Examinando por Autor "Castro, Marta"

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Extracellular granzyme A promotes colorectal cancer development by enhancing gut inflammation
(Cell Press, 2020-07-07) Santiago, Llipsy; Castro, Marta; Sanz-Pamplona, Rebeca; Garzón, Marcela; Ramirez-Labrada, Ariel; Tapia, Elena; Moreno, Víctor; Layunta, Elena; Gil-Gómez, Gabriel; Garrido, Marta; Peña, Raúl; Lanuza, Pilar M; Comas, Laura; Jaime-Sanchez, Paula; Uranga-Murillo, Iratxe; del Campo, Rosa; Pelegrín, Pablo; Martínez-Lostao, Luis; Muñoz, Guillermo; Uranga, Jose Antonio; Alcalde, Anabel; Galvez, Eva M; Ferrández, Ángel; Bird, Phillip; Metkar, Sunil; Maykel, Arias; Pardo, Julián
If not properly regulated, the inflammatory immune response can promote carcinogenesis, as evident in colorectal cancer (CRC). Aiming to gain mechanistic insight into the link between inflammation and CRC, we perform transcriptomics analysis of human CRC, identifying a strong correlation between expression of the serine protease granzyme A (GzmA) and inflammation. In a dextran sodium sulfate and azoxymethane (DSS/AOM) mouse model, deficiency and pharmacological inhibition of extracellular GzmA both attenuate gut inflammation and prevent CRC development, including the initial steps of cell transformation and epithelial- to-mesenchymal transition. Mechanistically, extracellular GzmA induces NF-kB-dependent IL-6 production in macrophages, which in turn promotes STAT3 activation in cultured CRC cells. Accordingly, colon tissues from DSS/AOM-treated, GzmA-deficient animals present reduced levels of pSTAT3. By identifying GzmA as a proinflammatory protease that promotes CRC development, these findings provide information on mechanisms that link immune cell infiltration to cancer progression and present GzmA as a therapeutic target for CRC.
Guanylate cyclase C: a current hot target, from physiology to pathology
(2018) Uranga, Jose Antonio; Castro, Marta; Abalo Delgado, Raquel
Abstract: Background: Guanylate cyclase C (GC-C) receptor is a transmembrane receptor, predominantly expressed in intestinal epithelial cells, which is considered to play a main role in homeostasis and function of the digestive tract. The endogenous ligands for this receptor are the paracrine hormones uroguanylin and guanylin. Upon ligand binding, GC-C receptors increase cyclic guanosine monophosphate (cGMP) levels, regulating a variety of key cell-type specific processes such as chloride and bicarbonate secretion, epithelial cell growth, regulation of intestinal barrier integrity and visceral sensitivity. It has been suggested that GC-C acts as an intestinal tumor suppressor with the potential to prevent the initiation and progression of colorectal cancer. In fact, loss of ligand expression is a universal step in sporadic colorectal carcinogenesis. Interestingly, the role of GC-C is not limited to the digestive tract but it has been extended to several other systems such as the cardiovascular system, kidney, and the central nervous system, where it has been involved in a gut-hypothalamus endocrine axis regulating appetite. Objetive: In this review we summarize the physiology of the GC-C receptor and its ligands, focusing on newly developed drugs like linaclotide, and their suggested role to reverse/prevent the diseases in which the receptor is involved. Conclusion: Available data points toward a relationship between uroguanylin and guanylin and their receptor and pathological processes like gastrointestinal and renal disorders, colorectal cancer, obesity, metabolic syndrome and mental disorders among others. Recent pharmacological developments in the regulation of GC-receptor may involve further improvements in the treatment of relevant diseases.
Radiographic and histopathological study of gastrointestinal dysmotility in lipopolysaccharide-induced sepsis in the rat
(Wiley, 2023) Castro, Marta; Valero, Marta Sofía; López-Tofiño, Yolanda; López-Gómez, Laura; Girón, Rocío; Martín-Fontelles, María Isabel; Uranga, José A.; Abalo, Raquel
BackgroundSepsis is a highly incident condition in which a cascade of proinflammatory cytokines is involved. One of its most frequent consequences is ileus, which can increase mortality. Animal models such as that induced by systemic administration of lipopolysaccharide (LPS) are useful to deeply evaluate this condition. The effects of sepsis on the gastrointestinal (GI) tract have been explored but, to our knowledge, in vivo studies showing the motor and histopathological consequences of endotoxemia in an integrated way are lacking. Our aim was to study in rats the effects of sepsis on GI motility, using radiographic methods, and to assess histological damage in several organs.MethodsMale rats were intraperitoneally injected with saline or E. coli LPS at 0.1, 1, or 5 mg kg−1. Barium sulfate was intragastrically administered, and X-rays were performed 0–24 h afterwards. Several organs were collected for organography, histopathology, and immunohistochemistry studies.Key ResultsAll LPS doses caused gastroparesia, whereas changes in intestinal motility were dose-and time-dependent, with an initial phase of hypermotility followed by paralytic ileus. Lung, liver, stomach, ileum, and colon (but not spleen or kidneys) were damaged, and density of neutrophils and activated M2 macrophages and expression of cyclooxygenase 2 were increased in the colon 24 h after LPS 5 mg kg−1.Conclusions and InferencesUsing radiographic, noninvasive methods for the first time, we show that systemic LPS causes dose-, time-, and organ-dependent GI motor effects. Sepsis-induced GI dysmotility is a complex condition whose management needs to take its time-dependent changes into account.