Browsing by Author "Pinto, Rui"
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- Anti-inflammatory effect of topiramate in a chronic model of TNBS-induced colitisPublication . Silva, Inês; Mendes, Priscila; Guerra, Sofia; Pinto, Rui; Mateus, VanessaInflammatory bowel disease (IBD) is characterized by a chronic and relapsing inflammatory response in the gastrointestinal tract, resulting in severe symptoms such as abdominal pain, vomiting, diarrhea, bloody stools, and weight loss. Currently, there is no cure, and the pharmacological treatment includes drugs that induce and keep the patient in remission, not reversing the underlying pathogenic mechanism. In the long term, these therapies may cause various side effects and complications, which has increased the need to investigate new, more effective, and safer pharmacological approaches. In preclinical studies, topiramate has demonstrated a potential anti-inflammatory effect by inhibiting the production of several pro-inflammatory cytokines. This study aimed to investigate the effect of topiramate in a chronic TNBS-induced colitis model in rodents. Experimental colitis was induced by four intrarectal administrations of 1% TNBS in female CD-1 mice. Topiramate 10 and 20 mg were administered intraperitoneally for 14 days. Several parameters were evaluated, such as body weight, alkaline phosphatase (ALP), fecal hemoglobin, fecal calprotectin, tumor necrosis factor (TNF)-α, and interleukin (IL)-10. Topiramate reduces TNBS-induced colonic damage in a model of chronic experimental colitis and normalizes stool consistency and anus appearance. Additionally, topiramate significantly reduced the concentration of ALP, fecal hemoglobin, fecal calprotectin, TNF-α, and IL-10, demonstrating it to be a promising pharmacological approach for treating IBD in the future.
- Blood count, endocrine, immunologic, renal, and hepatic markers in a case-control animal study of induced periodontitis in female rodentsPublication . Estarreja, João; Pimenta, Ana Clara; Botelho, João; Vilares, Arminda Maria; Mendes, José João; Rocha, João; Pinto, Rui; Mateus, Vanessa; Machado, VanessaIntroduction: Periodontitis is a non-communicable chronic inflammatory disease with a systemic burden. Animal models of induced periodontitis help elucidate the mechanisms by which periodontal inflammation drives systemic effects. Studying this systemic involvement over longer follow-up periods may provide a strong foundation for future research on the association between diseases and periodontitis, particularly in female rats. Therefore, we aimed to compare blood, endocrine, immunologic, renal, and hepatic markers in a rat model of induced periodontitis in females with their control counterparts. Methods: Experimental periodontitis was induced in 20 female Wistar rats by the application and maintenance of silk ligatures on the upper molars. The rats were then assessed for macroscopical analysis, complete blood count, and biochemical, endocrine, and immunologic markers at 21, 28, 42, and 56 days. Results: Chronic periodontal inflammation was observed after 42 days of exposure to the ligatures. Additionally, it was also possible to notice significant systemic manifestations, such as the reduction of triiodothyronine and thyroxine levels, along with an increase in the expression of alkaline phosphatase, gamma-glutamyl transpeptidase, and lactate dehydrogenase. Discussion: The study's findings imply that certain changes can be underscored to highlight a reduced risk of conception. Notably, previous investigations have indicated that subfertile women exhibit lower levels of thyroid hormones and elevated lactate dehydrogenase expression. Despite the absence of preclinical data delineating a possible association between periodontitis and female infertility, the results of this study may prove to be a crucial contribution to both the scientific and medical fields.
- Chemically induced colitis-associated cancer models in rodents for pharmacological modulation: a systematic reviewPublication . Modesto, Rita; Estarreja, João; Silva, Inês; Rocha, João; Pinto, Rui; Mateus, VanessaAnimal models for colitis-associated colorectal cancer (CACC) represent an important tool to explore the mechanistic basis of cancer-related inflammation, providing important evidence that several inflammatory mediators play specific roles in the initiation and perpetuation of colitis and CACC. Although several original articles have been published describing the CACC model in rodents, there is no consensus about the induction method. This review aims to identify, summarize, compare, and discuss the chemical methods for the induction of CACC through the PRISMA methodology. Methods: We searched MEDLINE via the Pubmed platform for studies published through March 2021, using a highly sensitive search expression. The inclusion criteria were only original articles, articles where a chemically-induced animal model of CACC is described, preclinical studies in vivo with rodents, and articles published in English. Results: Chemically inducible models typically begin with the administration of a carcinogenic compound (as azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)), and inflammation is caused by repeated cycles of colitis-inducing agents (such as 2,4,6-trinitrobenzenesulfonic acid (TNBS) or dextran sulfate sodium (DSS)). The strains mostly used are C57BL/6 and Balb/c with 5–6 weeks. To characterize the preclinical model, the parameters more used include body weight, stool consistency, and morbidity, inflammatory biomarkers such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, angiogenesis markers such as proliferating cell nuclear antigen (PCNA), a marker of proliferation Ki-67, and caspase 3, the presence of ulcers, thickness or hyperemia in the colon, and histological evaluation of inflammation. Conclusion: The AOM administration seems to be important to the CACC induction method since the carcinogenic effect is achieved with just one administration. DSS has been the more used inflammatory agent; however, the TNBS contribution should be more studied, since it allows a reliable, robust, and highly reproducible animal model of intestinal inflammation.
- Chronic experimental model of TNBS-induced colitis to study inflammatory bowel diseasePublication . Silva, Inês; Solas, João; Pinto, Rui; Mateus, VanessaBackground: Inflammatory bowel disease (IBD) is a world healthcare problem. In order to evaluate the effect of new pharmacological approaches for IBD, we aim to develop and validate chronic trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Methods: Experimental colitis was induced by the rectal administration of multiple doses of TNBS in female CD-1 mice. The protocol was performed with six experimental groups, depending on the TNBS administration frequency, and two control groups (sham and ethanol groups). Results: The survival rate was 73.3% in the first three weeks and, from week 4 until the end of the experimental protocol, the mice’s survival remained unaltered at 70.9%. Fecal hemoglobin presented a progressive increase until week 4 (5.8 ± 0.3 µmol Hg/g feces, p < 0.0001) compared with the ethanol group, with no statistical differences to week 6. The highest level of tumor necrosis factor-α was observed on week 3; however, after week 4, a slight decrease in tumor necrosis factor-α concentration was verified, and the level was maintained until week 6 (71.3 ± 3.3 pg/mL and 72.7 ± 3.6 pg/mL, respectively). Conclusions: These findings allowed the verification of a stable pattern of clinical and inflammation signs after week 4, suggesting that the chronic model of TNBS-induced colitis develops in 4 weeks.
- Development of TNBS-induced colitis: animal model to test new pharmacological approachesPublication . Mateus, Vanessa; Faísca, Pedro; Mota-Filipe, Helder; Sepodes, Bruno; Pinto, RuiIBD is a gastro-intestinal disorder marked with chronic inflammation of intestinal epithelium, damaging mucosal tissue and manifests into several intestinal and extra-intestinal symptoms. Currently used medical therapy is able to induce and maintain the patient in remission, however no modifies or reverses the underlying pathogenic mechanism. The research of other medical approaches is crucial to the treatment of IBD and, for this, it´s important to use animal models to mimic the characteristics of disease in real life. The aim of the study is to develop an animal model of TNBS-induced colitis to test new pharmacological approaches. TNBS was instilled intracolonic single dose as described by Morris et al. It was administered 2,5% TNBS in 50% ethanol through a catheter carefully inserted into the colon. Mice were kept in a Tredelenburg position to avoid reflux. On day 4 and 7, the animals were sacrificed by cervical dislocation. The induction was confirmed based on clinical symptoms/signs, ALP determination and histopathological analysis. At day 4, TNBS group presented a decreased body weight and an alteration of intestinal motility characterized by diarrhea, severe edema of the anus and moderate morbidity, while in the two control groups weren’t identified any alteration on the clinical symptoms/signs with an increase of the body weight. TNBS group presented the highest concentrations of ALP comparing with control groups. The histopathology analysis revealed severe necrosis of the mucosa with widespread necrosis of the intestinal glands. Severe hemorrhagic and purulent exsudates were observed in the submucosa, muscular and serosa. TNBS group presented clinical symptoms/signs and histopathological features compatible with a correct induction of UC. The peak of manifestations became maximal at day 4 after induction. This study allows concluding that it’s possible to develop a TNBS induced colitis 4 days after instillation.
- Effect of aqueous extract of phenolic compounds obtained from red wine in experimental model of colitis in micePublication . Mateus, Vanessa; Estarreja, João; Silva, Inês; Gonçalves, Fernando; Teixeira-Lemos, Edite; Pinto, RuiBackground: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder represented by Crohn’s disease and ulcerative colitis. Currently, there is no cure and pharmacological treatment aims to induce and maintain remission in patients. Because the therapy reveals relatively high toxicity, during a long-term utilization, it is essential to investigate new pharmacological approaches. Polyphenols, commonly present in red wine, have shown health-beneficial effects related to their antioxidant and anti-inflammatory effects through the inhibition of NF-kB activation, COX-2, and iNOS induction. In this sense, it would be interesting to study their effects in an IBD context. Therefore, this study aims to evaluate the effects of an aqueous extract of phenolic compounds in a 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced model of colitis. Method: Experimental colitis was induced in mice through an intrarectal administration of TNBS and then the mice were treated with an aqueous extract of phenolic compounds intraperitoneally for four days. Results and Discussion: The extract demonstrated an anti-inflammatory effect, reduced TNF-α levels in the colon, and had a beneficial effect on the extraintestinal manifestations related to IBD, without any significant side effects. The extract of phenolic compounds demonstrated to be a valuable object of study for the management of IBD in the future.
- Effect of carbamylated erythropoietin in a chronic model of TNBS-induced colitisPublication . Silva, Inês; Gomes, Mário; Alípio, Carolina; Vitoriano, Jéssica; Estarreja, João; Mendes, Priscila; Pinto, Rui; Mateus, VanessaBackground: Inflammatory bowel disease (IBD) is a public health issue with a growing prevalence, which can be divided into two phenotypes, namely Crohn's disease (CD) and ulcerative colitis (UC). Currently, used therapy is based only on symptomatic and/or palliative pharmacological approaches. These treatments seek to induce and maintain remission of the disease and ameliorate its secondary effects; however, they do not modify or reverse the underlying pathogenic mechanism. Therefore, it is essential to investigate new potential treatments. Carbamylated erythropoietin (cEPO) results from the modification of the Erythropoietin (EPO) molecule, reducing cardiovascular-related side effects from the natural erythropoiesis stimulation. cEPO has been studied throughout several animal models, which demonstrated an anti-inflammatory effect by decreasing the production of several pro-inflammatory cytokines. Aim: This study aimed to evaluate the efficacy and safety of cEPO in a chronic TNBS-induced colitis model in rodents. Methods: Experimental colitis was induced by weekly intrarectal (IR) administrations of 1% TNBS for 5 weeks in female CD-1 mice. Then, the mice were treated with 500 IU/kg/day or 1000 IU/kg/day of cEPO through intraperitoneal injections for 14 days. Results: cEPO significantly reduced the concentration of alkaline phosphatase (ALP), fecal hemoglobin, tumor necrosis factor (TNF)-α, and interleukin (IL)-10. Also, it demonstrated a beneficial influence on the extra-intestinal manifestations, with the absence of significant side effects of its use. Conclusion: Considering the positive results from cEPO in this experiment, it may arise as a new possible pharmacological approach for the future management of IBD.
- Effect of Cynara cardunculus L. var. altilis (DC) in inflammatory bowel diseasePublication . Mateus, Vanessa; Estarreja, João; Silva, Inês; Barracosa, Paulo; Teixeira-Lemos, Edite; Pinto, RuiBackground: Cynara cardunculus L. var. altilis (DC) is a plant generally associated as an ingredient in the Mediterranean diet. The polyphenols present in this plant provide pharmacological and nutritional properties. C. cardunculus L. has been used throughout animal studies, which demonstrated an anti-inflammatory effect. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Since there is not a known cure, the research of new possible pharmacological approaches is essential. This study aims to evaluate the effect of an aqueous extract of C. cardunculus L. dry leaves in a 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis model. Methods: CD-1 mice with TNBS-induced colitis received an intraperitoneal (IP) administration of C. cardunculus L. once per day for 4 days. Results: The C. cardunculus L. demonstrated a beneficial effect in this experimental model of IBD with anti-inflammatory action through the reduction of tumor necrosis factor (TNF)-α levels. It also demonstrated a beneficial influence on the extra-intestinal manifestations related to IBD, with the absence of significant side effects of its use. Conclusions: The extract of C. cardunculus L. dry leaves can become an interesting tool for new possible pharmacological approaches in the management of IBD.
- Efficacy and safety of erythropoietin in a chronic model of inflammatory bowel diseasePublication . Silva, Inês; Estarreja, João; Pinto, Rui; Mateus, VanessaBackground: Inflammatory Bowel Disease (IBD) is recognized as a group of chronic inflammatory disorders, localized in the gastrointestinal tract, which does not have a cure known. Indeed, the pharmacological approaches, commonly used, demonstrate significant toxicity, which highlights the need of investigating new possible treatments. Erythropoietin (EPO) is clinically used in anemic patients, with chronic renal insufficiency, due to its erythropoietic effect. However, it has also been described other non-erythropoietic effects, such as an anti-inflammatory role. There is already preclinical evidence about its anti-inflammatory effect in the IBD context, namely in an acute model of colitis in mice. Therefore, it is relevant to ascertain its anti-inflammatory effect in a chronic model, but mainly its hematopoietic side effect, during chronic treatment. Aim: This experiment aims to evaluate the efficacy and safety of EPO treatment in a chronic 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rodents. Methods: The induction of chronic colitis consisted of five weekly intrarectal administrations of 1% TNBS, and then mice were treated daily with 500 IU/Kg or 1000 IU/Kg of EPO, through intraperitoneal injections, for 14 days. Results: EPO demonstrated a significant anti-inflammatory effect, translated by a significant reduction of the concentration of tumor necrosis factor-α, fecal calprotectin, and fecal hemoglobin. Moreover, it has also been demonstrated to be safe, considering the cardiovascular system, in terms of extraintestinal manifestations, namely at renal and hepatic functions. Conclusions: EPO demonstrated to be a promising pharmacological approach to be considered in the management of IBD, being an interesting target for drug repositioning.
- Erythropoietin in animal models of inflammationPublication . Silva, Inês; Alípio, Carolina; Pinto, Rui; Mateus, VanessaBackground: Erythropoietin binds to the erythropoietin receptor to promote the proliferation and differentiation of red blood cells. This hypoxia-induced hormone is produced in adult kidneys with erythropoietin and non-erythropoietic effects. Since current anti-inflammatory therapies are not safe, erythropoietin emerges as a new pharmacological approach reverting the mechanism of inflammation with apparently lower toxicity. AIM: Evaluate the potential anti-inflammatory effect of erythropoietin observed in animal inflammatory disease models. Methods: A systematic review followed PRISMA statements in the electronic database MEDLINE via the PubMed platform. The inclusion criteria were: (1) original articles; (2) studies in animal models where erythropoietin was administered; (3) studies where inflammation was studied and/or evaluated; (4) non-clinical studies in vivo with rodents; and (5) articles published in English. Results: A total of 36 articles met the criteria for qualitative analysis. Exogenous erythropoietin was used in models of sepsis, traumatic brain injury, and autoimmune neuritis with anti-inflammatory effects. The average dose of exogenous erythropoietin was 3000 IU/kg of weight. Erythropoietin was associated with a significant reduction of biomarkers such as immune-related effectors, cytokines, reactive oxygen species, and prostaglandins. Erythropoietin analogues, such as ARA290 or carbamylated erythropoietin, have the crucial advantage of promoting the anti-inflammatory effect without the thromboembolic risk by the proliferation of red blood cells. Conclusion: Erythropoietin is recognized as a multifunctional cytokine with anti-inflammatory properties, showing its significant effect both in acute and chronic murine models of inflammation.
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