Synthesis, molecular modeling and preliminary biological evaluation of a set of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole as potential antibacterial, anti-Trypanosoma cruzi and antifungal agents

A series of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives was synthesized and their activity screened in vitro against Staphylococcus aureus, Trypanosoma cruzi, and Candida albicans. The bioactivity was expressed as minimum inhibitory concentration (MIC) for S. aureus strains, and as fifty-percent inhibitory concentration (IC(50)) of parasite population growth for T. cruzi. A molecular modeling approach was performed to establish qualitative relationships regarding the biological data and the compounds' physicochemical properties. The 5-(4-OC(4)H(9)Ph, 5l), and 5-(4-CO(2)CH(3)Ph, 5o) derivatives were the most active compounds for S. aureus ATCC 25923 (MIC=1.95-1.25 μg/mL) and T. cruzi (IC(50)=7.91 μM), respectively. Also, a preliminary evaluation against C. albicans involving some compounds was performed and the 5-(4-CH(3)Ph, 5e) derivative was the most active compound (MIC=3.28-2.95 μg/mL). In this preliminary study, all synthesized 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives were active against all microorganisms tested.     

Haptoglobin genotype predicts development of coronary artery calcification in a prospective cohort of patients with type 1 diabetes

Background

Soluble ST2, a member of the of the Toll/IL-1 superfamily, is a novel biomarker with exceptional predictive value in heart failure and myocardial infarction- related mortality as well as in acute dyspneic states. Soluble ST2 is considered a decoy receptor of IL 33 that blocks the protective effects of the cytokine in atherosclerosis and cardiac remodeling. In the present study we investigated the differences in the levels of soluble ST2, BNP and hs-CRP between healthy controls and patients with type 2 diabetes with and without left ventricular diastolic dysfunction. A secondary aim was to investigate correlations between sST2 and other biomarkers of type 2 diabetes, such as HbA1c.

Methods

158 volunteers were recruited and underwent a complete Doppler-echocardiographic evaluation of both systolic & diastolic cardiac function. All subjects with ejection fraction < 50% were excluded. The study population was divided in 4 groups as follows: A: 42 healthy controls, B: 18 subjects without diabetes with LVDD, C: 48 patients with type 2 diabetes without LVDD & D: 50 patients with type 2 diabetes & LVDD. ELISA technique was performed to measure sST2 levels. Statistical analysis was performed with Kruskal-Wallis & Mann-Whitney test (continuous variables), chi squared & Fischer exact test (discrete variables), Spearman coefficient (univariate analysis) and step-wise backward method (multivariate analysis).

Results

Patients with type 2 diabetes with (p < 0.001) or without LVDD (p = 0.007) had higher serum ST2 levels compared to healthy controls, state found also for hs-CRP levels but not for the corresponding BNP levels (p = 0.213 & p = 0.207 respectively). Patients with type 2 diabetes & LVDD had higher serum ST2 in relation to diabetic patients without LVDD (p = 0.001). In multivariate analysis HbA1c positively and independently correlated with sST2 levels in both groups of patients with type 2 diabetes.

Conclusions

Patients with type 2 diabetes exhibit higher sST2 levels compared to healthy controls. The presence of LVDD in patients with type 2 diabetes is associated with even higher sST2 levels. A significant correlation between glycemic control and sST2 levels was also revealed.     

A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer

BackgroundNatural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancerMethodsPatients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m² × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometryResultsTwenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30–65) years. Mean NK cell dose was 2.16 × 10⁷cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = < 0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansionConclusionsAdoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.     

<Emphasis Type="Italic">Rubus rosaefolius</Emphasis> Extract as a Natural Preservative Candidate in Topical Formulations

Even though the synthetic preservatives may offer a high antimicrobial efficacy, they are commonly related to adverse reactions and regarded as having potentially harmful effects caused by chronic consumption. The development of natural preservatives provides a way of reducing the amount of synthetic preservatives normally used in pharmaceutical and cosmetic preparations. In addition, these agents have less toxic effects and represent a possible natural and safer alternative of the preservatives. The purpose of this research was to evaluate the Rubus rosaefolius Smith extract efficiency as a natural preservative in base formulations. Of the extract, 0.2% (w/w) was assayed for its effectiveness of antimicrobial protection in two different base formulations (emulsion and gel). The microbial challenge test was performed following the standard procedures proposed by The United States Pharmacopoeia 33nd, European Pharmacopoeia 6th, Japanese Pharmacopoeia 15th, and the Cosmetics, Toiletries, and Fragrance Association using standardized microorganisms. The results demonstrated that R. rosaefolius extract at the studied concentration reduced the bacterial inocula, satisfying the criterion in all formulations, even though it was not able to present an effective preservative behavior against fungi. Thus, the investigation of new natural substances with preservative properties that could be applied in pharmaceutical and cosmetic products is relevant due to the possibility of substituting or decreasing the concentration of synthetic preservatives, providing a way for the development of safer formulas for the use of consumers.     

Morphometric variables related to metabolic profile in captive chimpanzees (Pan troglodytes)

Obesity is a risk factor for several diseases including type 2 diabetes and cardiovascular disease. The aim of this study was to compare the relationships of waist circumference and body weight with circulating markers of metabolic, cardiovascular, and hepatic function in chimpanzees (Pan troglodytes). After a 12-h fast, blood was collected from 39 adult captive chimpanzees for measurement of serum glucose, BUN, creatinine, albumin, cholesterol, ALT, AST, ALP, total and direct bilirubin, triglyceride, and insulin, and waist circumference and body weight were measured. Waist circumference was positively correlated with systolic and diastolic blood pressure, glucose, insulin resistance as estimated by the homeostatic model assessment method, and albumin in female chimpanzees and with triglyceride in female and male chimpanzees. Body weight was correlated significantly with systolic and diastolic blood pressure in female chimpanzees and triglyceride in male chimpanzees. Male chimpanzees were heavier and had lower diastolic blood pressure, greater creatinine, albumin, AST, ALP, total bilirubin, and direct bilirubin values than did female chimpanzees. The relationships between waist circumference and blood pressure and triglyceride are consistent with those reported in humans and other primate species. In conclusion, our study is the first work to demonstrate a relationship between waist circumference and metabolic risk factors in chimpanzees. Results demonstrated that waist circumference was associated with more metabolic risk factors than was body weight, particularly in female chimpanzees.     

Allee effect in exotic and introduced blowflies

We combined two models to investigate the theoretical dynamics of five exotic and native blowfly species in response to the Allee effect by using demographic parameters estimated from experimental populations. Most of the results suggest stabilization of dynamic behavior in response to the Allee effect. However, the results depended on the magnitude of the demographic parameters of each species, and also indicated chaotic fluctuations and limit cycles. The results are discussed in the context of larval aggregation, an important biological process for blowflies, which naturally incorporates the Allee effect.     

Biocellulose membranes as supports for dermal release of lidocaine

Biocellulose (BC) is a highly pure form of cellulose, produced in the form of a swollen membrane, with several applications in the biomedical area. In this study, the behavior of BC membranes as systems for topical delivery of lidocaine was evaluated. The BC-lidocaine membranes were prepared and characterized in terms of structural and morphological properties. A uniform distribution of the drug inside the BC membranes was observed. In vitro diffusion studies with Franz cells were conducted using human epidermal membranes and showed that the permeation rate of the drug in BC membranes was slightly slower than that obtained with the conventional systems, which was attributed to the establishment of interactions between the lidocaine molecules and the BC membrane, as evidenced by FTIR and NMR analysis. These results indicate that this methodology can be successfully applied for the dermal administration of lidocaine regarding the release profile and ease of application.