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  • 1.
    Abusabeib, Alyaa
    et al.
    Department of Bariatric Surgery/Bariatric Medicine, Hamad General Hospital, Doha, Qatar.
    El Ansari, Walid
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Department of Surgery, Hamad General Hospital, Doha, Qatar / College of Medicine, Qatar University, Doha, Qatar.
    Alobaidan, Jassim
    Department of Bariatric Surgery/Bariatric Medicine, Hamad General Hospital, Doha, Qatar.
    Elhag, Wahiba
    Department of Bariatric Surgery/Bariatric Medicine, Hamad General Hospital, Doha, Qatar.
    First Case Report of Fulminant Hepatitis After Laparoscopic Sleeve Gastrectomy Associated with Concomitant Maximal Therapeutic Dose of Acetaminophen Use, Protein Calorie Malnutrition, and Vitamins A and D, Selenium, and Glutathione Deficiencies2021Inngår i: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 31, nr 2, s. 899-903Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is increasingly being linked to obesity. Although laparoscopic sleeve gastrectomy (LSG) is effective for weight loss that can ultimately resolve NAFLD, an initial transient deterioration of liver functions could be observed during the first few months post-operatively, after which a subsequent improvement of the liver functions might occur. Rapid weight loss, nutritional deficiencies, and protein malnutrition can all contribute to hepatic dysfunction and can affect the metabolism of medications such as acetaminophen leading to more insult to a compromised liver. We report acute liver failure after LSG associated with protein calorie malnutrition, multiple nutritional deficiencies in addition to concomitant use of therapeutic doses of acetaminophen. Treatment with N-acetylcysteine, and replacement of deficient multivitamins and trace elements resulted in significant improvement in liver functions. 

    Fulltekst (pdf)
    fulltext
  • 2.
    Adawi, Rahim
    Högskolan i Skövde, Institutionen för ingenjörsvetenskap.
    Preventing fatal effects of overworking: Product design solution2018Independent thesis Basic level (university diploma), 20 poäng / 30 hpOppgave
    Abstract [en]

    “Overworking to death” is a phenomenon that has been noticeable in developing countries. The cause of death is mainly through ischemic strokes. While the victims’ occupations differed, they all shared a common characteristic, being positioned in a sedentary work, ranging from IT workers to doctors. This project’s aim was to develop a product that prevented or decreased the strokes that derived from sedentary overwork. This was mainly tackled by preventing one of the three causes of developing blood props, slowed blood flow. In order to gather rich data of the phenomenon, a qualitative study was conducted in China, during two months. By doing an extensive structured sampling, information rich data could be gathered during a short period of time. Data were derived from observations, questionnaires and an interview, which then was interpreted to customer needs and the final product specification. The final product became a trouser with an in built dynamic compression mechanic, that can compress the veins mostly during sitting activities, in order to prevent blood stasis. The compression mechanic works like the Chinese finger trap; compressing the calves while sitting and stretching the legs forward. It is made only out of polysaccharides fibres; cotton and corn.

    Fulltekst (pdf)
    PREVENTING FATAL EFFECTS OF OVERWORKING – PRODUCT DESIGN SOLUTION / Rahim_Adawi
  • 3.
    Bauzá-Thorbrügge, Marco
    et al.
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Peris, Eduard
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Zamani, Shabnam
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Micallef, Peter
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Paul, Alexandra
    Department of Biology and Biological Engineering, Division of Chemical Biology, Chalmers University of Technology, Gothenburg, Sweden ; The Department of Biomedical Engineering, University of Texas at Austin, TX, United States.
    Bartesaghi, Stefano
    Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Benrick, Anna
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Wernstedt Asterholm, Ingrid
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    NRF2 is essential for adaptative browning of white adipocytes2023Inngår i: Redox Biology, E-ISSN 2213-2317, Vol. 68, artikkel-id 102951Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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. 

    Fulltekst (pdf)
    fulltext
  • 4.
    Bergsten, Niklas
    Högskolan i Skövde, Institutionen för vård och natur.
    1,25(OH)2D3 and Prostate Cancer: The Effects on cAMP/PKA-dependent Gene Expression in LnCaP cells2010Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    Prostate cancer is the leading male cancer form i Sweden and maybe worldwide as well. Vitamin D is synthesized in the skin following the exposure to sunlight. Researcers have long been aware of the positive effect that vitamin D3 has on prostate tumour growth. 1,25(OH)2D3 have for a long time been the target of these studies and have shown good results. The steroid hormone induces cAMP accumulation and activiates the cAMP dependent protein kinaseA (PKA). PKA is then able to activate a transcription regulating protein. 1,25(OH)2D3 is known to cause LNCaP cells to accumulate in the G1 phase ofthe cell cycle. It has also been shown that 1,25(OH)2D3 is under negativefeedback control via 24-hydroxylase. In this study, PKA activity was observed by transfecting LNCaP cells with a viral vector carrying firefly and Renillaluciferase genes. The successfully transfected LNCaP cells would then express luciferase as a response to PKA gene expression. The LNCaP cells were then treated with 1,25(OH)2D3 and GDP-β-S (100μM), a G-protein coupled receptorinhibitor, in order to examine if 1,25(OH)2D3 regulate PKA dependent gene expression through a G-protein coupled receptor. The study could show that 1,25(OH)2D3 regulate gene expression in LNCaP cells through a PKAdependent pathway. Furthermore, the PKA dependent gene expression was demonstrated to be independent of G-protein coupled recpetor activation.

    Fulltekst (pdf)
    FULLTEXT01
  • 5.
    Dige, Anders
    et al.
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Magnusson, Maria K.
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Öhman, Lena
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hvas, Christian Lodberg
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Kelsen, Jens
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Wick, Mary Jo
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Agnholt, Jørgen
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Reduced numbers of mucosal DR(int) macrophages and increased numbers of CD103(+) dendritic cells during anti-TNF-α treatment in patients with Crohn's disease2016Inngår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 51, nr 6, s. 692-699Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Anti-TNF-α treatment constitutes a mainstay in the treatment of Crohn's disease (CD), but its mechanisms of action are not fully understood. We aimed to investigate the effects of adalimumab, a human monoclonal TNF-α antibody, on macrophage (MQ) and dendritic cell (DC) subsets in mucosal biopsies and peripheral blood.

    MATERIAL AND METHODS: Intestinal biopsies and blood samples were obtained from 12 different CD patients both before and 4 weeks after the initiation of the induction of adalimumab treatment. Endoscopic disease activity was estimated by the Simple Endoscopic Score for Crohn's Disease. Biopsies were obtained from inflamed and non-inflamed areas. The numbers of lamina propria CD14 (+) DR(int) and CD14 (+) DR(hi) MQs, CD141(+), CD141(-) and CD103(+ )DCs subsets, and circulating monocytes and DCs were analyzed using flow cytometry.

    RESULTS: At baseline, we observed higher numbers of DR(int) MQs and lower numbers of CD103(+ )DCs in inflamed versus non-inflamed mucosa [843 vs. 391/10(5) lamina propria mononuclear cells (LPMCs) (p < 0.05) and 9 vs. 19 × 10(5) LPMCs (p = 0.01), respectively]. After four weeks of adalimumab treatment, the numbers of DR(int) MQs decreased [843 to 379/10(5) LPMCs (p = 0.03)], whereas the numbers of CD103(+ )DCs increased [9-20 × 10(5) LPMCs (p = 0.003)] compared with baseline. In peripheral blood, no alterations were observed in monocyte or DC numbers between baseline and week 4.

    CONCLUSIONS: In CD, mucosal inflammation is associated with high numbers of DR(int) MQs and low numbers of CD103(+ )DCs. This composition of intestinal myeloid subsets is reversed by anti-TNF-α treatment. These results suggest that DR(int) MQs play a pivotal role in CD inflammation.

  • 6.
    Ekelund Ugge, Gustaf Magnus Oskar
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Lund University.
    Transcriptional biomarkers of toxicity – powerful tools or random noise?: An applied perspective from studies on bivalves2023Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Aquatic organisms are constantly at risk of being exposed to potentially harmful chemical compounds of natural or anthropogenic origin. Biological life can for instance respond to chemical stressors by changes in gene expression, and thus, certain gene transcripts can potentially function as biomarkers, i.e. early warnings, of toxicity and chemical stress. A major challenge for biomarker application is the extrapolation of transcriptional data to potential effects at the organism level or above. Importantly, successful biomarker use also requires basal understanding of how to distinguish actual responses from background noise. The aim of this thesis is, based on response magnitude and variation, to evaluate the biomarker potential in a set of putative transcriptional biomarkers of general toxicity and chemical stress.

    Specifically, I addressed a selection of six transcripts involved in cytoprotection and oxidative stress: catalase (cat), glutathione-S-transferase (gst), heat shock proteins 70 and 90 (hsp70, hsp90), metallothionein (mt) and superoxide dismutase (sod). Moreover, I used metal exposures to serve as a proxy for general chemical stress, and due to their ecological relevance and nature as sedentary filter-feeders, I used bivalves as study organisms.

    In a series of experiments, I tested transcriptional responses in the freshwater duck mussel, Anodonta anatina, exposed to copper or an industrial wastewater effluent, to address response robustness and sensitivity, and potential controlled (e.g. exposure concentration) and random (e.g. gravidness) sources of variation. In addition, I performed a systematic review and meta-analysis on transcriptional responses in metal exposed bivalves to (1) evaluate what responses to expect from arbitrary metal exposures, (2) assess the influence from metal concentration (expressed as toxic unit), exposure time and analyzed tissue, and (3) address potential impacts from publication bias in the scientific literature.

    Response magnitudes were generally small in relationship to the observed variation, both for A. anatina and bivalves in general. The expected response to an arbitrary metal exposure would generally be close to zero, based on both experimental observations and on the estimated impact from publication bias. Although many of the transcripts demonstrated concentration-response relationships, large background noise might in practice obscure the small responses even at relatively high exposures. As demonstrated in A. anatina under copper exposure, this can be the case already for single species under high resolution exposures to single pollutants. As demonstrated by the meta-regression, this problem can only be expected to increase further upon extrapolation between different species and exposure scenarios, due to increasing heterogeneity and random variation. Similar patterns can also be expected for time-dependent response variation, although the meta-regression revealed a general trend of slightly increasing response magnitude with increasing exposure times.

    In A. anatina, gravidness was identified as a source of random variability that can potentially affect the baseline of most assessed biomarkers, particularly when quantified in gills. Response magnitudes and variability in this species were generally similar for selected transcripts as for two biochemical biomarkers included for comparison (AChE, GST), suggesting that the transcripts might not capture early warnings more efficiently than other molecular endpoints that are more toxicologically relevant. Overall, high concentrations and long exposure durations presumably increase the likelihood of a detectable transcriptional response, but not to an extent that justifies universal application as biomarkers of general toxicity and chemical stress. Consequently, without a strictly defined and validated application, this approach on its own appears unlikely to be successful for future environmental risk assessment and monitoring. Ultimately, efficient use of transcriptional biomarkers might require additional implementation of complementary approaches offered by current molecular techniques.

    Fulltekst (pdf)
    Gustaf M.O. Ekelund Ugge - PhD thesis
  • 7.
    Ekelund Ugge, Gustaf Magnus Oskar
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Biology, Lund University, Sweden.
    Sahlin, Ullrika
    Centre for Environmental and Climate Science, Lund University, Sweden.
    Jonsson, Annie
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Berglund, Olof
    Department of Biology, Lund University, Sweden.
    Transcriptional Responses as Biomarkers of General Toxicity: A Systematic Review and Meta-Analysis on Metal-Exposed Bivalves2023Inngår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 42, nr 3, s. 628-641Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Through a systematic review and a series of meta-analyses, we evaluated the general responsiveness of putative transcriptional biomarkers of general toxicity and chemical stress. We targeted metal exposures performed on bivalves under controlled laboratory conditions, and selected six transcripts associated with general toxicity for evaluation: catalase (cat), glutathione-S-transferase (gst), heat shock proteins 70 and 90 (hsp70, hsp90), metallothionein (mt) and superoxide dismutase (sod). Transcriptional responses (n = 396) were extracted from published scientific articles (k = 22) and converted to log response ratios (lnRRs). By estimating toxic units (TUs), we normalized different metal exposures to a common scale, as a proxy of concentration. Using Bayesian hierarchical random effect models, we then tested the effects of metal exposure on lnRR, both for metal exposure in general and in meta-regressions using TU and exposure time as independent variables. Corresponding analyses were also repeated with transcript and tissue as additional moderators. Observed patterns were similar for general as for transcript- and tissue-specific responses. The expected overall response to arbitrary metal exposure was a lnRR of 0.50, corresponding to a 65 % increase relative a non-exposed control. However, when accounting for publication bias, the estimated ‘true’ response showed no such effect. Furthermore, expected response magnitude increased slightly with exposure time, but there was little support for general monotonic concentration-dependence with regards to TU. Altogether, this work reveals potential limitations that need consideration prior to applying the selected transcripts as biomarkers in environmental risk assessment. This article is protected by copyright. All rights reserved. Environ Toxicol Chem 2022;00:0–0. 

    Fulltekst (pdf)
    fulltext
  • 8.
    Karim, Md Rezaul
    et al.
    Rajshahi University, Bangladesh ; Islamic University, Bangladesh.
    Rahman, Mashiur
    Rajshahi University, Bangladesh.
    Islam, Khairul
    Rajshahi University, Bangladesh.
    Al Mamun, Abdullah
    Rajshahi University, Bangladesh.
    Hossain, Shakhawoat
    Rajshahi University, Bangladesh.
    Hossain, Ekhtear
    Rajshahi University, Bangladesh.
    Aziz, Abdul
    Rajshahi University, Bangladesh.
    Yeasmin, Fouzia
    Rajshahi University, Bangladesh.
    Agarwal, Smita
    Rajshahi University, Bangladesh.
    Hossain, Md Imam
    Rajshahi University, Bangladesh.
    Saud, Zahangir Alam
    Rajshahi University, Bangladesh.
    Nikkon, Farjana
    Rajshahi University, Bangladesh.
    Hossain, Mostaque
    Rajshahi University, Bangladesh.
    Mandal, Abul
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Jenkins, Richard O.
    De Montfort University, United Kingdom .
    Haris, Parvez I.
    De Montfort University, United Kingdom .
    Miyataka, Hideki
    Tokushima Bunri University, Japan.
    Himeno, Seiichiro
    Tokushima Bunri University, Japan.
    Hossain, Khaled
    Rajshahi University, Bangladesh.
    Increases in Oxidized Low-Density Lipoprotein and Other Inflammatory and Adhesion Molecules With a Concomitant Decrease in High-Density Lipoprotein in the Individuals Exposed to Arsenic in Bangladesh2013Inngår i: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 135, nr 1, s. 17-25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elevated exposure to arsenic has been suggested to be associated with atherosclerosis leading to cardiovascular disease (CVD). However, biochemical events underlying the arsenic-induced atherosclerosis have not yet been fully documented. The aim of this study was to investigate the associations of circulating molecules involved in atherosclerosis with arsenic exposure in the individuals exposed to arsenic in Bangladesh. A total of 324 study subjects, 218 from arsenic-endemic areas and 106 from nonendemic areas in Bangladesh, were recruited. Drinking water, hair, nail, and blood samples were collected from the study subjects for analysis. Total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels were lower in arsenic-endemic subjects than those of nonendemic subjects. Oxidized LDL (Ox-LDL), C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) levels were significantly higher in arsenic-endemic subjects than those in nonendemic subjects. All these circulating molecules showed significant correlations with arsenic exposure (water, hair, and nail arsenic concentrations), and all these relations were significant before and after adjusting for relevant covariates. Among the circulating molecules tested in this study, HDL, Ox-LDL, and CRP showed dose-response relationships with arsenic exposure. Ox-LDL/ HDL ratios were increased with the increasing concentrations of arsenic in the water, hair, and nails. Furthermore, non-HDL cholesterol and TC/ HDL ratios were significantly correlated with arsenic exposure before and after adjusting for relevant covariates. Thus, all the observed associations may be the major features of arsenic exposure-related atherosclerosis leading to CVD.

  • 9.
    Szekeres, Ferenc L. M.
    et al.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Division of Genetic Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Walum, Erik
    Glucox Biotech AB, Färentuna, Sweden.
    Wikström, Per
    Glucox Biotech AB, Färentuna, Sweden.
    Arner, Anders
    Division of Genetic Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockhom, Sweden ; Department of Clinical Sciences Lund, Thoracic Surgery, Lund University, c/o Igelösa Life Science AB, Lund, Sweden.
    A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia–reperfusion in the mouse heart2021Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikkel-id 11970Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The NADPH oxidase enzymes Nox2 and 4, are important generators of Reactive oxygen species (ROS). These enzymes are abundantly expressed in cardiomyocytes and have been implicated in ischemia–reperfusion injury. Previous attempts with full inhibition of their activity using genetically modified animals have shown variable results, suggesting that a selective and graded inhibition could be a more relevant approach. We have, using chemical library screening, identified a new compound (GLX481304) which inhibits Nox 2 and 4 (with IC50 values of 1.25 µM) without general antioxidant effects or inhibitory effects on Nox 1. The compound inhibits ROS production in isolated mouse cardiomyocytes and improves cardiomyocyte contractility and contraction of whole retrogradely (Langendorff) perfused hearts after a global ischemia period. We conclude that a pharmacological and partial inhibition of ROS production by inhibition of Nox 2 and 4 is beneficial for recovery after ischemia reperfusion and might be a promising venue for treatment of ischemic injury to the heart. 

    Fulltekst (pdf)
    fulltext
  • 10.
    Uvnäs-Moberg, Kerstin
    et al.
    Department of Animal Environment and Health, Swedish University of Agricultural Sciences, Skara, Sweden.
    Handlin, Linda
    Högskolan i Skövde, Institutionen för hälsa och lärande. Högskolan i Skövde, Forskningsspecialiseringen Hälsa och Lärande.
    Kendall-Tackett, Kathleen
    Texas Tech University School of Medicine, Amarillo, TX, USA.
    Petersson, Maria
    Department of Molecular Medicine and Surgery, Endocrine and Diabetes Unit, Karolinska Institutet, Sweden.
    Oxytocin is a principal hormone that exerts part of its effects by active fragments2019Inngår i: Medical Hypotheses, ISSN 0306-9877, E-ISSN 1532-2777, Vol. 133, s. 1-9, artikkel-id 109394Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Oxytocin is a nonapeptide consisting of a cyclic six amino-acid structure and a tail of three amino acids. It was originally known for its ability to induce milk ejection and to stimulate uterine contractions. More recently, oxytocin has been shown to stimulate social behaviors, and exert pain-relieving, anti-stress/anti-inflammatory and restorative effects. We hypothesize that oxytocin is a principal hormone that, in part, exerts its effects after degradation to active fragments with more specific effect profiles. Experimental findings on rats show that administered oxytocin exerts biphasic effects. For example, after an initial increase in pain threshold, a second more long-lasting increase follows. Blood pressure and cortisol levels initially increase and then reverse into a long-lasting decrease in blood pressure and cortisol. Whereas the initial effects are, the second-phase effects are not blocked by an oxytocin antagonist, but by an opioid mu-antagonist and by an alpha 2-adrenoreceptor antagonist, respectively, suggesting that other receptors are involved. Repeated administration of oxytocin induces multiple anti-stress effects, which are mediated by alpha 2-adrenoreceptors. Repeated administration of linear oxytocin and linear oxytocin fragments with a retained C-terminal reduce spontaneous motor activity, a sedative or anti-stress effect, suggesting that alpha 2-adrenoreceptors have been activated. In contrast, linear mid-fragments stimulate motor activity. Low-intensity stimulation of cutaneous nerves in rats, as well as breastfeeding and skin-to-skin contact between mothers and babies, trigger immediate anti-stress effects. Some of these effects are likely caused by open ring/linear C-terminal fragments activating alpha 2-adrenoreceptors. Oxytocin fragments may be pre-formed and released in the brain or created by metabolic conversion of the principal hormone oxytocin in the central nervous system. Oxytocin and its fragments may also be released from peripheral sites, such as peripheral nerves, the gastrointestinal tract, and blood vessels in response to decreased sympathetic or increased parasympathetic nervous tone. Smaller fragments of oxytocin produced in the periphery may easily pass the blood-brain barrier to induce effects in the brain. In conclusion, oxytocin is linked to many different, sometimes opposite effects. The intact cyclic molecule may act to initiate social interaction and associated psychophysiological effects, whereas linear oxytocin and C-terminal fragments may induce relaxation and anti-stress effects following social interaction. In this way, the principal hormone oxytocin and its fragments may take part in a behavioral sequence, ranging from approach and interaction to calm and relaxation. Linear fragments, with an exposed cysteine-residue, may exert anti-inflammatory and antioxidant effects and thereby contribute to the health-promoting effects of oxytocin. 

    Fulltekst (pdf)
    fulltext
  • 11.
    Wallner, Fredrik K.
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Redoxis AB/ProNoxis AB, Lund, Sweden / Wallner Medicinal Chemistry AB, Göteborg, Sweden.
    Hultquist Hopkins, Malin
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Woodworth, Nina
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Lindvall Bark, Therese
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Olofsson, Peter
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Tilevik, Andreas
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Correlation and cluster analysis of immunomodulatory drugs based on cytokine profiles2018Inngår i: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 128, s. 244-251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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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