Synthesis,Characterization, and Cytotoxicity of Some New 5-Aminopyrazole and Pyrazolo[1,5-a]pyrimidine Derivatives

5-Amino-N-aryl-3-[(4-methoxyphenyl)amino]-1H-pyrazole-4-carboxamides 4a–c were synthesized by the reaction of N-(aryl)-2-cyano-3-[(4-methoxyphenyl)amino]-3-(methylthio)acrylamides 3a–c with hydrazine hydrate in ethanol. The reaction of 5-amino-N-aryl-1H-pyrazoles 4a–c with acetylacetone 5 or 2-(4-methoxybenzylidene)malononitrile 8 yielded the pyrazolo[1,5-a]pyrimidine derivatives 7a–c and 10a–c, respectively. The structures of the synthesized compounds were established based on elemental analysis and spectral data (IR, MS, ¹H-NMR, and ¹³C-NMR). Representative examples of the new synthesized products were screened for their in vitro cytotoxic activity against Ehrlich Ascites Carcinoma (EAC) cells.     

Diagnostic Accuracy of Global Longitudinal Strain for Detecting Significant Coronary Artery Disease in Diabetic Patients without Regional Wall Motion Abnormality

AimsSpeckle-tracking imaging is a novel method for assessing left ventricular (LV) function and ischemic changes. The aim of this prospective study was to assess the diagnostic accuracy of global longitudinal strain (GLS) and regional longitudinal strain (RLS) parameters at rest in comparison to stress echocardiography findings for detecting significant coronary artery disease (CAD) in patients with diabetes mellitus (DM).MethodsWe prospectively studied echocardiographic characteristics at rest with Speckle tracking echocardiography (2D STE) measures; then stress echocardiography and coronary angiography data in 34 diabetic patients without regional wall motion abnormality (RWMA) at rest. Patients were grouped according to coronary angiography and stress echocardiography results into two groups CAD (+) vs control group CAD (−).ResultsGLS at rest was lower in the CAD (+) group ((-14.2 % ± 3.1 vs -17.8 % ± 3.1 in the control group CAD (−), P=0.004). GLS at rest had the highest area under the ROC curve (AUC) (AUC 0.78, sensitivity 61%, specificity 91%,P=0.009) with the cut-off of -14.5% which is equal to predictive power of wall motion scoring index (WMSI) at peak stress to detect significant CAD (AUC=0.76 (95% CI 0.58–0.94, P= 0.016) with the cut-off value of 1.21).ConclusionsGlobal longitudinal strain at rest by STE showed excellent specificity (>90%) and good sensitivity (60%) for the diagnosis of severe CAD among the diabetic population with unknown CAD. This is the first study showing that GLS at rest with cutoff value at -14.5% had good and equal diagnostic accuracy as WMSI at peak stress to detect significant CAD among the diabetic population.     

Minocycline attenuates HIV‐1 infection and suppresses chronic immune activation in humanized NOD/LtsZ‐scidIL‐2Rγnull mice

More than a quarter of a century of research has established chronic immune activation and dysfunctional T cells as central features of chronic HIV infection and subsequent immunodeficiency. Consequently, the search for a new immunomodulatory therapy that could reduce immune activation and improve T‐cell function has been increased. However, the lack of small animal models for in vivo HIV study has hampered progress. In the current study, we have investigated a model of cord blood haematopoietic progenitor cells (CB‐HPCs) ‐transplanted humanized NOD/LtsZ‐scidIL‐2Rγ^null mice in which progression of HIV infection is associated with widespread chronic immune activation and inflammation. Indeed, HIV infection in humanized NSG mice caused up‐regulation of several T‐cell immune activation markers such as CD38, HLA‐DR, CD69 and co‐receptor CCR5. T‐cell exhaustion markers PD‐1 and CTLA‐4 were found to be significantly up‐regulated on T cells. Moreover, increased plasmatic levels of lipopolysaccharide, sCD14 and interleukin‐10 were also observed in infected mice. Treatment with minocycline resulted in a significant decrease of expression of cellular and plasma immune activation markers, inhibition of HIV replication and improved T‐cell counts in HIV‐infected humanized NSG mice. The study demonstrates that minocycline could be an effective, low‐cost adjunctive treatment to regulate chronic immune activation and replication of HIV.     

Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors

In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G‐2, Hep‐2, and Caco‐2). Compounds 18b, 19b, 23, 25b , and 26 showed strong potencies against all tested cell lines with IC₅₀ values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 µM, comparable with those of doxorubicin (IC₅₀ values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 µM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC₅₀ = 0.97 ± 0.1 and 1.10 ± 0.1 µM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 µM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC₅₀ value of 37.06 ± 1.8 µM. Moreover, apoptosis and cell‐cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G‐2 cells. It has revealed cell‐cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl‐2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA–Topo II complex to examine the binding patterns of the synthesized compounds.     

Structure properties and dielectric relaxation of Ca0.1Na0.9Ti0.1Nb0.9O3 ceramic

In this paper, the synthesis of Ca_0.1Na_0.9Ti_0.1Nb_0.9O₃ (CNTN) ceramic by a solid-state reaction method is reported. The results of Rietveld refinement of X-ray diffraction (XRD) patterns at room temperature showed a pure tetragonal perovskite (P4mm space group). Raman spectroscopy analysis, ranging from of 50 to 1000 cm⁻¹, at room temperature, validates the results of XRD. The dielectric properties was studied by complex impedance spectroscopy examined in broad frequency range, 100 Hz to 200 kHz, at different temperatures. The dielectric permittivity for our CNTN compound confirms the typical relaxor behavior. The investigation of the diffuseness of the transition was conducted by fitting the experimental data with modified Curie–Weiss law; Gaussian distribution and Power law confirm the presence of a short-range association between the polar nanoregions (PNRs). The obtained values of the diffuseness coefficient are of the order 1.6, which corresponds to the diffuse phase transition (DPT) ascribed to the existence of various states of polarization, thus various relaxation times in different regions. The value of diffuseness is of the order 85 and the degree of relaxor (ΔT_cm = 65 K) is interesting as far as microelectric applications are concerned. Moreover, based on the frequency dependence of temperature at dielectric maxima using Vogel–Fulcher relationship, a strong evidence for a static freezing temperature with regards to thermally-activated polarization fluctuations was found.

In this paper, the synthesis of Ca_0.1Na_0.9Ti_0.1Nb_0.9O₃ (CNTN) ceramic by a solid-state reaction is reported. The results of Rietveld refinement of X-ray diffraction patterns at room temperature showed a pure tetragonal perovskite (P4mm space group).     

Adenocarcinoma at the site of ileo-anal anastomosis in Crohn's disease: report of a case

We reported a case of patient born in 1967 who has been operated on in 1987 on three years after the beginning of ulcerative colitis which became severe and resistant to the medical treatment. A total colectomy with an ileo-rectal anastomosis had been performed. The pathological diagnosis carried of the specimen was Ulcerative colitis Then a proctectomy, followed by ileo-anal anastomosis, was performed in 1993. After several episodes of pochitis and the appearance of intestinal lesions upstream the ileal pocket, the retained diagnosis was Crohn's colitis. Eight years after the ileo-anal anastomosis, the patient developed an adenocarcinoma in the ileal pocket. He has been operated on in 2002 and he had abdominoperineal resection, radiotherapy and chemotherapy. Re died in January 2003. The death was related to the recurrence of malignancy. Endoscopic controls with biopsies are mandatory doing to follow up dysplasia predictive of degeneration.     

Functions of alpha 2 macroglobulins in pregnancy

The alpha 2 macroglobulins (A2M) are a family of abundant plasma proteins produced predominantly by the mammalian liver. Pregnancy zone proteins (PZP) of humans and rats are A2M family members that bind a wide variety of macromolecules including the important pregnancy-associated molecules such as vascular endothelial growth factor, placenta growth factor and glycodelin (also called PP14). Recently, a mouse gene analogous to PZP (A2M of pregnancy or A2Mp) was cloned. A2Mp has a unique pattern of expression in reproductive and cardiovascular tissues and, unexpectedly, is not expressed by liver. Since changes in heart function and remodeling of renal and uterine vasculature are amongst the earliest maternal responses to pregnancy, the product of the A2Mp gene has been postulated to systemically regulate these changes. A2Ms with and without non-covalently bound ligands also down regulate immune cell activation but promote immune cell migration, additional features associated with gestational success. Here, we review the A2M gene families of mice and humans, the predicted structural relationships between A2M and its pregnancy induced forms and the postulated roles for this gene family in normal pregnancy.