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- Preliminary results of an animal model validation of chronic experimental colitisPublication . Silva, Inês; Pinto, Rui; Mateus, VanessaInflammatory bowel disease (IBD): chronic inflammatory disease of the gastrointestinal (GI) tract characterized by recurrent ulceration. IBD prevalence exceeding 0,5% of the population in westernized countries. IBD manifests into several intestinal and extra-intestinal symptoms, mainly related to inflammation. IBD includes Crohn’s disease and Ulcerative colitis. Aim of the study: evaluate the efficacy of new drugs in IBD through an animal model of TNBS-induced chronic colitis.
- New pharmacological approach for inflammatory bowel diseasePublication . Silva, Inês; Pinto, Rui; Mateus, VanessaInflammatory bowel disease includes Crohn's disease and ulcerative colitis. Chronic inflammatory disease of the gastrointestinal (GI) tract is characterized by recurrent ulceration. IBD affects 7–10% of people worldwide, mainly of Caucasian descent. It manifests into several intestinal and extra-intestinal symptoms, mainly related to oxidative stress, inflammation, and autoimmune reaction. Aim of the study: evaluate the influence of a new pharmacological approach with erythropoietin in the establishment and development of inflammation associated with IBD, through of an experimental colitis model in rodents.
- TNBS-induced colitis in rodents: preliminary results of a chronic modelPublication . Silva, Inês; Mateus, Vanessa; Pinto, RuiBackground: Inflammatory bowel disease (IBD) is a gastrointestinal disorder characterized by chronic inflammation of the intestinal epithelium. The symptoms of IBD depend on the intestinal affected segment and usually include diarrhea often with blood, colic abdominal pain, and fecal urgency. Beyond these, other unspecific symptoms may occur like fever, loss of appetite and weight, fatigue, and primary amenorrhea. Nowadays, used therapy in IBD consists of salicylates, corticosteroids, immunosuppressants, and biological therapy. These drugs aim to induce and/or maintain the patient in remission and ameliorate the disease’s secondary effects, rather than modifying or reversing the underlying pathogenic mechanism. Aim: Development of an animal model of trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis in order to evaluate the influence of new drugs in the IBD.
- The pharmacological effect of hemin in inflammatory-related diseases: protocol for a systematic reviewPublication . Estarreja, João; Caldeira, Gonçalo; Silva, Inês; Mendes, Priscila; Mateus, VanessaBackground: Hemin is a commonly used drug in the treatment of acute attacks of porphyria, due to its capability of restoring normal levels of hemoproteins and respiratory pigments. In addition, this drug has demonstrated the capacity to induce the heme oxygenase (HO) enzyme. At the moment, there are 3 known HO isoenzymes in mammals: HO-1, HO-2, and HO-3. The first of these shows cytoprotective, antioxidant, and anti-inflammatory effects. Currently, medicines used in inflammatory disorders have increased toxicity, especially over longer time frames, which highlights the need to investigate new, safer options. Indeed, the current nonclinical evidence demonstrates the potential that hemin has a significant anti-inflammatory effect in several animal models of inflammation-related diseases, such as experimental colitis, without significant side effects. However, the underlying mechanism(s) are still not fully understood. In addition, past nonclinical studies have applied different therapeutic regimens, making it relatively difficult to understand which is optimal. According to the literature, there is a lack of review articles discussing this topic, highlighting the need for a summary and analysis of the available preclinical evidence to elucidate the abovementioned issues. Therefore, a qualitative synthesis of the current evidence is essential for the research and medical communities. Objective: This systematic review aims to summarize and analyze currently available nonclinical data to ascertain the potential anti-inflammatory effect of hemin in animal models. Methods: Throughout the development of this protocol, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The comprehensive search strategy will be carried out in MEDLINE (PubMed), Web of Science, and Scopus without any filters associated with publication date. Only in vivo, nonclinical studies that evaluated the potential anti-inflammatory effect of hemin will be included. The evaluated outcomes will be the observed clinical signs, inflammatory and other biochemical markers, and macroscopic and microscopic evaluations. To analyze the potential risk of bias, we will use the risk of bias tool developed by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE). Results: Currently, it is not possible to disclose any results since the project is still in the initial steps. More specifically, we are currently engaged in the identification of eligible articles through the application of the inclusion and exclusion criteria. The work was initiated in April 2023, and it is expected to be finished at the end of 2023. Conclusions: Concerning the major gap in the literature regarding the underlying mechanism(s) and treatment-related properties, this systematic review will be essential to clearly summarize and critically analyze the nonclinical data available, promoting a clearer vision of the potential anti-inflammatory effect of hemin.
- Hemin ameliorates the inflammatory activity in the inflammatory bowel disease: a non-clinical study in rodentsPublication . Silva, Inês; Correia, Rita; Pinto, Rui; Mateus, VanessaBackground: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Currently, there is no cure, and pharmacological treatment aims to induce and maintain remission in patients, so it is essential to investigate new possible treatments. Hemin is a heme-oxygenase inducer that can confer anti-inflammatory, cytoprotective, and antiapoptotic effects; therefore, it can be considered an asset for different gastrointestinal pathologies, namely for IBD. Aim: This experiment aims to evaluate the efficacy and safety of hemin, in a chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model in rodents. Methods: The induction of chronic colitis consisted of five weekly intrarectal administrations of 1% TNBS. Then, the mice were treated daily with 5 mg/kg/day or 10 mg/kg/day of hemin, through intraperitoneal injections, for 14 days. Results: Hemin demonstrated an anti-inflammatory effect through the reduction in tumor necrosis factor (TNF)-α levels, fecal calprotectin, and fecal hemoglobin. It was also found to be safe in terms of extraintestinal manifestations since hemin did not promote renal and/or hepatic changes. Conclusions: Hemin could become an interesting tool for new possible pharmacological approaches in the management of IBD.
- Potencial da genisteína na reativação da expressão do gene da γ-globulina e indução da hemoglobina fetalPublication . Matos, Elisabete; Sousa, Daniela; Delgadinho, Mariana; Mateus, Vanessa; Silva, Inês; Ribeiro, Edna; Brito, MiguelProject goals: Identification of novel agents with higher HbF inducing activity and lower cytotoxicity accessible in low-income countries, has been one of the major challenges over the past few years. A naturally occurring isoflavone found in plant products ( lentils, and chickpeas). Potent inhibitor of the PTK and topoisomerase II G 2 /M cell cycle arrest) regulates MAPK pathways (p 38 MAPK and ERK 1 /ERK 2. Antioxidant, antineoplastic, antihelmintic antiangiogenic, and immunosuppressive properties. Structurally similar to estrogen (estradiol 17 β). Potential to mimic, enhance, or impair the estradiol biosynthesis pathway with high reported binding selectivity for ER β isoform.
- 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.
- O potencial da epigalocatequina-3-galato na reativação da expressão da y-globina e indução da hemoglobina fetalPublication . Sousa, Daniela; Matos, Elisabete; Delgadinho, Mariana; Ribeiro, Edna; Mateus, Vanessa; Silva, Inês; Brito, MiguelAs hemoglobinopatias estão entre as doenças genéticas mais comuns em todo o mundo, particularmente a doença falciforme (DF) e a β talassemia e são causadas por defeitos na estrutura da hemoglobina ou na expressão dos genes da globina durante a transição de hemoglobina fetal HbF pela hemoglobina adulta HbA. Novas abordagens terapêuticas estão a ser desenvolvidas para irem além do tratamento paliativo que impõe altos custos aos sistemas de saúde. Desta forma, uma terapia alternativa mais acessível e promissora é a indução farmacológica de HbF. A elevação da síntese da cadeia γ-globina fetal equilibra o excesso da cadeia α globina pela formação de HbF modulando a anemia severa nos pacientes com β talassemia maior e inibindo diretamente a polimerização da hemoglobina falciforme em pacientes com DF. A hidroxiureia (HU) é o único medicamento aprovado pela FDA para o tratamento de pacientes com DF e com β talassemia intermédia. No entanto, este fármaco inibe a replicação do ADN e a possibilidade de ser mutagénico e carcinogénico limita o seu uso clínico. Por este motivo, o desenvolvimento de novos compostos indutores de HbF com alta eficiência e menor toxicidade, estão a ser investigados. Os compostos biológicos da dieta, como a epigalocatequina galato (EGCG) estão associados a efeitos benéficos para a saúde devido aos seus efeitos anti inflamatórios e antioxidantes. A EGCG é a catequina mais abundante no chá verde e a sua propriedade anti inflamatória desempenha um papel crucial na regulação da expressão e transcrição relativa de genes. O objetivo deste projeto foi avaliar o potencial da EGCG, na reativação da expressão do gene da γ-globina e, deste modo, na indução de HbF.
- 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.
- 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.
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