| 1. |
- Agholme, Lotta, et al.
(författare)
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Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons
- 2014
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers. - 1381-6128 .- 1873-4286. ; 20:15, s. 2458-2468
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Tidskriftsartikel (refereegranskat)abstract
- The sporadic, late onset form of Alzheimers disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased beta-amyloid (A beta) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of A beta. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted A beta. Furthermore, accumulation of improperly degraded A beta in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric A beta can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, A beta accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of A beta causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced A beta clearance and subsequent A beta spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated A beta, it can be possible to remove it and avoid A beta-induced neurodegeneration without disturbing the endogenously important pool of secreted A beta. Additionally, drugs targeted to inhibit the spread of intracellular toxic A beta aggregates may also be useful in stopping the progression of pathology, without affecting the level of A beta that normally occurs in the brain.
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| 2. |
- Altai, Mohamed, et al.
(författare)
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Radiolabeled Probes Targeting Tyrosine-Kinase Receptors For Personalized Medicine
- 2014
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 20:14, s. 2275-2292
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Tidskriftsartikel (refereegranskat)abstract
- Receptor tyrosine kinases (RTK) are transmembrane receptors regulating cellular proliferation, differentiation, apoptosis, motility and recruitment of the vasculature. Aberrant expression and/or function of RTK have been detected in many malignant tumors and are considered to be a part of the transformed phenotype. The action of several classes of anti-cancer drugs is based on specific recognition of RTK. Monoclonal antibodies target extracellular binding domains, while tyrosine kinase inhibitors (TKI) bind to intracellular kinase domains to suppress RTK signaling. The issues regarding the efficient use of RTK targeting are the inter- and intra-patient heterogeneity of RTK expression and the changes of expression levels during the course of disease and in response to therapy. Radionuclide molecular imaging of RTK expression may aid in selecting patients who would benefit from RTK-targeting therapy and in identifying non-responders. Therefore, the therapy would be more personalized. Currently, radiolabeled proteins (monoclonal antibodies and their fragments, natural peptides ligands to RTK and de novo selected affinity proteins) and TKI and their analogues are under development for the visualization of RTK. In this review, we discuss the advantages and disadvantages of these approaches.
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| 3. |
- Caja, Laia, et al.
(författare)
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Context-dependent action of transforming growth factor β family members on normal and cancer stem cells
- 2012
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 18:27, s. 4072-4086
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Tidskriftsartikel (refereegranskat)abstract
- The transforming growth factor β (TGFβ) family embraces many growth factors including the Activins and bone morphogenetic proteins (BMPs). The pathways mediated by these growth factors are implicated in many fundamental biological processes such as early embryonic development, organ morphogenesis and adult tissue homeostasis and in a large number of pathologies including cancer. The action of these pathways is often contextual, which means that different cell types present different physiological responses to these ligands or that the response of one cell type to a certain ligand differs depending on the presence of other signaling proteins that stimulate the target cell together with TGFβ/BMP. The latter usually reflects developmental stage or progression to a specific pathological stage. Not only diverse growth factors and cytokines can influence the response of tissues to TGFβ/BMP, but a single cell type may also show drastically different physiological outcomes to TGFβ or Activin signaling as compared to BMP signaling. This review describes differential physiological outcomes of TGFβ and BMP signaling in normal embryonic or adult stem cells and eventually in cancer stem cells and the process of epithelial-mesenchymal transition. We also summarize evidence on the mechanistic antagonism between TGFβ and BMP signaling as established in vascular differentiation and the progression of tissue fibrosis and cancer. The article ends by discussing possible advantages that the acquired knowledge of these signaling mechanisms offers to new regimes of cancer therapy and the ever-lasting problem of drug resistance elicited by tumor initiating cells.
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| 4. |
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| 5. |
- Cederholm, Tommy, et al.
(författare)
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The Role of Malnutrition in Older Persons with Mobility Limitations
- 2014
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 20:19, s. 3173-3177
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Tidskriftsartikel (refereegranskat)abstract
- Movement disability has a high prevalence in elderly population, either healthy or with chronic disease. Impaired nutritional status is a very common condition in geriatric patients too, especially if we consider elderly subjects admitted to hospital. There are growing evidences that nutrition and disability are strictly interconnected. On the one side, nutritional status is one of the multiple elements that influence the onset and the course of a functional disability; on the other side, disability itself may contribute to malnutrition onset and worsening. Nutrition may not be the sole factor involved in movement impairment in the elderly, but consciousness of its importance in frail elderly population is growing among clinicians and scientific community. In this paper we review the existing knowledge of these complex relationships, discussing the main observational and interventional studies that explored the role of nutrition in movement disability onset and recovery. We also point out how specific kinds of diet, such as Mediterranean diet or high-protein diet, are involved in disability prevention. Finally, we take a look at the existing evidence of the role of single nutrient dietary intake, such as carotenoids, selenium or vitamin D, in mobility impairment in the elderly population.
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| 6. |
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| 7. |
- Ezzat, Kariem, et al.
(författare)
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Peptide-based matrices as drug delivery vehicles
- 2010
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Ingår i: Current pharmaceutical design. - 1381-6128 .- 1873-4286. ; 16:9, s. 1167-1178
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Forskningsöversikt (refereegranskat)abstract
- Peptides, polypeptides and proteins have been extensively studied for their various structural and functional roles in living organisms. However, breakthrough discoveries in the last decades identified some peptide-based matrices that posses the ability to traverse biological membranes, and many peptides, polypeptides and even complete proteins have been shown to have such properties. Hence, these matrices have been successfully used for the intracellular delivery of many therapeutic cargos including small molecules, proteins, peptides, oligonucleutides, plasmids and nanoparticles both in vitro and in vivo. Being neither toxic nor carcinogenic and meanwhile efficient in delivery, they are recognized as very promising vectors to overcome the shortcomings of the available technologies. The characteristics of these peptide-based matrices and their applications in drug delivery are here briefly illustrated together with current challenges and future prospects.
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| 8. |
- Gogvadze, V
(författare)
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Targeting mitochondria in fighting cancer
- 2011
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 17:36, s. 4034-4046
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Jiravanichpaisal, Pikul, et al.
(författare)
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Inflammation in Arthropods
- 2010
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Ingår i: Current pharmaceutical design. - 1381-6128 .- 1873-4286. ; 16:38, s. 4166-4174
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Forskningsöversikt (refereegranskat)abstract
- The inflammatory process in arthropods includes primarily the recruitment of circulating hemocytes to wounds or sites of microbial infections. Melanization, capsule formation and clotting reactions will finally result in the sealing of wounds. In this review we will focus on recent research about hemolymph clotting and melanization reactions, and the recruitment of hemocytes to wounds and infections. We further describe in more detail new knowledge about crustacean hematopoiesis that is crucial for hemocyte recruitment to the site of an infection and there develop an inflammatory response Moreover, we pay special attention to the gut as an important route of infection in arthropods. Since the gastrointestinal tract provides a first line of defense and regulation of the indigenous bacteria and the intestine often harbors loads of potential pathogenic microorganisms. Therefore the integrity of intestinal epithelium and to maintain the correct flora is crucial to animal health.
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| 10. |
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| 11. |
- Ketelhuth, DFJ, et al.
(författare)
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T cell-based therapies for atherosclerosis
- 2013
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 19:33, s. 5850-5858
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Tidskriftsartikel (refereegranskat)
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| 12. |
- Långsjö, Jaakko W., et al.
(författare)
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Harnessing anaesthesia and brain imaging for the study of human consciousness
- 2014
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers. - 1381-6128 .- 1873-4286. ; 20:26, s. 4211-4224
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Tidskriftsartikel (refereegranskat)abstract
- Philosophers have been trying to solve the mind-body problem for hundreds of years. Consciousness is the core of this problem: How do subjective conscious sensations, perceptions, feelings, and thoughts arise out of objective physical brain activities? How is this subjective conscious world in causal interaction with the objective sensory and motor mechanisms of the brain and the body? Although we witness the seamless interaction of the mental and the physical worlds in our everyday lives, no scientific theory can yet fully describe or explain it. The hard problem of consciousness, the question why and how any brain activity should be accompanied by any subjective experiences at all, remains a mystery and a challenge for modern science. Anesthesia offers a unique and safe way to directly manipulate the state of consciousness and can, thus, be used as a tool in consciousness research. With neuroimaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) performed at different states of consciousness, it is possible to visualize the state-related changes and pinpoint the brain structures or neural mechanisms related to changes in consciousness. With these tools, neurosciences now show promise in disentangling the eternal enigma of human consciousness. In this article, we will review the recent advancements in the field.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Rocha, Sandra, 1975
(författare)
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Targeted Drug Delivery Across the Blood Brain Barrier in Alzheimer's Disease
- 2013
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 19:37, s. 6635-6646
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of drugs for Alzheimer's disease (AD) therapy that can also permeate the blood brain barrier (BBB) is very difficult owing to its specificity and restrictive nature. The BBB disruption or the administration of the drug directly into the brain is not an option due to toxic effects and low diffusion of the therapeutic molecule in the brain parenchyma. A promising approach for drug systemic delivery to the central nervous system is the use of nanosized carriers. The therapeutic potential of certain nanopharmaceuticals for AD has already been demonstrated in vivo after systemic delivery. They are based on i) conjugates of drug and monoclonal antibodies against BBB endogenous receptors; ii) cationized or end terminal protected proteins/peptides; iii) liposomes and polymeric nanoparticles coated with polysorbate 80, cationic macromolecules or antibodies against BBB receptors/amyloid beta-peptides. Optimization and further validation of these systems are needed.
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| 17. |
- Ruiz-Perez, MV, et al.
(författare)
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Glutamine, glucose and other fuels for cancer
- 2014
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 20:15, s. 2557-2579
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Tidskriftsartikel (refereegranskat)
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| 18. |
- Sussman, Fredy, et al.
(författare)
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On the Active Site Protonation State in Aspartic Proteases : Implications for Drug Design
- 2013
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 19:23, s. 4257-4275
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Tidskriftsartikel (refereegranskat)abstract
- Aspartic proteases (AP) are a family of important hydrolytic enzymes in medicinal chemistry, since many of its members have become therapeutical targets for a wide variety of diseases from AIDS to Alzheimer. The enzymatic activity of these proteins is driven by the Asp dyad, a pair of active site Asp residues that participate in the hydrolysis of peptides. Hence, the protonation state of these and other acidic residues present in these enzymes determines the catalytic rate and the affinity for an inhibitor at a given pH. In the present work we have reviewed the effect of the protonation states of the titratable residues in AP's both on catalysis and inhibition in this family of enzymes. The first section focuses on the details of the catalytic reaction mechanism picture brought about by a large number of kinetic, crystallographic and computational chemistry analyses. The results indicate that although the mechanism is similar in both retroviral and eukaryotic enzymes, there are some clear differences. For instance, while in the former family branch the binding of the substrate induces a mono-ionic charge state for the Asp dyad, this charge state seems to be already present in the unbound state of the eukaryotic enzymes. In this section we have explored as well the possible existence of low barrier hydrogen bonds (LBHB's) in the enzymatic path. Catalytic rate enhancement in AP's could in part be explained by the lowering of the barrier for proton transfer in a hydrogen bond from donor to acceptor, which is a typical feature of LBHB's. Review of the published work indicates that the experimental support for this type of bonds is rather scarce and it may be more probable in the first stages of the hydrolytic mechanism in retroviral proteases. The second section deals with the effect of active site protonation state on inhibitor binding. The design of highly potent AP inhibitors, that could be the basis for drug leads require a deep knowledge of the protonation state of the active site residues induced by their presence. This vital issue has been tackled by experimental techniques like NMR, X-ray crystallography, calorimetric and binding kinetic techniques. Recently, we have developed a protocol that combines monitoring the pH effect on binding affinities by SPR methods and rationalization of the results by molecular mechanics based calculations. We have used this combined method on BACE-1 and HIV-1 PR, two important therapeutic targets. Our calculations are able to reproduce the inhibitor binding trends to either enzyme upon a pH increase. The results indicate that inhibitors that differ in the Asp dyad binding fragments will present different binding affinity trends upon a pH increase. Our calculations have enabled us to predict the protonation states at different pH values that underlie the above mentioned trends. We have found out that these results have many implications not only for in silico hit screening campaigns aimed at finding high affinity binders, but also (in the case of BACE-1) for the discovery of cell active compounds.
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| 19. |
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| 20. |
- Takano, A
(författare)
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The search of targets for novel antipsychotic drugs
- 2010
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 16:3, s. 308-308
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 21. |
- Vidal, Rebeca, et al.
(författare)
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New strategies in the development of antidepressants : towards the modulation of neuroplasticity pathways
- 2011
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 17:5, s. 521-533
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Tidskriftsartikel (refereegranskat)abstract
- Over the past five decades, the pharmacological treatment of depression has been based on the pathophysiological hypothesis of a deficiency in monoamines, mainly serotonin and noradrenaline. Antidepressants prescribed today, all of them designed to enhance central monoaminergic tone, present several important limitations, including a 2-5 weeks response lag and also a limited clinical efficacy. As it is increasingly evident that the abnormalities associated to depression go beyond monoamines, the development of better antide-pressants will depend on the identification and understanding of new cellular targets. In this regard, much evidence supports a role for cellular and molecular mechanisms of neuroplasticity, including neurotrophic inputs, in mood disorders, in parallel with the biological features associated to stress conditions. In order to illustrate the possible relevance of neuroplasticity-related pathways for the therapy of depressive states, we here review the biological evidence supporting some therapeutic strategies in a very initial phase of development (modulation of the Wnt/GSK-3β/β-catenin pathway, potentiation of endocannabinoid activity, agonism of 5-HT4 receptors), which involve modulation of downstream mechanisms and neuroplasticity circuits. These strategies also show the existence of mixed mechanisms of action, constituting a nexus between the "classic" aminergic theory and the "new" neuroplasticity hypothesis.
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| 22. |
- Vidal, Rebeca, et al.
(författare)
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Serotonin 5-HT4 receptors: A new strategy for developing fast acting antidepressants?
- 2014
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers. - 1381-6128 .- 1873-4286. ; 20:23, s. 3751-3762
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of the activity of brain monoaminergic systems has been the focus of attention of many studies since the first antidepressant drug emerged 50 years ago. The search for novel antidepressants is deeply linked to the search for fast-acting strategies, taking into account that 2-4 weeks of treatment with classical antidepressant are required before clinical remission of the symptoms becomes evident. In the recent years several hypotheses have been proposed on the basis of the existence of alterations in brain synaptic plasticity in major depression. Recent evidences support a role for 5-HT4 receptors in the pathogenesis of depression as well as in the mechanism of action of antidepressant drugs. In fact, chronic treatment with antidepressant drugs appears to modulate, at different levels, the signaling pathway associated to 5-HT4 receptors, as well as their levels of expression in the brain. Moreover, several experimental studies have identified this receptor subtype as a promising new target for fast-acting antidepressant strategy: the administration of partial agonists of this receptor induces a number of responses similar to those observed after chronic treatment with classical antidepressants, but with a rapid onset of action. They include efficacy in behavioral models of depression, rapid desensitization of 5-HT1A autoreceptors, and modifications in the expression of several molecular markers of brain neuroplasticity. Although much work remains to be done in order to clarify the real therapeutic potential of these drugs, the evidences reviewed below support the hypothesis that 5-HT4 receptor partial agonists could behave as rapid and effective antidepressants.
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| 23. |
- Wadenberg, Marie-Louise
(författare)
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Conditioned avoidance response in the development of new antipsychotics.
- 2010
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Ingår i: Current pharmaceutical design. - 1381-6128 .- 1873-4286. ; 16:3, s. 358-370
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Forskningsöversikt (refereegranskat)abstract
- Schizophrenia presents with positive/psychotic, negative and cognitive symptoms. Positive symptoms seems due to a dopamine mesolimbic overreactivity, while negative/cognitive symptoms may conversely be due to mesocortical hypo-dopaminergia. Traditional dopamine D2 receptor blocking antipsychotics (e.g. haloperidol) are effective against psychotic/positive symptoms, but less so against negative/cognitive symptoms. Some D2 receptor blockage, however, seems necessary for efficacy against psychotic symptoms. Therefore, current antipsychotic drug improvement strategies include modest D2 receptor blockage, or partial D2 stimulation, combined with adjunct pharmacological properties that may enhance: i) D2 blockage efficacy; and ii) cognitive functioning. There are also strategies with no direct D2 blockage. Clinical activity is often tested in animal screening tests (so called animal models). The screening test conditioned avoidance response in rats has shown particular sensitivity, with high predictive validity, for detection of drug antipsychotic activity. The present review assessed the significance, accuracy and use of the conditioned avoidance response test as a screening tool in current antipsychotic drug development. It was found that: i) the conditioned avoidance response test holds a strong position, is frequently used in current antipsychotic drug development, and is commonly considered a reliable screening tool, with high predictive validity, for the detection of potential antipsychotic activity; ii) in current antipsychotic drug development, the conditioned avoidance response test is able to detect pharmacological properties contributing to antipsychotic activity in the presence of sub-therapeutic D2 receptor blockade, as well as detecting antipsychotic activity of compounds having no direct D2 blocking properties.
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| 24. |
- Wadenberg, Marie-Louise
(författare)
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Current Pro-Cognitive Therapeutic Strategies for Improved Pharmacological Treatment in Schizophrenia
- 2014
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 20:31, s. 5045-5045
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Cognitive impairment influencing memory, attentional focus and executive functions in schizophrenia have a significant impact on social functioning and quality of life. Cognitive functions depend on normal functioning of brain prefrontal cortex. Attempts to explain cognitive impairment in schizophrenia include hypotheses (based on among others post-mortem, genetic and imaging data) of dysfunctions involving dopamine, glutamate, GABA as well as acetylcholine neural transmission. Current antipsychotic drugs are not sufficiently effective against cognitive symptoms. Thus, while pharmacological treatment strategies earlier primarily focused on managing psychotic (so called positive) symptoms, current pharmacological strategies aim at identifying compounds with pro-cognitive properties, suitable for treatment of cognitive symptoms as manifested in schizophrenia. To this end, scientists are primarily working along two lines: i) developing animal models/tests in rodents with relevance either to cognitive symptoms as presented in schizophrenia and/or to brain abnormalities in schizophrenia believed to be causing these symptoms; ii) identifying pro-cognitive compounds with pharmacological properties acting on brain neurotransmitter functions believed to be involved in cognitive dysfunction in schizophrenia. The present special issue on ‘Current pro-cognitive therapeutic strategies for improved pharmacological treatment in schizophrenia’ includes presentation and discussion of the use of the attentional set-shifting test as a relevant model for attentional/executive functioning in schizophrenia as well as for the identification of pro-cognitive compounds with relevance to schizophrenia treatment Tait et al. [1] and Goetghebeur and Dias [2], presentation of the neurodevelopmental prenatal methylazoxymethanol acetate (MAM) model of schizophrenia by Gill and Grace [3], and discussion of the novel object recognition (NOR) task for memory functions by Rajagopal et al. [6]. In addition, putative procognitive treatment strategies for schizophrenia treatment such as the use of GABAA receptor agonists [3], the use of compounds acting at nicotinic acetylcholine receptors from a clinical perspective Boggs et al. [4], as well as the therapeutic significance of compounds (phosphodiesterase, PDE, inhibitors) influencing intracellular signaling Snyder and Vanover [5] are presented and discussed. Finally, data on the effects of atypical antipsychotics, as well as 5-HT1A partial agonists, 5-HT7 antagonists, and D1 agonists in the NOR test are reviewed by Rajagopal et al. [6]. The contributors are all distinguished scientists, and issues discussed in the articles are timely and of great importance for the advancement of effective schizophrenia treatment strategies. Therefore, this special issue will hopefully be well received and appreciated in the scientific community dealing with these issues.
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| 25. |
- Webster, William S., et al.
(författare)
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Therapeutic Drugs that Slow the Heart Rate of Early Rat Embryos. Is there a Risk for the Human?
- 2014
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 20:34, s. 5364-5376
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Tidskriftsartikel (refereegranskat)abstract
- During the organogenic period of development the cardiovascular system of the embryo fulfills several functions including delivery of oxygen and nutrients and a hemodynamic role necessary for cardiac morphogenesis, angiogenesis and hematopoiesis. It is expected that at each stage of embryonic development there is an ideal embryonic heart rate and contractility that maintains the optimal blood flow and pressure to fulfill these various functions. In vitro rat embryo culture studies have revealed that many therapeutic drugs (antiarrhythmics, antidepressants, antipsychotics and anticonvulsants), that may be taken during human pregnancy, cause a concentration-dependent slowing of the embryonic heart and irregular heart rate at higher concentrations. The concentrations causing bradycardia in vitro are often close to human therapeutic plasma concentrations and raise concern that these drugs can potentially cause embryonic death or malformations, and that current reproductive toxicity testing does not adequately examine possible effects of drugs on the embryo's cardiac function.
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