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Träfflista för sökning "AMNE:(MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmacology and Toxicology) "

Sökning: AMNE:(MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmacology and Toxicology)

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  • Zhang, C., et al. (författare)
  • The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alc33oholic fatty liver disease
  • 2020
  • Ingår i: Molecular Systems Biology. - 1744-4292. ; 16:4
  • Tidskriftsartikel (refereegranskat)abstract
    • The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine by performing a 7-day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.
  • Ahlborg, Gunnar, 1948-, et al. (författare)
  • Reproductive effects of chemical exposures in health professions
  • 1995
  • Ingår i: Journal of Occupational and Environmental Medicine. - 1076-2752. ; 37:8, s. 957-61
  • Forskningsöversikt (refereegranskat)abstract
    • Numerous chemical substances are handled by persons working in the health care sector. At exposure levels that may occur in the occupational setting, some of these substances are potentially harmful to the reproductive processes. Among the potentially harmful substances are anesthetic gases, antineoplastic agents, and sterilants. The epidemiological evidence of increased risks for adverse reproductive effects (eg, subfertility, spontaneous abortions, congenital defects) from such exposure is not unequivocal. However, due to the toxic potential, exposures should be kept at a minimum, and this may be especially important for workers who are pregnant or are planning to achieve pregnancy.
  • Xu, Bo, 1980- (författare)
  • Evolutionary and Pharmacological Studies of NPY and QRFP Receptors
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The neuropeptide Y (NPY) system consists of 3-4 peptides and 4-7 receptors in vertebrates. It has powerful effects on appetite regulation and is involved in many other biological processes including blood pressure regulation, bone formation and anxiety. This thesis describes studies of the evolution of the NPY system by comparison of several vertebrate species and structural studies of the human Y2 receptor, which reduces appetite, to identify amino acid residues involved in peptide-receptor interactions.</p><p>The NPY system was studied in zebrafish (<em>Danio rerio</em>), western clawed frog (<em>Xenopus tropicalis)</em><em>, </em>and sea lamprey (<em>Petromyzon marinus</em>). The receptors were cloned and functionally expressed and their pharmacological profiles were determined using the native peptides in either binding studies or a signal transduction assay. Some peptide-receptor preferences were observed, indicating functional specialization.</p><p>A receptor family closely related to the NPY receptors, called the QRFP receptors, was investigated. A QRFP receptor was cloned from amphioxus, <em>Branchistoma floridae</em>, showing that the receptor arose before the origin of the vertebrates. Evolutionary studies demonstrated that the ancestral vertebrate had as many as four QRFP receptors, only one of which remains in mammals today. This correlates with the NPY receptor family, located in the same chromosomal regions, which had seven members in the ancestral vertebrate but only 4-5 in living mammals. Some vertebrates have considerably more complex NPY and QRFP receptor systems than humans and other mammals.</p><p>Two studies investigated interactions of NPY-family peptides with the human Y2 receptor. Candidate residues, selected based on structural modeling and docking, were mutated to disrupt possible interactions with peptide ligands. The modified receptors were expressed in cultured cells and investigated by measuring binding and functional responses. Several receptor residues were found to influence peptide-receptor interactions, some of which are involved in maintaining receptor structure. In a pilot study, the kinetics of peptide-receptor interaction were found to be very slow, of the order several hours.</p><p>In conclusion, this thesis clarifies evolutionary relationships for the complex NPY and QRFP peptide-receptor systems and improves the structural models of the human NPY-family receptors, especially Y2. These results will hopefully facilitate drug design for targeting of NPY-family receptors.</p>
  • Hassellöv, Martin, 1970-, et al. (författare)
  • REACH missar nano!
  • 2009
  • Ingår i: Miljöforskning. ; 3/4
  • Tidskriftsartikel (övrigt vetenskapligt)
  • Löfgren, Magnus, 1979- (författare)
  • Behavioral effects of female sex steroid hormones <em></em> models of PMS and PMDD in Wistar rats<em></em>
  • 2009
  • Ingår i: Stress- och könshormoners verkningar på centrala nervsystemet. - Umaå : Department of Clinical Sciences, Division of Obstetrics and Gynecology. - 978-91-7264-796-1
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background </strong>Animal models can be used to mimic human conditions of psychopathology, and also as pre-clinical models to evaluate candidate drugs. With hormonal treatment it is possible to produce behavior in the rat which corresponds to the mental symptoms of pre-menstrual syndrome (PMS), and pre-menstrual dysphoric disorder (PMDD). PMS affects 25-30 % of all women in fertile age and 3-8% are diagnosed with the more severe condition PMDD. The cardinal mental symptoms are; irritability, mood-swings, depression, anxiety, fatigue, insomnia, difficulties with concentration and memory and learning difficulties. The symptoms of PMS/PMDD occur in the luteal phase in conjunction with increasing concentrations of progesterone (P4) and P4-metabolites. In anovulatory cycles the symptoms are absent. The hormones which produce the monthly reoccurring negative symptoms on mood are foremost the neuroactive metabolites; allopregnanolone (ALLO) and tetrahydro-deoxycorticosterone (THDOC). ALLO is produced by the corpus luteum, but can also be synthesized in the brain, both ALLO and THDOC can also be released from the adrenal cortex during stress. These steroids are active on the inhibitory GABA neurotransmitter system through the GABA<sub>A</sub> receptor, and the effects are similar to that of alcohol and benzodiazepines. These steroids have strong sedative and hypnotic effects. A paradox is that some individuals seem to react with negative mood on sex steroids while all fertile women have the cyclical steroid changes during the menstrual cycle. Some individuals are more sensitive to neuroactive steroids with influences of personality, heritability and stress factors.</p> <p><strong>Aims </strong>The thesis aims were to develop pre-clinical animal models of PMS/PMDD and to investigate induction of ALLO tolerance, individual sensitivity to neurosteroids and the interactions between chronic social stress and neurosteroids.</p> <p><strong>Methods </strong>In these studies male and female Wistar rats were used to test steroid hormone effects on learning and memory and behaviors analogous to negative mood symptoms. This was accomplished through hormonal treatment and a subsequent withdrawal period from P4 (P4) + estradiol (E2) (PEWD), or ALLO. To assess tolerance, memory and learning in the Morris water maze (MWM) was studied. Anxiety-like behaviors were tested with the elevated plus maze (EPM), open field test (OFT), and the intruder test (IT). The EPM or OFT was used to classify the rats as high or low responders on risk-taking and explorative behavior (HR/LR). For social ranking order assessment the tube test (TT) and food competition test (FCT) were used. Chronic social stress was accomplished through co-habituation with two older rats (chronic subordination stress). In female rats the estrous cycle followed using staining of vaginal smears. Concentration of corticosterone (CORT) was measured by radio-immuno-assay (RIA).</p> <p><strong>Results </strong>In the MWM ALLO pre-treatment produced tolerance to the acute negative ALLO effects. Both male and female rats showed behavioral correlations between the EPM and OFT tests, and correlations were also seen in CORT levels. Individuals with the stable trait of high risk-taking and explorative behavior (HR) were more sensitive to PEWD induction of anxiety-like behavior. These animals also showed decreased CORT levels during withdrawal. Chronic subordination stress enhanced the response to PEWD on measures of locomotor activity and social anxiety-like behavior.</p> <p><strong>Conclusions </strong>It is possible to induce tolerance to the negative ALLO effects on learning and memory. The animal models of anxiety-like behavior show an individual PEWD response profile where HR rats are more sensitive. Exposure to chronic social stress enhanced the PEWD response. Hence there are both inherent and environmental factors behind the behavioral response to steroid hormones in rats.</p>
  • Scholz, Birger, et al. (författare)
  • Neuropeptidomic analysis of the embryonic Japanese quail diencephalon
  • 2010
  • Ingår i: ReproSafe.
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Background: Endogenous peptides such as neuropeptides are involved in numerous biological processes in the fully developed brain but very little is known about their role in brain development. Japanese quail is a commonly used bird model for studying sexual dimorphic brain development, especially adult male copulatory behavior in relation to manipulations of the embryonic endocrine system. This study uses a label-free liquid chromatography mass spectrometry approach to analyze the influence of age (embryonic days 12 vs 17), sex and embryonic day 3 ethinylestradiol exposure on the expression of multiple endogenous peptides in the developing diencephalon.</p> <p>Results: We identified a total of 65 peptides whereof 38 were sufficiently present in all groups for statistical analysis. Age was the most defining variable in the data and sex had the least impact. Most identified peptides were more highly expressed in embryonic day 17. The top candidates for EE2 exposure and sex effects were neuropeptide K (downregulated by EE2 in males and females), gastrin-releasing peptide (more highly expressed in control and EE2 exposed males) and gonadotropin-inhibiting hormone related protein 2 (more highly expressed in control males and displaying interaction effects between age and sex). We also report a new potential secretogranin-2 derived neuropeptide and previously unknown phosphorylations in the C-terminal flanking protachykinin 1 neuropeptide.</p> <p>Conclusions: This study is the first larger study on endogenous peptides in the developing brain and implies a previously unknown role for a number of neuropeptides in middle to late avian embryogenesis. It demonstrates the power of label-free liquid chromatography mass spectrometry to analyze the expression of multiple endogenous peptides and the potential to detect new putative peptide candidates in a developmental model.</p>
  • Andersson, Sören, 1957-, et al. (författare)
  • 2015
  • Patent (övrigt vetenskapligt)
  • Silva, A. V., et al. (författare)
  • A Probabilistic Approach to Evaluate the Risk of Decreased Total Triiodothyronine Hormone Levels following Chronic Exposure to PFOS and PFHxS via Contaminated Drinking Water
  • 2020
  • Ingår i: Environmental Health Perspectives. - 0091-6765. ; 128:7
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Extensive exposure to per- and polyfluoroalkyl substances (PFAS) have been observed in many countries. Current deterministic frameworks for risk assessment lack the ability to predict the likelihood of effects and to assess uncertainty. When exposure exceeds tolerable intake levels, these shortcomings hamper risk management and communication. OBJECTIVE: The integrated probabilistic risk assessment (IPRA) combines dose-response and exposure data to estimate the likelihood of adverse effects. We evaluated the usefulness of the IPRA for risk characterization related to decreased levels of total triiodothyronine (T-3) in humans following a real case of high exposure to PFAS via drinking water. METHODS: PFAS exposure was defined as serum levels from residents of a contaminated area in Ronneby, Sweden. Median levels were 270 ng/mL [perfluoroociane sulfonic acid (PFOS)] and 229 ng/mE [perfluorohexane sulfonic acid (PFHxS)] for individuals who resided in Ronneby 1 y before the exposure termination. This data was integrated with data from a subchronic toxicity study in monkeys exposed daily to PFOS. Benchmark dose modeling was employed to describe separate dose effect relationship for males and females, and extrapolation factor distributions were used to estimate the corresponding human benchmark dose. The critical effect level was defined as a 10% decrease in total T-3. RESULTS: The median probability of critical exposure, following a combined exposure to PFOS and PFHxS, was estimated to he [2.1% (90% CI: 0.4%-13. M)]. Gender-based analysis showed that this risk was almost entirely distributed among women, namely [3.9% (907; CI: 0.8%-21.6%)]. DISCUSSION: The IPRA was compared with the traditional deterministic Margin of Exposure (MoE) approach. We conclude that probabilistic risk characterization represents an important step forward in the ability to adequately analyze group-specific health risks. Moreover, quantifying the sources of uncertainty is desirable, as it improves the awareness among stakeholders and will guide future efforts to improve accuracy.
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