Online Education for Vaccination Competence Among Health Sciences Students

The EDUVAC project aims to develop and implement a web-based course on educating vaccination competence among health sciences students. In the current study students' feedback and evaluation is assessed which guided the partners' efforts to improve the final course content and learning material that will be available for open access. After completing the web-based course, most of the students (N=103, 75.1%) perceived their vaccination knowledge was up to date and their overall participating experience was "above average or excellent (N=119, 86.9%). While, almost all of the students (N=127, 92.7%) found that the web-based course has benefitted them and their future career. Our findings support that the web-based courses can provide satisfactory learning experience to University students and offer flexibility when needed especially in times that remote education is the only option

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed

Characterization and functional effects of cemtirestat a potent aldo keto reductase inhibitor in diabetes and inflammation

Aldo-keto reductases (AKR) are NAD(P)H dependent oxidoreductases that have been best characterized as glucose reducing agents, and have been implicated in diabetic pathophysiology. The first enzyme of the polyol pathway, aldose reductase (AKR1B1) is involved in the molecular mechanisms of glucose toxicity leading to diabetic complications, including microvascular, neurological, and macrovascular disorders, which are responsible for significant increase in morbidity and mortality of diabetic patients. These enzymes are also known to mediate an inflammatory response to lipid peroxidation metabolic products. Since chronic inflammation is associated with a number of pathological states, AKR1B1 has been implicated in various inflammatory diseases such as atherosclerosis, asthma, uveitis, sepsis, arthritis, periodontitis and several types of cancer related to chronic inflammation. Recently novel aldose reductase inhibitors based on carboxymethylated mercapto-triazino-indole scaffold have been designed [1]. Among the novel compounds, cemtirestat (Fig. 1) was the most promising inhibitor, with an IC50 in submicromolar range and high selectivity

Identification of Novel Aldose Reductase Inhibitors Based on Carboxymethylated Mercaptotriazinoindole Scaffold

Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5<i>H</i>-1,2,4-triazino­[5,6-<i>b</i>]­indole-5-acetic acid (<b>13</b>) was the most promising inhibitor, with an IC₅₀ in the submicromolar range and high selectivity, relative to aldehyde reductase. The crystal structure of aldose reductase complexed with <b>13</b> revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent “leadlikeness” of <b>13</b> as a promising candidate for further structure optimizations

[5-(Benzyloxy)-1H-indol-1-yl]acetic acid, an aldose reductase inhibitor and PPARγ ligand

Based on overlapping structural requirements for both efficient aldose reductase inhibitors and PPAR ligands, [5-(benzyloxy)-1H-indol-1-yl]acetic acid (compound 1) was assessed for inhibition of aldose reductase and ability to interfere with PPARγ. Aldose reductase inhibition by 1 was characterized by IC 50 in submicromolar and low micromolar range, for rat and human enzyme, respectively. Selectivity in relation to the closely related rat kidney aldehyde reductase was characterized by approx. factor 50. At organ level in isolated rat lenses, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner. To identify crucial interactions within the enzyme binding site, molecular docking simulations were performed. Based on luciferase reporter assays, compound 1 was found to act as a ligand for PPARγ, yet with rather low activity. On balance, compound 1 is suggested as a promising lead-like scaffold for agents with the potential to interfere with multiple targets in diabetes

The Effects of Prolonged Treatment with Cemtirestat on Bone Parameters Reflecting Bone Quality in Non-Diabetic and Streptozotocin-Induced Diabetic Rats

Cemtirestat, a bifunctional drug acting as an aldose reductase inhibitor with antioxidant ability, is considered a promising candidate for the treatment of diabetic neuropathy. Our study firstly examined the effects of prolonged cemtirestat treatment on bone parameters reflecting bone quality in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Experimental animals were assigned to four groups: non-diabetic rats, non-diabetic rats treated with cemtirestat, diabetic rats, and diabetic rats treated with cemtirestat. Higher levels of plasma glucose, triglycerides, cholesterol, glycated hemoglobin, magnesium, reduced femoral weight and length, bone mineral density and content, parameters characterizing trabecular bone mass and microarchitecture, cortical microarchitecture and geometry, and bone mechanical properties were determined in STZ-induced diabetic versus non-diabetic rats. Treatment with cemtirestat did not affect all aforementioned parameters in non-diabetic animals, suggesting that this drug is safe. In diabetic rats, cemtirestat supplementation reduced plasma triglyceride levels, increased the Haversian canal area and slightly, but insignificantly, improved bone mineral content. Nevertheless, the insufficient effect of cemtirestat treatment on diabetic bone disease does not support its use in the therapy of this complication of type 1 diabetes mellitus

2-Chloro-1,4-naphthoquinone derivative of quercetin as an inhibitor of aldose reductase and anti-inflammatory agent

The ability of flavonoids to affect multiple key pathways of glucose toxicity, as well as to attenuate inflammation has been well documented. In this study, the inhibition of rat lens aldose reductase by 3,7-di-hydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxyphenyl]-5-hydroxy-chromen-4-one (compound 1), was studied in greater detail in comparison with the parent quercetin (compound 2). The inhibition activity of 1, characterized by IC50 in low micromolar range, surpassed that of 2. Selectivity in relation to the closely related rat kidney aldehyde reductase was evaluated. At organ level in isolated rat lenses incubated in the presence of high glucose, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner, which indicated that 1 was readily taken up by the eye lens cells and interfered with cytosolic aldose reductase. In addition, compound 1 provided macroscopic protection of colonic mucosa in experimental colitis in rats. At pharmacologically active concentrations, compound 1 and one of its potential metabolite 2-chloro-3-hydroxy[1,4]-naphthoquinone (compound 3) did not affect osmotic fragility of red blood cells

Decreasing acidity in a series of aldose reductase inhibitors: 2-Fluoro-4-(1H-pyrrol-1-yl)phenol as a scaffold for improved membrane permeation

Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase inhibitors (ARIs) have been gaining attention over the years. In the present work, in order to address the poor membrane permeation of previously reported ARIs, derivatives of N-phenylpyrrole, bearing groups with putative pKa ≥ 7.4, were synthesized and evaluated for aldose reductase inhibitory activity. The 2-fluorophenol group proved the most promising moiety, and further modifications were explored. The most active compound (31), identified as a submicromolar inhibitor (IC50 = 0.443 μM), was also selective against the homologous enzyme aldehyde reductase. Cross-docking revealed that 31 displays a peculiar interaction network that may be responsible for high affinity. Physicochemical profiling of 31 showed a pKa of 7.64, rendering it less than 50% ionized in the physiological pH range, with potentially favorable membrane permeation. The latter was supported from the successful inhibition of sorbitol formation in rat lenses and the ability to permeate rat jejunum. © 2014 Elsevier Ltd. All rights reserved

[5-(Benzyloxy)-1H-indol-1-yl]acetic acid, an aldose reductase inhibitor and PPAR gamma ligand

Based on overlapping structural requirements for both efficient aldose reductase inhibitors and PPAR ligands, [5-(benzyloxy)-1H-indol-1-yl] acetic acid (compound 1) was assessed for inhibition of aldose reductase and ability to interfere with PPAR gamma. Aldose reductase inhibition by 1 was characterized by IC50 in submicromolar and low micromolar range, for rat and human enzyme, respectively. Selectivity in relation to the closely related rat kidney aldehyde reductase was characterized by approx. factor 50. At organ level in isolated rat lenses, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner. To identify crucial interactions within the enzyme binding site, molecular docking simulations were performed. Based on luciferase reporter assays, compound 1 was found to act as a ligand for PPAR gamma, yet with rather low activity. On balance, compound 1 is suggested as a promising lead-like scaffold for agents with the potential to interfere with multiple targets in diabetes