinal mast cells (MC) is increased in several types of colitis, but the mucosa of patients with chronic non-bloody diarrhea has not been studied. The current study sought to determine the relationship between MC counts and degranulation and the severity of symptoms in patients with chronic loose stools. Following a negative laboratory workup for the most common causes of chronic diarrhea, patients with chronic non-bloody loose stools were included in the study. Patients with macroscopic evidence of inflammation or organic disease were excluded after endoscopy with biopsies. Biopsies from the 179 patients in the study were stained with hematoxylin and eosin and anti-CD117 c-kit antibodies. Immunohistochemistry was used to assess the degree of MC degranulation. Out of the 179 patients, 128 had normal histologic findings suggestive of irritable bowel syndrome and were used as controls. Twenty-four presented with abnormally high MC counts (≥40 MC x HPF), 23 with ≥20 intraepithelial lymphocytes x HPF suggesting lymphocytic colitis, and 4 had both (≥40 MC and ≥20 intraepithelial lymphocytes x HPF). In the patients with high MC counts, figures were significantly higher in the right colon versus the left colon (p=0.016), but degranulation did not differ in the right versus the left colon (p=0.125). No age or sex-related difference was observed (p=0.527 and p=0.859 respectively). The prevalence of abdominal pain and bloating did not differ in the three groups (p=0.959 and p=0.140, respectively). Patients with lymphocytic colitis (p=0.008) and those with high MC counts (p=0.025) had significantly higher evacuation rates compared to controls. There was no difference between these two groups (p=0.831). Mast cell degranulation was not associated with the number of evacuations, abdominal pain, or bloating (p=0.51; p=0.41; p=0.42, respectively). The finding that a significantly higher number of evacuations was linked to increased MC in the colonic mucosa of a subset of patients with otherwise normal laboratory and endoscopic findings suggests that "mastocytic colitis" may be a new clinical-pathological entity responsible for chronic non-bloody diarrhea. Prospective studies with a larger number of patients, as well as endoscopic and histological follow-up, are needed to confirm this hypothesis.
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Colite Linfocítica , Colite Microscópica , Colite , Humanos , Mastócitos/patologia , Colite Linfocítica/complicações , Colite Linfocítica/patologia , Estudos Prospectivos , Colite/patologia , Colite Microscópica/complicações , Colite Microscópica/diagnóstico , Colite Microscópica/patologia , Diarreia/patologia , Dor Abdominal/complicações , Dor Abdominal/patologiaRESUMO
The intestinal extracellular matrix (ECM) represents a complex network of proteins that not only forms a support structure for resident cells but also interacts closely with them by modulating their phenotypes and functions. More than 300 molecules have been identified, each of them with unique biochemical properties and exclusive biological functions. ECM components not only provide a scaffold for the tissue but also afford tensile strength and limit overstretch of the organ. The ECM holds water, ensures suitable hydration of the tissue, and participates in a selective barrier to the external environment. ECM-to-cells interaction is crucial for morphogenesis and cell differentiation, proliferation, and apoptosis. The ECM is a dynamic and multifunctional structure. The ECM is constantly renewed and remodeled by coordinated action among ECM-producing cells, degrading enzymes, and their specific inhibitors. During this process, several growth factors are released in the ECM, and they, in turn, modulate the deposition of new ECM. In this review, we describe the main components and functions of intestinal ECM and we discuss their role in maintaining the structure and function of the intestinal barrier. Achieving complete knowledge of the ECM world is an important goal to understand the mechanisms leading to the onset and the progression of several intestinal diseases related to alterations in ECM remodeling.
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OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease globally. It is caused by a complex network of factors, including diet. The hallmark of NAFLD is the benign accumulation of triacylglycerols, however, this condition may worsen into non-alcoholic steatohepatitis (NASH), a more severe form associated with inflammation and fibrosis. Currently, no therapies are available, and diet modifications are the only strategy. Although there is increasing evidence emerging about how an abuse of carbohydrates could be involved in the progression of liver injury, a comprehensive understanding of the damage induced by an enriched carbohydrate diet is still far from complete. The aim of this study was to investigate and compare the effects of a low-fat/high-carbohydrate diet (LF-HCD) with high-fat (HFD) and standard (SD) diets in a nutritional mouse model of NAFLD/NASH. METHODS: Histologic, real-time polymerase chain reaction, and immunohistochemical evaluations were performed. RESULTS: The results showed that the prolonged abuse of both LF-HCDs and HFDs induced a significant increase in hepatic steatosis, inflammation, and fibrosis scores compared with SD. At the same time, both LF-HCDs and HFDs led to significant increases in the expression of the molecules involved in the progression of NAFLD that we assessed (perilipin, CD68, TGF-ß1, CTGF, leptin, leptin receptor, and α-SMA). CONCLUSIONS: The present study highlighted that the simple substitution of fats with carbohydrates is not a proper strategy to prevent or mitigate the progression of NAFLD/NASH. Further studies are required to define the best nutritional strategy to prevent NAFLD and its related metabolic syndrome.
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Hepatopatia Gordurosa não Alcoólica , Animais , Carboidratos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologiaRESUMO
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a persistent sinonasal mucosa inflammatory disease with still unclear pathophysiologic mechanisms that imply events of tissue repair and structural remodelling. Several cascades seem to have a considerable role in the onset and progression of mucosa hyperproliferation in nasal polyps including transforming growth factor ß/Small mother against decapentaplegic (TGFß/Smads), mitogenactivated protein kinases (MAPKs), advanced glycosylation end-products (AGEs) together with epithelial-tomesenchymal transition (EMT). Since many inflammatory mediators are reported to play important roles in the development of nasal polyps (NP) disease, this study aimed to analyse the correlation between the AGEs/receptor of advanced glycosylation end-products (RAGE)/extracellular signal-regulated kinase (ERK) signalling pathway and the main markers of EMT to better understand the influence that they exert on the remodelling of nasal mucous membranes in patients affected by CRSwNP vs normal controls. A total of 30 patients were enrolled in this study. Immunohistochemical analysis, using AGE, RAGE, p-ERK, MMP-3, TGF-ß1, Smad2/3, Collagen I-III, α-SMA, E-cadherin, IL-6 and Vimentin antibodies, was performed. AGE, RAGE, ERK, p-ERK and MMP3 were also evaluated using western blot analysis. We observed an overexpression of the AGE/RAGE/p-ERK and the main mesenchymal markers of EMT (Vimentin and IL-6) in CRSwNP vs controls whereas the TGF-ß/Smad3 pathway did not show any significant differences between the two groups of patients. These observations suggest a complex network of processes in the pathogenesis of NP, and the AGE/RAGE/ERK pathway and EMT might work together in promoting tissue remodelling in the formation of CRSwNP.
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Transição Epitelial-Mesenquimal/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Pólipos Nasais/etiologia , Sinusite/etiologia , Adulto , Doença Crônica , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Imuno-Histoquímica , Interleucina-6/metabolismo , Masculino , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Pólipos Nasais/fisiopatologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Sinusite/patologia , Sinusite/fisiopatologia , Vimentina/metabolismoRESUMO
[This corrects the article DOI: 10.18632/oncotarget.22760.].
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Metastatic castration resistant prostate cancer (mCRPC) relapses due to acquired resistance to docetaxel-based chemotherapy and remains a major threat to patient survival. In this report, we tested the effectiveness of a dual CXCR4/E-selectin antagonist, GM-I1359, in vitro and in vivo, as a single agent or in combination with docetaxel (DTX). This agent was compared to the single CXCR4 antagonist, CTCE-9908, and E-selectin antagonist, GMI-1271. Here we demonstrate that CXCR4 antagonism reduced growth and enhanced DTX treatment in PCa cell lines as well as restored DTX effectiveness in DTX-resistant cell models. The efficacy of dual antagonist was higher respect to those observed for single CXCR4 antagonism. GM1359 impacted bone marrow colonization and growth in intraventricular and intratibial cell injection models. The anti-proliferative effects of GMI-1359 and DTX correlated with decreased size, osteolysis and serum levels of both mTRAP and type I collagen fragment (CTX) in intra-osseous tumours suggesting that the dual CXCR4/E-selectin antagonist was a docetaxel-sensitizing agent for bone metastatic growth. Single agent CXCR4 (CTCE-9908) and E-selectin (GMI-1271) antagonists resulted in lower sensitizing effects compared to GMI-1359. These data provide a biologic rationale for the use of a dual E-selectin/CXCR4 inhibitor as an adjuvant to taxane-based chemotherapy in men with mCRPC to prevent and reduce bone metastases.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Docetaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/administração & dosagem , Animais , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Sinergismo Farmacológico , Selectina E/antagonistas & inibidores , Glicolipídeos/administração & dosagem , Glicolipídeos/farmacologia , Humanos , Masculino , Camundongos , Células PC-3 , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores CXCR4/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background. Glioblastoma multiforme (GBM) is a devastating disease showing a very poor prognosis. New therapeutic approaches are needed to improve survival and quality of life. GBM is a highly vascularized tumor and as such, chemotherapy and anti-angiogenic drugs have been combined for treatment. However, as treatment-induced resistance often develops, our goal was to identify and treat pathways involved in resistance to treatment to optimize the treatment strategies. Anti-angiogenetic compounds tested in preclinical and clinical settings demonstrated recurrence associated to secondary activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Aims. Here, we determined the sensitizing effects of the small molecule and oral available dual TORC1/TORC2 dissociative inhibitor, RES529, alone or in combination with the anti-VEGF blocking antibody, bevacizumab, or the tyrosine kinase inhibitor, sunitinib, in human GBM models. Results. We observed that RES529 effectively inhibited dose-dependently the growth of GBM cells in vitro counteracting the insurgence of recurrence after bevacizumab or sunitinib administration in vivo. Combination strategies were associated with reduced tumor progression as indicated by the analysis of Time to Tumor Progression (TTP) and disease-free survival (DSF) as well as increased overall survival (OS) of tumor bearing mice. RES529 was able to reduce the in vitro migration of tumor cells and tubule formation from both brain-derived endothelial cells (angiogenesis) and tumor cells (vasculogenic mimicry). Conclusions. In summary, RES529, the first dual TORC1/TORC2 dissociative inhibitor, lacking affinity for ABCB1/ABCG2 and having good brain penetration, was active in GBM preclinical/murine models giving credence to its use in clinical trial for patients with GBM treated in association with anti-angiogenetic compounds.
RESUMO
A concomitant action of multiple profibrotic mediators appears crucial in the development and progression of fibrosis. Sphingosine kinase/sphingosine 1 phosphate and transforming growth factor-ß/Smads pathways are both involved in pathogenesis of fibrosis in several organs by controlling differentiation of fibroblasts to myofibroblasts and the epithelial to-mesenchymal transition. However, their direct involvement in chronic colitis-associated fibrosis it is not yet known. In this study we evaluated the immunohistochemical expression of some proteins implicated in sphingosine kinase/sphingosine 1 phosphate and transforming growth factor-ß/Smads pathways in Dextrane Sodium Sulphate (DSS)-induced colorectal fibrosis in mice. Compared to control mice, DSS-induced chronic colitis mice developed a marked intestinal fibrosis associated with a concomitant overexpression of TGF-ß, p-Smad3, α-SMA, collagen I-III, SPHK1, RhoA, PI3K, Akt, p-Akt, p-mTOR. This study highlights the relationship between the two pathways and the possible role of SPHK1 in the intestinal fibrosis. These results, if confirmed by in vitro studies, may have important clinical implications in the development of new therapeutical approaches in inflammatory bowel disease.
Assuntos
Colite/imunologia , Colite/fisiopatologia , Intestinos/patologia , Lisofosfolipídeos/fisiologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Proteína Smad3/fisiologia , Esfingosina/análogos & derivados , Fator de Crescimento Transformador beta/fisiologia , Animais , Modelos Animais de Doenças , Fibrose/patologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Padrões de Referência , Transdução de Sinais , Esfingosina/fisiologiaRESUMO
Collagen and matrix metalloproteinases (MMP) play a pivotal role in the pathophysiology of Pelvic Organ Prolapse (POP) as a switch between type I and III collagen together with a simultaneous activation of MMPs have been observed in the vaginal wall. The aim of this study was to evaluate the Advanced Glycation End (AGE) products, ERK1/2 and transforming growth factor (TGF)-ß/Smad pathway expression in muscularis propria in women with POP compared with control patients. We examined 20 patients with POP and 10 control patients treated for uterine fibromatosis. Immunohistochemical analysis using AGE, RAGE, ERK1/2, Smads-2/3, Smad-7, MMP-3, and collagen I-III, TIMP, and α-SMA were performed. Smad-2/3, Smad-7, AGE, ERK1/2, p-ERK, and p-Smad3 were also evaluated using Western-blot analysis. POP samples from the anterior vaginal wall showed disorganization of the normal muscularis architecture. In POP samples, AGE, ERK1/2, Smad-2/3, MMP-3, and collagen III were upregulated in muscularis whereas in controls, Smad-7 and collagen I were increased. The receptor for AGEs (RAGE) was mild or absent both in controls and prolapse. We demonstrated the involvement of these markers in women with POP but further studies are required to elucidate if the overexpression of these molecules could play a crucial role in the pathophysiology of POP disease.