Synthesis of 1,2,3-triazole-linked pyrrolobenzodiazepine conjugates employing 'click' chemistry: DNA-binding affinity and anticancer activity

1,2,3-Triazole based molecules are useful pharmacophores for several DNA-alkylating and cross-linking agents. A series of A/C8, C/C2 and A/C8-C/C2-linked 1,2,3-triazole-PBD conjugates have been synthesized by employing 'click' chemistry. These molecules have exhibited promising DNA-binding affinity and anticancer activity in selected human cancer cell lines.     

Genetic Similarity Among Tunisian Olive Cultivars and Two Unknown Feral Olive Trees Estimated Through SSR Markers

We used eight informative microsatellite markers for fingerprinting and evaluation of genetic similarity among 15 Tunisian olive (Olea europaea L.) cultivars and two feral unknown trees named Soulela 1 and Soulela 2. Thirty-one alleles were revealed, and the number of alleles per SSR varied from 2 (UDO12) to 6 (GAPU71A). Cluster analysis grouped cultivars into three main clusters. The two unknown varieties could not be reliably classified into any of these cultivar groups. SSR analysis indicated the presence of three erroneous denominations of cultivars. We resolved two synonymy cases (Zalmati and Chemlali; Rkhami and Chetoui) and one case of homonymy (Chemlali Tataouine). Genetic analyses of DNA extracted from leaves, oils, and embryos of the two unknown cultivars and the two major Tunisian olive cultivars (Chemlali and Chetoui) were also studied. We conclude that the reliable identification of these two feral cultivars needs to be addressed by a larger set of markers.     

Application of computational approaches to study signalling networks of nuclear and Tyrosine kinase receptors

Background  

Nuclear receptors (NRs) and Receptor tyrosine kinases (RTKs) are essential proteins in many cellular processes and sequence variations in their genes have been reported to be involved in many diseases including cancer. Although crosstalk between RTK and NR signalling and their contribution to the development of endocrine regulated cancers have been areas of intense investigation, the direct coupling of their signalling pathways remains elusive. In our understanding of the role and function of nuclear receptors on the cell membrane the interactions between nuclear receptors and tyrosine kinase receptors deserve further attention.     

Societal Risk Perception in Arab Countries: The Case of Kuwait

The study was aimed at examining data on risk perception from an Arab country—Kuwait—in order to support the existence of an Arab group as regards the way hazards are perceived. The data were gathered in 2003 and 2004 on two Kuwaiti samples of young adults and adolescents. The questionnaire used was the one used in studies conducted in Egypt and France. It comprised 141 items. The overall mean value observed in the Kuwaiti sample was close to the one found in the Egyptian sample. The linear association between Kuwaiti and French ratings was moderate (0.70) and of the same magnitude as the one found between Egyptian and French ratings. The association between Kuwaiti and Egyptian ratings was greater (0.90). In 80% of the hazards, the specific differences observed between the Kuwaiti and French ratings were the same as the ones observed between Egyptian and French ratings. The whole set of findings supports the hypothesis that Kuwaitis and Egyptians, despite huge differences in the socioeconomic environments in which they live, perceive societal risks in a common way, a way that is different from the way Western Europeans perceive them.     

Intranasal Delivery of a Caspase-1 Inhibitor in the Treatment of Global Cerebral Ischemia

Caspase-1 is an enzyme implicated in neuroinflammation, a critical component of many diseases that affect neuronal degeneration. However, it is unknown whether a caspase-1 inhibitor can modify apoptotic neuronal damage incurred during transient global cerebral ischemia (GCI) and whether intranasal administration of a caspase-1 inhibitor is an effective treatment following GCI. The present study was conducted to examine the potential efficiency of post-ischemic intranasal administration of the caspase-1 inhibitor Boc-D-CMK in a 4-vessel occlusion model of GCI in the rat. Herein, we show that intranasal Boc-D-CMK readily penetrated the central nervous system, subsequently inhibiting caspase-1 activity, decreasing mitochondrial dysfunction, and attenuating caspase-3-dependent apoptotic pathway in ischemia-vulnerable hippocampal CA1 region. Further investigation regarding the mechanisms underlying Boc-D-CMK’s neuroprotective effects revealed marked inhibition of reactive gliosis, as well as reduction of the neuroinflammatory response via inhibition of the downstream pro-inflammatory cytokine production. Intranasal Boc-D-CMK post-treatment also significantly enhanced the numbers of NeuN-positive cells while simultaneously decreasing the numbers of TUNEL-positive and PARP1-positive cells in hippocampal CA1. Correspondingly, behavioral tests showed that deteriorations in spatial learning and memory performance, and long-term recognition memory following GCI were significantly improved in the Boc-D-CMK post-treated animals. In summary, the current study demonstrates that the caspase-1 inhibitor Boc-D-CMK coordinates anti-inflammatory and anti-apoptotic actions to attenuate neuronal death in the hippocampal CA1 region following GCI. Furthermore, our data suggest that pharmacological inhibition of caspase-1 is a promising neuroprotective strategy to target ischemic neuronal injury and functional deficits following transient GCI.     

Six chains of the human T cell antigen receptor.CD3 complex are necessary and sufficient for processing the receptor heterodimer to the cell surface

The T cell antigen receptor (TCR) plays a key role in the process of antigen recognition. It is a complex of at least seven peptide chains (alpha beta gamma delta epsilon zeta-zeta). It is found on the surface of mature T cells and functions in antigen binding in the presence of the major histocompatibility complex. It has been known for some time that physical associations between the CD3 proteins and the TCR chains are essential for efficient transport of either component to the surface of T cells. For example, T cells that lack either the alpha, beta, or delta chains synthesize partial complexes that are eventually degraded. cDNAs encoding the six chains of receptor have become available recently. We have used transfection techniques to generate a panel of Chinese hamster ovary cells that contain partial receptor complexes of known composition and also cells that express all six subunits of the TCR.CD3 complex. Cells in this panel were analyzed for the ability to form alpha-beta heterodimers and also an ability to transport the synthesized chains to the plasma membrane. These studies have allowed us to define the minimum requirements for TCR.CD3 expression on the cell surface.     

Immediate and one-year outcome of patients presenting with Acute Coronary Syndrome complicated by stroke: Findings from the 2nd Gulf Registry of Acute Coronary Events (Gulf RACE-2)

ABSTRACT: BACKGROUND: Stroke is a potential complication of acute coronary syndrome (ACS). The aim of this study was to identify the prevalence, risk factors predisposing to stroke, in-hospital and 1-year mortality among patients presenting with ACS in the Middle East. METHODS: For a period of 9 months in 2008 to 2009, 7,930 consecutive ACS patients were enrolled from 65 hospitals in 6 Middle East countries. RESULTS: The prevalence of in-hospital stroke following ACS was 0.70%. Most cases were ST segment elevation MI-related (STEMI) and ischemic stroke in nature. Patients with in-hospital stroke were 5 years older than patients without stroke and were more likely to have hypertension (66% vs. 47.6%, P = 0.001). There were no differences between the two groups in regards to gender, other cardiovascular risk factors, or prior cardiovascular disease. Patients with stroke were more likely to present with atypical symptoms, advanced Killip class and less likely to be treated with evidence-based therapies. Independent predictors of stroke were hypertension, advanced killip class, ACS type --STEMI and cardiogenic shock. Stroke was associated with increased risk of in-hospital (39.3% vs. 4.3%) and one-year mortality (52% vs. 12.3%). CONCLUSION: There is low incidence of in-hospital stroke in Middle-Eastern patients presenting with ACS but with very high in-hospital and one-year mortality rates. Stroke patients were less likely to be appropriately treated with evidence-based therapy. Future work should be focused on reducing the risk and improving the outcome of this devastating complication.     

Mivazerol, a Novel α2-Agonist and Potential Anti-Ischemic Drug, Inhibits KCl-Stimulated Neurotransmitter Release in Rat Nervous Tissue Preparations

Abstract: In this study, we have investigated the effect of mivazerol, [3-(1H-imidazol-4-yl)methyl-1]-2-hydroxy-benzamide hydrochloride, a new α₂-agonist lacking hypotensive properties and a potential anti-ischemic drug, on the evoked release of norepinephrine, aspartate, and glutamate in tissue preparations from hippocampus, spinal cord T1–T5 section, rostrolateral ventricular medulla, and nucleus tractus solitarii of the brainstem of rat. A simple and efficient in vitro procedure to study pharmacologically the release of norepinephrine and glutamate is described. Tissues were chopped into (0.3 × 0.2 × 0.2 mm³) sections and the resulting minces were used for this study. Exposure to KCl (10–75 mM) for 5 min served as a stimulus for the release response. One, S (for aspartate and for glutamate release), or two such stimuli, S₁ and S₂ (for norepinephrine release) were conducted. The release of norepinephrine (+150% above baseline) was inhibited in a dose-dependent manner by mivazerol in hippocampus (IC₅₀ = 1.5 × 10^?8M), spinal cord (IC₅₀ = 5 × 10^?8M), rostrolateral ventricular medulla (IC₅₀ = 10^?7M), and nucleus tractus solitarii (IC₅₀ = 7.5 × 10^?8M), and by clonidine in hippocampus (IC₅₀ = 5 × 10^?8M), spinal cord (IC₅₀ = 4.5 × 10^?8M), rostrolateral ventricular medulla (IC₅₀ = 2.5 × 10^?7M), and nucleus tractus solitarii (IC₅₀ = 10^?7M). This effect was counteracted by the selective α₂-antagonists yohimbine and rauwolscine. A significant glutamate and aspartate release response was also induced by KCl (35 mmol/L) in hippocampus (+250 and +135%, respectively) and spinal cord (+120 and +55%, respectively), in vitro. However, neither mivazerol nor clonidine, at doses up to 10 µM, had any significant effect on KCl-induced glutamate release in spinal cord, whereas mivazerol blocked completely the release of both amino acids in hippocampus and only the release of aspartate in spinal cord. On the other hand, clonidine (1 µM) was only effective in reducing by 40% the release of aspartate in hippocampus. These data indicate that (1) inhibition of KCl-induced norepinephrine release by mivazerol is mediated by its action on α₂-adrenergic receptors; (2) at concentrations selective for α₂-adrenergic receptors, only mivazerol was effective in blocking the KCl-induced glutamate release in hippocampal tissue; and (3) at the same concentrations, both mivazerol and clonidine were unable to inhibit glutamate release in the spinal cord. These data suggest that prevention of hyperadrenergic activity by mivazerol in perioperative patients may be mediated through its effect on the release of norepinephrine and/or the release of glutamate and aspartate in regions of the CNS that are involved in the control of cardiovascular homeostasis.     

Erratum to: Synthesis and Anticancer Activity of Functionalized Thieno[2,3-d]pyrimidine Compounds and Their Triazinyl and Tetrazinyl Derivatives

Russian Journal of Bioorganic Chemistry - erratum