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1.	Abbas, Abdul-Karim, 1959, et al. (författare) Long-term potentiation and insult conditioning in hippocampal slices from young rats: a role for protein synthesis under chemical stress? 2010 Ingår i: The 10th Biennial Meeting of the Asia-Pacific Society for Neurochemistry (APSN), October 17-20, 2010, Phuket, Thailand. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract We have previously demonstrated that in young rats (12-20-day-old) a sustained long-term potentiation (LTP) can still be induced under conditions of protein synthesis inhibition. It was therefore suggested that sufficient and necessary proteins were already available at the induction time to accomplish LTP maintenance for several hours. Against this background, we have questioned whether hippocampal slices subjected to certain insult conditions might be more sensitive to protein synthesis inhibitors. High K+ concentration has previously been reported to cause an amnesic effect in vivo as well as increasing protein turnover in vitro. We have here employed a K+ insult model under conditions when protein synthesis was inhibited. Recordings were obtained from hippocampal slices for up to 9 h, with or without a cocktail of protein synthesis inhibitors, containing cycloheximide (60 µM) and anisomycin (25 µM). High potassium (50 mM) was transiently applied (5-15 min) shortly after inducing LTP in one of two separate pathways stimulated alternatively. Additionally, an NMDA-receptor antagonist AP5 was supplied after LTP induction to minimize effects related to depolarization-induced glutamate release. Following elimination of all responses for about 30 min, both test and control responses partly recovered. The degree of remaining LTP, defined as test/control ratio, was reduced in both groups of slices (NMDA-independent depotentiation) but was significantly smaller in the drug-treated ones. We are also running an insult model based on oxidative stress, applying hydrogen peroxide (4-5 mM) before or after LTP induction; however, the results are still insufficient for a final conclusion. The potency of cycloheximide, anisomycin or cocktail of the drugs was verified by measurement of incorporation of [3H]-leucine into trichloracetic acid (TCA) precipitable macromolecules. Cycloheximide, anisomycin or cocktail, at concentrations used here caused 95%, 97% and 95% blocking effect, respectively. Our data confirm the idea that sufficient and necessary constitutive proteins are available in the young hippocampus to maintain LTP under conditions of protein synthesis inhibition. They also reveal that LTP in slices subjected to certain insult conditions early after the induction is sensitive to protein synthesis inhibition, probably due to increase in constitutive proteins turnover.
2.	Bauzá-Thorbrügge, Marco, et al. (författare) NRF2 is essential for adaptative browning of white adipocytes. 2023 Ingår i: Redox biology. - : Elsevier. - 2213-2317. ; 68 Tidskriftsartikel (refereegranskat)abstract White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.
3.	Solinas, Giovanni, et al. (författare) An adipoincretin effect links adipostasis with insulin secretion. 2024 Ingår i: Trends in endocrinology and metabolism: TEM. - 1879-3061. ; 35:6, s. 466-477 Forskningsöversikt (refereegranskat)abstract The current paradigm for the insulin system focuses on the phenomenon of glucose-stimulated insulin secretion and insulin action on blood glucose control. This historical glucose-centric perspective may have introduced a conceptual bias in our understanding of insulin regulation. A body of evidence demonstrating that in vivo variations in blood glucose and insulin secretion can be largely dissociated motivated us to reconsider the fundamental design of the insulin system as a control system for metabolic homeostasis. Here, we propose that a minimal glucose-centric model does not accurately describe the physiological behavior of the insulin system and propose a new paradigm focusing on the effects of incretins, arguing that under fasting conditions, insulin is regulated by an adipoincretin effect.
4.	Tjondro, Harry C., et al. (författare) Hyper-truncated Asn355- And Asn391-glycans modulate the activity of neutrophil granule myeloperoxidase 2021 Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 296 Tidskriftsartikel (refereegranskat)abstract Myeloperoxidase (MPO) plays essential roles in neutrophil-mediated immunity via the generation of reactive oxidation products. Complex carbohydrates decorate MPO at discrete sites, but their functional relevance remains elusive. To this end, we have characterised the structure–biosynthesis–activity relationship of neutrophil MPO (nMPO). Mass spectrometry demonstrated that nMPO carries both characteristic under-processed and hyper-truncated glycans. Occlusion of the Asn355/Asn391-glycosylation sites and the Asn323-/Asn483-glycans, located in the MPO dimerisation zone, was found to affect the local glycan processing, thereby providing a molecular basis of the site-specific nMPO glycosylation. Native mass spectrometry, mass photometry and glycopeptide profiling revealed significant molecular complexity of diprotomeric nMPO arising from heterogeneous glycosylation, oxidation, chlorination and polypeptide truncation variants and a previously unreported low-abundance monoprotomer. Longitudinal profiling of maturing, mature, granule-separated and pathogen-stimulated neutrophils demonstrated that nMPO is dynamically expressed during granulopoiesis, unevenly distributed across granules and degranulated upon activation. We also show that proMPO-to-MPO maturation occurs during early/mid-stage granulopoiesis. While similar global MPO glycosylation was observed across conditions, the conserved Asn355-/Asn391-sites displayed elevated glycan hyper-truncation, which correlated with higher enzyme activities of MPO in distinct granule populations. Enzymatic trimming of the Asn355-/Asn391-glycans recapitulated the activity gain and showed that nMPO carrying hyper-truncated glycans at these positions exhibits increased thermal stability, polypeptide accessibility and ceruloplasmin-mediated inhibition potential relative to native nMPO. Finally, molecular modelling revealed that hyper-truncated Asn355-glycans positioned in the MPO-ceruloplasmin interface are critical for uninterrupted inhibition. Here, through an innovative and comprehensive approach, we report novel functional roles of MPO glycans, providing new insight into neutrophil-mediated immunity.
5.	Lindberg, Frida A., et al. (författare) SLC38A10 knockout mice display a decreased body weight and an increased risk-taking behavior in the open field test 2022 Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media S.A.. - 1662-5153. ; 16 Tidskriftsartikel (refereegranskat)abstract The solute carrier 38 family (SLC38) is a family of 11 members. The most commonsubstrate among these are alanine and glutamine, and members are present in a widerange of tissues with important functions for several biological processes, such as liverand brain function. Some of these transporters are better characterized than others and,in this paper, a behavioral characterization of SLC38A10−/− mice was carried out. Abattery of tests for general activity, emotionality, motor function, and spatial memorywere used. Among these tests, the elevated plus maze, Y-maze, marble burying, andchallenging beamwalk have not been tested on the SLC38A10−/− mice previously, whilethe open field and the rotarod tests have been performed by the International MousePhenotyping Consortium (IMPC). Unlike the results from IMPC, the results from this studyshowed that SLC38A10−/− mice spend less time in the wall zone in the open field testthan WT mice, implying that SLC38A10-deficient mice have an increased explorativebehavior, which suggests an important function of SLC38A10 in brain. The present studyalso confirmed IMPC’s data regarding rotarod performance and weight, showing thatSLC38A10−/− mice do not have an affected motor coordination impairment and havea lower body weight than both SLC38A10+/− and SLC38A10+/+ mice. These resultsimply that a complete deficiency of the SLC38A10 protein might affect body weighthomeostasis, but the underlying mechanisms needs to be studied further.
6.	Lindberg, Frida A., et al. (författare) SLC38A10 Deficiency in Mice Affects Plasma Levels of Threonine and Histidine in Males but Not in Females : A Preliminary Characterization Study of SLC38A10(-/-) Mice 2023 Ingår i: Genes. - : MDPI. - 2073-4425. ; 14:4 Tidskriftsartikel (refereegranskat)abstract Solute carriers belong to the biggest group of transporters in the human genome, but more knowledge is needed to fully understand their function and possible role as therapeutic targets. SLC38A10, a poorly characterized solute carrier, is preliminary characterized here. By using a knockout mouse model, we studied the biological effects of SLC38A10 deficiency in vivo. We performed a transcriptomic analysis of the whole brain and found seven differentially expressed genes in SLC38A10-deficient mice (Gm48159, Nr4a1, Tuba1c, Lrrc56, mt-Tp, Hbb-bt and Snord116/9). By measuring amino acids in plasma, we found lower levels of threonine and histidine in knockout males, whereas no amino acid levels were affected in females, suggesting that SLC38A10(-/-) might affect sexes differently. Using RT-qPCR, we investigated the effect of SLC38A10 deficiency on mRNA expression of other SLC38 members, Mtor and Rps6kb1 in the brain, liver, lung, muscle, and kidney, but no differences were found. Relative telomere length measurement was also taken, as a marker for cellular age, but no differences were found between the genotypes. We conclude that SLC38A10 might be important for keeping amino acid homeostasis in plasma, at least in males, but no major effects were seen on transcriptomic expression or telomere length in the whole brain.
7.	Lehmann, Anders, et al. (författare) Discovery of New Drugs for Weight Loss and Prevention of Weight Regain 2016 Ingår i: Neuroendocrinology of Appetite. S Dickson & J Mercer (eds.). - Chichester, UK : John Wiley & Sons, Ltd. - 9781118839324 ; , s. 247-284 Bokkapitel (refereegranskat)
8.	Eriksson, Leif A., 1964-, et al. (författare) Tetrazole derivatives as cytochrome p450 inhibitors 2019 Patent (populärvet., debatt m.m.)abstract According to the invention there is provided a compound of formula I, wherein R1 and R2 have meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.
9.	Trägårdh, Karin, et al. (författare) Risk Profiles of Female Perpetrators of Severe Violence 2019 Ingår i: 13th Nordic Symposium on Forensic Psychiatry. August 20-22, Gothenburg, Sweden. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Female offenders without a severe mental disorder show more criminogenic factors than those with. Both groups are characterized by mental health problems. We need to further characterize female offenders. Background Offenders of lethal/severe violence are in a majority of cases male, about 90% (Falk et al., 2014), and research has to a considerable extent focused on male violent offenders. Although less is known about female violent offenders than male offenders, previous research has indicated significant differences between male and female offenders of lethal/severe violence (Trägårdh et al., 2016; Yourstone et al., 2008). Since a majority of female perpetrators of lethal violence undergo a forensic psychiatric investigation (RPU/FPI), these documents contains important information about this group. Purpose The aim of this ongoing study is to characterize female perpetrators of severe violent crimes, and to compare female perpetrators sentenced to forensic psychiatric compulsory care with those sentenced to correctional treatment. Method This is an exploratory and descriptive study with a cross-sectional design. All forensic evaluations (FPI) made in Sweden between 2000-2014 (from The National Board of Forensic Medicine/RMV), and the subsequent court verdicts, in cases where women had used lethal/severe violence (n≈180) where used as the basis for data collection in this study. The present preliminary analyses (2-tests and ANOVA) contains approx. 26% (n=47) of the total group. Group differences were investigated regarding: Mental health (FPI) Risk factors (HCR-20 and PCL-R) Victim relation (FPI) Criminal behavior (FPI) Results Female offenders with and without a Severe mental disorder (SMD) seems to differ in some respects. For female offenders with a SMD, the crime was more likely to have been conducted in a less criminal context (see Table). For female offenders without a SMD, the following characteristics were more frequently present: Victim gender – male Substance abuse + Under the influence of substance (offender and victim) Previous violence between victim and offender Previous registered criminality Also, several common features between the SMD and non-SMD group of female offenders were found. The majority of all female offenders had: Previous psychiatric contact and diagnoses Previously attempted suicide No previously registered criminality Conclusions Preliminary results of the female perpetrators who had underwent a FPI seems to identify both substantial differences and similarities between those with versus without a SMD, where those without show more criminogenic factors. Both groups were also characterized by a high amount of mental illness. Also, these results supports previous research that female and male offenders of severe violence differ in important ways. Since a majority of female perpetrators of lethal violence undergo a forensic psychiatric investigation, these results should be generalizable to this group as a whole in Sweden. Based on these results, a great need to further characterize female offenders of severe/lethal violence remain.
10.	Izsak, Julia, et al. (författare) Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function 2021 Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11 Tidskriftsartikel (refereegranskat)abstract Lithium salts are used as mood-balancing medication prescribed to patients suffering from neuropsychiatric disorders, such as bipolar disorder and major depressive disorder. Lithium salts cross the blood-brain barrier and reach the brain parenchyma within few hours after oral application, however, how lithium influences directly human neuronal function is unknown. We applied patch–clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (<1 mM) and overdose concentrations (>1 mM) of lithium chloride (LiCl) to assess how therapeutically effective and overdose concentrations of LiCl directly influence human neuronal electrophysiological function at the synapse, single-cell, and neuronal network level. We describe that human iPSC-cortical neurons exposed to lithium showed an increased neuronal activity under all tested concentrations. Furthermore, we reveal a lithium-induced, concentration-dependent, transition of regular synchronous neuronal network activity using therapeutically effective concentration (<1 mM LiCl) to epileptiform-like neuronal discharges using overdose concentration (>1 mM LiCl). The overdose concentration lithium-induced epileptiform-like activity was similar to the epileptiform-like activity caused by the GABAA-receptor antagonist. Patch–clamp recordings reveal that lithium reduces action potential threshold at all concentrations, however, only overdose concentration causes increased frequency of spontaneous AMPA-receptor mediated transmission. By applying the AMPA-receptor antagonist and anti-epileptic drug Perampanel, we demonstrate that Perampanel suppresses lithium-induced epileptiform-like activity in human cortical neurons. We provide insights in how therapeutically effective and overdose concentration of lithium directly influences human neuronal function at synapse, a single neuron, and neuronal network levels. Furthermore, we provide evidence that Perampanel suppresses pathological neuronal discharges caused by overdose concentrations of lithium in human neurons.
11.	Molinaro, Angela, et al. (författare) Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kα and PI3Kβ Activities and Is Promoted by RAS. 2019 Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 29:6 Tidskriftsartikel (refereegranskat)abstract Phosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kα and PI3Kβ activities, whereas PI3Kδ and PI3Kγ are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kα. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kα and PI3Kβ should bedosed below their hyperglycemic threshold to achieve isoform selectivity.
12.	Mondal, Tanmoy, 1981, et al. (författare) Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis 2018 Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 33:3 Tidskriftsartikel (refereegranskat)abstract Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.
13.	Mottahedin, Amin (författare) Developing brain and systemic inflammation: a "Toll-like" link with consequences 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The developing brain is vulnerable to external insults, and perinatal brain injury (PBI) is a major cause of life-long neurological syndromes such as cerebral palsy. Currently, no pharmaceutical intervention is available. Hypoxia/ischemia (HI), infections and inflammation are implicated in the pathogenesis of PBI. However, the crosstalk between these etiologies is not fully understood. Toll-like receptors (TLR) 3 and TLR2 are responsible for sensing viral and bacterial infections and initiating the inflammatory response. The aim of this thesis was to investigate the effect of systemic inflammation induced by activation of these TLRs on neonatal HI brain injury. We demonstrate that intraperitoneal administration of TLR3 and TLR2 ligands (PolyI:C and P3C, respectively) prior to HI increases the brain injury in neonatal mice. PolyI:C and P3C induced neuroinflammation and altered microglial phenotype as assessed by RT-qPCR, multiplex cytokine assay or flow cytometry. PolyI:C also upregulated the pro-apoptotic gene, Fasl, expression and reduced activation of pro-survival signaling molecule Akt. On the other hand, P3C suppressed mitochondrial respiration, a major mechanism of cellular energy production. P3C, unlike other TLR agonists, induced marked infiltration of leukocytes to the cerebral spinal fluid and brain of neonatal mice and rats. Confocal microscopy, Cre recombinase-mediated gene targeting and in vitro cell transmigra-tion assay revealed the choroid plexus as a site of leukocyte entry. RNA sequencing of the choroid plexus followed by transcriptome cluster analysis and Ingenuity Pathway Analysis revealed potential mechanisms of leukocyte infiltration, including a specific chemotaxis signature and cytoskeleton-related pathways. Finally, we show that N-acetylcysteine treatment inhibits TLR2-mediated leukocyte trafficking in vivo and in vitro. To conclude, this thesis describe a TLR-mediated link between systemic inflammation and developing brain with detrimental consequences on HI brain injury, suggesting potential novel therapeutic strategies.
14.	Rostami, Elham, 1979-, et al. (författare) β-adrenoreceptor activation in brain, lung and adipose tissue, measured by microdialysis in pig. 2012 Ingår i: Advances in Medical Sciences. - : Elsevier BV. - 1896-1126 .- 1898-4002. ; 57:1, s. 136-141 Tidskriftsartikel (refereegranskat)
15.	Winder, Michael, 1980 (författare) The ambiguous role of nitric oxide in the urinary bladder 2017 Ingår i: 7th National Symposium on Advances in Gastrointestinal & Urogenital Research, 2017, Gold Coast, Australia. Konferensbidrag (övrigt vetenskapligt/konstnärligt)
16.	Rube, Tanja, et al. (författare) Development of the Swedish anticholinergic burden scale (Swe-ABS). 2023 Ingår i: BMC geriatrics. - 1471-2318. ; 23:1 Tidskriftsartikel (refereegranskat)abstract Drugs with anticholinergic properties are associated with cognitive adverse effects, especially in patients vulnerable to central muscarinic antagonism. A variety of drugs show weak, moderate or strong anticholinergic effects. Therefore, the cumulative anticholinergic burden should be considered in patients with cognitive impairment. This study aimed to develop a Swedish Anticholinergic Burden Scale (Swe-ABS) to be used in health care and research.A systematic literature review was conducted in PubMed and Ovid Embase to identify previously published tools quantifying anticholinergic drug burden (i.e., exposure). Drugs and grading scores (0-3, no to high anticholinergic activity) were extracted from identified lists. Enteral and parenteral drugs authorized in Sweden were included. Drugs with conflicting scores in the existing lists were assessed by an expert group. Two drugs that were not previously assessed were also added to the evaluation process.The systematic literature search identified the following nine anticholinergic burden scales: Anticholinergic Activity Scale, Anticholinergic Burden Classification, updated Anticholinergic Cognitive Burden scale, Anticholinergic Drug Scale, Anticholinergic Load Scale, Anticholinergic Risk Scale, updated Clinician-rated Anticholinergic Scale, German Anticholinergic Burden Scale and Korean Anticholinergic Burden Scale. A list of drugs with significant anticholinergic effects provided by The Swedish National Board of Health and Welfare was included in the process. The suggested Swe-ABS consists of 104 drugs scored as having weak, moderate or strong anticholinergic effects. Two hundred and fifty-six drugs were listed as having no anticholinergic effects based on evaluation in previous scales. In total, 62 drugs were assessed by the expert group.Swe-ABS is a simplified method to quantify the anticholinergic burden and is easy to use in clinical practice. Publication of this scale might make clinicians more aware of drugs with anticholinergic properties and patients' total anticholinergic burden. Further research is needed to validate the Swe-ABS and evaluate anticholinergic exposure versus clinically significant outcomes.
17.	Mohammadi, Elyas, et al. (författare) Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning 2020 Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:9, s. 1-24 Forskningsöversikt (refereegranskat)abstract Simple Summary Drug repurposing is an accelerated route for drug development and a promising approach for finding medications for orphan and common diseases. Here, we compiled databases that comprise both computationally- or experimentally-derived data, and categorized them based on quiddity and origin of data, further focusing on those that present high throughput omic data or drug screens. These databases were then contextualized with genome-wide screening methods such as CRISPR/Cas9 and RNA interference, as well as state of art systems biology approaches that enable systematic characterizations of multi-omic data to find new indications for approved drugs or those that reached the latest phases of clinical trials. Modern drug discovery through de novo drug discovery entails high financial costs, low success rates, and lengthy trial periods. Drug repositioning presents a suitable approach for overcoming these issues by re-evaluating biological targets and modes of action of approved drugs. Coupling high-throughput technologies with genome-wide essentiality screens, network analysis, genome-scale metabolic modeling, and machine learning techniques enables the proposal of new drug-target signatures and uncovers unanticipated modes of action for available drugs. Here, we discuss the current issues associated with drug repositioning in light of curated high-throughput multi-omic databases, genome-wide screening technologies, and their application in systems biology/medicine approaches.
18.	Lai, Kuei-Hung (författare) Studies on anti-leukemic terpenoids from medicinal mushrooms and marine sponges with ChemGPS-NP-based targets investigation of lead compounds 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract This thesis investigates the anti-leukemic activity of terpenoids isolated from medicinal mushrooms and marine sponges, as well as their possible targets and mechanisms of action.In the first section, we focused on studying the triterpenoidal components of three triterpenoid-enriched medicinal mushrooms Antrodia cinnamomea, Ganoderma lucidum, and Poria cocos, which have been used in folk medicine for centuries and also developed into several contemporary marketed products. We isolated the major and characteristic triterpenoids from these mushrooms, together with six new lanostanoids (II-1–II-6). The anti-leukemic activity of the isolates was evaluated in vitro using MTT proliferative assay and seven of them exhibited potential anti-leukemic effect. The active lead compounds were further subjected to computational analyses utilizing the ChemGPS-NP tool. We established a database for the anti-leukemic relevant chemical space of triterpenoids isolated from these three medicinal mushrooms, which could be used as a reference database for further research on anti-leukemic triterpenoids. Our results indicated that the anti-leukemic effect of the active lead compounds was mediated not only through topoisomerases inhibition but also through inhibiting DNA polymerases.The second and third sections focused on isolation of anti-leukemic sesterterpenoids from sponges. The investigation of Carteriospongia sp. led to the isolation of two new scalarane-type sesterterpenoids (III-1 and III-2) and one known tetraprenyltoluquinol-related metabolite (III-3). All isolates exhibit an apoptotic mechanism of action against Molt 4 cells, found to be mediated through the disruption of the mitochondrial membrane potential (MMP) and inhibition of topoisomerase IIα expression. Detailed investigation of the apoptotic mechanism of action using molecular docking analysis revealed that compound III-1 might target Hsp90 protein. The apoptotic-inducing effect of III-3 was supported by in vivo experiment by suppressing the volume of xenograft tumor growth (47.58%) compared with the control.In the final section of this thesis we studied manoalide and its derivatives, sesterterpenoids isolated from the sponge Luffariella sp.. Manoalide has been studied as a potential anti-inflammatory agent for the last thirty years with more than 200 publications and 40 patents. However, the configurations at positions 24 and 25 were never revealed. In the current study, ten manoalide-type sesterterpenoids (IV-1–IV-10) were isolated from Luffariella sp. and their stereoisomers at positions 24 and 25 were identified and separated for the first time. The configuration at positions 24 and 25 showed to have a significant effect on the anti-leukemic activity of manoalide derivatives, with the 24R,25S-isomer exhibiting the most potent anti-leukemic activity. The apoptotic mechanism of action of compound IV-7 against Molt 4 cells was investigated, and the compound was found to trigger MMP disruption and intracellular reactive oxygen species (ROS) generation. Compound IV-7 also inhibited activity against both human topoisomerases, I and II. The in vivo experiment further supported the anti-leukemic effect of IV-7 with a 66.11% tumor volume suppression compared to the control.
19.	Di Gennaro, A., et al. (författare) Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm 2018 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:8, s. 1907-1912 Tidskriftsartikel (refereegranskat)abstract Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.
20.	Bhandage, Amol K., 1988- (författare) Glutamate and GABA signalling components in the human brain and in immune cells 2016 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Glutamate and γ-aminobutyric acid (GABA) are the principal excitatory and inhibitory neurotransmitters in the central nervous system (CNS). They both can activate their ionotropic and metabotropic receptors. Glutamate activates ionotropic glutamate receptors (iGlu - AMPA, kainate and NMDA receptors) and GABA activates GABA-A receptors which are modulated by many types of drugs and substances including alcohol. Using real time quantitative polymerase chain reaction, I have shown that iGlu and/or GABA-A receptor subunits were expressed in the hippocampus dentate gyrus (HDG), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), central amygdala (CeA), caudate and putamen of the human brain and their expression was altered by chronic excessive alcohol consumption. It indicates that excitatory and inhibitory neurotransmission may have been altered in the brain of human alcoholics. It is possible that changes in one type of neurotransmitter system may drive changes in another. These brain regions also play a role in brain reward system. Any changes in them may lead to changes in the normal brain functions.Apart from the CNS, glutamate and GABA are also present in the blood and can be synthesised by pancreatic islet cells and immune cells. They may act as immunomodulators of circulating immune cells and can affect immune function through glutamate and GABA receptors. I found that T cells from human, rat and mouse lymph nodes expressed the mRNAs and proteins for specific GABA-A receptor subunits. GABA-evoked transient and tonic currents recorded using the patch clamp technique demonstrate the functional GABA-A channel in T cells. Furthermore, the mRNAs for specific iGlu, GABA-A and GABA-B receptor subunits and chloride cotransporters were detected in peripheral blood mononuclear cells (PBMCs) from men, non-pregnant women, healthy and depressed pregnant women. The results indicate that the expression of iGlu, GABA-A and GABA-B receptors is related to gender, pregnancy and mental health and support the notion that glutamate and GABA receptors may modulate immune function. Intra- and interspecies variability exists in the expression and it is further influenced by physiological conditions.
21.	Turanli, Beste, et al. (författare) Drug Repositioning for Effective Prostate Cancer Treatment 2018 Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 9 Tidskriftsartikel (refereegranskat)abstract Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved non-cancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-kappa B inhibition, Wnt/beta - Catenin pathway inhibition, DNMT1 inhibition, and GSK-3 beta inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time- and cost-efficiency comparing to conventional drug discovery and development process.
22.	Rostami, Elham, 1979- (författare) Traumatic brain injury in humans and animal models 2012 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)
23.	Lindberg, Frida A. (författare) The Biological Importance of the Amino Acid Transporter SLC38A10 : Characterization of a Knockout Mouse 2022 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The biggest group of transporters, the solute carriers (SLCs), has more than 400 members, and about 30% of these are still orphan. In order to decipher their biological function and possible role in disease, there is a need for characterization of these. Around 25% of SLCs are estimated to have amino acids as substrates, including transporters belonging to the SLC38 family. The SLC38 members are sometimes referred to their alternative name: sodium-coupled neutral amino acid transporters (SNATs). One of these transporters, SNAT10 (or SLC38A10), has been characterized as a bidirectional transporter of glutamate, glutamine, alanine and aspartate, as well as having an efflux of serine, and is ubiquitously expressed in the body. However, its biological importance is not yet understood. The aim with this thesis was to characterize a mouse model deficient in SNAT10 protein in order to find the biological importance of this transporter. In paper I, this is done by using a series of behavioral tests, including the open field test, elevated plus maze, rotarod and Y-maze, among others. The SNAT10 knockout mouse was found to have an increased risk-taking behavior, but no motor or spatial working memory impairments. Furthermore, the knockout mouse was found to have a decreased body weight. In paper II, an additional behavioral characterization was performed by using the multivariate concentric square field™ (MCSF) test. The MCSF test is an arena with different zones associated to different behavioral traits, which generates a behavioral profile depending on where the mouse spends its time. The result from this test implies that the SNAT10 deficient mouse has a lower explorative behavior than its wild type littermates. In paper III, gene expression was studied in whole brain and some genes related to cell cycle regulation and p53 expression were found to be differentially expressed in the knockout brain. Additional gene expression was studied in kidney, liver, lung and muscle, but no changes were found. Plasma levels of histidine and threonine were altered in males, but no altered amino acid levels were found in knockout females, suggesting a possible sex-specific effect. These studies together imply that SNAT10 might be involved in processes related to risk-taking and explorative behavior in the open field and MCSF tests. SNAT10 deficiency also affected amino acid levels in plasma, indicating a disrupted amino acid homeostasis.
24.	Sukhovey, Yurij G., et al. (författare) Functional Conjugation of the Different Regulatory Responses to the Stress Stimuli in Healthy Human Subjects 2016 Ingår i: Open Journal of Applied Sciences. - : Scientific Research Publishing, Inc.. - 2165-3917 .- 2165-3925. ; 6, s. 489-500 Tidskriftsartikel (refereegranskat)abstract Present article discusses the physiological mechanisms of the state employees adaptation duringactive training in temporary groups. It is suggested that adaptive mechanisms to adverse effectsmay be studied basing on the concept of functional isomorphism of the psychic and immune systems.Adaptive mechanisms were studied through the monitoring of the stress factors’ impact upon thelaw enforcement officers when training outside the places of permanent deployment. The specificpurpose of present study was to evaluate the physiological indicators of the psychic, immune andendocrine systems dynamics at different stages of adaptation of the live organism to a stressfulsituation, hoping to get better insight into possible relations between psychic and immune domains.Through monitoring of the dynamics of the endocrine and immune responses to the psychic stimuli,it was possible to correlate the stages of the stress onset to the phases of specific immune reactions.Strong correlations between the parameters characterizing activation of the psychic and immuneresponses support the hypothesis of the presence of “strong cooperation” between psychic andimmune domains. It supports earlier hypothesis that we are monitoring
25.	Lind, Thomas, et al. (författare) Vitamin a is a negative regulator of osteoblast mineralization 2013 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12, s. e82388- Tidskriftsartikel (refereegranskat)
26.	Rodríguez-Piñeiro, Ana María, et al. (författare) The colonic mucus protection depends on the microbiota 2015 Ingår i: Gut microbes. - : Informa UK Limited. - 1949-0976 .- 1949-0984. ; 6:5, s. 326-30 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract The intestinal mucus is a pivotal part of our intestinal protection. It provides slow diffusion of protective molecules, trapping of luminal material as bacteria and smooth transport in the small intestine. In colon it restricts bacterial access to the epithelium limiting the responses to the enormous bacterial load present at this location. The development of these systems depends on the microbiota composition as seen in our recent study comparing the mucus phenotype in 2 colonies kept in different husbandries within the same SPF animal facility. One colony had impenetrable colonic mucus while the other colony had more penetrable mucus. The mucus phenotypes were transmitted via the microbiota and clear differences in its composition could be detected. Candidates associated with the different colonies were identified but the observed mucus difference could not be assigned to a specific bacterium.
27.	Fritz, Michael, 1981-, et al. (författare) Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion 2018 Ingår i: Brain, behavior, and immunity. - Maryland Heights : Academic Press. - 0889-1591 .- 1090-2139. ; 67, s. 54-58 Tidskriftsartikel (refereegranskat)abstract Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-ɣ (IFN-ɣ) in the aversive response to systemic inflammation induced by a low dose (10μg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-ɣ expression in the blood and deletion of IFN-ɣ or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-ɣ action. Collectively, these findings show that circulating IFN-ɣ that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.
28.	Klawonn, Anna, 1985- (författare) Molecular Mechanisms of Reward and Aversion 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Various molecular pathways in the brain shape our understanding of good and bad, as well as our motivation to seek and avoid such stimuli. This work evolves around how systemic inflammation causes aversion; and why general unpleasant states such as sickness, stress, pain and nausea are encoded by our brain as undesirable; and contrary to these questions, how drugs of abuse can subjugate the motivational neurocircuitry of the brain. A common feature of these various disease states is involvement of the motivational neurocircuitry - from mesolimbic to striatonigral pathways. Having an intact motivational system is what helps us evade negative outcomes and approach natural positive reinforcers, which is essential for our survival. During disease-states the motivational neurocircuitry may be overthrown by the molecular mechanisms that originally were meant to aid us.In study I, to investigate how inflammation is perceived as aversive, we used a behavioral test based on Pavlovian place conditioning with the aversive inflammatory stimulus E. coli lipopolysaccharide (LPS). Using a combination of cell-type specific gene deletions, pharmacology, and chemogenetics, we uncovered that systemic inflammation triggered aversion by MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Moreover, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, inflammation-induced aversion was not an indirect consequence of fever or anorexia but constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic circuitry is a key mechanism underlying inflammation-induced aversion.In study II, we investigate the role of peripheral IFN-γ in LPS induced conditioned place aversion by employing a strategy based on global and cell-type specific gene deletions, combined with measures of gene-expression. LPS induced IFN-ɣ expression in the blood, and deletion of IFN-ɣ or its receptor prevented conditioned place aversion (CPA) to LPS. LPS increased the expression of chemokine Cxcl10 in the striatum of normal mice. This induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion. Collectively, these findings demonstrate that circulating IFN-ɣ binding to receptors on brain endothelial cells which induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.In study III, we explored the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice in CPA to various stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain and kappa opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference towards most of the aversive stimuli, but were indifferent to pain. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine-dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were re-expressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in a MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.The neurotransmitter acetylcholine has been implied in reward learning and drug addiction. However, the role of cholinergic receptor subtypes in such processes remains elusive. In study IV we investigated the function of muscarinic M4Rs on dopamine D1R expressing neurons and acetylcholinergic neurons, using transgenic mice in various reward-enforced behaviors and in a “waiting”-impulsivity test. Mice lacking M4-receptors from D1-receptor expressing neurons exhibited an escalated reward seeking phenotype towards cocaine and natural reward, in Pavlovian conditioning and an operant self-administration task, respectively. In addition, the M4-D1RCre mice showed impaired waiting impulsivity in the 5-choice-serial-reaction-time-task. On the contrary, mice without M4Rs in acetylcholinergic neurons were unable to learn positive reinforcement to natural reward and cocaine, in an operant runway paradigm and in Pavlovian conditioning. Immediate early gene expression mirrored the behavioral findings arising from M4R-D1R knockout, as cocaine induced cFos and FosB was significantly increased in the forebrain of M4-D1RCre mice, whereas it remained normal in the M4R-ChatCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality.
29.	Hogenkamp, Pleunie S, et al. (författare) Sweet taste perception not altered after acute sleep deprivation in healthy young men. 2013 Ingår i: Somnologie : Schlafforschung und Schlafmedizin = Somnology : sleep research and sleep medicine. - : Springer Science and Business Media LLC. - 1432-9123 .- 1439-054X. ; 17:2, s. 111-114 Tidskriftsartikel (refereegranskat)abstract We hypothesized that acutely sleep-deprived participants would rate ascending concentrations of sucrose as more intense and pleasant, than they would do after one night of normal sleep. Such a finding would offer a potential mechanism through which acute sleep loss could promote overeating in humans.
30.	Deyou, Tsegaye, et al. (författare) Isoflavones and Rotenoids from the Leaves of Millettia oblata ssp teitensis 2017 Ingår i: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 80:7, s. 2060-2066 Tidskriftsartikel (refereegranskat)abstract A new isoflavone, 8-prenylmilldrone (1), and four new rotenoids, oblarotenoids A-D (2-5), along with nine known compounds (6-14), were isolated from the CH2Cl2/CH3OH (1:1) extract of the leaves of Millettia oblata ssp. teitensis by chromatographic separation. The purified compounds were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of the rotenoids were established on the basis of chiroptical data and in some cases by single-crystal X-ray crystallography. Maximaisoflavone J (11) and oblarotenoid C (4) showed weak activity against the human breast cancer cell line MDA-MB-231 with IC50 values of 33.3 and 93.8 mu M, respectively.
31.	Mabeyo, P. E., et al. (författare) Selenium Accumulating Leafy Vegetables Are a Potential Source of Functional Foods 2015 Ingår i: International Journal of Food Science. - : Hindawi Limited. - 2356-7015 .- 2314-5765. ; 2015 Tidskriftsartikel (refereegranskat)abstract Selenium deficiency in humans has been associated with various diseases, the risks of which can be reduced through dietary supplementation. Selenium accumulating plants may provide a beneficial nutrient for avoiding such illnesses. Thus, leafy vegetables such as Amaranthus hybridus, Amaranthus sp., Cucurbita maxima, Ipomoea batatas, Solanum villosum, Solanum scabrum, and Vigna unguiculata were explored for their capabilities to accumulate selenium when grown on selenium enriched soil and for use as a potential source of selenium enriched functional foods. Their selenium contents were determined by spectrophotometry using the complex of 3,3′-diaminobenzidine hydrochloride (DABH) as a chromogen. The mean concentrations in the leaves were found to range from to μg/g dry weight (DW), with C. maxima accumulating the most selenium. In stems, the accumulated selenium content ranged from μg/g in Amaranthus sp. to μg/g DW in C. maxima and was hence significantly different (). The cancer cell line MDA-MB-231 was used in cytotoxicity assays to determine the anticancer potential of these extracts. With exception of S. scabrum and S. villosum, no cytotoxicity was detected for the selenium enriched vegetable extracts up to 100μg/mL concentration. Hence, following careful evaluation the studied vegetables may be considered as selenium enriched functional foods.
32.	Makungu, Marco, et al. (författare) Pterocarpans and isoflavones from the roots of Millettia micans and of Millettia dura 2016 Ingår i: Advances in Drug Discovery and Development. ; 1:1, s. 1-8 Tidskriftsartikel (refereegranskat)abstract From the CH2Cl2/CH3OH (1:1) extract of the root bark of Millettia micans, a new pterocarpan, (6aR,11aR)-7,8,9-trimethoxy-3-hydroxypterocarpan (1), named micanspterocarpan, was isolated. Similarinvestigation of the CH2Cl2/CH3OH (1:1) extract of the root bark of Millettia dura gave a further new pterocarpan,3-O-prenylmaackiain (2) along with six known isoflavones (3-8) and a chalcone (9). All purifiedcompounds were identified by NMR and MS, and the absolute configuration of 1 was established by quantumchemical CD calculation. The isolated constituents, calopogonium isoflavone B (3) and isoerythrin A-4'-(3-methylbut-2-enyl) ether (4) showed marginal activities against the 3D7 and the Dd2 strains of Plasmodiumfalciparum (70-90% inhibition at 40 M). Maximaisoflavone B (5) and 7,2'-dimethoxy-4',5'-methylenedioxyisoflavone (7) were weakly cytotoxic (IC50 153.5 and 174.1 uM, respectively) against theMDB-MB-231 human breast cancer cell line. None of the tested compounds showed toxicity against theHEK-293 human embryonic kidney cell line at 40 uM.
33.	Nyandoro, Stephen S., 1975, et al. (författare) N-Cinnamoyltetraketide Derivatives from the Leaves of Toussaintia orientalis 2015 Ingår i: Journal of natural products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 78:8, s. 2045-2050 Tidskriftsartikel (refereegranskat)abstract Seven N-cinnamoyltetraketides (1–7), including the new Z-toussaintine E (2), toussaintine F (6), and toussaintine G (7), were isolated from the methanol extract of the leaves of Toussaintia orientalis using column chromatography and HPLC. The configurations of E-toussaintine E (1) and toussaintines A (3) and D (5) are revised based on single-crystal X-ray diffraction data from racemic crystals. Both the crude methanol extract and the isolated constituents exhibit antimycobacterial activities (MIC 83.3–107.7 μM) against the H37Rv strain of Mycobacterium tuberculosis. Compounds 1, 3, 4, and 5 are cytotoxic (ED50 15.3–105.7 μM) against the MDA-MB-231 triple negative aggressive breast cancer cell line.
34.	Nyandoro, Stephen S., 1975, et al. (författare) Polyoxygenated Cyclohexenes and Other Constituents of Cleistochlamys kirkii Leaves 2017 Ingår i: Journal of natural products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 80:1, s. 114-125 Tidskriftsartikel (refereegranskat)abstract Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (1), cleistodienol B (3), cleistenechlorohydrins A (4) and B (5), cleistenediols A–F (6–11), cleistenonal (12), and the butenolide cleistanolate (13), 2,5-dihydroxybenzyl benzoate (cleistophenolide, 14), and eight known compounds (2, 15–21) were isolated from a MeOH extract of the leaves of Cleistochlamys kirkii. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds 1, 17, and 19 were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound 2 was revised based on comparison of its NMR spectroscopic features and optical rotation to those of 1, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in C. kirkii is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against Plasmodium falciparum (3D7, Dd2), with IC50 values of 0.2–40 μM, and against HEK293 mammalian cells (IC50 2.7–3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC50 values ranging from 0.03–8.2 μM. Compound 1 showed the most potent antiplasmodial (IC50 0.2 μM) and cytotoxic (IC50 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM.
35.	Dinér, Peter, 1976, et al. (författare) Preparation of 3-Substituted-1-Isopropyl-1H-pyrazolo 3,4-d pyrimidin-4-amines as RET Kinase Inhibitors 2012 Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:10, s. 4872-4876 Tidskriftsartikel (refereegranskat)abstract A series of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines have been designed, synthesized, and evaluated as RET protein kinase inhibitors. On the basis of docking results, a small library of pyrazolopyrimidine compounds with an extended hydrophobic side arm was synthesized. The most promising of the compounds (7a) displayed efficient inhibition in vitro and good selectivity when tested on a panel of kinases. Furthermore, 7a inhibited GDNF-induced RET phosphorylation of ERK1/2 in MCF-7 breast cancer cells at concentrations as low as 100 nM.
36.	Adermark, Louise, 1974, et al. (författare) Weight gain and neuroadaptations elicited by high fat diet depend on fatty acid composition. 2021 Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 126 Tidskriftsartikel (refereegranskat)abstract Overconsumption of food is a major health concern in the western world. Palatable food has been shown to alter the activity of neural circuits, and obesity has been linked to alterations in the connectivity between the hypothalamus and cortical regions involved in decision-making and reward processing, putatively modulating the incentive value of food. Outlining neurophysiological adaptations induced by dietary intake of high fat diets (HFD) is thus valuable to establish how the diet by itself may promote overeating. To this end, C57BL/6 mice were fed HFD rich in either saturated fatty acids (HFD-S) or polyunsaturated fatty acids (HFD-P), or a low-fat control diet (LFD) for four weeks. Food and energy intake were monitored and ex vivo electrophysiology was employed to assess neuroadaptations in lateral hypothalamus (LH) and corticostriatal circuits, previously associated with food intake. In addition, the effects of dietary saturated and polyunsaturated fatty acids on the gene expression of NMDA, AMPA and GABAA receptor subunits in the hypothalamus were investigated. Our data shows that mice fed HFD-P had increased daily food and energy intake compared with mice fed HFD-S or LFD. However, this increase in energy intake had no obesogenic effects. Electrophysiological recordings demonstrated that HFD-P had a selective effect on glutamatergic neurotransmission in the LH, which was concomitant with a change in mRNA expression of AMPA receptor subtypes Gria1, Gria3 and Gria4, with no effect on the mRNA expression of NMDA receptor subtypes or GABAA receptor subtypes. Furthermore, while synaptic output from corticostriatal subregions was not significantly modulated by diet, synaptic plasticity in the form of long-term depression (LTD) was impaired in the dorsomedial striatum of mice fed HFD-S. In conclusion, this study suggests that the composition of fatty acids in the diet not only affects weight gain, but may also modulate neuronal function and plasticity in brain regions involved in food intake.
37.	Giddaluru, Sudheer, et al. (författare) Genetics of structural connectivity and information processing in the brain 2016 Ingår i: Brain Structure and Function. - : Springer Science and Business Media LLC. - 1863-2653 .- 1863-2661. ; 221:9, s. 4643-4661 Tidskriftsartikel (refereegranskat)abstract Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10(-08)). Suggestive associations (Meta P value <1 × 10(-06)) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10(-08)). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10(-07)). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10(-08)), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10(-07)) and the multimodal analysis (Fisher P value = 1 × 10(-07)). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.
38.	Hall, Håkan, et al. (författare) In vitro autoradiography of carcinoembryonic antigen in tissue from patients with colorectal cancer using multifunctional antibody TF2 and 67/68Ga-labeled haptens by pretargeting 2012 Ingår i: American Journal of Nuclear Medicine and Molecular Imaging. - 2160-8407. ; 2:2, s. 141-150 Tidskriftsartikel (refereegranskat)abstract The carcinoembryonic antigen (CEA) was visualized in vitro in tissue from patients with colorectal cancer with trivalent bispecific antibody TF2 and two hapten molecules, [(67/68)Ga]Ga-IMP461 and [(67/68)Ga]Ga-IMP485 by means of pretargeting. Colorectal cancer tissue samples obtained from surgery at Uppsala University Hospital, were frozen fresh and cryosectioned. The two hapten molecules comprising 1,4,7-triazacyclononanetriacetic acid chelate moiety (NOTA) were labeled with (67)Ga or (68)Ga. The autoradiography was conducted by incubating the tissue samples with the bispecific antibody TF2, followed by washing and incubation with one of the radiolabeled hapten molecules. After washing, drying and exposure to phosphor imager plates, the autoradiograms were analyzed and compared to standard histochemistry (hematoxylin-eosin). Pronounced binding was found in the tissue from colorectal cancer using the bispecific antibody TF2 and either of the haptens [(67/68)Ga]Ga-IMP461 and [(67/68)Ga]Ga-IMP485. Distinct binding was also detected in the epithelium of most samples of neighboring tissue, taken at a minimum of 10 cm from the site of the tumor. It is concluded that pretargeting CEA with the bispecific antibody TF2 followed by the addition of (67/68)Ga-labeled hapten is extremely sensitive for visualizing this marker for colorectal cancer. This methodology is therefore a very specific complement to other histochemical techniques in the diagnosis of biopsies or in samples taken from surgery. Use of the pretargeting technique in vivo may also be an advance in diagnosing patients with colorectal cancer, either using (67)Ga and SPECT or (68)Ga and PET.
39.	Ullgren, A, et al. (författare) Altered plasma protein profiles in genetic FTD - a GENFI study 2023 Ingår i: Molecular neurodegeneration. - : Springer Nature. - 1750-1326. ; 18:1, s. 85- Tidskriftsartikel (refereegranskat)
40.	Lundälv, Jörgen, 1966 (författare) Blogga tryggt med etik och etikett. Föredrag vid Onsdagsakademin, Sahlgrenska Akademin den 30 september 2015. 2015 Ingår i: Föredrag vid Onsdagsakademin, Sahlgrenska Akademin den 30 september 2015.. Konferensbidrag (övrigt vetenskapligt/konstnärligt)
41.	Altay, Özlem, et al. (författare) Current Status of COVID-19 Therapies and Drug Repositioning Applications 2020 Ingår i: Iscience. - : Elsevier BV. - 2589-0042. ; 23:7 Tidskriftsartikel (refereegranskat)abstract The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Drug repositioning is an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. In addition, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2.
42.	Xin, D. L., et al. (författare) Effectiveness of conservative interventions for sickness and pain behaviors induced by a high repetition high force upper extremity task 2017 Ingår i: BMC Neuroscience. - : BioMed Central. - 1471-2202. ; 18 Tidskriftsartikel (refereegranskat)abstract Background: Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. We have reported increased serum inflammatory cytokines in a rat model of repetitive strain injury (rats perform an upper extremity reaching task for prolonged periods). Here, we sought to determine if sickness behaviors are induced in this model and the effectiveness of conservative treatments.Methods: Experimental rats underwent initial training to learn a high force reaching task (10 min/day, 5 days/week for 6 weeks), with or without ibuprofen treatment (TRHF vs. TRHF + IBU rats). Subsets of trained animals went on to perform a high repetition high force (HRHF) task for 6 or 12 weeks (2 h/day, 3 days/week) without treatment, or received two secondary interventions: ibuprofen (HRHF + IBU) or a move to a lower demand low repetition low force task (HRHF-to-LRLF), beginning in task week 5. Mixed-effects models with repeated measures assays were used to assay duration of social interaction, aggression, forepaw withdrawal thresholds and reach performance abilities. One-way and two-way ANOVAs were used to assay tissue responses. Corrections for multiple comparisons were made.Results: TRHF + IBU rats did not develop behavioral declines or systemic increases in IL-1beta and IL-6, observed in untreated TRHF rats. Untreated HRHF rats showed social interaction declines, difficulties performing the operant task and forepaw mechanical allodynia. Untreated HRHF rats also had increased serum levels of several inflammatory cytokines and chemokines, neuroinflammatory responses (e.g., increased TNFalpha) in the brain, median nerve and spinal cord, and Substance P and neurokinin 1 immunoexpression in the spinal cord. HRHF + IBU and HRHF-to-LRLF rats showed improved social interaction and reduced inflammatory serum, nerve and brain changes. However, neither secondary treatment rescued HRHF-task induced forepaw allodynia, or completely attenuated task performance declines or spinal cord responses.Conclusions: These results suggest that inflammatory mechanisms induced by prolonged performance of high physical demand tasks mediate the development of social interaction declines and aggression. However, persistent spinal cord sensitization was associated with persistent behavioral indices of discomfort, despite use of conservative secondary interventions indicating the need for prevention or more effective interventions.
43.	Nijs, Jo, et al. (författare) Nociceptive, neuropathic, or nociplastic low back pain? : The low back pain phenotyping (BACPAP) consortium's international and multidisciplinary consensus recommendations 2024 Ingår i: The Lancet Rheumatology. - : Elsevier. - 2665-9913. ; 6:3, s. e178-e188 Tidskriftsartikel (refereegranskat)abstract The potential to classify low back pain as being characterised by dominant nociceptive, neuropathic, or nociplastic mechanisms is a clinically relevant issue. Preliminary evidence suggests that these low back pain phenotypes might respond differently to treatments; however, more research must be done before making specific recommendations. Accordingly, the low back pain phenotyping (BACPAP) consortium was established as a group of 36 clinicians and researchers from 13 countries (five continents) and 29 institutions, to apply a modified Nominal Group Technique methodology to develop international and multidisciplinary consensus recommendations to provide guidance for identifying the dominant pain phenotype in patients with low back pain, and potentially adapt pain management strategies. The BACPAP consortium's recommendations are also intended to provide direction for future clinical research by building on the established clinical criteria for neuropathic and nociplastic pain. The BACPAP consortium's consensus recommendations are a necessary early step in the process to determine if personalised pain medicine based on pain phenotypes is feasible for low back pain management. Therefore, these recommendations are not ready to be implemented in clinical practice until additional evidence is generated that is specific to these low back pain phenotypes.
44.	Adermark, Louise, 1974 (författare) Astrocyte Function in Alcohol Reward and Addiction 2015 Ingår i: Journal of Alcoholism & Drug Dependence. - : OMICS Publishing Group. - 2329-6488. ; 3 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Glial cells, particularly astrocytes, play essential roles in the regulation of neurotransmission, metabolism, and supply of energy substrates for synaptic transmission. One astrocyte can receive inputs from several hundreds of synapses, and synchronized neuronal activity correlates with astrocyte calcium signaling. Astrocyte pathology is a common feature of ethanol exposure in both humans and animal models, and brief alcohol intake is sufficient to cause long-lasting changes in astrocyte gene expression, activity and proliferation. Recent research also suggests that astrocytes shape the rewarding sensation of ethanol, and might be involved in modulating alcohol consumption. Considering the role of astrocytes in regulating glutamate homeostasis, a crucial component of alcohol abuse disorders, the astrocyte might be an important target for the development of new pharmacological treatments of alcoholism.
45.	Bauzá-Thorbrügge, Marco, et al. (författare) Adiponectin stimulates Sca1+CD34−-adipocyte precursor cells associated with hyperplastic expansion and beiging of brown and white adipose tissue 2024 Ingår i: Metabolism. - : Elsevier. - 0026-0495 .- 1532-8600. ; 151 Tidskriftsartikel (refereegranskat)abstract Background: The adipocyte hormone adiponectin improves insulin sensitivity and there is an inverse correlation between adiponectin levels and type-2 diabetes risk. Previous research shows that adiponectin remodels the adipose tissue into a more efficient metabolic sink. For instance, mice that overexpress adiponectin show increased capacity for hyperplastic adipose tissue expansion as evident from smaller and metabolically more active white adipocytes. In contrast, the brown adipose tissue (BAT) of these mice looks “whiter” possibly indicating reduced metabolic activity. Here, we aimed to further establish the effect of adiponectin on adipose tissue expansion and adipocyte mitochondrial function as well as to unravel mechanistic aspects in this area. Methods: Brown and white adipose tissues from adiponectin overexpressing (APN tg) mice and littermate wildtype controls, housed at room and cold temperature, were studied by histological, gene/protein expression and flow cytometry analyses. Metabolic and mitochondrial functions were studied by radiotracers and Seahorse-based technology. In addition, mitochondrial function was assessed in cultured adiponectin deficient adipocytes from APN knockout and heterozygote mice. Results: APN tg BAT displayed increased proliferation prenatally leading to enlarged BAT. Postnatally, APN tg BAT turned whiter than control BAT, confirming previous reports. Furthermore, elevated adiponectin augmented the sympathetic innervation/activation within adipose tissue. APN tg BAT displayed reduced metabolic activity and reduced mitochondrial oxygen consumption rate (OCR). In contrast, APN tg inguinal white adipose tissue (IWAT) displayed enhanced metabolic activity. These metabolic differences between genotypes were apparent also in cultured adipocytes differentiated from BAT and IWAT stroma vascular fraction, and the OCR was reduced in both brown and white APN heterozygote adipocytes. In both APN tg BAT and IWAT, the mesenchymal stem cell-related genes were upregulated along with an increased abundance of Lineage−Sca1+CD34− “beige-like” adipocyte precursor cells. In vitro, the adiponectin receptor agonist Adiporon increased the expression of the proliferation marker Pcna and decreased the expression of Cd34 in Sca1+ mesenchymal stem cells. Conclusions: We propose that the seemingly opposite effect of adiponectin on BAT and IWAT is mediated by a common mechanism; while reduced adiponectin levels are linked to lower adipocyte OCR, elevated adiponectin levels stimulate expansion of adipocyte precursor cells that produce adipocytes with intrinsically higher metabolic rate than classical white but lower metabolic rate than classical brown adipocytes. Moreover, adiponectin can modify the adipocytes' metabolic activity directly and by enhancing the sympathetic innervation within a fat depot.
46.	Boknäs, Niklas, 1979- (författare) Studies on interfaces between primary and secondary hemostasis 2016 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Our conceptual understanding of hemostasis is still heavily influenced by outdated experimental models wherein the hemostatic activity of platelets and coagulation factors are understood and studied in isolation. Although perhaps convenient for researchers and clinicians, this reductionist view is negated by an ever increasing body of evidence pointing towards an intimate relationship between the two phases of hemostasis, marked by strong interdependence. In this thesis, I have focused on factual and proposed interfaces between primary and secondary hemostasis, and on how these interfaces can be studied.In my first project, we zoomed in on the mechanisms behind the well-known phenomenon of thrombin-induced platelet activation, an important event linking secondary to primary hemostasis. In our study, we examined how thrombin makes use of certain domains for high-affinity binding to substrates, called exosite I and II, to activate platelets via PAR4. We show that thrombin-induced platelet activation via PAR4 is critically dependent on exosite II, and that blockage of exosite II with different substances virtually eliminates PAR4 activation. Apart from providing new insights into the mechanisms by which thrombin activates PAR4, these results expand our knowledge of the antithrombotic actions of various endogenous proteins such as members of the serpin superfamily, which inhibit interactions with exosite II. Additionally, we show that inhibition of exosite II could be a feasible pharmacological strategy for achieving selective blockade of PAR4.In my second project, we examined the controversial issue of whether platelets can initiate the coagulation cascade by means of contact activation, a hypothesis which, if true, could provide a direct link between primary and secondary hemostasis. In contrast to previous results, our findings falsify this hypothesis, and show that some of the erroneous conclusions drawn from earlier studies can be explained by inappropriate experimental models unsuitable for the study of plateletcoagulation interfaces.My third project comprised an assessment of the methodological difficulties encountered when trying to measure the ability of platelets to initiate secondary hemostasis by the release of microparticles expressing tissue factor. Our study shows that the functional assays available for this purpose are highly susceptible to error caused by artificial contact activation. These results could help to improve the methodology of future research and thus pave the way for new insights into the roles of tissue factor-bearing microparticles in the pathophysiology of various thrombotic disorders.From a personal perspective, my PhD project has been a fascinating scientific odyssey into the largely unexplored interfaces between primary and secondary hemostasis. Looking forward, my ambition is to continue our work exploring platelet-coagulation interactions and to translate these insights into clinically meaningful information, which may someday improve the treatment of patients with bleeding and/or thrombosis.
47.	Delsing, Louise, et al. (författare) Models of the blood-brain barrier using iPSC-derived cells 2020 Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431 .- 1095-9327. ; 107 Tidskriftsartikel (refereegranskat)abstract The blood-brain barrier (BBB) constitutes the interface between the blood and the brain tissue. Its primary function is to maintain the tightly controlled microenvironment of the brain. Models of the BBB are useful for studying the development and maintenance of the BBB as well as diseases affecting it. Furthermore, BBB models are important tools in drug development and support the evaluation of the brain-penetrating properties of novel drug molecules. Currently used in vitro models of the BBB include immortalized brain endothelial cell lines and primary brain endothelial cells of human and animal origin. Unfortunately, many cell lines and primary cells do not recreate physiological restriction of transport in vitro. Human-induced pluripotent stem cell (iPSC)-derived brain endothelial cells have proven a promising alternative source of brain endothelial-like cells that replicate tight cell layers with low paracellular permeability. Given the possibility to generate large amounts of human iPSC-derived brain endothelial cells they are a feasible alternative when modelling the BBB in vitro. iPSC-derived brain endothelial cells form tight cell layers in vitro and their barrier properties can be enhanced through co-culture with other cell types of the BBB. Currently, many different models of the BBB using iPSC-derived cells are under evaluation to study BBB formation, maintenance, disruption, drug transport and diseases affecting the BBB. This review summarizes important functions of the BBB and current efforts to create iPSC-derived BBB models in both static and dynamic conditions. In addition, it highlights key model requirements and remaining challenges for human iPSC-derived BBB models in vitro.
48.	Gharpure, Anant, et al. (författare) Agonist Selectivity and Ion Permeation in the alpha 3 beta 4 Ganglionic Nicotinic Receptor 2019 Ingår i: Neuron. - : CELL PRESS. - 0896-6273 .- 1097-4199. ; 104:3, s. 501- Tidskriftsartikel (refereegranskat)abstract Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The alpha 3 beta 4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the alpha 3 beta 4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the alpha 3 beta 4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.
49.	Karlsson, Oskar, et al. (författare) Neonatal exposure to the cyanobacterial toxin BMAA induces changes in protein expression and neurodegeneration in adult hippocampus. 2012 Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-0929 .- 1096-6080. ; 130:2, s. 391-404 Tidskriftsartikel (refereegranskat)abstract The cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) has been proposed to contribute to neurodegenerative disease. We have previously reported a selective uptake of BMAA in the mouse neonatal hippocampus and that exposure during the neonatal period causes learning and memory impairments in adult rats. The aim of this study was to characterize effects in the brain of 6-month-old rats treated neonatally (postnatal days 9-10) with the glutamatergic BMAA. Protein changes were examined using the novel technique Matrix-Assisted Laser Desorption Ionization (MALDI) imaging mass spectrometry (IMS) for direct imaging of proteins in brain cryosections, and histological changes were examined using immunohistochemistry and histopathology. The results showed long-term changes including a decreased expression of proteins involved in energy metabolism and intracellular signaling in the adult hippocampus at a dose (150 mg/kg) that gave no histopathological lesions in this brain region. Developmental exposure to a higher dose (460 mg/kg) also induced changes in the expression of S100β, histones, calcium- and calmodulin-binding proteins, and guanine nucleotide-binding proteins. At this dose, severe lesions in the adult hippocampus including neuronal degeneration, cell loss, calcium deposits, and astrogliosis were evident. The data demonstrate subtle, sometimes dose-dependent, but permanent effects of a lower neonatal dose of BMAA in the adult hippocampus suggesting that BMAA could potentially disturb many processes during the development. The detection of BMAA in seafood stresses the importance of evaluating the magnitude of human exposure to this neurotoxin.
50.	Lindberg, Olle R, et al. (författare) Epidermal growth factor treatment of the adult brain subventricular zone leads to focal microglia/macrophage accumulation and angiogenesis. 2014 Ingår i: Stem cell reports. - : Elsevier BV. - 2213-6711. ; 2:4, s. 440-8 Tidskriftsartikel (refereegranskat)abstract One of the major components of the subventricular zone (SVZ) neurogenic niche is the specialized vasculature. The SVZ vasculature isthought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF) is a mitogen witha wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion,dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis inthe adult brain.

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