Assessing the reaction to and efficacy of the Screener drug discovery and development board game as a pedagogical tool in postgraduate courses.

Screener, a board game supplemented with online resources, was introduced and distributed by the Brazilian Society of Pharmacology and Experimental Therapeutics to postgraduate programs as an instructional tool for the process of drug discovery and development (DDD). In this study, we provided a comprehensive analysis of five critical aspects for evaluating the quality of educational games, namely: 1) description of the intervention; 2) underlying pedagogical theory; 3) identification of local educational gaps; 4) impact on diverse stakeholders; and 5) elucidation of iterative quality enhancement processes. We also present qualitative and quantitative assessments of the effectiveness of this game in 11 postgraduate courses. We employed the MEEGA+ online survey, comprising thirty-three close-ended unipolar items with 5-point Likert-type response scales, to assess student perceptions of the quality and utility of Screener. Based on 115 responses, the results indicated a highly positive outlook among students. In addition, we performed a preliminary evaluation of learning outcomes in two courses involving 28 students. Pre- and post-quizzes were applied, each consisting of 20 True/False questions directly aligned with the game's content. The analysis revealed significant improvement in students' performance following engagement with the game, with scores rising from 8.4 to 13.3 (P<0.0001, paired t-test) and 9.7 to 12.7 (P<0.0001, paired t-test). These findings underscore the utility of Screener as an enjoyable and effective tool for facilitating a positive learning experience in the DDD process. Notably, the game can also reduce the educational disparities across different regions of our continental country.

Preclinical toxicity of innovative molecules: In vitro, in vivo and metabolism prediction.

The lack of predictivity of animal's models has increased the failure rate of drug candidates. Thus, the reversion of this scenario using preliminary in vitro assays and metabolism prediction can reduce the unnecessary use of animals, as well as predict toxic effects at preclinical and clinical stages. The present study aimed to evaluate safety of four biologically active molecules (RN104, RI78, ICH, PCH) with potential therapeutic applications synthesized in our laboratory. Initially, we used MTT cytotoxicity against A549, H9C2, HepG2, LLC-PK1 and NEURO-2 cell lines. RN104 showed the lowest cytotoxicity and further studies were conducted with it. The neutral red (NR) test was performed according to OECD-129 and then acute toxicity test (OECD-423). According to NR results we administered at 300 mg/kg on animals; however, no toxic effect was observed, while 2,000 mg/kg resulted in the death of one animal per group. After, metabolism prediction studies, performed using both ligand-based and structure-based, suggests three potential metabolites. In silico results suggested that potential metabolites could be fast eliminated and, then, this could be an explanation for lower observed toxicity in in vivo experiments. The results showed limitations of the NR as a predictor of the initial dose for the acute toxicity study, which may be related to metabolism. Therefore, the combination of theoretical and experimental studies is relevant to a general understanding of new molecule's toxicity.

International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

BACKGROUND: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. METHODS: A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. RESULTS: Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients' age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: <1y, 36% (n = 46); 1-10y, 59% (n = 74); 11-16y, 3% (n = 4); and >16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. CONCLUSIONS: Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

Butyrate reduces high-fat diet-induced metabolic alterations, hepatic steatosis and pancreatic beta cell and intestinal barrier dysfunctions in prediabetic mice.

In this study, we investigated the effect of diet supplementation with sodium butyrate (5% w/w), a short-chain fatty acid produced by the intestinal microbiota, on metabolic parameters, body adiposity, hepatic and pancreatic lipid accumulation, beta cell function/mass as well as on the structure and function of the tight junction-mediated intestinal epithelial barrier in both normal and obese/prediabetic C57 mice fed a regular (control) or high-fat diet for 60 days, respectively. Butyrate treatment significantly inhibited all the high-fat-induced metabolic dysfunctions evaluated, i.e. significantly reduced the weight gain and body adiposity as well as the insulin resistant state, hyperglycemia and hyperinsulinemia, without changing food intake. In addition, high-fat-fed mice treated with this short-chain fatty acid displayed no compensatory hyperplasia of pancreatic beta cells nor marked hepatic steatosis as seen in prediabetic mice after high-fat diet only. Isolated pancreatic islets from high-fat-fed mice treated with butyrate showed improvement of the insulin secretion, which was associated with a significant decrease in lipid accumulation within the pancreas. Butyrate enhanced the intestinal epithelial barrier, as revealed by the FITC-Dextran permeability assay, which was accompanied by a significant increase in the junctional content of the tight junction-associated claudin-1 in intestinal epithelia of jejunum, ileum, and colon of both control and high-fat mice. In conclusion, our results showed that diet supplementation with butyrate inhibits the deleterious effects of high-fat diet intake on metabolic parameters and structure/function of several tissues/organs associated with type 2 diabetes mellitus in a mouse model, suggesting a potential use of this short-chain fatty acid in the treatment of this endocrine-metabolic disorder. Impact statement Butyrate is a short-chain fatty acid produced by the intestinal microbiota through the fermentation of non-absorbable carbohydrates and proteins (e.g. fibers). Sodium butyrate incorporated into the diet displayed a protective action on metabolic, hepatic, pancreatic and intestinal alterations induced by high-fat diet in mice, resulting in significant inhibition of the development of a prediabetic state. Thus, our data suggest that butyrate may have a potential therapeutic use in the treatment of type 2 diabetes and related disorders.

Exercise training, creatine supplementation, and bone health in ovariectomized rats.

UNLABELLED: Evidence suggests that creatine may have some beneficial effects on bone. The study aimed to investigate the effects of exercise alone or combined with creatine on bone health in ovariectomized rats. Findings show that exercise, but not creatine, has an important role in improving bone health. INTRODUCTION: The aim of this study was to investigate the effects of exercise training alone or combined with creatine supplementation on bone health parameters in ovariectomized rats. METHODS: Wistar rats were randomly allocated into one of five groups: (i) sham-operated, (ii) ovariectomized non-trained placebo-supplemented, (iii) ovariectomized non-trained creatine-supplemented, (iv) ovariectomized exercise-trained placebo-supplemented, and (v) ovariectomized exercise-trained creatine-supplemented. Downhill running training and/or creatine supplementation (300 mg/kg body weight) were administered for 12 weeks. Bone mineral content (BMC), bone mineral density (BMD), and biomechanical and histomorphometric parameters were assessed. RESULTS: No interaction effects were observed for BMC and BMD at whole body, femur, and lumbar spine (p > 0.05). Importantly, a main effect of training was detected for whole body BMC and BMD (p = 0.003 and p < 0.001, respectively), femoral BMC and BMD (p = 0.005 and p < 0.001, respectively), and lumbar spine BMC and BMD (p < 0.001 and p < 0.001, respectively), suggesting that the trained animals had higher bone mass, irrespective of creatine supplementation. Main effects of training were also observed for maximal load (p < 0.001), stiffness (p < 0.001), and toughness (p = 0.046), indicating beneficial effects of exercise training on bone strength. Neither a main effect of supplementation nor an interaction effect was detected for biomechanical parameters (p > 0.05). No main or interaction effects were observed for any of the histomorphometric parameters evaluated (p > 0.05). CONCLUSIONS: Exercise training, but not creatine supplementation, attenuated ovariectomy-induced bone loss in this rat model.

Δ-lactam derivative from thermophilic soil fungus exhibits in vitro anti-allergic activity.

From cultures of thermophilic soil fungus Humicola grisea var thermoidea, a δ-lactam derivative (3-(2-(4-hydroxyphenyl)-2-oxoethyl)-5,6-dihydropyridin-2(1H)-one) that displayed anti-allergic activity was isolated, which was predicted by in silico computational chemistry approaches. The in vitro anti-allergic activity was investigated by ß-hexosaminidase release assay in rat basophilic leukaemia RBL-2H3 cells. The δ-lactam derivative exhibited similar anti-allergic activity (IC(50) = 18.7 ± 6.7 µM) in comparison with ketotifen fumarate (IC(50) = 15.0 ± 1.3 µM) and stronger anti-allergic activity than azelastine (IC(50) = 32.0 µM). Also, the MTT cytotoxicity assay with RBL-2H3 cells showed that δ-lactam does not display cytotoxicity at concentrations lower than 50 µM. This study suggests that the δ-lactam derivative has the potential to be used as a lead compound in the development of anti-allergic drugs for clinical use in humans.

Short report: comparison of the effects of sublingual nifedipine and isosorbide dinitrate on oesophageal emptying in patients with Chagasic achalasia.

The effects of sublingual nifedipine and isosorbide dinitrate on oesophageal emptying were compared in 11 patients with Chagasic achalasia. The oesophageal emptying of a radiolabelled test meal was assessed three times in each patient by a scintigraphic technique. No treatment preceded one of the studies (basal study). Nifedipine (20 mg) by the sublingual route 30 min before the meal, preceded one study. Isosorbide dinitrate, 5 mg by the sublingual route 5 min before the meal, preceded the third study. The order of the studies was allocated randomly for each patient. Oesophageal retention at the completion of the meal was significantly less (P less than 0.01) after isosorbide dinitrate (median: 54%, range: 5-87%) than after sublingual nifedipine (median: 78%, range: 7-99%) or after the control study (median: 83%, range: 5-100%). This difference persisted up to 20 min after the meal. Values measured in the control study and after sublingual nifedipine were not different (P greater than 0.10). These results show that isosorbide dinitrate, but not sublingual nifedipine, enhances oesophageal emptying in Chagasic achalasia.