Further insights into biological evaluation of new anti-Trypanosoma cruzi 5-nitroindazoles

Twelve molecules from a series of 35 new 5-nitroindazole derivatives, selected from a successful primary screening on Trypanosoma cruzi epimastigotes, have been evaluated against intracellular amastigotes according to the previous results of their trypanocidal activity and unspecific cytotoxicity. 2-Benzyl-1-propyl (22), 2-benzyl-1-isopropyl (23), and 2-benzyl-1-butyl (24) 5-nitroindazolin-3-ones have inhibited the growth of amastigotes similarly to the reference drugs benznidazole and nifurtimox, inducing complete growth inhibition at concentrations lower than 8 μM (IC₅₀?<?5 μM) and accomplishing great selectivity indexes on the intracellular form of the parasite (SI?>?30). Further in vivo assays were developed only for two of the most active molecules (22 and 24), reaching significant reductions in parasitemia levels (52 % and 77 %, respectively) after their oral administration to infected mice. In addition, none of the mice in experimental and benznidazole groups died, unlike in the control group which is only treated with the vehicle. The trypanocidal properties found in some of the 5-nitroindazole derivatives assayed in the present work represent an interesting contribution to the urgent need for searching new antichagasic drugs.     

Effect that an educational program for cystic fibrosis patients and caregivers has on the contamination of home nebulizers

OBJECTIVE:

To describe the pathogens found in home nebulizers and in respiratory samples of cystic fibrosis (CF) patients, and to evaluate the effect that a standardized instruction regarding cleaning and disinfection of nebulizers has on the frequency of nebulizer contamination.

METHODS:

We included 40 CF patients (22 males), all of whom used the same model of nebulizer. The median patient age was 11.2 ± 3.74 years. We collected samples from the nebulizer mouthpiece and cup, using a sterile swab moistened with sterile saline. Respiratory samples were collected by asking patients to expectorate into a sterile container or with oropharyngeal swabs after cough stimulation. Cultures were performed on selective media, and bacteria were identified by classical biochemical tests. Patients received oral and written instructions regarding the cleaning and disinfection of nebulizers. All determinations were repeated an average of two months later.

RESULTS:

Contamination of the nebulizer (any part) was detected in 23 cases (57.5%). The nebulizer mouthpiece and cup were found to be contaminated in 16 (40.0%) and 19 (47.5%), respectively. After the standardized instruction had been given, there was a significant decrease in the proportion of contaminated nebulizers (43.5%).

CONCLUSIONS:

In our sample of CF patients, nebulizer contamination was common, indicating the need for improvement in patient practices regarding the cleaning and disinfection of their nebulizers. A one-time educational intervention could have a significant positive impact.     

Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs

Metabolomic fingerprint of breast cancer cells treated with the antidiabetic drug metformin revealed a significant accumulation of 5-formimino-tetrahydrofolate, one of the tetrahydrofolate forms carrying activated one-carbon units that are essential for the de novo synthesis of purines and pyrimidines. De novo synthesis of glutathione, a folate-dependent pathway interconnected with one-carbon metabolism was concomitantly depleted in response to metformin. End-product reversal studies demonstrated that thymidine alone leads to a significant but incomplete protection from metformin's cytostatic effects. The addition of the substrate hypoxanthine for the purine salvage pathway produces major rightward shifts in metformin's growth inhibition curves. Metformin treatment failed to activate the DNA repair protein ATM kinase and the metabolic tumor suppressor AMPK when thymidine and hypoxanthine were present in the extracellular milieu. Our current findings suggest for the first time that metformin can function as an antifolate chemotherapeutic agent that induces the ATM/AMPK tumor suppressor axis secondarily following the alteration of the carbon flow through the folate-related one-carbon metabolic pathways.     

Inflamación y apoptosis en la hipertensión arterial. Importancia de la extensión de la lesión de órgano diana

Introduction and objectives

To investigate the relationship between inflammatory and apoptotic parameters and the severity and extent of target organ damage in patients with essential hypertension.

Methods

We studied 159 consecutive patients with treated essential hypertension. An exhaustive evaluation of damage to heart, kidney, and blood vessels was performed and plasma levels of inflammatory (interleukin 6 and soluble receptor of tumor necrosis factor-alpha type 2) and apoptotic markers (soluble receptor of tumor necrosis factor-alpha type 1 and soluble Fas receptor) were determined. Patients were categorized into four groups: a) no organ damage (33 patients); b) 1 organ damaged (52 patients); c) 2 organs damaged (44 patients), and d) 3 organs damaged (30 patients).

Results

Serum levels of interleukin 6, soluble receptor of tumor necrosis factor-alpha type 1 and soluble receptor of tumor necrosis factor-alpha type 2 were higher in patients with target organ damage than in hypertensive patients without organ damage. Increasing levels of these molecules were progressively associated with an increase in the number of organs damaged, and the highest levels were observed in the group with damage to 3 organs (heart, kidney, and blood vessels). There were no differences in soluble Fas receptor levels between groups. Logistic regression analysis showed that age, smoking, diabetes mellitus, abdominal circumference, interleukin 6, and soluble receptor of tumor necrosis factor-alpha type 1 were independently related to the number of target organs damaged.

Conclusions

Extensive hypertensive disease with involvement of more target organs was associated with greater inflammatory and apoptotic activation in these hypertensive patients.Full English text available from:www.revespcardiol.org