Molecular docking to Toxoplasma gondii thymidylate synthase-dihydrofolate reductase and efficacy of raltitrexed in infected mice

Parasitology Research - Toxoplasmosis is a zoonosis of worldwide distribution. Currently, two drugs, pyrimethamine and sulfadiazine, are used as a reference in the treatment of toxoplasmosis, but...     

Anti-inflammatory activity of Agaricus blazei in different basidiocarp maturation phases

Agaricus blazei Murrill ss. Heinemann (Agaricus brasiliensis Wasser et al.; Agaricus subrufescens Peck) has raised interest in the scientific community due to its therapeutic properties. Although there are numerous studies about this fungus a few of them study the anti-inflammatory activity and the relationship with basidiocarp development phases. Thus, the objective of this study was to evaluate the effect of A. blazei extracts of closed and opened basidiocarp on the cell migration of rats submitted to an inflammatory challenge. The basidiocarp extracts were administered by gavage at 55 or 110 mg/kg. The inflammatory challenge was performed by administering phlogistic agent (carrageenan 2%) in an air-pouch induced in the animal subcutaneous tissue. It was concluded that the extracts affect leukocyte mobilisation regulation; closed basidiocarp extract in doses of 55 and 110 mg/kg and opened basidiocarp extract in 110 mg/kg modulate the anti-inflammatory response.     

Lipophilicity as a determinant of binding of procaine analogs to rat α3β4 nicotinic acetylcholine receptor

Nicotinic acetylcholine receptors (nAChRs) have been studied in detail with regard to their interaction with therapeutic and drug addiction-related compounds. Using a structure-activity approach, we have examined the relationship among the molecular features of a set of eight para-R-substituted N,N-[(dimethylamino)ethyl] benzoate hydrochlorides, structurally related to procaine and their affinity for the α(3)β(4) nAChR heterologously expressed in KXα3β4R2 cells. Affinity values (log[1/IC50]) of these compounds for the α(3)β(4) nAChR were determined by their competition with [(3)H]TCP binding. Log(1/IC50) values were analyzed considering different hydrophobic and electronic parameters and those related to molar refractivity. These have been experimentally determined or were taken from published literature. In accordance with literature observations, the generated cross-validated quantitative structure-activity relationship (QSAR) equations indicated a significant contribution of hydrophobic term to binding affinity of procaine analogs to the receptor and predicted affinity values for several local anesthetics (LAs) sets taken from the literature. The predicted values by using the QSAR model correlated well with the published values both for neuronal and for electroplaque nAChRs. Our work also reveals the general structure features of LAs that are important for interaction with nAChRs as well as the structural modifications that could be made to enhance binding affinity.     

Anxiolytic-like effects of acute and chronic treatment with Achillea millefolium L. extract

Ethnopharmacological relevance

Achillea millefolium L. (Asteraceae), known as yarrow (“mil folhas”), has been used as folk medicine for gastrointestinal disorders, inflammation, anxiety, and insomnia.

Aim

To evaluate the potential anxiolytic-like effect of hydroalcoholic extract of Achillea millefolium L. in animal models.

Methods

The present study evaluated the effects of the hydroalcoholic extract from the aerial parts of Achillea millefolium L. in mice subjected to the elevated plus-maze, marble-burying, and open-field tests. Additionally, the GABA_A/benzodiazepine (BDZ) mediation of the effects of Achillea millefolium was evaluated by pretreatment with the noncompetitive GABA_A receptor antagonist picrotoxin and the BDZ antagonist flumazenil and by [³H]-flunitrazepam binding to the BDZ site on the GABA_A receptor.

Results

Achillea millefolium exerted anxiolytic-like effects in the elevated plus-maze and marble-burying test after acute and chronic (25 days) administration at doses that did not alter locomotor activity. This behavioral profile was similar to diazepam. The effects of Achillea millefolium in the elevated plus-maze were not altered by picrotoxin pretreatment but were partially blocked by flumazenil. Furthermore, Achillea millefolium did not induce any changes in [³H]-flunitrazepam binding.

Conclusion

The results indicate that the orally administered hydroalcoholic extract of Achillea millefolium L. exerted anxiolytic-like effects that likely were not mediated by GABA_A/BDZ neurotransmission and did not present tolerance after short-term, repeated administration.     

Dynamic prognostic profile for acute myocardial infarction

A prognostic profile for patients with acute myocardial infarction (AMI) treated in a coronary care unit has been constructed by applying a modified sequential statistical analysis. The profile represents a dynamic system which enables the physician to predict hospital prognosis simply and rapidly on the basis of daily changing clinical and laboratory parameters. The procedure was tested prospectively on a population of AMI patients and was found to be a reliable prognostic tool. Comparing this scale with that of popular prognostic indices, it was found that prediction was more accurate with this technique.     

Cell Cycle Regulation During Neurogenesis in the Embryonic and Adult Brain

Throughout the development of the central nervous system, neural crest cells and the primary neural stem cells originate several non-neuronal and neuronal cell types. Undifferentiated stem cells exist in the adult brain, mainly in the dentate gyrus of the hippocampus and in the subventricular zone of the lateral ventricles, and can produce new neurons, participating in brain plasticity and tissue regeneration. Neurogenesis in the embryonic and adult brain occurs under the control of intrinsic and extrinsic factors. However, the mechanisms, by which cell cycle components control neural stem cell proliferation and consequently neurogenesis, still lack further investigation. We discuss here recent knowledge obtained on cell cycle components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain.     

Involvement of bradykinin and prostaglandins in the diuretic effects of Achillea millefolium L. (Asteraceae)

Ethnopharmacological relevance

Achillea millefolium L. (Asteraceae), popularly known as “mil-folhas”, is well recognized and widely used in Brazilian folk medicine to treat heart and kidney disorders. Among its popularly described effects are diuretic and hypotensive actions.

Aim of the study

The diuretic activity of Achillea millefolium L. extracts and its semi-purified fractions, as well as the mechanisms involved, were evaluated in male Wistar rats.

Material and methods

An aqueous extract (AEAM, 125–500 mg/kg), hydroethanolic extract (HEAM, 30–300 mg/kg), dichloromethane subfractions (DCM-2, 10 and 30 mg/kg), or hydrochlorothiazide (10 mg/kg), were orally administered and the animals were kept in metabolic cages for 8 h for urine collection. To evaluate the involvement of bradykinin and prostaglandins in the diuretic action of Achillea millefolium, selected groups of rats received HOE-140 (1.5 mg/kg, i.p.) or indomethacin (5 mg/kg, p.o.), before treatment with a DCM-2 subfraction (30 mg/kg). The urinary volume, conductivity, pH, density and electrolyte excretion were measured.

Results

Similar to hydrochlorothiazide, both HEAM and DCM-2, but not AEAM, increased urinary volume and the excretion of Na⁺ and K⁺ when compared with the control group (vehicle). The diuretic effect of DCM-2 was abolished by HOE-140 (a bradykinin B2 receptor antagonist), as well as by indomethacin (a cyclooxygenase inhibitor).

Conclusion

The present study reveals that extracts obtained from Achillea millefolium are able to effectively increase diuresis when orally administered in rats. This effect depends on both the activation of bradykinin B2 receptors and the activity of cyclooxygenases.     

Antihypertensive effects of isoquercitrin and extracts from Tropaeolum majus L.: evidence for the inhibition of angiotensin converting enzyme

Aim of the study

Previous studies have shown that the extracts obtained from Tropaeolum majus L. exhibit pronounced diuretic properties. In the present study, we assessed whether the hypotensive and/or antihypertensive mechanism of hydroethanolic extract (HETM), semi-purified fraction (TMLR) obtained from T. majus and the flavonoids isoquercitrin (ISQ) and kaempferol (KPF) can be mediated by their interaction with angiotensin converting enzyme (ACE).

Methods and methods

Firstly, to evaluate changes in mean arterial pressure (MAP), different groups of normotensive and spontaneously hypertensive rats (SHR) were orally and intraduodenally treated with HETM (10-300 mg/kg) and TMLR (12.5-100 mg/kg) and intravenously treated with ISQ and KPF being later anesthetized with ketamine (100 mg/kg) and xylazine (20 mg/kg). The left femoral vein and the right carotid artery were isolated, and polyethylene catheters were inserted for ISQ and KPF (0.5-4 mg/kg) administration and blood pressure recording, respectively. The plasmatic ACE activity was evaluated to indirect fluorimetry, in serum samples after orally treatment with HETM, TMLR, ISQ and KPF.

Results

The oral administration of the HETM and its TMLR significantly reduced, in a dose-dependent manner, the MAP in both normotensive and SHR. In addition, these preparations significantly decreased the MAP for up to 3 h after the administration of the extract. Additionally, the intravenous administration of ISQ, but not KPF, decreased MAP in rats. Otherwise, neither the extracts nor ISQ affected the heart rate. The oral administration of the HETM, TMLR or ISQ reduced ACE activity in serum samples at 90 min after administration. Finally, the intravenous administration of ISQ caused a significant reduction in the hypertensive response to angiotensin I, but not angiotensin II in normotensive rats.

Conclusion

Our results show that the hypotensive effects caused by the HETM, as well as by its TMLR, may be associated with the high levels of the flavonoid ISQ found in this plant. In addition, ISQ-induced hypotension in rats is an event dependent on the inhibition of angiotensin II generation by ACE.     

Involvement of arginine-vasopressin in the diuretic and hypotensive effects of Pereskia grandifolia Haw. (Cactaceae)

Ethnopharmacological relevance

Pereskia grandifolia Haw. (Cactaceae), popularly known as “ora-pro-nobis” is well recognized in Brazilian traditional medicine as a diuretic agent, although no scientific data have been published to support this effect. The aim of this work is to evaluate the diuretic and hypotensive activities of the infusion (INFPG) and the ethanol extract (HEPG) of Pereskia grandifolia and possible mechanism of action.

Materials and methods

The infusions (2.5–10%) and the HEPG (3–100 mg/kg) were orally administered in a single dose or daily (for seven days) to rats. The urine excretion rate, pH, density, conductivity and content of Na⁺, K⁺, Cl⁻ and HCO₃⁻ were measured in the urine of saline-loaded animals. In collected serum samples the concentration of electrolytes, urea, creatinine, aldosterone, vasopressin and angiotensin converting enzyme (ACE) activity were evaluated. The involvement of V₂ vasopressin receptor in the diuretic activity and the hypotensive effect of HEPG were also determined.

Results

Water excretion rate was significantly increased by HEPG, while the urinary K⁺ and Cl⁻ excretion was significantly reduced in acute and prolonged treatment. The oral administration of the HEPG (30 mg/kg) significantly reduced serum levels of vasopressin and the mean arterial pressure (MAP) in normotensive rats. All other evaluated parameters have not been affected by any treatment.

Conclusion

The results showed that HEPG could present compound(s) responsible for aquaretic activities with no signs of toxicity, and this effect could involve a reduction in the arginine-vasopressin release.     

Diuretic and potassium-sparing effect of isoquercitrin-an active flavonoid of Tropaeolum majus L

Aim of the study

Previous studies have shown that the extracts obtained from Tropaeolum majus L. exhibit pronounced diuretic effects supporting the ethnopharmacological use of this plant as diuretic. In the present work, phytochemical investigation, guided by bio-assay in spontaneously hypertensive rats (SHR), was carried out in order to identify the compounds responsible for diuretic action.

Material and methods

Chromatographic fractionation of the hydroethanolic extract yielded an active fraction (TMLR) rich in isoquercitrin. TMLR (25-100 mg/kg) and isoquercitrin (5-10 mg/kg), as well the reference drug hydrochlorothiazide (10 mg/kg) were orally administered in a single dose or daily for 7 days to SHR. The urine excretion rate, pH, density, conductivity and content of sodium (Na⁺) and potassium (K⁺) electrolytes were measured in the urine of saline-loaded animals.

Results

The urinary excretion rate was dose-dependently increased in both TMLR and isoquercitrin groups, as well as Na⁺. Despite the changes in urinary excretion of electrolytes, the plasmatic levels of Na⁺ and K⁺ had not been changed. In addition, we did not find any evidence of renal toxicity or other adverse effects in these animals, even after prolonged treatment with TMLR or isoquercitrin.

Conclusion

This research supports and extends the ethnomedicinal use of T. majus as diuretic. This activity seems to be associated to the presence of the flavonol isoquercitrin.