| 1. |
- Ekström, Per, et al.
(författare)
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Novel In Situ Activity Assays for the Quantitative Molecular Analysis of Neurodegenerative Processes in the Retina
- 2014
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Ingår i: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673. ; 21:30, s. 3478-3493
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms of neuronal cell death are still only poorly understood, which has hindered the advancement of therapies for many currently untreatable neurodegenerative diseases. This calls for the development of new methods which reveal critical molecular mechanisms of the celldeath machinery with both high sensitivity and cellular resolution. Using animal models for hereditary neurodegeneration in the retina, we have developed or adapted different biochemical assays to determine the enzymatic activities of calpain, poly-ADP-ribose-polymerase (PARP), and histone deacetylase (HDAC) directly and in situ. Additionally, the enzymatic activity of cGMP-dependent protein kinase (PKG) was assessed indirectly using in situ immunohistological techniques to detect PKG-activity-dependent products. Combining these assays with in situ cell death markers revealed close temporospatial correlations, suggesting causal connections between the PKG, HDAC, PARP and calpain activities and neuronal cell death. Using different pharmacological and genetic manipulations, causality could indeed be demonstrated. Surprisingly, the often dramatic rises in metabolic activities didnot match by corresponding increases in expression, highlighting the importance of analyses of protein activities at the cellular level. The above mentioned studies identified a number of metabolic processes previously unknownto be involved in inherited retinal degeneration. Comparing different animal retinal degeneration models uncovered striking similarities in enzymatic activities, suggesting a generality of the destructive pathways. Taken together, these findings provided a number of novel targets for neuroprotection and as such opened up new perspectives for the therapy of hereditary neurodegeneration in the retina and possibly other parts of the central nervous system.
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| 2. |
- El-Seedi, Hesham R., et al.
(författare)
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Recent insights into the biosynthesis and biological activities of natural xanthones
- 2010
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Ingår i: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 17:9, s. 854-901
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Forskningsöversikt (refereegranskat)abstract
- This review focuses on recent advances in our understanding of the complex biosynthetic pathways and diverse biological activities of naturally occurring xanthones. The biosynthesis section covers studies published from 1989 to 2008 on xanthone production in plants and fungi, while the bioactivity review presents tabulated activities of more than 250 xanthones described in studies published from 2001 to 2008, together with structural information and indications of their wide-ranging potential uses as pharmacological tools. A large number of relevant papers have been published on these subjects (128 cited here), illustrating the diversity of the xanthones and their possible uses.
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| 3. |
- Eriksson, Staffan
(författare)
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Is the Expression of Deoxynucleoside Kinases and 5 '-nucleotidases in Animal Tissues Related to the Biological Effects of Nucleoside Analogs?
- 2013
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Ingår i: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 20, s. 4241-4248
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Tidskriftsartikel (refereegranskat)abstract
- Nucleoside analogs serve as important chemotherapeutic agents in a number of severe diseases such as cancer and viral infections. These agents are pro-drugs that have to be taken up and phosphorylated in several steps to be trapped in the cells and transformed to active metabolites that inhibit essential steps in the replication of viruses or malignant cells. The anabolic deoxynucleoside kinases (dNKs) and catabolic 5'- nucleotidases(5'-NTs) are involved in maintaining substrate cycles, and act as regulators for the intracellular pools of active nucleotide metabolites. In this chapter the expression patterns of the four dNKs i.e. cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) and the mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) as well as the six intracellular 5'-NTs: cN-IA, cN-IB, cN-II, cN-III, cdN, mdN, present in animal cells and tissues will be described. Their role as primary controllers of the accumulation and activation of important anti viral and anti cancer nucleoside analogs in different tissues involved in the pathophysiology of these diseases will be evaluated. The predictability of using the ratios between the activities of the dNKs and 5'-NTs for estimating efficacy and side effects of nucleoside drug candidates will be discussed as well as recommendations on how to use this information to improve future therapies with nucleoside drugs.
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| 4. |
- Faa, G., et al.
(författare)
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A Developmental Approach to Drug-induced Liver Injury in Newborns and Children
- 2012
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Ingår i: Current Medicinal Chemistry. - 0929-8673. ; 19:27, s. 4581-4594
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Forskningsöversikt (refereegranskat)abstract
- The liver represents the major site of drug metabolism in humans. The developmental changes that occur in the liver's metabolic activity during fetal life and in the perinatal period are at the basis of the varied sensitivity of human newborns to many drugs. The decreased capacity of the fetal and newborn liver to metabolize, detoxify, and excrete drugs - total cytochrome P450 content in the fetal liver being 30% to 60% of adult values - may explain the prolonged actions of many drugs in the newborn, as well as less their potential toxicity. On the other hand, the low levels of phase I (activation) enzymes, producing more polar reactive and often toxic metabolites, could explain the lower incidence of adverse effects of some drugs reported in newborns. Moreover, the greater capacity of newborns to synthesize glutathione is at the basis of their ability in inactivating many toxic metabolites. Here we review the acute and chronic liver toxicity due to the most widely used drugs in the neonate. We will discuss in detail the biochemical profile of the fetal and neonatal liver, and the toxic metabolites formed during the metabolism of the most widely used drugs in the neonate. The histological picture of liver disease related to the therapeutic use of drugs will be discussed, with particular emphasis on the mode of cell death involved in hepatitis induced by different drugs most frequently utilized in the neonatal intensive care units.
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| 5. |
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| 8. |
- Labropoulou, V. T., et al.
(författare)
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Pathophysiology and Pharmacological Targeting of Tumor-Induced Bone Disease : Current Status and Emerging Therapeutic Interventions
- 2011
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Ingår i: Current Medicinal Chemistry. - 0929-8673 .- 1875-533X. ; 18:11, s. 1584-1598
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Forskningsöversikt (refereegranskat)abstract
- Bone disease is a common complication of metastatic solid tumors but also of primary hematological malignancies such as multiple myeloma. Our understanding of the molecular mechanisms underlying the development of bone disease by solid tumors and multiple myeloma has been significantly improved. A complex inter-dependence exists between bone disease and malignant cell growth, creating a vicious cycle of extensive bone destruction and tumor progression. Although myeloma and solid tumors share a number of common molecular pathogenetic mechanisms, they involve distinct pathophysiological pathways, resulting in osteoclastic bone resorption and inhibition of bone formation. In this review, we analyze the molecular mechanisms, involved in tumor-induced bone disease and discuss the current therapeutic approaches and the most recent clinical developments of emerging targeted therapies.
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| 9. |
- Larsson, Rikard, et al.
(författare)
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Clinical Trial Update and Novel Therapeutic Approaches for Metastatic Prostate Cancer.
- 2011
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Ingår i: Current Medicinal Chemistry. - 0929-8673. ; 18, s. 4440-4453
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Tidskriftsartikel (refereegranskat)abstract
- Recurrent prostate cancer (PCa) remains a major clinical challenge. Invasive and metastatic PCa lesions often exhibit a partial and time-limited response to therapy before the cancer progresses and the patient succumbs to the disease. Despite recent advances in early diagnosis and treatment, approximately one-third of treated patients will relapse and become resistant to currently available treatments. In this review we evaluate current treatment practices and recent advances in therapy for localized prostate malignancy and advanced, metastatic prostate cancer. Some of the promising new drugs for PCa treatment include MDV3100, an androgen receptor (AR) antagonist that prevents androgens from binding to the AR and nuclear translocation and co-activator recruitment of the ligand-receptor complex; abiraterone, an orally administered drug that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17; and several newer cytotoxic drugs (epothilones, satraplatin). Key new insights are that cancer stem cells play a role in PCa and that PCa cells are dependent on the AR for proliferation, even in the hormone refractory state of the disease. We also discuss potential molecular targets for new drug candidates for the treatment of metastatic PCa.
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| 10. |
- Linusson, Anna, et al.
(författare)
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Statistical molecular design of balanced compound libraries for QSAR modeling
- 2010
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Ingår i: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 17:19, s. 2001-2016
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Forskningsöversikt (refereegranskat)abstract
- A fundamental step in preclinical drug development is the computation of quantitative structure-activity relationship (QSAR) models, i.e. models that link chemical features of compounds with activities towards a target macromolecule associated with the initiation or progression of a disease. QSAR models are computed by combining information on the physicochemical and structural features of a library of congeneric compounds, typically assembled from two or more building blocks, and biological data from one or more in vitro assays. Since the models provide information on features affecting the compounds' biological activity they can be used as guides for further optimization. However, in order for a QSAR model to be relevant to the targeted disease, and drug development in general, the compound library used must contain molecules with balanced variation of the features spanning the chemical space believed to be important for interaction with the biological target. In addition, the assays used must be robust and deliver high quality data that are directly related to the function of the biological target and the associated disease state. In this review, we discuss and exemplify the concept of statistical molecular design (SMD) in the selection of building blocks and final synthetic targets (i.e. compounds to synthesize) to generate information-rich, balanced libraries for biological testing and computation of QSAR models.
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