196,278 research outputs found
Alzheimer's disease: new diagnostic and therapeutic tools
No full textAbstract On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related diseases was held in Palermo, Italy. Here, the lectures of M. Racchi on History and future perspectives of Alzheimer Biomarkers and of G. Scapagnini on Cellular Stress Response and Brain Ageing are summarized. Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for clinica dementia. AD prevention is an important goal of ongoing research. Two objectives must be accomplished to make prevention feasible: i) individuals at high risk of AD need to be identified before the earliest symptoms become evident, by which time extensive neurodegeneration has already occurred and intervention to prevent the disease is likely to be less successful and ii) safe and effective interventions need to be developed that lead to a decrease in expression of this pathology. On the whole, data here reviewed strongly suggest that the measurement of conformationally altered p53 in blood cells has a high ability to discriminate AD cases from normal ageing, Parkinson's disease and other dementias. On the other hand, available data on the involvement of curcumin in restoring cellular homeostasis and rebalancing redox equilibrium, suggest that curcumin might be a useful adjunct in the treatment of neurodegenerative illnesses characterized by inflammation, such as AD.</p
Glyphosate tolerance in maize (Zea mays L.) 1. Differential response among inbred lines.
No full textVariation in susceptibility to the safe broad-spectrum herbicide glyphosate was investigated in maize. Eleven inbred lines, grown in a growth chamber, were evaluated for their tolerance to the herbicide at 2.4 mM (0.2 kg a.i. in 400 I ha-1 of water). Following treatment with glyphosate at the three-leaf stage, significant variation in damage, expressed as visual injury ratings scored 7, 14 and 21 days after the application of the herbicide, was found. Effects on dry weight and shoot height were consistent with visual scores and the carbon-exchange rate was found to be a sensitive index of differential injury.
Biochemical characterization of 5-enol-pyruvyl-shikimate-3-phosphate (EPSP) synthase, the main target of the herbicide, ruled out the possibility that this differential susceptibility was due to variations in the sensitivity of the enzyme. On the contrary, a positive correlation was found between in vivo tolerance and EPSP synthase levels, measured at different stages during seedling growth. This result suggests that a naturally occurring difference in EPSP synthase levels in the tissues may contribute to the differential response observed in vivo in maize inbreds
Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside?
No full textElisa Mura,1 Stefano Govoni,1 Marco Racchi,1 Valeria Carossa,1 Guglielmina Nadia Ranzani,2 Massimo Allegri,3,4 Ron HN van Schaik5 1Department of Drug Sciences, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy; 2Department of Biology and Biotechnology, University of Pavia, Pavia, Italy; 3Pain Therapy Service, Foundation IRCCS San Matteo Hospital, Pavia, Italy; 4Department of Clinical, Surgical Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; 5Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands Abstract: The 118A>G single nucleotide polymorphism (SNP) in the µ-opioid receptor (OPRM1) gene has been the most described variant in pharmacogenetic studies regarding opioid drugs. Despite evidence for an altered biological function encoded by this variant, this knowledge is not yet utilized clinically. The aim of the present review was to collect and discuss the available information on the 118A>G SNP in the OPRM1 gene, at the molecular level and in its clinical manifestations. In vitro biochemical and molecular assays have shown that the variant receptor has higher binding affinity for ß-endorphins, that it has altered signal transduction cascade, and that it has a lower expression compared with wild-type OPRM1. Studies using animal models for 118A>G have revealed a double effect of the variant receptor, with an apparent gain of function with respect to the response to endogenous opioids but a loss of function with exogenous administered opioid drugs. Although patients with this variant have shown a lower pain threshold and a higher drug consumption in order to achieve the analgesic effect, clinical experiences have demonstrated that patients carrying the variant allele are not affected by the increased opioid consumption in terms of side effects. Keywords: µ-opioid receptor, opioids, pharmacogenetics, pain, analgesi
Activation of the Notch pathway in Down syndrome: cross-talk of Notch and APP.
No full textABSTRACT Down syndrome (DS) patients suffer
from mental retardation, but also display enhanced
-APP production and develop cortical amyloid
plaques at an early age. As -APP and Notch are both
processed by -secretase, we analyzed expression of the
Notch signaling pathway in the adult DS brain and in a
model system for DS, human trisomy 21 fibroblasts by
quantitative PCR. In adult DS cortex we found that
Notch1, Dll1 and Hes1 expression is up-regulated.
Moreover, DS fibroblasts and Alzheimer disease cortex
also show overexpression of Notch1 and Dll1, indicating
that enhanced -APP processing found in both DS
and AD could be instrumental in these changes. Using
pull-down studies we could demonstrate interaction of
APP with Notch1, suggesting that these transmembrane
proteins form heterodimers, but independent of
-secretase. We could demonstrate binding of the intracellular
domain of Notch1 to the APP adaptor
protein Fe65. Furthermore, activated Notch1 can transactivate
an APP target gene, Kai1, and vice versa,
activated APP can trans-activate the classical Notch
target gene Hes1. These data suggest that Notch expression
is activated in Down syndrome, possibly
through cross-talk with APP signaling. This interaction
might affect brain development, since the Notch pathway
plays a pivotal role in neuron-glia differentiation.—
Activation of the Notch pathway in Down syndrome:
cross-talk of Notch and APP. Fischer, D. F., van Dijk,
R., Sluijs, J. A., Nair, S. M., Racchi, M., Levelt, C. N.,
van Leeuwen, F. W., Hol, E. M. FASEB J. 19, 1451–1458
(2005
A glyphosate-resistant 5-enolpyruvilshikimate-3-phosphate synthase confers tolerance to a maize cell line
No full textAmong a few cell lines of maize (Zea mays L., cv. Black Mexican Sweet (BMS)) tested, one showed a natural, remarkable tolerance to glyphosate at concentrations as high as 10 mM. Two activities of 5-enol-pyruvyl-shikimate-3-phosphate (EPSP) synthase, the target enzyme of the herbicide, were separated in the tolerant culture by anion-exchange chromatography. One peak of activity was not significantly inhibited by glyphosate even at millimolar concentrations. While the glyphosate-sensitive isoform persisted throughout the growth cycle of the culture, the glyphosate-resistant EPSP synthase increased only after the onset of exponential growth and declined in the stationary phase. Tolerance to the herbicide was accompanied by a reduced affinity of the enzyme for the substrate phospho-enol-pyruvic acid
Molecular characterization of membrane steroid receptors in hormone-sensitive cancers
No full textCancer is one of the most common causes of death worldwide, and its development is a re-sult of the complex interaction of genetic factors, environmental cues, and aging. Hormone-sensitive cancers depend on the action of one or more hormones for their development and progression. Sex steroids and corticosteroids can regulate different physiological functions, including metabolism, growth, and proliferation, through their interaction with specific nuclear receptors, that can tran-scriptionally regulate target genes via their genomic actions. Therefore, interference with hormones’ activities, e.g., deregulation of their production and downstream pathways or the exposition to exogenous hormone-active substances such as endocrine-disrupting chemicals (EDCs), can affect the regulation of their correlated pathways and trigger the neoplastic transformation. Although nuclear receptors account for most hormone-related biologic effects and their slow genomic responses are well-studied, less-known membrane receptors are emerging for their ability to mediate steroid hormones effects through the activation of rapid non-genomic responses also involved in the development of hormone-sensitive cancers. This review aims to collect pre-clinical and clinical data on these extranuclear receptors not only to draw attention to their emerging role in cancer development and progression but also to highlight their dual role as tumor microenvironment players and potential candidate drug targets
Immunomodulators inspired by nature: A review on curcumin and Echinacea
No full textThe immune system is an efficient integrated network of cellular elements and chemicals developed to preserve the integrity of the organism against external insults and its correct functioning and balance are essential to avoid the occurrence of a great variety of disorders. To date, evidence from literature highlights an increase in immunological diseases and a great attention has been focused on the development of molecules able to modulate the immune response. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of herbal medicines as integrative, complementary and preventive therapy. The active components in medical plants have always been an important source of clinical therapeutics and the study of their molecular pharmacology is an enormous challenge since they offer a great chemical diversity with often multi-pharmacological activity. In this review, we mainly analysed the immunomodulatory/antinflammatory activity of Echinacea spp. and Curcuma longa, focusing on some issues of the phytochemical research and on new possible strategies to obtain novel agents to supplement the present therapies
Endocrine-disrupting chemicals’ (Edcs) effects on tumour microenvironment and cancer progression: Emerging contribution of rack1
No full textEndocrine disruptors (EDCs) can display estrogenic and androgenic effects, and their exposure has been linked to increased cancer risk. EDCs have been shown to directly affect cancer cell regulation and progression, but their influence on tumour microenvironment is still not completely elucidated. In this context, the signalling hub protein RACK1 (Receptor for Activated C Kinase 1) could represent a nexus between cancer and the immune system due to its roles in cancer progression and innate immune activation. Since RACK1 is a relevant EDCs target that responds to steroid-active compounds, it could be considered a molecular bridge between the endocrine-regulated tumour microenvironment and the innate immune system. We provide an analysis of immunomodulatory and cancer-promoting effects of different EDCs in shaping tumour microenvironment, with a final focus on the scaffold protein RACK1 as a pivotal molecular player due to its dual role in immune and cancer contexts
Purification and characterization of mouse liver xanthine oxidase
No full text: Xanthine oxidase (EC 1.1.3.22) is purified to homogeneity from mouse liver after induction with bacterial lipopolysaccharide. The enzyme has an apparent molecular weight of 300,000 in its native state and it is suggested to be constituted of two identical subunits of Mr 150,000 each. The isoelectric point is 6.7 and the apparent Km value for xanthine is 3.4 microM. The amino acid composition of mouse xanthine oxidase is quite similar to that of Drosophila xanthine dehydrogenase
Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea
No full textThe immune system is an efficient integrated network of cellular elements and chemicals developed to preserve the integrity of the organism against external insults and its correct functioning and balance are essential to avoid the occurrence of a great variety of disorders. To date, evidence from literature highlights an increase in immunological diseases and a great attention has been focused on the development of molecules able to modulate the immune response. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of herbal medicines as integrative, complementary and preventive therapy. The active components in medical plants have always been an important source of clinical therapeutics and the study of their molecular pharmacology is an enormous challenge since they offer a great chemical diversity with often multi-pharmacological activity. In this review, we mainly analysed the immunomodulatory/antinflammatory activity of Echinacea spp. and Curcuma longa, focusing on some issues of the phytochemical research and on new possible strategies to obtain novel agents to supplement the present therapies
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