Examinando por Autor "Uranga, Jose Antonio"

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Alterations of colonic sensitivity and gastric dysmotility after acute cisplatin and granisetron
(Wiley Online Library, 2018-11-06) Marta Martin‐Ruíz; Uranga, Jose Antonio; Paula Mosinska; Jakub Fichna; Kulmira Nurgali; Mª Isabel Martín‐Fontelles; Abalo, Raquel
Background: Cisplatin is a highly emetogenic antineoplastic drug and induces peripheral neuropathy when given in cycles. Granisetron, a 5‐HT3 antagonist, is clinically used to prevent chemotherapy‐induced nausea/emesis and abdominal pain in irritable bowel syndrome. The effects of cisplatin on visceral sensitivity and those of granisetron in the context of cancer chemotherapy are not well known. Methods: Adult male Wistar rats received two intraperitoneal injections 30 minutes apart: granisetron (1 mg kg−1)/vehicle and cisplatin (6 mg kg−1)/vehicle. Thereafter, nausea‐like behavior was measured as bedding intake for 4 hours, and gastric dysmotility was measured radiographically for 8 hours. Gastric weight and size were determined ex vivo and samples of the forestomach, corpus, ileum, and colon were obtained for histological analysis at 4 and 30 hours after cisplatin/vehicle. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation 2 hours after cisplatin/vehicle. Key Results: Cisplatin‐induced bedding intake and gastric dysmotility, and granisetron blocked these effects, which occurred in the absence of frank mucositis. Visceral sensitivity was reduced to a similar extent by both drugs alone or in combination. Conclusions and Inferences: Cisplatin‐induced bedding intake and gastric dysmotility were blocked by granisetron, confirming the involvement of serotonin acting on 5‐HT3 receptors. Unexpectedly, visceral sensitivity to colonic distension was reduced, to the same extent, by cisplatin, granisetron, and their combination, suggesting important mechanistic differences with nausea and gastric dysmotility that warrant further investigation.
Alterations of the small intestinal wall and motor function after repeated cisplatin in the rat.
(Wiley Online Library, 2017-06-08) Uranga, Jose Antonio; García-Martínez, Jose Manuel; García-Jiménez, Custodia; Vera, Gema; Martín-Fontelles, Isabel; Abalo, Raquel
Background. Gastrointestinal adverse effects occurring during cancer chemotherapy are well known and feared; those persisting once treatment has finished are relatively unknown. We characterized the alterations occurring in the rat small intestine, after repeated treatment with cisplatin. Methods: Male Wistar rats received saline or cisplatin (2 mg kg-1 week-1, for 5 weeks, ip). Gastric motor function was studied non-invasively throughout treatment (W1-W5) and one week after treatment finalization (W6). During W6, upper gastrointestinal motility was also invasively studied and small intestinal samples were collected for histopathological and molecular studies. Structural alterations of the small intestinal wall, mucosa, submucosa, muscle layers, and lymphocytic nodules were histologically studied. PAS staining and immunohistochemistry for Ki-67, chromogranin A and neuronal specific enolase (NSE) were used to detect secretory, proliferating, endocrine and neural cells, respectively. The expression of different markers in the tunica muscularis was analyzed by RT/qPCR. Key results: Repeated cisplatin induced motility alterations during and after treatment. After treatment (W6), the small intestinal wall showed histopathological alterations in most parameters measured, including a reduction in the thickness of circular and longitudinal muscle layers. Expression of c-KIT (for interstitial cells of Cajal, ICC), nNOS (for inhibitory motor neurons), pChAT and cChAT (for excitatory motor neurons) increased significantly (although both ChATs to a lesser extent). Conclusions and inferences: Repeated cisplatin induces relatively long-lasting gut dysmotility in the rat associated to important histopathological and molecular alterations of the small intestinal wall. In cancer survivors, the possible chemotherapy-induced histopathological, molecular and functional intestinal sequelae should be evaluated.
Aluminum exposure for 60 days at an equivalent human dietary level promotes peripheral dysfunction in rats
(Elsevier, 2017-08-25) Caroline Silveira Martinez; Uranga, Jose Antonio; Franck Maciel Peçanha; Dalton Valentim Vassallo; Vera, Gema; Miguel, Marta; Giulia Alessandra Wiggers
Aluminum (Al) is a neurotoxic associated with a number of chronic human diseases. We investigated the effects of Al exposure at doses similar to human dietary levels on the peripheral nervous system over a 60 day period. Wistar male rats were divided into two major groups and received orally: 1) Low aluminum level - rats were subdivided and treated for 60 days as follows: a) Untreated - ultrapure water; b) AlCl3 at a dose of 8.3 mg/kg bw for 60 days, representing human Al exposure by diet; and 2) High aluminum level - rats were subdivided and treated for 42 days as follows: C) Untreated – ultrapure water; d) AlCl3 at 100 mg/kg bw for 42 days, representing a high level of human exposure to Al. Von Frey hair and plantar tests were used to verify the tactile and thermal sensitivities, respectively. The presence of catalepsy behavior and the spontaneous motor activity were investigated by “ring test” and using individual photocell activity chambers. Reactive oxygen species, lipid peroxidation and total antioxidant capacity in plasma, were measured. Immunohistochemistry to investigate the nerve inflammation and, the specific presence of Al in the sciatic nerve fibers were investigated. Al exposure at a representative human dietary level promotes the development of mechanical allodynia, catalepsy behavior, increased the number of activated macrophages in the sciatic nerve, systemic oxidative stress and, is able to be retained among the sciatic nerve fibers. The effects of Al in the peripheral nervous system were similar to those found in rats exposed to Al at a dose much higher (100 mg/kg). Therefore, our findings suggest that Al may be considered toxic for the peripheral nervous system, thus inducing peripheral dysfunction.
Antiproliferative and palliative activity of flavonoids in colorectal cancer
(Elsevier, 2021) Fernandez, Javier; Silván Ros, Blanca; Uranga, Jose Antonio; Entrialgo, Rodrigo; Villar, Claudio; Capasso, Raffaele; Lombo, Felipe; Abalo, Raquel
Flavonoids are plant bioactive compounds of great interest in nutrition and pharmacology, due to their remarkable properties as antioxidant, anti-inflammatory, antibacterial, antifungal and antitumor drugs. More than 5000 different flavonoids exist in nature, with a huge structural diversity and a plethora of interesting pharmacological properties. In this work, five flavonoids were tested for their potential use as antitumor drugs against three CRC cell lines (HCT116, HT-29 and T84). These cell lines represent three different stages of this tumor, one of which is metastatic. Xanthohumol showed the best antitumor activity on the three cancer cell lines, even better than that of the clinical drug 5-fluorouracil (5-FU), although no synergistic effect was observed in the combination therapy with this drug. On the other hand, apigenin and luteolin displayed slightly lower antitumor activities on these cancer cell lines but showed a synergistic effect in combination with 5-FU in the case of HTC116, which is of potential clinical interest. Furthermore, a literature review highlighted that these flavonoids show very interesting palliative effects on clinical symptoms such as diarrhea, mucositis, neuropathic pain and others often associated with the chemotherapy treatment of CRC. Flavonoids could provide a double effect for the combination treatment, potentiating the antitumor effect of 5-FU, and simultaneously, preventing important side effects of 5-FU chemotherapy.
Bioaccesibility, Metabolism, and Excretion of Lipids Composing Spent Coffee Grounds
(MDPI, 2019-06-23) Iriondo, Amaia; Santillán, Fresia; Fernández-Gómez, Beatriz; Vera, Gema; Guisantes, Eduardo; Gómez, Sergio; San Andrés, Manuel Ignacio; Sanchez-Fortún, Sebastián; López Gómez, Laura; Uranga, Jose Antonio; Abalo, Raquel; del Castillo, Mª Dolores
The bioaccessibility, metabolism, and excretion of lipids composing spent coffee grounds (SCGs) were investigated. An analysis of mycotoxins and an acute toxicity study in rats were performed for safety evaluation. Total fat, fatty acids, and diterpenes (cafestol and kahweol) were determined in SCGs and their digests obtained in vitro. A pilot repeated intake study was carried out in Wistar rats using a dose of 1 g SCGs/kg b.w. for 28 days. Fat metabolism was evaluated by analysis of total fat, cholesterol, and histology in liver. The dietary fiber effect of SCGs was measured radiographically. The absence of mycotoxins and toxicity was reported in SCGs. A total of 77% of unsaturated fatty acids and low amounts of kahweol (7.09 _g/g) and cafestol (414.39 _g/g) were bioaccessible after in vitro digestion. A significantly lower (p < 0.1) accumulation of lipids in the liver and a higher excretion of these in feces was found in rats treated with SCGs for 28 days. No lipid droplets or liver damage were observed by histology. SCGs acutely accelerated intestinal motility in rats. SCGs might be considered a sustainable, safe, and healthy food ingredient with potential for preventing hepatic steatosis due to their effect as dietary fiber with a high fat-holding capacity.
Cannabinoid pharmacology and therapy in gut disorders
(2018) Uranga, Jose Antonio; Vera, Gema; Abalo, Raquel
Cannabis sp. and their products (marijuana, hashish…), in addition to their recreational, industrial and other uses, have a long history for their use as a remedy for symptoms related with gastrointestinal diseases. After many reports suggesting these beneficial effects, it was not surprising to discover that the gastrointestinal tract expresses endogenous cannabinoids, their receptors, and enzymes for their synthesis and degradation, comprising the so-called endocannabinoid system. This system participates in the control of tissue homeostasis and important intestinal functions like motor and sensory activity, nausea, emesis, the maintenance of the epithelial barrier integrity, and the correct cellular microenvironment. Thus, different cannabinoid-related pharmacological agents may be useful to treat the main digestive pathologies. To name a few examples, in irritable bowel syndrome they may normalize dysmotility and reduce pain, in inflammatory bowel disease they may decrease inflammation, and in colorectal cancer, apart from alleviating some symptoms, they may play a role in the regulation of the cell niche. This review summarizes the main recent findings on the role of cannabinoid receptors, their synthetic or natural ligands and their metabolizing enzymes in normal gastrointestinal function and in disorders including irritable bowel syndrome, inflammatory bowel disease, colon cancer and gastrointestinal chemotherapy-induced adverse effects (nausea/vomiting, constipation, diarrhea).
Cardiovascular Toxicity Induced by Chronic Vincristine Treatment
(Frontiers, 2021-07-21) Herradón, Esperanza; González, Cristina; González, Antonio; Uranga, Jose Antonio; López Miranda, Visitación
Vincristine is an effective anticancer agent for treating leukemias, lymphomas, and other solid tumors. Vincristine’s better-known severe side effects include bone marrow depression, hyponatremia, peripheral neuropathy, and gastrointestinal distress. In recent years, cardiovascular damage also has been described during vincristine treatments. However, the vascular toxicity induced by vincristine is little studied. The aim of the present is to evaluate whether these alterations remain after the suspension of chemotherapy treatment (sequelae) and the possible mechanisms involved in this vascular damage. Adult male Wistar rats were used. The animals were divided into four treatment groups: two groups of saline (0.9% NaCl; saline, sequelae saline) and two groups of vincristine (100 μg/kg; vincristine, sequelae vincristine). Saline or vincristine was administered intraperitoneally in two cycles of 5 days each, leaving a rest period between cycles of 2 days. The final cumulative vincristine dose administered was 1 mg/kg. Sequelae groups correspond to 2 weeks after stopping treatment with the antitumor agent. At the end of the different experimental protocols, cardiac and vascular functions were analyzed. Alterations in the expression of different proteins in the cardiovascular tissues were also investigated. Chronic treatment with vincristine did not produce significant changes in basal cardiac function but provoked significant endothelial dysfunction in the aorta and a significant decrease in the mesenteric contractile function. These cardiovascular functional alterations disappeared 2 weeks after the suspension of chemotherapy treatment. Vincristine treatment caused a significant increase in the expression of tumor necrosis factor-alpha (TNFα), endothelial and inducible nitric oxide synthases (eNOS and iNOS), and connexin 43 in cardiac tissue. In the aorta, the chronic treatment with vincristine caused a slight non-significant increase in TNFα expression, a significant increase in eNOS and iNOS, and a significant decrease in connexin 43. After 2 weeks of vincristine treatment (sequelae group), the expression of TNFα increased and eNOS and iNOS expressions disappeared, but a significant decrease in the expression of connexin 43 was still observed in the aorta. In mesenteric arteries, similar data to those found in the aorta were observed. In conclusion, chronic treatment with vincristine causes functional alterations in the vascular function of both conductance and resistance vessels and changes in the expressions of TNFα, eNOS, iNOS, and connexin 43 in cardiovascular tissues, implicating direct toxicity during its treatment. These functional alterations are transitory and disappear after the suspension of its treatment.
Changes in Fatty Acid Dietary Profile Affect the Brain-Gut Axis Functions of Healthy Young Adult Rats in a Sex-Dependent Manner.
(Nutrients, 2021) Jacenik, Damian; Bagüés, Ana; López - Gómez, Laura; López - Tofiño, Yolanda; Iriondo-DeHond, Amaia; Serra, C; Banovcanová, L; Gálvez-Robleño, Carlos; Fichna, Jakub; Del Castillo, Maria Dolores; Uranga, Jose Antonio; Abalo, Raquel
Dietary modifications, including those affecting dietary fat and its fatty acid (FA) composition, may be involved in the development of brain-gut axis disorders, with different manifestations in males and females. Our aim was to evaluate the impact of three purified diets with different FA composition on the brain-gut axis in rats of both sexes. Male and female Wistar rats fed a cereal-based standard diet from weaning were used. At young adult age (2-3 months old), animals were divided into three groups and treated each with a different refined diet for 6 weeks: a control group fed on AIN-93G diet containing 7% soy oil (SOY), and two groups fed on AIN-93G modified diets with 3.5% soy oil replaced by 3.5% coconut oil (COCO) or 3.5% evening primrose oil (EP). Different brain-gut axis parameters were evaluated during 4-6 weeks of dietary intervention. Compared with SOY diet (14% saturated FAs, and 58% polyunsaturated FAs), COCO diet (52.2% saturated FAs and 30% polyunsaturated FAs) produced no changes in brain functions and minor gastrointestinal modifications, whereas EP diet (11.1% saturated FAs and 70.56% polyunsaturated FAs) tended to decrease self-care behavior and colonic propulsion in males, and significantly increased exploratory behavior, accelerated gastrointestinal transit, and decreased cecum and fecal pellet density in females. Changes in FA composition, particularly an increase in ω-6 polyunsaturated FAs, seem to facilitate the development of brain-gut axis alterations in a sex-dependent manner, with a relatively higher risk in females.
Changes in the diet composition of fatty acids and fiber affect the lower gastrointestinal motility but have no impact on cardiovascular parameters: In vivo and in vitro studies
(Wiley Online Library, 2019-05-30) Paula Mosińska; Marta Martin‐Ruiz; Antonio González; López Miranda, Visitación; Herradón, Esperanza; Uranga, Jose Antonio; Vera, Gema; Adrián Sanchez‐Yáñez; Mª Isabel Martin‐Fontelles; Jakub Fichna; Abalo, Raquel
Background: Food and diet are central issues for proper functioning of the cardiovascular (CV) system and gastrointestinal (GI) tract. We hypothesize that different types of dietary FAs affect CV parameters as well as GI motor function and visceral sensitivity. Methods: Male Wistar rats were fed with control diet (CTRL), diet supplemented with 7% soybean oil (SOY), SOY + 3.5% virgin coconut oil (COCO), and SOY + 3.5% evening primrose oil (EP) for 4 weeks. The content of insoluble fiber in CTRL was higher than in SOY, COCO, or EP. Body weight gain and food/water intake were measured. At day 28, biometric, biochemical, CV parameters, GI motor function (X‐ray and colon bead expulsion test), and visceral sensitivity were evaluated. Changes in propulsive colonic activity were determined in vitro. The colon and adipose tissue were histologically studied; the number of mast cells (MCs) in the colon was calculated. Results: SOY, COCO, and EP had increased body weight gain but decreased food intake vs CTRL. Water consumption, biometric, biochemical, and CV parameters were comparable between groups. SOY increased the sensitivity to colonic distention. All groups maintained regular propulsive neurogenic contractions; EP delayed colonic motility (P < 0.01). SOY, COCO, and EP displayed decreased size of the cecum, lower number and size of fecal pellets, and higher infiltration of MCs to the colon (P < 0.001). Conclusions and Inferences: Dietary FAs supplementation and lower intake of insoluble fiber can induce changes in the motility of the lower GI tract, in vivo and in vitro, but CV function and visceral sensitivity are not generally affected.
Chronic mercury at low doses impairs white adipose tissue plasticity
(Elsevier, 2019-02-23) Rizzetti, Danize Aparecida; Corrales, Patricia; Piagette, Janaina Trindade; Uranga, Jose Antonio; Vera, Gema; Peçanha, Franck Maciel; Vassallo, Dalton Valentim; Miguel, Marta; Wiggers, Giulia Alessandra
Introduction: The toxic effects of mercury (Hg) are involved in homeostasis of energy systems such as lipid and glucose metabolism, and white adipose tissue dysfunction is considered as a central mechanism leading to metabolic disorders. Objective: The aim of this study was to determine the effects of chronic inorganic Hg exposure at low doses on the lipid and glycemic metabolism. Methods: Male Wistar rats were divided into two groups and treated for 60 days with: saline solution, i.m. (Untreated) and mercury chloride, i.m. - 1st dose 4.6 μg/kg, subsequent doses 0.07 μg/kg/day - (Mercury). Histological analyses, Hg levels measurement and GRP78, CHOP, PPARα, PPARγ, leptin, adiponectin and CD11 mRNA expressions were performed in epididymal white adipose tissue (eWAT). Glucose, triglycerides, total cholesterol and insulin plasma levels were also measured. Results: Hg exposure reduced the absolute and relative eWAT weights, adipocyte size, plasma insulin levels, glucose tolerance, antioxidant defenses and increased plasma glucose and triglyceride levels. In addition, CHOP, GRP78, PPARα, PPARγ, leptin and adiponectin mRNA expressions were increased in Hg-treated animals. No differences in Hg concentration were found in eWAT between the untreated and Hg groups. These results suggest that the reduction in adipocyte size is related to the impaired antioxidant defenses, endoplasmic reticulum (ER) stress, the disrupted PPARs and adipokines mRNA expression induced by the metal in eWAT. These disturbances possibly induced a decrease in circulating insulin levels, an imbalance between lipolysis and lipogenesis mechanisms in eWAT, with an increase in fatty acids mobilization, a reduction in glucose uptake and an activation of pro-apoptotic pathways, leading to hyperglycemia and hyperlipidemia. Conclusions: Hg is a powerful environmental WAT disruptor that influences signaling events and impairs metabolic activity and hormonal balance of adipocytes.
Effects of chronic dietary exposure to monosodium glutamate on feeding behavior, adiposity, gastrointestinal motility, and cardiovascular function in healthy adult rats
(Wiley Online Library, 2015-08-24) López Miranda, Visitación; Soto Montenegro, M Luisa; Uranga, Jose Antonio; Vera, Gema; Herradón, Esperanza; González, Cristina; Blas, C; MARTINEZ-VILLALUENGA, M; LOPEZ-PEREZ, Ana Esther; Desco, Manuel; Abalo, Raquel
Background Monosodium glutamate (MSG) is a flavor- enhancer widely used as a food additive. However, its safe dietary concentration and its toxicity, including its possible implication in the recent metabolic syndrome pandemia, is still a controversial issue. Therefore, a deep knowledge of its effects upon regular dietary use is needed. Our aim was to evaluate the effects of chronic exposure to MSG on feeding behavior, abdominal fat, gastrointestinal motility, and cardiovascular function in rats. Methods Two groups of adult male Wistar rats were used: control and treated with MSG (4 g/L in drinking water) for 6 weeks. Different functional parameters were determined and the histological structure was analyzed in tissues of interest. Key Results Compared to control animals, chronic MSG increased water intake but did not modify food ingestion or body weight gain. Neither the abdominal fat volume nor the fat fraction, measured by magnetic resonance imaging, was modified by MSG. Monosodium glutamate did not alter general gastrointestinal motility, but significantly increased the colonic response to mechanical stimulation. It slightly reduced endothelium-dependent relaxation in aorta, without significantly modifying any other cardiovascular parameters. No significant histological alterations were detected in salivary glands, intestinal wall, aorta, heart, and kidney. Conclusions & Inferences Chronic treatment with MSG in the adult rat increased water intake. This supports its potential to improve acceptance of low-fat regimens and to increase hydration in the elderly and sportspeople, often at risk of dehydration. Changes in colonic contractility and cardiovascular function could have some long-term repercussions warranting further research.
Effects of Commercial Probiotics on Colonic Sensitivity after Acute Mucosal Irritation
(MDPI, 2022-05-26) López-Gómez, Laura; Antón, Jaime; López-Tofiño, Yolanda; Pomana, Bianca; Uranga, Jose Antonio; Abalo, Raquel
Gastrointestinal pathologies associated with abdominal pain, such as irritable bowel syndrome or inflammatory bowel disease, lack sufficiently effective treatments. In our study we have used a rat model of visceral pain (72 animals; n = 8-13 per experimental group) to analyze the consequences of intracolonic administration of the irritant acetic acid on visceral sensitivity, histology of the colonic wall, and inflammatory response. Moreover, we have studied the possible beneficial effects of a pretreatment with a commercial probiotic (Actimel®). Contrary to expectations, acetic acid application (7 cm proximal to the anus) decreased the nociceptive response to intracolonic mechanical stimulation, with a slight increase in the histological damage of colonic mucosa. The intensity of these changes depended on the concentration (4% or 0.6%) and the time of application (30 or 60 min). Pretreatment with probiotics (by daily gavage, for 1 week) normalized the values obtained in the visceral sensitivity test but revealed an increase in the number of macrophages. These results suggest a possible activation of inhibitory mechanisms early after colonic irritation, not previously described (which need further experimental confirmation), and the ability of probiotics to normalize the effects of acetic acid. In addition, pretreatment with probiotics has a direct effect on immune functions, stimulating macrophagic activity.
Effects of the food additive monosodium glutamate on cisplatin-induced gastrointestinal dysmotility and peripheral neuropathy in the rat
(Wiley Online Library, 2020-10-28) Yolanda López-Tofiño; Vera, Gema; López Gómez, Laura; Girón, Rocío; Nurgali, Kulmira; Uranga, Jose Antonio; Abalo, Raquel
Background: Cisplatin is an antineoplastic drug known to produce intense vomiting, gastric dysmotility, and peripheral neuropathy. Monosodium glutamate (MSG) is a flavor enhancer with prokinetic properties potentially useful for cancer patients under chemotherapy. Our aim was to test whether MSG may improve gastrointestinal motor dysfunction and other adverse effects induced by repeated cisplatin in rats. Methods: Male Wistar rats were exposed or not to MSG (4 g L−1) in drinking water from week 0 to 1 week after treatment. On the first day of weeks 1–5, rats were treated with saline or cisplatin (2 mg kg−1 week−1, ip). Gastrointestinal motility was measured by radiological methods after first and fifth administrations, as well as 1 week after treatment finalization. One week after treatment, the threshold for mechanical somatic sensitivity was recorded. Finally, samples of stomach, terminal ileum and kidneys were evaluated in sections using conventional histology. The myenteric plexus was immunohistochemically evaluated on distal colon whole-mount preparations. Key Results: Monosodium glutamate prevented the development of cisplatin-induced neuropathy and partially improved intestinal transit after the fifth cisplatin administration with little impact on gastric dysmotility. MSG did not improve the histological damage of gut wall, but prevented the changes induced by cisplatin in the colonic myenteric plexus. Conclusion and Inferences: Our results suggest that MSG can improve some dysfunctions caused by anticancer chemotherapy in the gut and other systems, associated, at least partially, with neuroprotectant effects. The potentially useful adjuvant role of this food additive to reduce chemotherapy-induced sequelae warrants further evaluation.
Egg White Hydrolysate as a functional food ingredient to prevent cognitive dysfunction in rats following long-term exposure to aluminum
(Nature, 2019-02-12) Silveira Martinez, Caroline; Alterman, Caroline; Vera, Gema; Márquez, Antonio; Uranga, Jose Antonio; Peçanha, Franck Maciel; Vassallo, Dalton Valentim; Exley, Christopher; Mello-Carpes, Pamela; Miguel, Marta; Wiggers, Giulia
Aluminum (Al), which is omnipresent in human life, is a potent neurotoxin. Here, we have tested the potential for Egg White Hydrolysate (EWH) to protect against changes in cognitive function in rats exposed to both high and low levels of Al. Indeed, EWH has been previously shown to improve the negative effects induced by chronic exposure to heavy metals. Male Wistar rats received orally: Group 1) Low aluminum level (AlCl3 at a dose of 8.3 mg/kg b.w. during 60 days) with or without EWH treatment (1 g/kg/day); Group 2) High aluminum level (AlCl3 at a dose of 100 mg/kg b.w. during 42 days) with or without EWH treatment (1 g/kg/day). After 60 or 42 days of exposure, rats exposed to Al and EWH did not show memory or cognitive dysfunction as was observed in Al-treated animals. Indeed, co-treatment with EWH prevented catalepsy, hippocampal oxidative stress, cholinergic dysfunction and increased number of activated microglia and COX-2-positive cells induced by Al exposure. Altogether, since hippocampal inflammation and oxidative damage were partially prevented by EWH, our results suggest that it could be used as a protective agent against the detrimental effects of long term exposure to Al.
Egg white hydrolysates improve vascular damage in obese Zucker rats by its antioxidant properties
(Wiley Online Library, 2019-10-01) Garcés-Rimón, Marta; Cristina González; Raquel Hernanz; Esperanza Herradón; Angela Martín; Roberto Palacios; María Jesús Alonso; Uranga, Jose Antonio; López Miranda, Visitación; Miguel, Marta
Metabolic Syndrome (MS) is related to increased risk of early death due to cardiovascular complications, among others. Dietary intervention has been suggested as the safest and most cost‐effective alternative for treatment of those alterations in patients with MS. The aim of this study was to investigate the effects of different egg white hydrolysates (HEW1 and HEW2) in obese Zucker rats, focus on the development of cardiovascular complications. Blood pressure, heart rate, basal cardiac function and vascular reactivity in aorta and mesenteric resistance arteries were evaluated. Reactive oxygen species production by dihydroethidium‐emitted fluorescence, NOX‐1 mRNA levels by qRT‐PCR, angiotensin‐converting enzyme activity by fluorimetry and kidney histopathology were also analysed. Both hydrolysates improve the endothelial dysfunction occurring in resistance arteries. Additionally, HEW2 reduced vascular oxidative stress. Practical applications Egg white is a good source of bioactive peptides, some of them with high antioxidant activity. They may be used as functional foods ingredients and could serve as an alternative therapeutic option to decrease some Metabolic Syndrome‐related complications. This study suggests that these hydrolysates could be an interesting nonpharmacological tool to control cardiovascular complications related to Metabolic Syndrome.
Egg white-derived peptides prevent male reproductive dysfunction induced by mercury in rats
(Elsevier, 2016-12-30) Danize Aparecida Rizzetti; Caroline Silveira Martinez; Alyne Goulart Escobar; Taiz Martins da Silva; Uranga, Jose Antonio; Franck Maciel Peçanha; Dalton Valentim Vassallo; Marta, Castro; Giulia Alessandra Wiggers
Oxidative stress in known to contribute to the male reproductive dysfunction induced by mercury (Hg). Our study tested the hypothesis that the egg white hydrolysate (EWH), a potent antioxidant in vitro, is able to prevent the effects of prolonged Hg exposure on male reproductive system in rats. For this, rats were treated for 60 days with: a) Untreated - saline solution (i.m.); b) Hydrolysate - EWH (1 g/kg/day, gavage); c) Mercury - HgCl2 (1st dose 4.6 mg/kg, subsequent doses 0.07 mg/kg/day, i.m.); d) Hydrolysate- Mercury. At the end of the treatment, sperm motility, count and morphological studies were performed; Reactive Oxygen Species (ROS) levels, lipid peroxidation, antioxidant capacity, histological and immu- nohistochemical assays on testis and epididymis were also carried out. As results, HgCl2-treatment decreased sperm number, increased sperm transit time in epididymis and impaired sperm morphology. However, these harmful effects were prevented by EWH. HgCl2-treatment also increased ROS levels, lipid peroxidation and antioxidant capacity in testis and epididymis as well as promoted testicular inflammation and histological changes in epididymis. EWH improved histological and immunohistochemical alterations, probably due to its antioxidant property. In conclusion, the EWH could represent a powerful natural alternative to protect the male reproductive system against Hg-induced sperm toxicity.
Expression enhancement in brown adipose tissue of genes related to thermogenesis and mitochondrial dynamics after administration of pepsin egg white hydrolysate
(2018) Moreno-Fernández, Silvia; Garcés-Rimón, Marta; Uranga, Jose Antonio; Julien, Astier; Landrier, JF; Miguel, Marta
Nutritional compounds could be a safe and less expensive treatment for complications associated with obesity and metabolic syndrome (MetS). The aim of this study was to investigate the mechanism of action and the target tissues of a pepsin egg white hydrolysate (EWH) which had previously been demonstrated to improve some obesity-related disorders on a high-fat/high-glucose rat model. Wistar rats were used and divided into 3 groups: Control group (C), High-fat/high-glucose diet (MS) and high-fat/high-glucose diet + EWH (MSH). The rats were fed for 20 weeks and the EWH was administered from the 9th week. At the end of the study, white adipose tissue (WAT), brown adipose tissue (BAT) and muscle samples were collected for RT-qPCR analyses and immunohistochemistry. Our results showed a gene expression enhancement (2-fold basal level) in BAT of genes related to thermogenesis and mitochondrial dynamics. Mitochondrial DNA quantification and immunohistochemistry results also showed an increase of the mitochondrial content in this tissue. In conclusion, our results show the potential metabolic effect of this pepsin EWH by enhancing mitochondrial proliferation and gene expression related to thermogenesis in BAT. The EWH could be used as a functional food ingredient which is able to increase energy expenditure and counteract obesity-related MetS in a chronically obese society.
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.
Food, nutrients and nutraceuticals affecting the course of inflammatory bowel disease
(Springer, 2016-06-03) Uranga, Jose Antonio; López Miranda, Visitación; Felipe, Lombo; Abalo, Raquel
Inflammatory bowel diseases (ulcerative colitis; Crohn’s disease) are debilitating relapsing inflammatory disorders affecting the gastrointestinal tract, with deleterious effect on quality of life, and increasing incidence and prevalence. Mucosal inflammation, due to altered microbiota, increased intestinal permeability and immune system dysfunction underlies the symptoms and may be caused in susceptible individuals by different factors (or a combination of them), including dietary habits and components. In this review we describe the influence of the Western diet, obesity, and different nutraceuticals/functional foods (bioactive peptides, phytochemicals, omega 3-polyunsaturated fatty acids, vitamin D, probiotics and prebiotics) on the course of IBD, and provide some hints that could be useful for nutritional guidance. Hopefully, research will soon offer enough reliable data to slow down the spread of the disease and to make diet a cornerstone in IBD therapy.
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.