Neuroimaging diagnosis in neurodegenerative diseases

Dementia affects about 8% of people age 65 years and older. Identification of dementia is particularly difficult in its early phases when family members and physicians often incorrectly attribute the patient’s symptoms to normal aging. The most frequently occurring ailments that are connected with neurodegeneration are: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. A variety of powerful techniques that have allowed visualization of organ structure and function with exact detail have been introduced in the last twenty-five years. One such neuroimaging technique is positron emission tomography (PET), which measures in detail the functioning of distinct areas of the human brain and as a result plays a critical role in clinical and research applications. Radiotracer-based functional imaging provides a sensitive means of recognizing and characterizing the regional changes in brain metabolism and receptor binding associated with cognitive disorders. The next functional imaging technique widely used in the diagnosis of cognitive disorders is single photon emission computed tomography (SPECT). New radiotracers are being developed and promise to expand further the list of indications for PET. Prospects for developing new tracers for imaging other organ diseases also appear to be very promising. In this review, we present current opportunities of neuroimaging techniques in the diagnosis and differentiation of neurodegenerative disorders. Nuclear Med Rev 2010; 13, 1: 23–3

Effects of hypoxia on tumor metabolism

Cechą charakterystyczną guzów litych jest ich niedotlenienie, które istotnie wpływa na biologię nowotworu orazodpowiedź na standardowe schematy leczenia (chemioterapię i radioterapię), co w konsekwencji decyduje o stopniuzaawansowania choroby nowotworowej pacjentów. Odpowiedź adaptacyjna komórek nowotworowych do warunkówhipoksji jest związana ze stymulacją angiogenezy i erytropoezy oraz zmianą metabolizmu komórek guza. W komórkachnowotworowych następuje przestrojenie metabolizmu, które prowadzi do wzrostu glikolizy, zahamowania fosforylacjioksydacyjnej i zwiększenia syntezy kwasów tłuszczowych de novo. Niedotlenienie powoduje aktywację czynnikatranskrypcyjnego HIF-1, który odgrywa kluczową rolę w przeprogramowaniu metabolizmu komórek nowotworowychpoprzez aktywację transkrypcji genów kodujących transportery glukozy i enzymy glikolityczne, co umożliwia zwiększenieglikolizy. Ponadto HIF-1 aktywuje kinazę dehydrogenazy pirogronianowej 1 (pyruvate dehydrogenase kinase1, PDK1), która powoduje zmniejszenie oddychania mitochondrialnego. Przesunięcie oksydacyjnego metabolizmuw stronę glikolizy beztlenowej pozwala na utrzymanie homeostazy redoks i umożliwia przeżycie oraz proliferacjękomórek nowotworowych w warunkach niedotlenienia.A major feature of solid tumors is hypoxia which affects cancer biology, increases resistance to treatment and patientprognosis. Adaptive responses of cells to hypoxia include stimulation of angiogenesis, erythropoiesis and alterationof cellular metabolism. Cancer cells are characterized by reprogramming of metabolism leading to increased glycolysis,attenuation of oxidative phosphorylation and de novo synthesis of fatty acids. Hypoxia-induced activation ofhypoxia-inducible factor (HIF-1) plays an important role in the reprogramming of cancer metabolism by activatingtranscription of genes encoding glucose transporters and glycolytic enzymes leading to increased glucose uptake,and pyruvate dehydrogenase kinase 1 (PDK1), which diminished mitochondrial respiration. The shift from oxidativeto glycolytic metabolism allows maintenance of redox homeostasis, survival and continued proliferation of cancercells under hypoxic conditions

Zastosowanie nanocząsteczek w leczeniu i diagnostyce nowotworów

Nanotechnologia jest nowym interdyscyplinarnym działem nauki, zajmującym się konstrukcją nanocząsteczek, i jejosiągniecia są wykorzystywane w farmacji i medycynie. Choroby nowotworowe są jedną z głównych przyczyń zgonówna świecie. Stosunkowo późne wykrycie zmian nowotworowych oraz mała skuteczność standardowych metodleczenia — ze względu na brak specyfi czności i dużą toksyczność — niekorzystnie wpływają na rokowanie pacjentów.Wykorzystanie nanocząsteczek w diagnostyce molekularnej umożliwia wczesne wykrycie guzów i tym samych rozpoczęciewcześniejszego leczenia. Nanocząsteczki mają również ogromne zastosowanie w terapii przeciwnowotworowejjako nośniki związków terapeutycznych, co powoduje wzrost ich biodostępności i akumulacji w obszarze guzówi zapewnia dostarczenie leków w efektywnych dawkach. Opłaszczenie nanocząsteczek specyfi cznymi ligandami lubprzeciwciałami umożliwia celowaną terapię, co nie tylko zwiększa skuteczność leczenia, ale także istotnie zmniejszacytotoksyczność na komórki prawidłowe. Na uwagę zasługują wielofunkcyjne nanoczasteczki, które są stosowanedo jednoczesnego wykrycia zmian nowotworowych i ich leczenia. Wykorzystanie nanocząsteczek w onkologii dajemożliwość wczesnej diagnozy, dostarczenia leków specyfi cznie do komórek nowotworowych w skutecznej dawceoraz monitorowanie postępów terapii

Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM) may predispose to Alzheimer’s disease (AD). The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE) activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE) and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition) and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE) at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition) and BuChE (IC50 = 28 nmol/mL, mixed type inhibition), while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL). Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future

Adaptation of High-Throughput Screening in Drug Discovery—Toxicological Screening Tests

High-throughput screening (HTS) is one of the newest techniques used in drug design and may be applied in biological and chemical sciences. This method, due to utilization of robots, detectors and software that regulate the whole process, enables a series of analyses of chemical compounds to be conducted in a short time and the affinity of biological structures which is often related to toxicity to be defined. Since 2008 we have implemented the automation of this technique and as a consequence, the possibility to examine 100,000 compounds per day. The HTS method is more frequently utilized in conjunction with analytical techniques such as NMR or coupled methods e.g., LC-MS/MS. Series of studies enable the establishment of the rate of affinity for targets or the level of toxicity. Moreover, researches are conducted concerning conjugation of nanoparticles with drugs and the determination of the toxicity of such structures. For these purposes there are frequently used cell lines. Due to the miniaturization of all systems, it is possible to examine the compound’s toxicity having only 1–3 mg of this compound. Determination of cytotoxicity in this way leads to a significant decrease in the expenditure and to a reduction in the length of the study

Diagnostics and therapy of Alzheimer’s disease

315-325Alzheimer’s Disease (AD) is described as a degenerative disease of the central nervous system characterized by a noticeable cognitive decline defined by a loss of memory and learning ability, together with a reduced ability to perform basic activities of daily living. In the brain of an AD patients is the dramatic decrease in cholinergic innervation in the cortex and hippocampus due to the loss of neurons in the basal forebrain. The above findings led to the development of the cholinergic hypothesis, which proposes that the cognitive loss associated with AD is related to decreased cortical cholinergic neurotransmission. In brain of Alzheimer’s patient’s one ascertained presence of neuritic plaques containing the beta-amyloid peptide and protein tau. Biochemical and genetics studies implicated a central role for beta-amyloid in the pathological cascade of events in AD. The most therapeutic strategies in AD have been directed to two main targets: the beta-amyloid peptide and the cholinergic neurotransmission. The first approach is to act on the amyloid precursor protein (APP) processing. The second main approach is to slow of decline of neuronal degeneration or increasing cholinergic transmission. Diagnosis of AD is very difficult and to date no specific diagnostic tests of the disease are available. Intellectual function testing to determine the degree of cognitive status during routine medical examination is a useful supplementary method of diagnosing dementia. The permissible result, come down from radiopharmacy, which is an integral part of a nuclear medicine. A radiopharmaceutical may be defined as a pharmaceutical substance containing radioactive atoms. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are capable of mapping the distribution of radionuclides in three dimensions, producing maps of brain biochemical and physiological processes. The techniques are reasonably sensitive and specific in differentiating AD from other dementias

Biological Evaluation of the Activity of Some Benzimidazole-4,7-dione Derivatives

The study presented here is a follow up of the authors’ interest in the approach to selective and cytotoxic bioreductive anticancer prodrugs. The current work is devoted to explore both the biological activity of some previously obtained compounds and the search for an explanation of their target(s) in hypoxic pathways. In this work the biological activity of some benzimidazole-4,7-diones was evaluated. These compounds were examined as potential bioreductive agents specific for the hypoxic environment found in tumor cells. The main aim was concerned with establishing their cytotoxic properties by using proliferation, apoptosis and DNA destruction tests on selected tumor cells. Their cytotoxic effects on two tumor cell lines (human lung adenocarcinoma A549 cells line and human malignant melanoma WM115) was compared by means of a WST-1 test. Next, the mode of cytotoxicity behind the selected tumor cells’ death was determined by the caspase 3/7 test. The last point referred to the DNA destruction of A549 and WM115 cells and the in situ DNA Assay Kit test was applied. The cytotoxic tests confirmed their activity against the tumor cells and target hypoxia (compounds 2b, 2a, 2d). The screening test of the caspase-dependent apoptosis proved that the exposure of the tested tumor cells in hypoxia to these benzimidazole-4,7-diones promoted the apoptotic cell death. Additionally, the DNA damage test established that benzimidazole-4,7-diones can be potential hypoxia-selective agents for tumor cells, especially compound 2b. All results classify the tested benzimidazole-4,7-diones as promising, lead molecules and provide a rationale for further molecular studies to explain their usefulness as potential inhibitors of the hypoxia-inducible factor 1 (HIF1)