| 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. |
- Albofetileh, Mehdi, et al.
(författare)
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Seaweed Proteins as a Source of Bioactive Peptides
- 2021
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 27:11, s. 1342 -1352
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Forskningsöversikt (refereegranskat)abstract
- Seaweeds have gained great attention as a vegetarian and sustainable marine source of protein which do not need irrigation, arable land and fertilization. Besides, seaweeds are considered as an untapped resource for discovering bioactive compounds with health benefits where bioactive peptides have shown outstanding potential. This review provides a detailed overview of available scientific knowledge on production methods, bioactivity and application of peptides from seaweed proteins. The emphasize is on the effects form seaweed varieties and peptide production condition on the bioactivity of the peptides and their potential health benefits. Bioactive properties of seaweed peptides including antioxidant, antihypertensive, antidiabetic, anti-inflammatory, anticancer activities and other potential health benefits have been discussed. It also covers current challenges and required future research and innovations for the successful application of seaweeds proteins as a sustainable source of bioactive peptides. Effects from seasonal variation of seaweed composition on the bioactivity of their peptides, difficulties in the extraction of proteins from seaweed complex structure, scalability and reproducibility of the developed methods for the production of bioactive peptides, the safety of the peptides are examples of highlighted challenges. Further studies on the bioavailability of the seaweed bioactive peptides and validation of the results in animal models and human trials are needed before their application as functional foods or pharmaceutical ingredients.
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| 3. |
- 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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| 4. |
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| 5. |
- Birnir, Bryndis, et al.
(författare)
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The impact of sub-cellular location and intracellular neuronal proteins on properties of GABA(A) receptors
- 2007
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:31, s. 3169-3177
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Tidskriftsartikel (refereegranskat)abstract
- Most studies of GABA(A) receptor accessory proteins have focused on trafficking, clustering and phosphorylation state of the channel-forming subunits and as a result a number of proteins and mechanisms have been identified that can influence the GABA(A) channel expression and function in the cell plasma membrane. In the light of a growing list of intracellular and transmembrane neuronal proteins shown to affect the fate, function and pharmacology of the GABA(A) receptors in neurons, the concept of what constitutes the native GABA(A) receptor complex may need to be re-examined. It is perhaps more appropriate to consider the associated proteins or some of them to be parts of the receptor channel complex in the capacity of ancillary proteins. Here we highlight some of the effects the intracellular environment has on the GABA-activated channel function and pharmacology. The studies demonstrate the need for co-expression of accessory proteins with the GABA(A) channel-forming subunits in heterologous expression systems in order to obtain the full repertoire of GABA(A) receptors characteristics recorded in the native neuronal environment. Further studies e.g. on gene-modified animal models are needed for most of the accessory proteins to establish their significance in normal physiology and in pathophysiology of neurological and psychiatric diseases. The challenge remains to elucidate the effects that the accessory proteins and processes (e.g. phosphorylation) plus the sub-cellular location have on the "fine-tuning" of the functional and pharmacological properties of the GABA(A) receptor channels.
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| 6. |
- 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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| 7. |
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| 8. |
- 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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| 9. |
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| 10. |
- El-Salhy, Magdy, 1951-
(författare)
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Triple treatment with octreotide, galanin and serotonin is a promising therapy for colorectal cancer
- 2005
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 11:16, s. 2107-2117
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Tidskriftsartikel (refereegranskat)abstract
- In patients with colorectal cancer, low levels of colonic somatostatin, galanin and serotonin have been found. Based on these findings, the effects of triple treatment with octreotide (a somatostatin analogue), galanin and serotonin on colorectal cancer has been studied. Triple therapy was found to reduce the volume and weight of both rat and human colon carcinoma in xenografts, apparently by necrosis, but also by reducing proliferation and expression of epidermal growth factor of cancer cells, and also by inducing apoptosis. It has been suggested that tumour necrosis results from ischemia in the tumour caused by a reduction in the tumour blood flow, a consequence of reduced number of tumour-feeding blood vessels and by constricting of tumour feeding arterioles. The effects of treating rat colorectal cancer using single, double and triple therapy with octreotide, galanin and serotonin were studied. Of these substances, galanin alone achieved a significant reduction in tumour-feeding blood vessels. Single and double regimes had some effect, but were not nearly so successful as triple treatment. The optimum treatment dose of triple therapy lies between 40 and 80 μg/kg/day, smaller doses had no effect on the tumours at all, while larger doses had no additional effect. The optimal administration route is continuous i.p. infusion, for 14 days. Triple therapy gave no obvious side effects, and had equivalent anti-tumour and therapeutic efficacy as standard treatment with 5-fluorouracil/leucovorin. Although this treatment appears to be a promising option, clinical trials need be conducted to establish whether it can be beneficial in clinical use. © 2005 Bentham Science Publishers Ltd.
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| 11. |
- Enlund, Mats, et al.
(författare)
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Rationale and Design of the CAN Study : An RCT of Survival after Propofol- or Sevoflurane-based Anesthesia for Cancer Surgery
- 2019
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Ingår i: Current pharmaceutical design. - : BENTHAM SCIENCE PUBL LTD. - 1381-6128 .- 1873-4286. ; 25:28, s. 3028-3033
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Tidskriftsartikel (refereegranskat)abstract
- Background: Based on animal data only, some clinicians have adopted pmpofol-based anesthesia for cancer surgery with the aim of increased survival.Objective: Our objective is to verify or refute the hypothesis that survival increases after cancer surgery with propofol compared with sevoflurane for anesthesia maintenance. This aim deserves a large-scale randomized study. The primary hypothesis is an absolute increase of minimum 5%-units in 1- and 5-year survival with propofol-based anesthesia for breast or colorectal cancer after radical surgery, compared with sevoflurane-based anesthesia.Method: Ethics and medical agency approvals were received and pre-study registrations at clinicaltrial.gov and EudraCT were made for our now ongoing prospective, randomized, open-label, multicenter study. A power analysis based on a retrospective study, including a safety margin for drop outs, resulted in a total requirement of 8,000 patients. The initial inclusion period constituted a feasibility phase with an emphasis on the functionality of the infrastructure at the contributing centers and at the monitoring organization, as well as on protocol adherence.Conclusion: The infrastructure and organization work smoothly at the different contributing centers. Protocol adherence is good, and the monitors are satisfied. We expect this trial to be able to either verify or refute that propofol is better than sevoflurane for cancer surgery.
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| 12. |
- 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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| 13. |
- 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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| 14. |
- Grzybowski, Andrzej, et al.
(författare)
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Endophthalmitis Prophylaxis in Cataract Surgery : Overview of Current Practice Patterns Around the World
- 2017
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Ingår i: Current pharmaceutical design. - : BENTHAM SCIENCE PUBL LTD. - 1381-6128 .- 1873-4286. ; 23:4, s. 565-573
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Forskningsöversikt (refereegranskat)abstract
- Background: Acute-onset postoperative endophthalmitis after cataract surgery remains a rare but important cause of visual loss. There is no global consensus regarding the optimal strategies for prophylaxis of endophthalmitis and practices vary substantially around the world, especially with respect to the use of intracameral antibiotics. The European Society of Cataract & Refractive Surgeons in a randomized clinical trial (2007) reported an approximately 5-fold reduction in endophthalmitis rates associated with the use of intracameral cefuroxime. Despite this report, the use of intracameral antibiotics has not been universally adopted. Methods: Various endophthalmitis prophylaxis patterns around the world (including the United States, Canada, Australia/New Zealand, Japan, China, India, Indonesia, South Africa, Argentina, Russia, Sweden and Mexico) are compared. Each contributing author was asked to provide similar information, including endophthalmitis rates based on published studies, current practice patterns, and in some cases original survey data. Various methods were used to obtain this information, including literature reviews, expert commentary, and some new survey data not previously published. Results: Many different practice patterns were reported from around the world, specifically with respect to the use of intracameral antibiotics. Conclusion: There is no worldwide consensus regarding endophthalmitis prophylaxis with cataract surgery.
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| 15. |
- Hellström, Ann, 1959, et al.
(författare)
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IGF-1 as a Drug for Preterm Infants : A Step-Wise Clinical Development
- 2017
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 23:38, s. 5964-5970
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Insulin-like growth factor 1 (IGF-1) is a mitogenic hormone involved in many processes such as growth, metabolism, angiogenesis and differentiation. After very preterm birth, energy demands increase while maternal supplies of nutrients and other factors are lost and the infant may become dependent on parenteral nutrition for weeks. Low postnatal IGF-1 concentrations in preterm infants are associated with poor weight gain, retinopathy of prematurity (ROP) and other morbidities. We will describe the process by which we aim to develop supplementation with recombinant human (rh) IGF-1 and its binding protein rhIGFBP-3 as a possible therapy to promote growth and maturation and reduce morbidities in extremely preterm infants.METHODS: In order to calculate a dose of IGF-1 tolerated by neonates, a pharmacokinetic study of transfusion with fresh frozen plasma was performed, which provided a relatively low dose of IGF-1, (on average 1.4 µg/kg), that increased serum IGF-1 to levels close to those observed in fetuses and preterm infants of similar GAs. Thereafter, a Phase I 3 hours IV infusion of rhIGF-1/rhIGFBP-3 was conducted in 5 infants, followed by a Phase II study with four sections (A-D). In the Phase II, sections A-D studies, time on infusion increased and younger gestational ages were included.RESULTS: IV infusion increased IGF-1 but with short half-life (0.5h) implying a need for continuous infusion. In order to obtain in utero levels of IGF-I, the dose was increased from 100 to 250 µg/kg/24 h and the infusion was prolonged from 3 weeks postnatal age until a postmenstrual age of 29 weeks and 6 days.CONCLUSION: The purpose has been to ensure high-quality research into the development of a new drug for preterm infants. We hope that our work will help to establish a new standard for the testing of medications for preterm infants.
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| 16. |
- Jekell, Andreas, et al.
(författare)
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Treatment of hypertensive left ventricular hypertrophy
- 2018
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 24:37, s. 4391-4396
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Forskningsöversikt (refereegranskat)abstract
- Background: The development and risk potential of hypertension-induced left ventricular (LV) hypertrophy has been well described in epidemiological studies. Regression of LV hypertrophy reduces cardiovascular morbidity and mortality. However, the best treatment strategy is still debated, as well as the appropriate blood pressure target in these patients. Objective: We here review the treatment of LV hypertrophy and the potential benefit on clinical outcomes, against a background of the epidemiology and pathophysiology. Results: Both hemodynamic and non-hemodynamic mechanisms contribute to hypertensive LV hypertrophy, which is characterized by an inappropriate myocardial fibrosis. Stringent blood pressure control reduces LV hypertrophy. Blockers of the renin-angiotensin-aldosterone system may have valuable effects on cardiac and electrophysiological remodelling beyond the effects of blood pressure reduction. Thus, they represent a cornerstone in the treatment of hypertensive LV hypertrophy, but most often other antihypertensive drug classes need to be added. Current guidelines indicate a blood pressure target in most patients with hypertensive LV hypertrophy of 120–130/80 mmHg. Conclusions: LV hypertrophy and myocardial fibrosis are important characteristics of hypertensive heart disease and associated with untoward prognosis. Regression of LV hypertrophy reduces cardiovascular morbidity and mortality. New drugs under development may add additional benefit.
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| 17. |
- 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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| 18. |
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| 19. |
- Karlsson, Miriam, et al.
(författare)
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New proposals for testing drugs with IKr-blocking activity to determine their teratogenic potential
- 2007
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:29, s. 2979-2988
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Forskningsöversikt (refereegranskat)abstract
- Drugs blocking the potassium current IKr, either as an intended pharmacologic effect (eg antiarrhythmics dofetilide and almokalant) or as an unwanted side-effect (eg antihistamine astemizole, propulsive drug cisapride, antidepressive drugs and macrolide antibiotics) are potential human teratogens. It is the contention of this paper that the existing repeat dose regimen used in teratology studies to fulfil regulatory requirements, does not properly identify the teratogenic risk of these drugs. Results from conventional studies for dofetilide and almokalant showed high rates of postimplantation embryonic death with few malformed fetuses. For astemizole and cisapride only embryonic death was seen. These latter results were not considered important because they occurred either in the presence of maternal toxicity and/or at high doses. Subsequent studies have shown that IKr-blockers are highly teratogenic when administered on single gestational days (GD) during a sensitive period of rat pregnancy (GD 10-14) when they induce a high incidence of stage-specific malformations. This teratogenic activity of astemizole and cisapride was missed in the original teratology studies. Mechanistically IKr-blockers cause bradycardia and arrhythmia of the embryonic heart and while an embryo may be able to survive a single day exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. With this review we suggest that new drugs identified at the preclinical stage of development as having IKr-blocking properties, should undergo more comprehensive teratology testing including single GD dosing and studies using embryo culture. This would further help identify and characterise their teratogenic potential.
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| 20. |
- 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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| 21. |
- Koussounadis, Antonis I., et al.
(författare)
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Analysis of Fish IL-1beta and Derived Peptide Sequences Indicates Conserved Structures with Species-Specific IL-1 Receptor Binding: Implications for Pharmacological Design
- 2004
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 10:31, s. 3857-3871
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Tidskriftsartikel (refereegranskat)abstract
- A large number of IL-1 protein sequences have become available recently from a range of vertebrate species and especially from bony fish. However, 3D structures are still only known for mammalian IL-1. In this review, we use a multiple sequence alignment of all published non-mammalian vertebrate IL-1beta proteins to locate the structurally important residues critical for maintaining the beta-trefoil fold and we investigate the degree to which functionally important residues involved in receptor binding are conserved across vertebrate species. We find that although there is a high level of variability of positions involved in receptor binding, the mode of binding and overall shape of the ligand-receptor complex is probably maintained. This implies that each species has evolved its own unique interleukin-1 signalling system through ligand-receptor co-evolution. Nonetheless, the IL-1beta processing mechanism in non-mammalian vertebrates remains unclear because, with the exception of three bony fish, all non-mammalian IL-1beta sequences discovered so far lack an ICE (Interleukin Converting Enzyme) cut site. The IL-1 system has become an important drug target because of its significance in inflammatory diseases. Research on peptides derived from IL-1beta has identified peptides that possess agonist activity in humans and in trout, and peptides with antagonist activity. The agonist peptides map to two distinct loop regions of IL-1beta that are known to interact with the flexible domain III of the corresponding receptor. Further analysis of the IL-1 system may prove useful in engineering IL-1 with improved features and in suggesting new avenues for therapeutic intervention.
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| 22. |
- Kushwaha, Sandeep Kumar
(författare)
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Recent Advances and Computational Approaches in Peptide Drug Discovery
- 2019
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 25, s. 3358-3366
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Forskningsöversikt (refereegranskat)abstract
- Background: Drug design and development is a vast field that requires huge investment along with a long duration for providing approval to suitable drug candidates. With the advancement in the field of genomics, the information about druggable targets is being updated at a fast rate which is helpful in finding a cure for various diseases.Methods: There are certain biochemicals as well as physiological advantages of using peptide-based therapeutics. Additionally, the limitations of peptide-based drugs can be overcome by modulating the properties of peptide molecules through various biomolecular engineering techniques. Recent advances in computational approaches have been helpful in studying the effect of peptide drugs on the biomolecular targets. Receptor - ligand-based molecular docking studies have made it easy to screen compatible inhibitors against a target. Furthermore, there are simulation tools available to evaluate stability of complexes at the molecular level. Machine learning methods have added a new edge by enabling accurate prediction of therapeutic peptides.Results: Peptide-based drugs are expected to take over many popular drugs in the near future due to their bio-safety, lower off-target binding chances and multifunctional properties.Conclusion: This article summarises the latest developments in the field of peptide-based therapeutics related to their usage, tools, and databases.
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| 23. |
- Lubberink, Mark
(författare)
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Kinetic models for measuring P-glycoprotein function at the blood-brain barrier with Positron Emission Tomography
- 2016
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 22:38, s. 5786-5792
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Tidskriftsartikel (refereegranskat)abstract
- P-glycoprotein function is associated with a number of neurodegenerative and psychiatric diseases as well as with pharmacoresistance to for example antiepileptic drugs. The ability to measure P-gp function in vivo would allow for an increased understanding of the mechanisms of disease and treatment. This review assesses the various approaches to in vivo quantification of P-gp function using currently available P-gp tracers and PET in humans. First, the use of compartment models, and their interpretation in terms of P-gp function at the blood-brain barrier, is discussed. Then, the methods that have been used to quantify PET data of the P-gp tracers [11C]verapamil, [11C]N-desmetyl-loperamide (dLop), [11C]laniquidar, [11C]phenytoin, [11C]tariquidar and [11C]elacridar are reviewed. In summary, the extraction of P-gp substrate PET tracers, which is their plasma to tissue rate constant K1 corrected for variations in regional cerebral blood flow, is generally considered to be the preferred measure of P-gp function.
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| 24. |
- 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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| 25. |
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| 26. |
- Meng, Ling-Yan, et al.
(författare)
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Cellulose-based Nanocarriers as Platforms for Cancer Therapy
- 2017
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Ingår i: Current pharmaceutical design. - : BENTHAM SCIENCE PUBL LTD. - 1381-6128 .- 1873-4286. ; 23:35, s. 5292-5300
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Forskningsöversikt (refereegranskat)abstract
- Cellulose is an important environmentally-friendly renewable polymer on the earth. Cellulose has been widely used as feedstocks for the synthesis of biomaterials, biofuels and biochemicals. Recently, cellulose and cellulose derivatives have received intense attention in biomedical applications, such as tissue engineering, scaffold, artificial blood vessel, skin grafts, artificial skin, drug carrier, and chronic skin diseases, many of which are somehow related to cancer therapy. In this mini-review, we focus on the up-to-date development of cellulose-based nanocarriers used for cancer therapy. Various cellulose-based nanocarriers such as bacterial cellulose (BC), cellulose acetate, microcrystalline cellulose, carboxymethyl cellulose, cellulose nanocrystals, cellulose nanofibrills, etc, are reviewed in terms of being used in drug delivery systems for cancer treatment. Different strategies for the synthesis of cellulose-based nanocarriers are summarized. Special attention is paid on the structure and properties of cellulose-based drug carriers for cancer therapy via some representative examples. Finally, the problems and future developments of these promising polymeric nanocarriers are raised and proposed.
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| 27. |
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| 28. |
- Nasr, Patrik, 1987-, et al.
(författare)
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Modifiers of Liver-Related Manifestation in the Course of NAFLD
- 2020
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Ingår i: Current pharmaceutical design. - : BENTHAM SCIENCE PUBL LTD. - 1381-6128 .- 1873-4286. ; 26:10, s. 1062-1078
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Forskningsöversikt (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease affecting approximately 25% of the global population. There is a strong association between the severity, of NAFLD and the components of the metabolic syndrome. NAFLD is also independently associated with cardiovascular disease and type 2 diabetes mellitus (T2DM). The progressive potential of non-alcoholic fatty liver disease (NAFLD) is indisputable today, and the histological spectrum of NAFLD ranges from isolated steatosis to nonalcoholic steatohepatitis (NASH), with risk of developing :fibrosis and subsequent cirrhosis and hepatocellular carcinoma. There is a substantial inter-patient variation in disease progression, therefore, this review will focus on potential modifiers of fibrosis progression, development of liver cirrhosis, decompensation and liver-related mortality. The potential drivers of disease progression that is discussed are; T2DM and Insulin Resistance, body weight, alcohol consumption, genetics (including HFE and alfa-1-antitrypsin) as well as histological features predictive of disease progression.
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| 29. |
- Nejabati, H. R., et al.
(författare)
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N1-Methylnicotinamide : Is it Time to Consider it as a Dietary Supplement for Athletes?
- 2022
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 28:10, s. 800-805
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Forskningsöversikt (refereegranskat)abstract
- Exercise is considered to be a “medicine” due to its modulatory roles in metabolic disorders, such as diabetes and obesity. The intensity and duration of exercise determine the mechanism of energy production by various tissues of the body, especially by muscles, in which the requirement for adenosine triphosphate (ATP) increases by as much as 100-fold. Naturally, athletes try to improve their exercise performance by dietary supplementation with, e.g., vitamins, metabolites, and amino acids. MNAM, as a vitamin B3 metabolite, reduc-es serum levels and liver contents of triglycerides and cholesterol, and induces lipolysis. It stimulates gluconeo-genesis and prohibits liver cholesterol and fatty acid synthesis through the expression of sirtuin1 (SIRT1). It seems that MNAM is not responsible for the actions of NNMT in the adipose tissues as MNAM inhibits the activity of NNMT in the adipose tissue and acts as an inhibitor of its activity. NNMT-MNAM axis is more activated in the muscles of individuals undergoing the high-volume-low-intensity exercise and caloric restriction. Therefore, MNAM could be an important myokine during exercise and fasting where it provides the required energy for muscles through the induction of lipolysis and gluconeogenesis in the liver and adipose tissues, respectively. Increased levels of MNAM in exercise and fasting led us to propose that the consumption of MNAM during training, especially endurance training, could boost exercise capacity and improve perfor-mance. Therefore, in this review, we shed light on the potential of MNAM as a dietary supplement in sports medicine.
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| 30. |
- Nilvebrant, Johan, et al.
(författare)
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Engineered Autonomous Human Variable Domains
- 2016
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers B.V. - 1381-6128 .- 1873-4286. ; 22:43, s. 6527-6537
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Forskningsöversikt (refereegranskat)abstract
- Background: The complex multi-chain architecture of antibodies has spurred interest in smaller derivatives that retain specificity but can be more easily produced in bacteria. Domain antibodies consisting of single variable domains are the smallest antibody fragments and have been shown to possess enhanced ability to target epitopes that are difficult to access using multidomain antibodies. However, in contrast to natural camelid antibody domains, human variable domains typically suffer from low stability and high propensity to aggregate. Methods: This review summarizes strategies to improve the biophysical properties of heavy chain variable domains from human antibodies with an emphasis on aggregation resistance. Several protein engineering approaches have targeted antibody frameworks and complementarity determining regions to stabilize the native state and prevent aggregation of the denatured state. Conclusion: Recent findings enable the construction of highly diverse libraries enriched in aggregation-resistant variants that are expected to provide binders to diverse antigens. Engineered domain antibodies possess unique advantages in expression, epitope preference and flexibility of formatting over conventional immunoreagents and are a promising class of antibody fragments for biomedical development.
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| 31. |
- Odoemelam, Chiemela S. S., et al.
(författare)
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Computational Investigation of Ligand Binding of Flavonoids in Cytochrome P450 Receptors
- 2022
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 28:45, s. 3637-3648
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The cytochrome P450 enzymes play a significant role in regulating cellular and physiological processes by activating endogenous compounds. They also play an essential role in the detoxification process of xenobiotics. Flavonoids belong to a class of polyphenols found in food, such as vegetables, red wine, beer, and fruits, which modulate biological functions in the body. Methods: The inhibition of CYP1A1 and CYP1B1 using nutritional sources has been reported as a strategy for cancer prevention. This study investigated the interactions of selected flavonoids binding to the cytochrome P450 enzymes (CYP1A1 and CYP1B1) and their ADMET properties in silico. From docking studies, our findings showed flavonoids, isorhamnetin and pedalitin, to have the strongest binding energies in the crystal structures 6DWM and 6IQ5. Results: The amino acid residues Asp 313 and Phe 224 in 6DWM interacted with all the ligands investigated, and Ala 330 in 6IQ5 interacted with all the ligands examined. The ligands did not violate any drug-likeness parameters. Conclusion: These data suggest roles for isorhamnetin and pedalitin as potential precursors for natural product-derived therapies.
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| 32. |
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| 33. |
- Oyarzun-Ampuero, Felipe, et al.
(författare)
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Nanoparticles for the Treatment of Wounds
- 2015
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers. - 1381-6128 .- 1873-4286. ; 21:29, s. 4329-4341
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Tidskriftsartikel (refereegranskat)
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- 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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| 38. |
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| 39. |
- Rostami, Elham, 1979-, et al.
(författare)
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Microdialysis in neurointensive care.
- 2004
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 10:18, s. 2145-2152
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Tidskriftsartikel (refereegranskat)abstract
- Microdialysis is a technique for sampling the chemistry of the interstitial fluid of tissues and organs in animal and man. It is minimally invasive and simple to perform in a clinical setting. Although microdialysis samples essentially all small molecular substances present in the interstitial fluid the use of microdialysis in neurointensive care has focused on markers of ischemia and cell damage. The lactate / pyruvate ratio is a well-known marker of changes in the redox state of cells caused by ischemia Glycerol is an integral component of cell membranes. Loss of energy due to ischemia eventually leads to an influx of calcium and a decomposition of cell membranes, which liberates glycerol into the interstitial fluid. Thus the lactate / pyruvate ratio and glycerol have become the most important markers of ischemia and cell membrane damage. While the primary insult at the site of the accident is beyond our control, secondary insults during intensive care should be avoided by all means. Therefore, the single most important finding from microdialysis studies is the dramatic difference in the vulnerability of the penumbra surrounding a lesion as compared to normal brain tissue allowing early detection of secondary insults after traumatic brain injury as well as the onset of vasospasm after subarachnoid hemorrhage.
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| 40. |
- Rubboli, Guido, et al.
(författare)
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Management of antiepileptic treatment after epilepsy surgery - practices and problems.
- 2017
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1873-4286 .- 1381-6128. ; 23:37, s. 5749-5759
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Forskningsöversikt (refereegranskat)abstract
- Although epilepsy surgery is a recognized treatment option for drug-resistant epilepsies since several decades, the management of antiepileptic drugs (AEDs) after successful surgery still remains one of the most difficult and unsolved therapeutic challenges. Indeed, no systematic controlled trials have been specifically conducted so far and no consensus or standardized guidelines regarding postsurgical drug discontinuation policy and procedures are available.In this paper, we aim to provide an updated overview on the the present knowledge on this topic, which is based mainly on retrospective studies reporting practices used in individual centers.Currently available data suggest that: 1) rate of seizure recurrence appears to be higher in patients undergoing early (before 6 months or 9 months according to different studies) AED withdrawal; 2) seizures that recur during AED tapering are easier to control than unprovoked postoperative seizure relapses; 3) there is no evidence to support negative long-term implications on seizure outcomes in patients who attempted AED withdrawal. In the pediatric age group, shorter intervals from surgery to AED reduction and to complete AED discontinuation predict seizure relapse during or after AED reduction/withdrawal. However, this does not correlate with the chances of regaining seizure freedom after drug reintroduction.Carefully conducted prospective longitudinal studies and randomized controlled trials are warranted to establish the correct post-surgical pharmacologic treatment and to identify the best candidates for AEDs discontinuation.
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| 41. |
- 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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| 42. |
- Severance, Emily G., et al.
(författare)
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The Gut Microbiota and the Emergence of Autoimmunity : Relevance to Major Psychiatric Disorders
- 2016
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 22:40, s. 6076-6086
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Forskningsöversikt (refereegranskat)abstract
- Background: Autoimmune phenotypes are prevalent in major psychiatric disorders. Disequilibria of cellular processes occurring in the gastrointestinal (GI) tract likely contribute to immune dysfunction in psychiatric disorders. As the venue of a complex community of resident microbes, the gut in a homeostatic state equates with a functional digestive system, cellular barrier stability and properly regulated recognition of self and non-self antigens. When gut processes become disrupted as a result of environmental or genetic factors, autoimmunity may ensue. Methods: Here, we review the issues pertinent to autoimmunity and the microbiome in psychiatric disorders and show that many of the reported immune risk factors for the development of these brain disorders are in fact related and consistent with dysfunctions occurring in the gut. We review the few human microbiome studies that have been done in people with psychiatric disorders and supplement this information with mechanistic data gleaned from experimental rodent studies. Results: These investigations demonstrate changes in behavior and brain biochemistry directly attributable to alterations in the gut microbiome. We present a model by which autoantigens are produced by extrinsically-derived food and microbial factors bound to intrinsic components of the gut including receptors present in the enteric nervous system. Conclusion: This new focus on examining activities outside of the CNS for relevance to the etiology and pathophysiology of psychiatric disorders may require new modalities or a re-evaluation of pharmaceutical targets found in peripheral systems.
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| 43. |
- Sharma, Hari Shanker, et al.
(författare)
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Drugs of abuse-induced hyperthermia, blood-brain barrier dysfunction and neurotoxicity : neuroprotective effects of a new antioxidant compound H-290/51
- 2007
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:18, s. 1903-1923
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Forskningsöversikt (refereegranskat)abstract
- The psychostimulants, morphine and methamphetamine are well known drugs of abuse that induce brain pathology and/or neurodegeneration resulting in a huge burden on our society. The possible mechanisms of psychostimulants induced neuropathology and neurodegeneration are still not well known. The drugs of abuse results in profound hyperthermia and widespread alterations in neurochemical metabolism in the central nervous system (CNS). It appears that psychostimulants induced hyperthermia and/or release of neurochemicals influence the blood-brain barrier (BBB) dysfunction leading to brain pathology. The drugs of abuse also induce oxidative stress resulting in generation of free radicals and lipid peroxidation. Thus, further research is needed to understand the basic function of BBB disruption and temperature regulation by psychostimulants and to modify them pharmacologically to attenuate brain dysfunction and neuropathology. This review is focused on the problems of morphine and methamphetamine induced hyperthermia and their effects on breakdown of the BBB function leading to brain damage. Works done in our laboratory suggest that hyperthermia caused by these drugs is responsible for BBB disruption and neurodegeneration. This hypothesis is further supported by our observation that pretreatment with a portent antioxidant compound H-290/51 attenuates the BBB disruption and induces marked neuroprotection following morphine induced withdrawal and methamphetamine induced neurotoxicity. The possible mechanisms and functional significance of these findings are discussed.
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| 44. |
- Sharma, Hari Shanker
(författare)
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Neurodegeneration and neuroregeneration : recent advancements and future perspectives.
- 2007
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:18, s. 1825-1827
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Tidskriftsartikel (refereegranskat)abstract
- Neuroprotection: Non-Neural Cells Regulate Neuronal Functions The term “Neuroprotection” normally denotes rescue of nerve cells. However, the non-neural cells, i.e., glial cells and endothelial cells are equally important for brain function in normal and in pathological conditions [1,2]. The number of glial cells and endothelial cells far exceeds the number of neural cells in the CNS [2,3]. In spite of this fact, most attention is still focused to rescue nerve cells following CNS injuries and the role of non-neural cells in neurodegeneration or neuroprotection is largely ignored. Thus, the term “neuroprotection” is normally misleading as neurons are in the minority in the CNS and their function depends on the survival of non-neural cells and vice versa. To restore the normal function of the CNS by pharmacological manipulation, revival of glial cells and endothelial cell functions are equally important [4-6]. The nerve cell function is largely dependent on the normal endothelial cell and glial function. Thus, it is imperative that in pathological conditions, reducing damage to endothelial cells and/or glial cells by pharmacological agents will improve nerve cell function. Alternatively, glial cells, endothelial cells are all working to maintain and regulate neuronal function in health and disease [7,8]. Taken together, it appears that both the neural and non-neural components of the CNS are working in synergy for maintaining normal brain function and alterations in any neural or non-neural component will have severe impact on CNS structure and function. Blood-Brain vs. Brain Blood Barriers Our CNS is well equipped with the blood-brain barrier that is anatomically located within the endothelial cells of the brain microvasculature [1]. It is assumed that both the luminal and the abluminal cell membranes of the endothelium are equally “tight” to maintain an effective barrier between blood to brain and brain to blood [1,2]. Interestingly, the endothelial cell function and membrane transport from brain to blood (brain-blood barrier) in relation to neurodegeneration and neurorepair mechanisms are still largely ignored [see7,8]. Thus, it is still unclear whether luminal barrier disruption always accompanied with identical damage to the abluminal barrier function. However, there are reasons to believe that when luminal membrane is permeable, the abluminal side is also showing some alteration in the membrane function. A direct evidence to support or reject this hypothesis is still lacking. Studies carried out in our laboratory suggest that hyperthermia induced breakdown of the blood-brain barrier is also associated with a leaky brain blood-barrier [5,9]. Thus, serotonin transport occurs from brain to the blood causing a massive accumulation of the amine in the circulation leading to a generalized and widespread disruption of the blood-brain barrier [9]. This large increase in plasma serotonin is largely prevented by destruction of the serotoninergic neurons into the brain [see 5,9]. This treatment did not allow brain serotonin to increase and thus, the plasma serotonin concentration is much lower resulting in a minor breakdown of the blood-brain barrier in hyperthermia [5]. This suggests that various endogenous substances, e.g., cytokines, growth factors, growth hormone etc. are released from brain in extra quantity following injury that could be transported into the blood stream to have a generalized effect on the cerebral circulation and/or brain function. However, this is entirely a new subject and requires additional investigation in details to achieve better neuroprotection in future. In this volume, the term “Neuroprotection” is employed in its widest sense to include protection of all the “neural” and “nonneural” components of the CNS. This issue highlights the role of non-neural cells; especially the function of endothelial cells and its surrounding glial cells in neurodegeneration and repair process.......
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| 45. |
- Sharma, Hari Shanker, et al.
(författare)
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Neuroprotective effects of melanocortins in CNS injury
- 2007
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:19, s. 1929-1941
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Forskningsöversikt (refereegranskat)abstract
- New compounds having affinity to various melanocortin receptors have recently been identified as possible neuroprotective agents. This review is focused on the role of neuroprotective effects of melanocortins in CNS injury and repair mechanisms. Using selective non-peptidic compounds with varying affinity to melanocortin receptors, our laboratory has shown their anti-edematous effects in the spinal cord injury. This effect of the compounds is related with their ability to attenuate blood-spinal cord barrier permeability. The functional significance and possible therapeutic strategies of these compounds in CNS injury are discussed.
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| 46. |
- Sharma, Hari Shanker
(författare)
-
Neurotrophic factors in combination : a possible new therapeutic strategy to influence pathophysiology of spinal cord injury and repair mechanisms
- 2007
-
Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:18, s. 1841-1874
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Tidskriftsartikel (refereegranskat)abstract
- Several neurotrophic factors are known to induce neuroprotection in traumatic injuries to the central nervous system (CNS). However, many neurotrophins are unable to attenuate cell death following CNS injuries. New data generated in our laboratory show that a suitable combination of neurotrophic factors may enhance the neuroprotective efficacy of neurotrophins on cell and tissue injury and improve sensory motor functions. This novel aspect of neurotrophins treatment in combination in spinal cord injury (SCI) induced behavioral dysfunctions and spinal cord pathology is examined in a rat model. Our investigations suggest that a suitable combination of neurotrophins will attenuate both neural and non-neural (glial cells and endothelial cells) damage in SCI leading to enhanced neuroprotection. The possible cellular and molecular mechanisms of synergistic effects of some neurotrophins in combination are still speculative and require further investigation.
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| 47. |
- Sohel, Md, et al.
(författare)
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Chemotherapeutic Activities of Dietary Phytoestrogens against Prostate Cancer : From Observational to Clinical Studies
- 2022
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Ingår i: Current pharmaceutical design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 28:19, s. 1561-1580
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Forskningsöversikt (refereegranskat)abstract
- Prostate cancer remains one of the most frequent and deadliest malignancies in males, where the rate of disease progression is closely associated with the type of dietary intake, specifically a Western-style diet. Indeed intake of the Asian diet, which contains abundant phytoestrogens, is inversely correlated with a higher risk of prostate cancer, suggesting a chemoprotective effect of phytoestrogen against cancer progression. Although the role of phytoestrogens in cancer treatment has been well documented, their impact on prostate cancer is not well understood. Therefore, the present review discusses the possible chemopreventive effect of phytoestrogens, emphasizing their efficacy at the different stages of carcinogenesis. Furthermore, phytoestrogens provide a cytoprotective effect in conventional chemotherapy and enhance chemosensitivity to tumor cells, which have also been discussed. This compilation provides a solid basis for future research on phytoestrogens as a promising avenue for anticancer drug development and also recommends these beneficiary compounds in the daily diet to manage and prevent prostate cancer.
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| 48. |
- 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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| 49. |
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| 50. |
- 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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