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-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (13) 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 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent "leadlikeness" of 13 as a promising candidate for further structure optimizations.

Microwave ablation at 2.45 GHz is gaining popularity as an alternative therapy to hepatic resection with a higher overall survival rate than external beam radiation therapy and proton beam therapy. It also offers better long-term recurrence-free overall survival when compared with radiofrequency ablation. To improve the design and optimization of microwave ablation procedures, numerical models can provide crucial information. A three-dimensional model of the antenna and targeted tissue without homogeneity assumptions are the most realistic representation of the physical problem. Due to complexity and computational resources consumption, most of the existing numerical studies are based on using two-dimensional axisymmetric models to emulate actual three-dimensional cancers and surrounding tissue, which is often far from reality. The main goal of this study is to develop a fully three-dimensional model of a multislot microwave antenna immersed into liver tissue affected by early-stage hepatocellular carcinoma. The geometry of the tumor is taken from the 3D-IRCADb-01 liver tumors database. Simulations were performed involving the temperature dependence of the blood perfusion, dielectric and thermal properties of both healthy and tumoral liver tissues. The water content changes during the ablation process are also included. The optimal values of the input power and the ablation time are determined to ensure complete treatment of the tumor with minimal damage to the healthy tissue. It was found that a multislot antenna is designed to create predictable, large, spherical zones of the ablation that are not influenced by varying tissue environments. The obtained results may be useful for determining optimal conditions necessary for microwave ablation to be as effective as possible for treating early-stage hepatocellular carcinoma, with minimized invasiveness and collateral damages.

The aim of the present work was to study the effect of 3mercapto-5H-1,2,4-triazino [5,6-b]indole-5-acetic acid (CMTI), an efficient aldose reductase inhibitor, on sorbitol accumulation in selected organs of streptozotocin-induced diabetic rats in vivo. In addition, the effect of CMTI on aldose reductase back reaction and on sorbitol dehydrogenase was determined. The model of experimental diabetes in male Wistar rats induced by streptozotocin was used. Experimental diabetes was induced by triple intraperitoneal doses of streptozotocin on three consecutive days. In diabetic rats, significant elevation of sorbitol concentration in the sciatic nerve and eye lenses was recorded.CMTI administered intragastrically (50 mg/kg/day) for five consecutive days significantly inhibited sorbitol accumulation in the sciatic nerve, yet it was without effect in eye lenses of diabetic animals. For aldose reductase back reaction, the substrate affinity of glycerol to aldose reductase was one order lower than that of glyceraldehyde in forward reaction. In addition, the back reaction was much slower, characterized by V max value of about 30 times lower than that of the forward reaction. Inhibition of aldose reductase by CMTI was characterized by closely related IC 50 values in submicromolar range for both forward and back reactions. No significant inhibition of the second enzyme of the polyol pathway, sorbitol dehydrogenase, by 100 μM CMTI was recorded (I=0.9±2.7 %, n=3). To conclude, the presented results showed the ability of CMTI to affect the polyol pathway in diabetic rats in vivo and represent thus a further step in a complex preclinical evaluation of CMTI as a potential agent for treatment of chronic diabetic complications.

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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 IC 50 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.

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