Search results for "Secondary"
showing 10 items of 1765 documents
A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells
2021
New and potent agents that evade multidrug resistance (MDR) and inhibit epigenetic modifications are of great interest in cancer drug development. Here, we describe that a moniliformin derivative (IUPAC name: 3-(naphthalen-2-ylsulfanyl)-4-{[(2Z)-1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene]methyl}cyclobut-3-ene-1,2-dione; code: MCC1381) bypasses P-gp-mediated MDR. Using transcriptomics, we identified a large number of genes significantly regulated in response to MCC1381, which affected the cell cycle and disturbed cellular death and survival. The potential targets of MCC1381 might be histone deacetylases (HDACs) as predicted by SwissTargetPrediction. In silico studies confirmed that MCC13…
Membrane protein oxidation determines neuronal degeneration
2015
Oxidative stress is an early hallmark in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. However, the critical biochemical effector mechanisms of oxidative neurotoxicity have remained surprisingly elusive. In screening various peroxides and potential substrates of oxidation for their effect on neuronal survival, we observed that intramembrane compounds were significantly more active than aqueous or amphiphilic compounds. To better understand this result, we synthesized a series of competitive and site-specific membrane protein oxidation inhibitors termed aminoacyllipids, whose structures were designed on the basis of amino acids frequently found at the protein-lipi…
Identification of new P-glycoprotein inhibitors derived from cardiotonic steroids
2014
P-glycoprotein (ABCB1, MDR1) is capable of extruding chemotherapeutics outside the cell and its overexpression in certain cancer cells may cause failure of chemotherapy. Many attempts were carried out to identify potent inhibitors of this transporter and numerous compounds were shown to exert inhibitory effects in vitro, but so far none were able to make their way to the clinic due to serious complications. Natural compounds represent a great source of therapeutics, which are believed to be safe and effective. Therefore, we have screened a large library of naturally occurring cardiotonic steroids and their derivatives using high throughput flow cytometry. We were able to identify six compou…
Central and Peripheral Secondary Cell Death Processes after Transient Global Ischemia in Nonhuman Primate Cerebellum and Heart
2019
Cerebral ischemia and its pathological sequelae are responsible for severe neurological deficits generally attributed to the neural death within the infarcted tissue and adjacent regions. Distal brain regions, and even peripheral organs, may be subject to more subtle consequences of the primary ischemic event which can initiate parallel disease processes and promote comorbid symptomology. In order to characterize the susceptibility of cerebellar brain regions and the heart to transient global ischemia (TGI) in nonhuman primates (NHP), brain and heart tissues were harvested 6 months post-TGI injury. Immunostaining analysis with unbiased stereology revealed significant cell death in lobule II…
The Functional Role of the Second NPXY Motif of the LRP1 β-Chain in Tissue-type Plasminogen Activator-mediated Activation of N-Methyl-D-aspartate Rec…
2008
The low density lipoprotein receptor-related protein 1 (LRP1) emerges to play fundamental roles in cellular signaling pathways in the brain. One of its prominent ligands is the serine proteinase tissue-type plasminogen activator (tPA), which has been shown to act as a key activator of neuronal mitogen-activated protein kinase pathways via the N-methyl-D-aspartate (NMDA) receptor. However, here we set out to examine whether LRP1 and the NMDA receptor might eventually act in a combined fashion to mediate tPA downstream signaling. By blocking tPA from binding to LRP1 using the receptor-associated protein, we were able to completely inhibit NMDA receptor activation. Additionally, inhibition of …
Comparison between tumors in plants and human beings: Mechanisms of tumor development and therapy with secondary plant metabolites
2019
Abstract Background Human tumors are still a major threat to human health and plant tumors negatively affect agricultural yields. Both areas of research are developing largely independent of each other. Treatment of both plant and human tumors remains unsatisfactory and novel therapy options are urgently needed. Hypothesis The concept of this paper is to compare cellular and molecular mechanisms of tumor development in plants and human beings and to explore possibilities to develop novel treatment strategies based on bioactive secondary plant metabolites. The interdisciplinary discourse may unravel commonalities and differences in the biology of plant and human tumors as basis for rational …
The Process-inducing Activity of Transmembrane Agrin Requires Follistatin-like Domains
2009
Clustering or overexpression of the transmembrane form of the extracellular matrix proteoglycan agrin in neurons results in the formation of numerous highly motile filopodia-like processes extending from axons and dendrites. Here we show that similar processes can be induced by overexpression of transmembrane-agrin in several non-neuronal cell lines. Mapping of the process-inducing activity in neurons and non-neuronal cells demonstrates that the cytoplasmic part of transmembrane agrin is dispensable and that the extracellular region is necessary for process formation. Site-directed mutagenesis reveals an essential role for the loop between beta-sheets 3 and 4 within the Kazal subdomain of t…
The cortical representation of pain.
1999
Anatomical and physiological studies in animals, as well as functional imaging studies in humans have shown that multiple cortical areas are activated by painful stimuli. The view that pain is perceived only as a result of thalamic processing has, therefore, been abandoned, and has been replaced by the question of what functions can be assigned to individual cortical areas. The following cortical areas have been shown to be involved in the processing of painful stimuli: primary somatosensory cortex, secondary somatosensory cortex and its vicinity in the parietal operculum, insula, anterior cingulate cortex and prefrontal cortex. These areas probably process different aspects of pain in para…
Effects of irrigation on fruit ripening behavior and metabolic changes in olive
2012
Olive (Olea europaea, cv Leccino) fruits grown under different water regimes were analyzed by metabolomics and specific transcript accumulation analyses. The fruit from non-irrigated (rain-fed) and irrigated trees cultivated under field conditions, with a seasonal water amount equivalent to the calculated crop evapotranspiration (ETc) was compared in the last developmental phase and, in particular, at commercial harvest. Metabolomics (GC-MS) analysis identified several hundred metabolites in ripe mesocarp, 46 of which showed significantly different contents in the rain-fed and irrigated samples. Some compounds involved in primary metabolism (carbohydrates, amino acids, organic acids) and se…
MOLECULAR AND METABOLIC ANALYSES IN DEVELOPING OLIVE FRUIT IN RELATION TO DIFFERENT WATER REGIMES
2011
Despite the global economic importance of olive (Olea europaea L.), little is known about the molecular and metabolic changes during fruit development and the modulation of quality-related metabolic pathways during drought stress. In this work, we report the expression pattern of genes involved in important pathways of secondary metabolism (polyphenols, terpenoids) during fruit development in rainfed or fully irrigated olive plants. Phenolic compounds represent a complex mixture in both olive fruits and oil. The interest on these compounds is due to their demonstrated anti-atherogenic and anti-cancerogenic effects providing to the olive oil important nutraceutical properties. Several parame…