Determination of pharmacological interactions of uliginosin B, a natural phloroglucinol derivative, with amitriptyline, clonidine and morphine by isobolographic analysis

AbstractUliginosin B is a natural phloroglucinol derivative, obtained from Hypericum species native to South America. Previous studies have shown that uliginosin B presents antidepressant-like and antinociceptive effects. Although its mechanism of action is still not completely elucidated, it is known that it involves the activation of monoaminergic neurotransmission. The aim of the current study was to further investigate the antinociceptive mechanism of action of uliginosin B by combining it with different drugs used for treating pain in clinical practice. The intraperitoneal administration of uliginosin B, morphine, amitriptyline and clonidine, alone or in mixture, produced a dose-dependent antinociceptive effect in the hot-plate assay in mice. The effect of the mixtures of drugs was studied using an adapted isobologram analysis at the effect level of 50% of the maximal effect observed. The analysis showed that the interactions between uliginosin B and morphine was synergistic, while the interactions between uliginosin B and amitriptyline or clonidine were additive. These findings point to uliginosin B as a potential adjuvant for pain pharmacotherapy, especially for opioid analgesia

Antidepressant-like effect of Valeriana glechomifolia Meyer (Valerianaceae) in mice

AbstractThe antidepressant-like effect of a supercritical CO2 (SCCO2) Valeriana glechomifolia extract enriched in valepotriates was investigated in a mice tail suspension test (TST) and forced swimming test (FST). The SCCO2 extract decreased mice immobility in the FST (0.5–20mg/kg p.o.) and elicited a biphasic dose–response relationship in the TST (1–20mg/kg p.o.) with no alterations in locomotor activity and motor coordination (assessed in the open-field and rota-rod tests, respectively). The anti-immobility effect of the SCCO2 extract (5mg/kg, p.o.) was prevented by mice pre-treatment with yohimbine (1mg/kg, i.p., an α2 adrenoceptor antagonist), SCH 23390 (15μg/kg, s.c., D1 dopamine receptor antagonist) and sulpiride (50mg/kg, i.p., D2 dopamine receptor antagonist). However, mice pre-treatments with prazosin (1mg/kg, i.p., α1 adrenoceptor antagonist) and p-chlorophenilalanine methyl ester (4×100mg/kg/day, i.p., a serotonin synthesis inhibitor) were not able to block the anti-immobility effect of the SCCO2 extract. Administration (p.o.) of the SCCO2 extract (0.25mg/kg) and imipramine (10mg/kg), desipramine (5mg/kg) and bupropion (3mg/kg) at sub-effective doses significantly reduced mice immobility time in the FST. These data provide the first evidence of the antidepressant-like activity of V. glechomifolia valepotriates, which is due to an interaction with dopaminergic and noradrenergic neurotransmission

Uliginosin B, a natural phloroglucinol derivative with antidepressant-like activity, increases Na+,K+-ATPase activity in mice cerebral cortex

AbstractUliginosin B, a phloroglucinol isolated from Hypericum polyanthemum Klotzsch ex Reichardt, Hypericaceae, has antidepressant-like effect in the forced swimming test in rodents and inhibits monoamines neuronal reuptake without binding to their neuronal carriers. Studies showed the involvement of Na+,K+-ATPase brain activity in depressive disorders, as well as the dependence of neuronal monoamine transport from Na+ gradient generated by Na+,K+-ATPase. This study aimed at evaluating the effect of uliginosin B on Na+,K+-ATPase activity in mice cerebral cortex and hippocampus (1 and 3h after the last administration) as well as the influence of veratrine, a Na+ channel opener, on the antidepressant-like effect of uliginosin B. Mice were treated (p.o.) with uliginosin B single (10mg/kg) or repeated doses (10mg/kg/day, 3 days). Acute administration reduced the immobility in the forced swimming test and tail suspension test and increased Na+,K+-ATPase activity in cerebral cortex 1h after treating, whereas the repeated treatment induced the antidepressant-like effect and increased the Na+,K+-ATPase activity at both times evaluated. None treatment affected the hippocampus enzyme activity. Veratrine pretreatment prevented uliginosin B antidepressant-like effect in the forced swimming test, suggesting the involvement of Na+ balance regulation on this effect. Altogether, these data indicate that uliginosin B reduces the monoamine uptake by altering Na+ gradient

Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans

From 2nd Latin American Congress of Clinical and Laboratorial Toxicology Porto Alegre, Brazil. 3-6 June 2018Background: Chagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic. Hence, the aim of this work is to find a good antitrypanosomal drug with less toxicity. The use of simple organism models has become increasingly attractive for planning and simplifying efficient drug discovery. Within these models, Caenorhabditis elegans has emerged as a convenient and versatile tool with significant advantages for the toxicological potential identification for new compounds. Methods: Trypanocidal activity: Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC50). Toxicity assays: Lethal dose 50% (LD50) and Body Area were determined by Caenorhabditis elegans N2 strain (wild type) after acute exposure. Structure-activity relationship: A classificatory model was built using 3D descriptors. Results: Two of these coumarins demonstrated near equipotency to Nifurtimox (IC50 = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC50 = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC50 = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD50 assay and the evaluation of the development of worms. It is possible to observe that the efficacy between Nfx and the synthesized compounds (11 h and 11 g) are similar. On the other hand, the toxicity of Nfx is approximately three times higher than that of the compounds. Results from the QSAR-3D study indicate that the volume and hydrophobicity of the substituents have a significant impact on the trypanocidal activities for derivatives that cause more than 50% of inhibition. These results show that the C. elegans model is efficient for screening potentially toxic compounds. Conclusion: Two coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD50 and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs

The E-cadherin repressor slug and progression of human extrahepatic hilar cholangiocarcinoma

<p>Abstract</p> <p>Objectives</p> <p>This study explored the expression and function of Slug in human extrahepatic hilar cholangiocarcinoma (EHC) to identify its role in tumor progression.</p> <p>Methods</p> <p>The expression of Snail and Slug mRNA in 52 human tissue samples of EHC was investigated. The mRNA of Snail and Slug were quantified using reverse transcriptase-PCR, and correlations with E-cadherin expression and clinicopathological factors were investigated. We then investigated transfection of Slug cDNA in endogenous E-cadherin-positive human EHC FRH0201 cells, selectively induced the loss of E-cadherin protein expression, and then small interfering RNA (siRNA) for inhibition of Slug expression in endogenous Slug-positive human EHC QBC939 cells, selectively induced the loss of Slug protein expression. A Boyden chamber transwell assay was used for invasion.</p> <p>Results</p> <p>Slug mRNA was overexpressed in 18 cases (34.6%) of EHC compared with adjacent noncancerous tissue. E-Cadherin protein expression determined in the same 52 cases by immunohistochemistry was significantly down-regulated in those cases with Slug mRNA overexpression (P = 0.0001). The tumor and nontumor ratio of Slug mRNA was correlated with nodal metastasis(p = 0.0102), distant metastasis (p = 0.0001)and Survival time(p = 0.0443). However, Snail mRNA correlated with neither E-cadherin expression nor tumor invasiveness. By inhibiting Slug expression by RNA interference, we found that reduced Slug levels upregulated E-cadherin and decreased invasion in QBC939 cell. When the QBC939 cells was infected with Slug cDNA,, significant E-cadherin was downregulated and increased invasion in QBC939 cell.</p> <p>Conclusions</p> <p>The results suggested that Slug expression plays an important role in both the regulation of E-cadherin expression and in the acquisition of invasive potential in human EHC. Slug is possibly a potential target for an antitumor therapy blocking the functions of invasion and metastasis in human EHCs.</p

The asthma epidemic and our artificial habitats

BACKGROUND: The recent increase in childhood asthma has been a puzzling one. Recent views focus on the role of infection in the education of the immune system of young children. However, this so called hygiene hypothesis fails to answer some important questions about the current trends in asthma or to account for environmental influences that bear little relation to infection. DISCUSSION: The multi-factorial nature of asthma, reflecting the different ways we tend to interact with our environment, mandates that we look at the asthma epidemic from a broader perspective. Seemingly modern affluent lifestyles are placing us increasingly in static, artificial, microenvironments very different from the conditions prevailed for most part of our evolution and shaped our organisms. Changes that occurred during the second half of the 20th century in industrialized nations with the spread of central heating/conditioning, building insulation, hygiene, TV/PC/games, manufactured food, indoor entertainment, cars, medical care, and sedentary lifestyles all seem to be depriving our children from the essential inputs needed to develop normal airway function (resistance). Asthma according to this view is a manifestation of our respiratory maladaptation to modern lifestyles, or in other words to our increasingly artificial habitats. The basis of the artificial habitat notion may lie in reduced exposure of innate immunity to a variety of environmental stimuli, infectious and non-infectious, leading to reduced formulation of regulatory cells/cytokines as well as inscribed regulatory pathways. This could contribute to a faulty checking mechanism of non-functional Th2 (and likely Th1) responses, resulting in asthma and other immuno-dysregulation disorders. SUMMARY: In this piece I discuss the artificial habitat concept, its correspondence with epidemiological data of asthma and allergy, and provide possible immunological underpinning for it from an evolutionary perspective of health and disease