| 1. |
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| 2. |
- Albinsson, Sebastian, et al.
(författare)
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Targeting smooth muscle microRNAs for therapeutic benefit in vascular disease.
- 2013
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 75:April,22, s. 28-36
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Forskningsöversikt (refereegranskat)abstract
- In view of the bioinformatic projection that a third of all protein coding genes and essentially all biological pathways are under control of microRNAs (miRNAs), it is not surprising that this class of small RNAs plays roles in vascular disease progression. MiRNAs have been shown to be involved in cholesterol turnover, thrombosis, glucose homeostasis and vascular function. Some miRNAs appear to be specific for certain cells, and the role that such cell-specific miRNAs play in vascular disease is only beginning to be appreciated. A notable example is the miR-143/145 cluster which is enriched in mature and highly differentiated smooth muscle cells (SMCs). Here we outline and discuss the recent literature on SMC-expressed miRNAs in major vascular diseases, including atherosclerosis, neointima formation, aortic aneurysm formation, and pulmonary arterial hypertension. Forced expression of miR-145 emerges as a promising strategy for reduction and stabilization of atherosclerotic plaques as well as for reducing neointimal hyperplasia. It is concluded that if obstacles in the form of delivery and untoward effects of antimirs and mimics can be overcome, the outlook for targeting of SMC-specific miRNAs for therapeutic benefit in vascular disease is bright.
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| 3. |
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| 4. |
- Chen, Yihong, et al.
(författare)
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Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular repair responses and angiogenesis
- 2024
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Ingår i: Pharmacological Research. - 1096-1186. ; 205
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Tidskriftsartikel (refereegranskat)abstract
- The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.
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| 5. |
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| 6. |
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| 7. |
- Dludla, Phiwayinkosi V., et al.
(författare)
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Uncoupling proteins as a therapeutic target to protect the diabetic heart
- 2018
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 137, s. 11-24
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Forskningsöversikt (refereegranskat)abstract
- Myocardial remodeling and dysfunction caused by accelerated oxidative damage is a widely reported phenomenon within a diabetic state. Altered myocardial substrate preference appears to be the major cause of enhanced oxidative stress-mediated cell injury within a diabetic heart. During this process, exacerbated free fatty acid flux causes an abnormal increase in mitochondrial membrane potential leading to the overproduction of free radical species and subsequent cell damage. Uncoupling proteins (UCPs) are expressed within the myocardium and can protect against free radical damage by modulating mitochondrial respiration, leading to reduced production of reactive oxygen species. Moreover, transgenic animals lacking UCPs have been shown to be more susceptible to oxidative damage and display reduced cardiac function when compared to wild type animals. This suggests that tight regulation of UCPs is necessary for normal cardiac function and in the prevention of diabetes-induced oxidative damage. This review aims to enhance our understanding of the pathophysiological mechanisms relating to the role of UCPs in a diabetic heart, and further discuss known pharmacological compounds and hormones that can protect a diabetic heart through the modulation of UCPs.
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| 8. |
- El-Seedi, Hesham R., et al.
(författare)
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Cardenolides : Insights from chemical structure and pharmacological utility
- 2019
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Ingår i: Pharmacological Research. - : Academic Press. - 1043-6618 .- 1096-1186. ; 141, s. 123-175
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac glycosides (CGs) are a class of naturally occurring steroid-like compounds, and members of this class have been in clinical use for more than 1500 years. They have been used in folk medicine as arrow poisons, abortifacients, heart tonics, emetics, and diuretics as well as in other applications. The major use of CGs today is based on their ability to inhibit the membrane-bound Na + /K + -ATPase enzyme, and they are regarded as an effective treatment for congestive heart failure (CHF), cardiac arrhythmia and atrial fibrillation. Furthermore, increasing evidence has indicated the potential cytotoxic effects of CGs against various types of cancer. In this review, we highlight some of the structural features of this class of natural products that are crucial for their efficacy, some methods of isolating these compounds from natural resources, and the structural elucidation tools that have been used. We also describe their physicochemical properties and several modern biotechnological approaches for preparing CGs that do not require plant sources.
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| 9. |
- Eussen, Simone R. B. M., et al.
(författare)
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Simultaneous intake of oat bran and atorvastatin reduces their efficacy to lower lipid levels and atherosclerosis in LDLr-/- mice
- 2011
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 64:1, s. 36-43
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Tidskriftsartikel (refereegranskat)abstract
- The present study aimed to investigate the effects of separate and simultaneous dietary intake of atorvastatin (ATO) and the soluble fiber oat bran on serum and hepatic lipid levels and the degree of atherosclerosis. Ninety female LDL-receptor-deficient (LDLr-/-) mice were fed a Western-type diet containing either low dose (0.0025%), high dose (0.01%) or no ATO, with or without oat bran (27%) (n = 15 per group) for 16 weeks. Both ATO and oat bran were effective in reducing serum total cholesterol levels (low ATO: -5.48, high ATO: -9.12, oat bran: -3.82 mmol/l, compared to control (no ATO/no oat bran), all p < 0.0001). When oat bran was added to a low dose ATO, the cholesterol-lowering effects of this combination were 50% smaller compared to the low dose ATO diet alone (between-group difference: 2.77 mmol/l, p = 0.002), whereas total cholesterol decreased to a similar extent in the groups fed a high dose ATO, with or without oat bran (between-group difference: 1.10 mmol/l, p = 0.21). Serum LDL- and HDL-cholesterol, triglycerides, hepatic lipid levels and atherosclerotic lesion development showed a similar pattern. In conclusion, the efficacy of oat bran and atorvastatin to lower lipid levels and atherosclerosis is reduced after simultaneous intake. We hypothesize that oat bran inhibits the intestinal absorption of atorvastatin, and consequently its cholesterol-lowering effects. The effects are likely dependent on the type of statin and dietary fiber, and on the relative timing of intake of the statin and the dietary fiber. Future studies should focus on these aspects to provide further insight into the exact mechanism of this food-drug interaction. (C) 2011 Elsevier Ltd. All rights reserved.
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| 10. |
- Fredin, Maria Fritsch, 1970, et al.
(författare)
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The application and relevance of ex vivo culture systems for assessment of IBD treatment in murine models of colitis
- 2008
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 58:3-4, s. 222-231
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the relevance of mouse ex vivo cultures as a first screening model for new therapeutic agents of Inflammatory Bowel Disease (IBD). Two murine models (dextran sodium sulphate (DSS)-induced colitis and Gαi2-deficient mice) and two anti-inflammatory agents (methyl-prednisolone and the proteasome inhibitor MG132) were evaluated. The in vivo effects of methyl-prednisolone were assessed in both models. Ex vivo colonic tissue from both mouse models were cultured in the presence or absence of the drugs and TaqMan Low-Density arrays were used to assess the regulation of inflammatory genes before and after drug treatment. Colitis induced a similar inflammatory gene profile in both mouse models in in vivo studies and in ex vivo cultures. The differences encountered reflected the different phases of colitis in the models, e.g. innate cytokine/chemokine profile in the DSS model and T cell related markers in Gαi2-deficient mice. After steroid treatment, a similar pattern of genes was suppressed in the two mouse models. We confirmed the suppression of inflammatory gene expression for IL-1β, IL-6 and iNOS in ex vivo and in vivo colons from both mouse models by quantitative RT-PCR. Importantly, the inflammatory responses in the murine ex vivo culture system reflected the in vivo response in the inflamed colonic tissue as assessed by changes in inflammatory gene expression, suggesting that the murine culture system can be used for validation of future IBD therapies.
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| 11. |
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| 12. |
- Hilscher, Markus M., 1987-, et al.
(författare)
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The alpha2 nicotinic acetylcholine receptor, a subunit with unique and selective expression in inhibitory interneurons associated with principal cells
- 2023
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Ingår i: Pharmacological Research. - : Elsevier. - 1043-6618 .- 1096-1186. ; 196
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Tidskriftsartikel (refereegranskat)abstract
- Nicotinic acetylcholine receptors (nAChRs) play crucial roles in various human disorders, with the α7, α4, α6, and α3-containing nAChR subtypes extensively studied in relation to conditions such as Alzheimer's disease, Parkinson's disease, nicotine dependence, mood disorders, and stress disorders. In contrast, the α2-nAChR subunit has received less attention due to its more restricted expression and the scarcity of specific agonists and antagonists for studying its function. Nevertheless, recent research has shed light on the unique expression pattern of the Chrna2 gene, which encodes the α2-nAChR subunit, and its involvement in distinct populations of inhibitory interneurons. This review highlights the structure, pharmacology, localization, function, and disease associations of α2-containing nAChRs and points to the unique expression pattern of the Chrna2 gene and its role in different inhibitory interneuron populations. These populations, including the oriens lacunosum moleculare (OLM) cells in the hippocampus, Martinotti cells in the neocortex, and Renshaw cells in the spinal cord, share common features and contribute to recurrent inhibitory microcircuits. Thus, the α2-nAChR subunit's unique expression pattern in specific interneuron populations and its role in recurrent inhibitory microcircuits highlight its importance in various physiological processes. Further research is necessary to uncover the comprehensive functionality of α2-containing nAChRs, delineate their specific contributions to neuronal circuits, and investigate their potential as therapeutic targets for related disorders.
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| 13. |
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| 14. |
- Johnsen, J. I., et al.
(författare)
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Molecular mechanisms and therapeutic targets in neuroblastoma
- 2018
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 131, s. 164-176
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is the most common extracranical tumor of childhood and the most deadly tumor of infancy. It is characterized by early age onset and high frequencies of metastatic disease but also the capacity to spontaneously regress. Despite intensive therapy, the survival for patients with high-risk neuroblastoma and those with recurrent or relapsed disease is low. Hence, there is an urgent need to develop new therapies for these patient groups. The molecular pathogenesis based on high-throughput omics technologies of neuroblastoma is beginning to be resolved which have given the opportunity to develop personalized therapies for high-risk patients. Here we discuss the potential of developing targeted therapies against aberrantly expressed molecules detected in sub-populations of neuroblastoma patients and how these selected targets can be drugged in order to overcome treatment resistance, improve survival and quality of life for these patients and also the possibilities to transfer preclinical research into clinical testing. (C) 2018 The Authors
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| 15. |
- Katsiki, Niki, et al.
(författare)
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Statin therapy in athletes and patients performing regular intense exercise - Position paper from the International Lipid Expert Panel (ILEP)
- 2020
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Ingår i: Pharmacological Research. - : Elsevier. - 1043-6618 .- 1096-1186. ; 155
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Tidskriftsartikel (refereegranskat)abstract
- Acute and chronic physical exercises may enhance the development of statin-related myopathy. In this context, the recent (2019) guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) for the management of dyslipidemias recommend that, although individuals with dyslipidemia should be advised to engage in regular moderate physical exercise (for at least 30 min daily), physicians should be alerted with regard to myopathy and creatine kinase (CK) elevation in statin-treated sport athletes. However it is worth emphasizing that abovementioned guidelines, previous and recent ESC/EAS consensus papers on adverse effects of statin therapy as well as other previous attempts on this issue, including the ones from the International Lipid Expert Panel (ILEP), give only general recommendations on how to manage patients requiring statin therapy on regular exercises. Therefore, these guidelines in the form of the Position Paper are the first such an attempt to summary existing, often scarce knowledge, and to present this important issue in the form of step-by-step practical recommendations. It is critically important as we might observe more and more individuals on regular exercises/athletes requiring statin therapy due to their cardiovascular risk.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
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| 20. |
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| 21. |
- Luo, Jinhai, et al.
(författare)
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Critical review on anti-obesity effects of phytochemicals through Wnt/β-catenin signaling pathway
- 2022
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 184
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Forskningsöversikt (refereegranskat)abstract
- Phytochemicals have been used as one of the sources for the development of anti-obesity drugs. Plants are rich in a variety of bioactive compounds including polyphenols, saponins and terpenes. Phytochemicals inhibit adipocyte differentiation by inhibiting the transcription and translation of adipogenesis transcription factors such as C/EBPα and PPARγ. It has been proved that phytochemicals inhibit the genes and proteins associated with adipogenesis and lipid accumulation by activating Wnt/β-catenin signaling pathway. The activation of Wnt/β-catenin signaling pathway by phytochemicals is multi-target regulation, including the regulation of pathway critical factor β-catenin and its target gene, the downregulation of destruction complex, and the up-regulation of Wnt ligands, its cell surface receptor and Wnt antagonist. In this review, the literature on the anti-obesity effect of phytochemicals through Wnt/β-catenin signaling pathway is collected from Google Scholar, Scopus, PubMed, and Web of Science, and summarizes the regulation mechanism of phytochemicals in this pathway. As one of the alternative methods of weight loss drugs, Phytochemicals inhibit adipogenesis through Wnt/β-catenin signaling pathway. More progress in relevant fields may pose phytochemicals as the main source of anti-obesity treatment.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Mukaida, Saori, et al.
(författare)
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Adrenoceptors promote glucose uptake into adipocytes and muscle by an insulin-independent signaling pathway involving mechanistic target of rapamycin complex 2
- 2017
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 116, s. 87-92
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Tidskriftsartikel (refereegranskat)abstract
- Uptake of glucose into skeletal muscle and adipose tissue plays a vital role in metabolism and energy balance. Insulin released from beta-islet cells of the pancreas promotes glucose uptake in these target tissues by stimulating translocation of CLUT4 transporters to the cell surface. This process is complex, involving signaling proteins including the mechanistic (or mammalian) target of rapamycin (mTOR) and Akt that intersect with multiple pathways controlling cell survival, growth and proliferation. mTOR exists in two forms, mTOR complex 1 (mTORC1), and mTOR complex 2 (mTORC2). mTORC1 has been intensively studied, acting as a key regulator of protein and lipid synthesis that integrates cellular nutrient availability and energy balance. Studies on mTORC2 have focused largely on its capacity to activate Akt by phosphorylation at Ser473, however recent findings demonstrate a novel role for mTORC2 in cellular glucose uptake. For example, agonists acting at beta(2)-adrenoceptors (ARs) in skeletal muscle or beta(3)-ARs in brown adipose tissue increase glucose uptake in vitro and in vivo via mechanisms dependent on mTORC2 but not Akt. In this review, we will focus on the signaling pathways downstream of beta-ARs that promote glucose uptake in skeletal muscle and brown adipocytes, and will highlight how the insulin and adrenergic pathways converge and interact in these cells. The identification of insulin-independent mechanisms that promote glucose uptake should facilitate novel treatment strategies for metabolic disease.
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| 26. |
- Nicolussi, Simon, et al.
(författare)
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Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice
- 2014
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 80, s. 52-65
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Tidskriftsartikel (refereegranskat)abstract
- High-content screening led to the identification of the N-isobutylamide guineensine from Piper nigrum as novel nanomolar inhibitor (EC50= 290 nM) of cellular uptake of the endocannabinoid anandamide (AEA). Noteworthy, guineensine did not inhibit endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) nor interact with cannabinoid receptors or fatty acid binding protein 5 (FABP5), a major cytoplasmic AEA carrier. Activity-based protein profiling showed no inhibition of serine hydrolases. Guineensine also inhibited the cellular uptake of 2-arachidonoylglycerol (2-AG). Preliminary structure-activity relationships between natural guineensine analogs indicate the importance of the alkyl chain length interconnecting the pharmacophoric isobutylamide and benzodioxol moieties for AEA cellular uptake inhibition. Guineensine dose-dependently induced cannabimimetic effects in BALB/c mice shown by strong catalepsy, hypothermia, reduced locomotion and analgesia. The catalepsy and analgesia were blocked by the CBI receptor antagonist rimonabant (SR141716A). Guineensine is a novel plant natural product which specifically inhibits endocannabinoid uptake in different cell lines independent of FAAH. Its scaffold may be useful to identify yet unknown targets involved in endocannabinoid transport.
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| 27. |
- Nordström, Anders
(författare)
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Hydroxycarboxylic acid receptor 3 and GPR84-Two metabolite-sensing G protein-coupled receptors with opposing functions in innate immune cells & nbsp
- 2022
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 176
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Tidskriftsartikel (refereegranskat)abstract
- G protein-coupled receptors (GPCRs) are key regulatory proteins of immune cell function inducing signaling in response to extracellular (pathogenic) stimuli. Although unrelated, hydroxycarboxylic acid receptor 3 (HCA(3)) and GPR84 share signaling via G alpha(i/o) proteins and the agonist 3-hydroxydecanoic acid (3HDec). Both receptors are abundantly expressed in monocytes, macrophages and neutrophils but have opposing functions in these innate immune cells. Detailed insights into the molecular mechanisms and signaling components involved in immune cell regulation by GPR84 and HCA(3) are still lacking. Here, we report that GPR84-mediated pro-inflammatory signaling depends on coupling to the hematopoietic cell-specific G alpha(15) protein in human macro-phages, while HCA(3) exclusively couples to G alpha(i) protein. We show that activated GPR84 induces G alpha(15)-dependent ERK activation, increases intracellular Ca2+ and IP3 levels as well as ROS production. In contrast, HCA(3) activation shifts macrophage metabolism to a less glycolytic phenotype, which is associated with anti-inflammatory responses. This is supported by an increased release of anti-inflammatory IL-10 and a decreased secretion of pro-inflammatory IL-1 beta. In primary human neutrophils, stimulation with HCA(3) agonists counteracts the GPR84-induced neutrophil activation. Our analyses reveal that 3HDec acts solely through GPR84 but not HCA(3) activation in macrophages. In summary, this study shows that HCA(3) mediates hyporesponsiveness in response to metabolites derived from dietary lactic acid bacteria and uncovers that GPR84, which is already targeted in clinical trials, promotes pro-inflammatory signaling via G alpha(15) protein in macrophages.
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| 28. |
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| 29. |
- Poornima, Paramasivan, et al.
(författare)
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Network pharmacology of cancer : From understanding of complex interactomes to the design of multi-target specific therapeutics from nature
- 2016
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 111, s. 290-302
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Tidskriftsartikel (refereegranskat)abstract
- Despite massive investments in drug research and development, the significant decline in the number of new drugs approved or translated to clinical use raises the question, whether single targeted drug discovery is the right approach. To combat complex systemic diseases that harbour robust biological networks such as cancer, single target intervention is proved to be ineffective. In such cases, network pharmacology approaches are highly useful, because they differ from conventional drug discovery by addressing the ability of drugs to target numerous proteins or networks involved in a disease. Pleiotropic natural products are one of the promising strategies due to their multi-targeting and due to lower side effects. In this review, we discuss the application of network pharmacology for cancer drug discovery. We provide an overview of the current state of knowledge on network pharmacology, focus on different technical approaches and implications for cancer therapy (e.g. polypharmacology and synthetic lethality), and illustrate the therapeutic potential with selected examples green tea polyphenolics, Eleutherococcus senticosus, Rhodiola rosea, and Schisandra chinensis). Finally, we present future perspectives on their plausible applications for diagnosis and therapy of cancer.
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| 30. |
- Previtali, Stefano C., et al.
(författare)
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Rimeporide as a first- in-class NHE-1 inhibitor : Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy
- 2020
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 159
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Tidskriftsartikel (refereegranskat)abstract
- Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide's anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6-11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies.
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| 31. |
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| 32. |
- Sabetsky, Vladimir, et al.
(författare)
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Insulin : A new era for an old hormone
- 2010
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 61:1, s. 1-4
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Tidskriftsartikel (refereegranskat)abstract
- All forms of diabetes have been treatable since insulin became medically available in 1921. While insulin alone produces a substantial reduction in blood-glucose levels and is thus the mainstay of treating type-1 diabetes, today's peroral agents used in treating type-2 diabetes struggle to achieve satisfactory clinical results in the absence of endogenous or exogeneous insulin. Emerging evidence suggests that insulin may not only produce symptomatic effects; recent data suggest that insulin may stimulate beta-cell recovery. In fact, short-term insulin therapy appears to result in long-term improvement in blood-glucose control, especially when administered in early stages of type-2 diabetes. During the last decade the pharmaceutical industry has largely failed to introduce new agents that can fundamentally improve the course of diabetes and the safety of artificial insulin analogs is undergoing thorough investigation. in contrast, new delivery approaches that present natural recombinant insulin to the enterohepatic circulation holds the promise of radically improving the treatment of type-2 diabetes.
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| 33. |
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| 34. |
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Sun, Yongxin, et al.
(författare)
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Pravastatin inhibits pro-inflammatory effects of Alzheimer's peptide Abeta(1-42) in glioma cell culture in vitro.
- 2003
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Ingår i: Pharmacological Research. - 1096-1186 .- 1043-6618. ; 47:2, s. 119-126
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Tidskriftsartikel (refereegranskat)abstract
- Statins are known to exert a number of biological effects apart from reducing cholesterol synthesis. The results of recent studies indicate that patients treated with pravastatin have a lower prevalence of diagnosed Alzheimer’s disease (AD). These observations prompted us to examine the effects of pravastatin on Alzheimer’s peptide (Aβ1–42)-induced pro-inflammatory activation in the human glioma cell line in vitro. Cells alone or cells pre-treated with pravastatin (0.1 mg ml−1) for 24 h were stimulated with 5 μM of freshly dissolved Aβ1–42 for the next 24 h. The pre-treatment of cells with pravastatin diminished the capacity of Aβ to induce metalloproteinases, cytokine IL-6 and free radical levels. Although both pravastatin and Aβ1–42 separately increased PPARγ activity, the combination of Aβ1–42 and pravastatin resulted in no effect on PPARγ expression. These data indicate that soluble forms of Aβ1–42, which are a potent stimulus of pro-inflammatory activation of glioma cells in vitro, could be a good target for pravastatin.
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| 39. |
- Teerlink, Tom, et al.
(författare)
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Cellular ADMA : regulation and action.
- 2009
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 60:6, s. 448-460
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Forskningsöversikt (refereegranskat)abstract
- Asymmetric (N(G),N(G)) dimethylarginine (ADMA) is present in plasma and cells. It can inhibit nitric oxide synthase (NOS) that generates nitric oxide (NO) and cationic amino acid transporters (CATs) that supply intracellular NOS with its substrate, l-arginine, from the plasma. Therefore, ADMA and its transport mechanisms are strategically placed to regulate endothelial function. This could have considerable clinical impact since endothelial dysfunction has been detected at the origin of hypertension and chronic kidney disease (CKD) in human subjects and may be a harbinger of large vessel disease and cardiovascular disease (CVD). Indeed, plasma levels of ADMA are increased in many studies of patients at risk for, or with overt CKD or CVD. However, the levels of ADMA measured in plasma of about 0.5micromol.l(-1) may be below those required to inhibit NOS whose substrate, l-arginine, is present in concentrations many fold above the Km for NOS. However, NOS activity may be partially inhibited by cellular ADMA. Therefore, the cellular production of ADMA by protein arginine methyltransferase (PRMT) and protein hydrolysis, its degradation by N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH) and its transmembrane transport by CAT that determines intracellular levels of ADMA may also determine the state of activation of NOS. This is the focus of the review. It is concluded that cellular levels of ADMA can be 5- to 20-fold above those in plasma and in a range that could tonically inhibit NOS. The relative importance of PRMT, DDAH and CAT for determining the intracellular NOS substrate:inhibitor ratio (l-arginine:ADMA) may vary according to the pathophysiologic circumstance. An understanding of this important balance requires knowledge of these three processes that regulate the intracellular levels of ADMA and arginine.
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| 40. |
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| 41. |
- Wallner, Fredrik K., et al.
(författare)
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Correlation and cluster analysis of immunomodulatory drugs based on cytokine profiles
- 2018
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Ingår i: Pharmacological Research. - : Elsevier. - 1043-6618 .- 1096-1186. ; 128, s. 244-251
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Tidskriftsartikel (refereegranskat)abstract
- Drug discovery is a constant struggle to overcome hurdles posed by the complexity of biological systems. One of these hurdles is to find and understand the molecular target and the biological mechanism of action. Although the molecular target has been determined, the true biological effect may be unforeseen also for well-established drugs. Hence, there is a need for novel ways to increase the knowledge of the biological effects of drugs in the developmental process. In this study, we have determined cytokine profiles for 26 non-biological immunomodulatory drugs or drug candidates and used these profiles to cluster the compounds according to their effect in a preclinical ex vivo culture model of arthritis. This allows for prediction of functions and drug target of a novel drug candidate based on profiles obtained in this study. Results from the study showed that the JAK inhibitors tofacitinib and ruxolitinib formed a robust cluster and were found to have a distinct cytokine profile compared to the other drugs. Another robust cluster included the calcineurin inhibitors cyclosporine A and tacrolimus and the protein kinase inhibitors fostamatinib disodium and sotrastaurin acetate, which caused a strong overall inhibition of the cytokine production. The results of this methodology indicate that cytokine profiles can be used to provide a fingerprint-like identification of a drug as a tool to benchmark novel drugs and to improve descriptions of mode of action.
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| 42. |
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| 43. |
- Xu, Yanting, et al.
(författare)
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Targeted inhibition of ATP5B gene prevents bone erosion in collagen-induced arthritis by inhibiting osteoclastogenesis.
- 2021
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 165
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Tidskriftsartikel (refereegranskat)abstract
- Bone resorption by osteoclasts is an energy consuming activity, which depends on mitochondrial ATP. ATP5B, a mitochondrial ATP synthase beta subunit, is a catalytic core involved in producing ATP. Here, we investigated the contribution of ATP5B in osteoclast differentiation and joint destruction. ATP5B (LV-ATP5B) targeting or non-targeting (LV-NC) siRNA containing lentivirus particles were transduced into bone marrow macrophage derived osteoclasts or locally administered to arthritic mouse joints. Inhibition of ATP5B reduced the expression of osteoclast related genes and proteins, suppressed bone resorption by significantly impairing F-actin formation and decreased the levels of adhesion-associated proteins. In addition, ATP5B deficiency caused osteoclast mitochondrial dysfunction and, impaired the secretion of vacuole protons and MMP9. Importantly, inhibition of ATP5B expression, protected arthritis mice from joint destructions although serum levels of inflammatory mediators (TNF-α, IL-1β) and IgG2α antibodies were unaffected. These results demonstrate an essential function of ATP5B in osteoclast differentiation and bone resorption, and suggest it as a potential therapeutic target for protecting bones in RA.
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| 44. |
- Zelvyté, Inga, et al.
(författare)
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Modulation of inflammatory mediators and ppargammaand nfkappab expression by pravastatin in response to lipoproteins in human monocytes in vitro.
- 2002
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 45:2, s. 147-154
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Tidskriftsartikel (refereegranskat)abstract
- Statins are inhibitors of the rate-limiting step of cellular cholesterol synthesis. In vitro and in vivo studies suggest that statins have anti-inflammatory properties independent of their cholesterol-lowering effects. These observations prompted us to examine the effects of pravastatin (50 mgr; M) and native or oxidized low density lipoprotein (nLDL or oxLDL) (50 mgr; g ml(minus sign1)) on primary human monocytes. We found that cells treated with pravastatin prior to nLDL and cells pre-treated with oxLDL prior to pravastatin showed increased activity of peroxisome proliferator-activated receptor gamma (PPAR gamma). Treatment of cells with drug either before incubation with oxLDL or afterwards suppressed nuclear factor kappa B (NF kappa B) expression and reduced uptake of(125)I-oxLDL by 1.7- and 1.5-fold, respectively. Pravastatin also increased PPAR gamma levels and abolished NF kappa B activity in non-stimulated monocytes. Statin added to monocytes prior to or after treatment with nLDL or oxLDL significantly inhibited generation of matrix metalloproteinases (MMPs), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor alpha (TNF- alpha). These data corroborate previous findings of the pleiotropic role of statins and also suggest the involvement of transcription factors such as PPAR gamma and NF kappa B in the modulation of the inflammatory processes by statins. Copyright 2002 Elsevier Science Ltd.
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| 45. |
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| 46. |
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| 47. |
- Zhang, Yaping, et al.
(författare)
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MAPK/NF-kappa B-dependent upregulation of kinin receptors mediates airway hyperreactivity: A new perspective for the treatment
- 2013
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 71, s. 9-18
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Forskningsöversikt (refereegranskat)abstract
- Airway hyperreactivity (AHR) is a major feature of asthmatic and inflammatory airways. Cigarette smoke exposure, and bacterial and viral infections are well-known environmental risk factors for AHR, but knowledge about the underlying molecular mechanisms on how these risk factors lead to the development of AHR is limited. Activation of intracellular mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-kappa B) and their related signal pathways including protein kinase C (PKC), phosphoinositide 3-kinase (PI3K) and protein kinase A (PKA) signaling pathways may result in airway kinin receptor upregulation, which is suggested to play an important role in the development of AHR. Environmental risk factors trigger the production of pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) and interleukins (ILs) that activate intracellular MAPK- and NF-kappa B-dependent inflammatory pathways, which subsequently lead to AHR via kinin receptor upregulation. Blockage of intracellular MAPK/NF-kappa B signaling prevents kinin B-1 and B-2 receptor expression in the airways, resulting in a decrease in the response to bradykinin (kinin B-2 receptor agonist) and des-Arg(9)-bradykinin (kinin B-1 receptor agonist). This suggests that MAPK- and NF-kappa B-dependent kinin receptor upregulation can provide a novel option for treatment of AHR in asthmatic as well as in other inflammatory airway diseases. (C) 2013 Elsevier Ltd. All rights reserved.
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| 48. |
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| 49. |
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| 50. |
- Beeres, D., et al.
(författare)
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Evaluation of the Swedish school-based program “tobacco-free DUO” in a cluster randomized controlled trial (TOPAS study). Results at 2-year follow-up
- 2022
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Ingår i: Preventive Medicine. - : Elsevier BV. - 0091-7435 .- 1096-0260. ; 155
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Tidskriftsartikel (refereegranskat)abstract
- Friends' and parents' tobacco use are strong predictors of tobacco uptake among adolescents, however the effectiveness of interventions based on public commitments and agreements to remain tobacco-free are not established. Here, we evaluated the effectiveness of the school-based Swedish program Tobacco-Free Duo (T-Duo) in preventing adolescents from initiating tobacco use (TOPAS study). T-Duo is a multi-component intervention witha formal agreement between a student and an adult partner to remain tobacco-free during the entire 3-year study period as core component. The standardized educational component of the same program was used as comparator (control). Primary outcome was the probability to “remain a non-user” of i) cigarettes and secondary outcomes ii) other types of tobacco at second (21-month) follow-up. Analysis was conducted according to Intention To Treat. In total 1776 adolescents (51% female) aged 12–13 in grade 7 from 34 participating high schools in Sweden were included at baseline in 2018, of which 1489 were retained after 21 months. The Risk Ratio (RR) of not having tried cigarettes 21-months after initiation of the intervention was 1.03(CI 0.98–1.08), Bayes Factor(BF) = 0.93, Absolute Risk Difference(ARD) = 3.1%. Similar associations were found for never smoked a whole cigarette and never use of other tobacco/nicotine products. There was a minimal reduction of tobacco use initiation among Swedish adolescents assigned to a multi-component intervention (T-Duo) compared to those assigned to standardized classroom education after 2 schoolyears. However, for most outcomes' findings were inconclusive and not reliably different from zero. Trial registration: ISRCTN5285808 (doi:https://doi.org/10.1186/ISRCTN52858080); Study protocol: DERR1-https://doi.org/10.2196/21100. Registration: Current Controlled Trials ISRCTN52858080 Date: January 4, 2019, retrospectively registered. Protocol: Galanti, M.R., Pulkki-Brännström, A.-M., Nilsson, M., 2020. Tobacco-free duo adult-child contract for prevention of tobacco use among adolescents and parents: protocol for a mixed-design evaluation. JMIR Res. Protoc. 9, e21100. doi:10.2196/21100. © 2021
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