Effects of vincristine and monosodium glutamate on gastrointestinal motility and visceral sensitivity

Background Chemotherapy‐induced adverse effects are an unresolved nightmare. In preclinical studies in rats, the food additive monosodium glutamate (MSG) improved some of the side effects caused by cisplatin, but its effects in other models of chemotherapy‐treated animals are not well known. The aim of this study was to test if MSG may improve some of the adverse effects induced by vincristine in rats. Methods Young male Wistar rats were exposed or not to MSG (4 g L−1) in drinking water from week 0 till 1 week after treatment (week 3). Rats received two cycles of five daily intraperitoneal (ip) injections (Monday to Friday, weeks 1 and 2) of either saline (2 mL kg−1) or vincristine (0.1 mg kg−1). Gastrointestinal motility was measured in vivo by radiological methods after the first and tenth ip administrations. On week 3, the threshold for mechanical somatic and colorectal sensitivity was recorded using Von Frey filaments applied to the paws and an intracolonic balloon, respectively. Finally, samples of the terminal ileum and distal colon were histologically evaluated in sections. Key Results Vincristine reduced body weight gain, food intake, and upper gastrointestinal transit, caused somatic (but not visceral) hypersensitivity and increased the thickness of the submucosal and muscle layers of the small intestine. In vincristine‐treated animals, MSG partially prevented gastrointestinal dysmotility and reduced visceral sensitivity but did not improve structural alterations of the small intestine. Conclusions and Inferences MSG could be used as an adjuvant to conventional treatments to improve some gastrointestinal dysfunctions caused by chemotherapy

Effects of chronic dietary exposure to monosodium glutamate on feeding behavior, adiposity, gastrointestinal motility, and cardiovascular function in healthy adult rats

[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.This work was supported by Fundacion Mapfre (Ayudas a la Investigacion-Promocion de la Salud 2011 and 2012); Ministerio de Educacion y Ciencia y Ministerio de Ciencia e Innovacion (SAF2009-12422-C02-01, SAF2012-40075-C02-01, PI11/00616, PI14/00860, CPII14/00005, and PI10/02986); and CIBERSAM.Peer Reviewe

Pepsin egg white hydrolysate ameliorates obesity-related oxidative stress, inflammation and steatosis in Zucker fatty rats

The aim of this work was to evaluate the effect of the administration of egg white hydrolysates on obesity-related disorders, with a focus on lipid metabolism, inflammation and oxidative stress, in Zucker fatty rats. Obese Zucker rats received water, pepsin egg white hydrolysate (750 mg/kg/day) or Rhizopus aminopeptidase egg white hydrolysate (750 mg/kg/day) for 12 weeks. Lean Zucker rats received water. Body weight, solid and liquid intakes were weekly measured. At the end of the study, urine, faeces, different organs and blood samples were collected. The consumption of egg white hydrolysed with pepsin significantly decreased the epididymal adipose tissue, improved hepatic steatosis, and lowered plasmatic concentration of free fatty acids in the obese animals. It also decreased plasma levels of tumor necrosis factor-alpha and reduced oxidative stress. Pepsin egg white hydrolysate could be used as a tool to improve obesity-related complications.This study has received financial support from the project AGL2012-32387 and SAF2012-40075-C02-01 from the Spanish Ministry of Economy and Competitiveness (MINECO).Peer Reviewe

Pradimicin and Benanomicin Antibiotics: From Antifungal Polyketide Natural Products to Antiviral Agents with a Unique Carbohydrate-Binding Mode of Action

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Characterization of Cardiovascular Alterations Induced by Different Chronic Cisplatin Treatments

In the last years, many clinical studies have revealed that some cisplatin-treated cancer survivors have a significantly increased risk of cardiovascular events, being cisplatin-induced cardiovascular toxicity an increasing concern. The aim of the present work was to evaluate the cardiovascular alterations induced by different chronic cisplatin treatments, and to identify some of the mechanisms involved. Direct blood pressure, basal cardiac (left ventricle and coronary arteries) and vascular (aortic and mesenteric) functions were evaluated in chronic (5 weeks) saline- or cisplatin-treated male Wistar rats. Three different doses of cisplatin were tested (1, 2, and 3 mg/kg/week). Alterations in cardiac and vascular tissues were also investigated by immunohistochemistry, Western Blot, and or quantitative RT-PCR analysis. Cisplatin treatment provoked a significant modification of arterial blood pressure, heart rate, and basal cardiac function at the maximum dose tested. However, vascular endothelial dysfunction occurred at lower doses. The expression of collagen fibers and conexin-43 were increased in cardiac tissue in cisplatin-treated rats with doses of 2 and 3 mg/kg/week. The expression of endothelial nitric oxide synthase was also modified in cardiac and vascular tissues after cisplatin treatment. In conclusion, chronic cisplatin treatment provokes cardiac and vascular toxicity in a dose-dependent manner. Besides, vascular endothelial dysfunction occurs at lower doses than cardiac and systemic cardiovascular toxicity. Moreover, some structural changes in cardiac and vascular tissues are also patent even before any systemic cardiovascular alterations.This study was supported by grants from Ministerio de Educación y Ciencia SAF2009-12422-C02-01, MAPFRE. Ayudas a la Investigación 2011 (Promoción de la Salud: Alimentación y Ejercicio Físico) and Ministerio de Ciencia e Innovación-MICINN (SAF2012-40075-C02-01).Peer reviewedPeer Reviewe

Cardiovascular Toxicity Induced by Chronic Vincristine Treatment

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.This study was supported by grants from Ministerio de Ciencia e Innovación-MICINN (SAF 2012-40075-C02-01) and Laboratorios Esteve S.A

Use of multifuncional bioactive products derived from the enzymatic hydrolysis of egg white proteins for treating metabolic syndrome

El síndrome metabólico es un desorden multifactorial en el que confluyen varias alteraciones que habitualmente requieren de tratamiento farmacológico diferenciado para cada uno de ellas. La presente invención se refiere al uso de un producto bioactivo multifuncional derivado de la hidrólisis enzimática de proteínas de clara de huevo, en la preparación de una composición farmacéutica y/o una composición alimentaria funcional, que presentan utilidad para el tratamiento global de las alteraciones del síndrome metábolico.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Universidad Rey Juan CarlosB1 Patente sin examen previ

Uso de productos bioactivos multifuncionales derivados de la hidrólisis enzimática de proteínas de clara de huevo para el tratamiento del síndrome metabólico

[EN] Metabolic syndrome is a multifactorial disorder which is associated with various disturbances that usually require a different pharmacological treatment for each one. The invention relates to the use of a multifunctional bioactive product derived from the enzymatic hydrolysis of egg white proteins in the production of a pharmaceutical composition and/or a functional food composition which can be used for the comprehensive treatment of the disturbances of metabolic syndrome.[ES] El síndrome metabólico es un desorden multifactorial en el que confluyen varias alteraciones que habitualmente requieren de tratamiento farmacológico diferenciado para cada uno de ellas. La presente invención se refiere al uso de un producto bioactivo multifuncional derivado de la hidrólisis enzimática de proteínas de clara de huevo, en la preparación de una composición farmacéutica y/o una composición alimentaria funcional, que presentan utilidad para el tratamiento global de las alteraciones del síndrome metábolico.Peer reviewedConsejo Superior de Investigaciones Científicas, Universidad Rey Juan CarlosA1 Solicitud de adición a la patent

Cisplatin cycles treatment sustains cardiovascular and renal damage involving TLR4 and NLRP3 pathways

Cisplatin is clinically proven to combat different cancers, including sarcomas, soft tissue cancers, bones, muscles, and blood. However, renal and cardiovascular toxicities are important limitations in cisplatin therapeutical use. Immunoinflammation could be key factor in cisplatin-induced toxicity. The aim of the present study was to evaluate the activation of the inflammatory TLR4/NLRP3 pathway as a common mechanism for cardiovascular and renal cisplatin's cycles treatment toxicity. Adult male Wistar rats were treated with saline, cisplatin 2 mg/kg or cisplatin 3 mg/kg (intraperitoneally once a week, for five experimental weeks). After treatments, plasma, cardiac, vascular, and renal tissues were collected. Plasma malondialdehyde (MDA) and inflammatory cytokines were determined. TLR4, MyD88, NF-κβ p65, NLRP3, and procaspase-1 tissue expressions were also analyzed. Cisplatin treatment induced a dose-dependent increase in plasma MDA and IL-18. In cardiovascular system, an increase in NLRP3 and in cleaved caspase-1 were observed in cardiac tissue and a moderate increase in TLR4, MyD88 appeared in mesenteric artery. In kidney, a significant dose-dependent increase in TLR4, MyD88 and NLRP3 and cleaved caspase 1 expressions were observed after cisplatin treatments. In conclusion, cisplatin cycles provoke a low grade pro-inflammatory systemic state. Kidney was more sensitive than cardiovascular tissues to this pro-inflammatory state. TLR4 and NLRP3 are key pathways involved in renal tissue damage, NLRP3 is the main pathway involved in cardiac toxicity and TLR4 pathway in resistance vessel toxicity.This study was supported by grants from Ministerio de Ciencia e Innovación-MICINN (SAF 2012-40075-C02- 01) and Laboratorios Esteve S.A

Pepsin Egg White Hydrolysate Improves Glucose Metabolism Complications Related to Metabolic Syndrome in Zucker Fatty Rats

The purpose of this study was to evaluate the effect of the administration of two egg white hydrolysates on glucose metabolism complications related to Metabolic Syndrome (MS) in Zucker fatty rats (ZFR). ZFR were given 750 mg/kg/day of egg white hydrolyzed with pepsin (HEW1) or with aminopeptidase (HEW2) for 12 weeks in their drinking water or just water. Zucker lean rats (ZLR), which received water, were used as a control. The presence of tactile allodynia, which is a sign of peripheral neuropathy, was assessed. Blood samples and pancreas were collected to determine the effect of the hydrolysates on glucose metabolism. The intake of HEW1 significantly lowered plasma insulin levels and improved the quantitative indexes of insulin resistance, insulin sensitivity, and pancreatic β-cell functionality (HOMA-IR, HOMA-β, and QUICKI, respectively), but non-significant changes were observed in group treated with HEW2. Compared to ZLR, ZFR showed tactile allodynia, but the consumption of both hydrolysates significantly increased mechanical sensitivity in ZFR. In conclusion, HEW1 pepsin could improve the glucose metabolism abnormalities associated with MS in obese Zucker rats