RESUMEN
Opisthorchiosis is a parasitic liver disease found in mammals that is widespread throughout the world and causes systemic inflammation. Praziquantel remains the drug of choice for the treatment of opisthorchiosis, despite its many adverse effects. An anthelmintic effect is attributed to the main curcuminoid of Curcuma longa L. roots-curcumin (Cur)-along with many other therapeutic properties. To overcome the poor solubility of curcumin in water, a micellar complex of curcumin with the disodium salt of glycyrrhizic acid (Cur:Na2GA, molar ratio 1:1) was prepared via solid-phase mechanical processing. In vitro experiments revealed a noticeable immobilizing effect of curcumin and of Cur:Na2GA on mature and juvenile Opisthorchis felineus individuals. In vivo experiments showed that curcumin (50 mg/kg) had an anthelmintic effect after 30 days of administration to O. felineus-infected hamsters, but the effect was weaker than that of a single administration of praziquantel (400 mg/kg). Cur:Na2GA (50 mg/kg, 30 days), which contains less free curcumin, did not exert this action. The complex, just as free curcumin or better, activated the expression of bile acid synthesis genes (Cyp7A1, Fxr, and Rxra), which was suppressed by O. felineus infection and by praziquantel. Curcumin reduced the rate of inflammatory infiltration, whereas Cur:Na2GA reduced periductal fibrosis. Immunohistochemically, a decrease in liver inflammation markers was found, which is determined by calculating the numbers of tumor-necrosis-factor-positive cells during the curcumin treatment and of kynurenine-3-monooxygenase-positive cells during the Cur:Na2GA treatment. A biochemical blood test revealed a normalizing effect of Cur:Na2GA (comparable to that of curcumin) on lipid metabolism. We believe that the further development and investigation of therapeutics based on curcuminoids in relation Opisthorchis felineus and other trematode infections will be useful for clinical practice and veterinary medicine.
RESUMEN
The combination of 4-week repeated social defeat stress (RSDS) and Opisthorchis felineus infection was modeled in C57BL/6 mice. Various parameters were compared between three experimental groups of male mice (SS: mice subjected to RSDS, OF: mice infected with O. felineus, and OF + SS: mice subjected to both adverse factors) and behavior-tested and intact (INT) controls. The combination caused liver hypertrophy and increased the blood level of proinflammatory cytokine interleukin 6 and proteolytic activity of cathepsin B in the hippocampus. Meanwhile, hypertrophy of the spleen and of adrenal glands was noticeable. Anxious behavior in the elevated plus-maze test was predominantly due to the infection, with synergistic effects of an interaction of the two adverse factors on multiple parameters in OF + SS mice. Depression-like behavior in the forced swimming test was caused only by RSDS and was equally pronounced in SS mice and OF + SS mice. Helminths attenuated the activities of cathepsin B in the liver and hypothalamus (which were high in SS mice) and increased cathepsin L activity in the liver. The highest blood level of corticosterone was seen in SS mice but was decreased to control levels by the trematode infection. OF mice had the lowest level of corticosterone, comparable to that in INT mice. Thus, the first data were obtained on the ability of O. felineus helminths-even at the immature stage-to modulate the effects of RSDS, thereby affecting functional connections of the host, namely "helminths â liverâbrain axis."
Asunto(s)
Opistorquiasis , Animales , Biomarcadores , Encéfalo , Catepsina B , Corticosterona , Hipertrofia , Masculino , Ratones , Ratones Endogámicos C57BL , Derrota SocialRESUMEN
Nimesulide (NIM, N-(4-nitro-2-phenoxyphenyl)methanesulfonamide) is a relatively new nonsteroidal anti-inflammatory analgesic drug. It is practically insoluble in water (<0.02 mg/mL). This very poor aqueous solubility of the drug may lead to low bioavailability. The objective of the present study was to investigate the possibility of improving the solubility and the bioavailability of NIM via complexation with polysaccharide arabinogalactan (AG), disodium salt of glycyrrhizic acid (Na2GA), hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and MgCO3. Solid dispersions (SD) have been prepared using a mechanochemical technique. The physical properties of nimesulide SD in solid state were characterized by differential scanning calorimetry and X-ray diffraction studies. The characteristics of the water solutions which form from the obtained solid dispersions were analyzed by reverse phase and gel permeation HPLC. It was shown that solubility increases for all complexes under investigation. These phenomena are obliged by complexation with auxiliary substances, which was shown by 1H-NMR relaxation methods. The parallel artificial membrane permeability assay (PAMPA) was used for predicting passive intestinal absorption. Results showed that mechanochemically obtained complexes with polysaccharide AG, Na2GA, and HP-ß-CD enhanced permeation of NIM across an artificial membrane compared to that of the pure NIM. The complexes were examined for anti-inflammatory activity on a model of histamine edema. The substances were administered per os to CD-1 mice. As a result, it was found that all investigated complexes dose-dependently reduce the degree of inflammation. The best results were obtained for the complexes of NIM with Na2GA and HP-ß-CD. In noted case the inflammation can be diminished up to 2-fold at equal doses of NIM.