| 1. |
- Hammarlund, Maria, et al.
(författare)
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The Alpha 7 Nicotinic Acetylcholine Receptor Does Not Affect Neonatal Brain Injury
- 2022
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation plays a central role in the development of neonatal brain injury. The alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) can modulate inflammation and has shown promising results as a treatment target in rodent models of adult brain injury. However, little is known about the role of the alpha 7nAChR in neonatal brain injury. Hypoxic-ischemic (HI) brain injury was induced in male and female C57BL/6 mice, alpha 7nAChR knock-out (KO) mice and their littermate controls on postnatal day (PND) 9-10. C57BL/6 pups received i.p. injections of alpha 7nAChR agonist PHA 568487 (8 mg/kg) or saline once daily, with the first dose given directly after HI. Caspase-3 activity and cytokine mRNA expression in the brain was analyzed 24 h after HI. Motor function was assessed 24 and 48 h after HI, and immunohistochemistry was used to assess tissue loss at 24 h and 7 days after HI and microglial activation 7 days after HI. Activation of alpha 7nAChR with the agonist PHA 568487 significantly decreased CCL2/MCP-1, CCL5/RANTES and IL-6 gene expression in the injured brain hemisphere 24 h after HI compared with saline controls in male, but not female, pups. However, alpha 7nAChR activation did not alter caspase-3 activity and TNF alpha, IL-1 beta and CD68 mRNA expression. Furthermore, agonist treatment did not affect motor function (24 or 48 h), neuronal tissue loss (24 h or 7 days) or microglia activation (7 days) after HI in either sex. Knock-out of alpha 7nAChR did not influence neuronal tissue loss 7 days after HI. In conclusion, targeting the alpha 7nAChR in neonatal brain injury shows some effect on dampening acute inflammatory responses in male pups. However, this does not lead to an effect on overall injury outcome.
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| 2. |
- Hammarlund, Maria, et al.
(författare)
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The selective alpha7 nicotinic acetylcholine receptor agonist AR‑R17779 does not affect ischemia-reperfusion brain injury in mice.
- 2021
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Ingår i: Bioscience reports. - 1573-4935. ; 41:6
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation plays a central role in stroke-induced brain injury. The alpha7 nicotinic acetylcholine receptor (α7nAChR) can modulate immune responses in both the periphery and the brain. The aims of this study were to investigate α7nAChR expression in different brain regions and evaluate the potential effect of the selective α7nAChR agonist AR-R17779 on ischemia-reperfusion brain injury in mice. Droplet digital PCR (ddPCR) was used to evaluate the absolute expression of the gene encoding α7nAChR (Chrna7) in hippocampus, striatum, thalamus and cortex in adult, naïve mice. Mice subjected to transient middle cerebral artery occlusion (tMCAO) or sham surgery were treated with α7nAChR agonist AR-R17779 (12 mg/kg) or saline once daily for five days. Infarct size and microglial activation seven days after tMCAO were analyzed using immunohistochemistry. Chrna7 expression was found in all analyzed brain regions in naïve mice, with the highest expression in cortex and hippocampus. At sacrifice, white blood cell count was significantly decreased in AR-R17779 treated mice compared with saline controls in the sham groups, although, no effect was seen in the tMCAO groups. Brain injury and microglial activation was evident seven days after tMCAO. However, no difference was found between mice treated with saline or AR‑R17779. In conclusion, α7nAChR expression varies in different brain regions and, despite a decrease in white blood cells in sham mice receiving AR-R17779, this compound does not affect stroke-induced brain injury.
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| 3. |
- Key, Timothy J., et al.
(författare)
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Consumption of Meat, Fish, Dairy Products, Eggs and Risk of Ischemic Heart Disease : A Prospective Study of 7198 Incident Cases Among 409,885 Participants in the Pan-European EPIC Cohort
- 2019
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Ingår i: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 139:25, s. 2835-2845
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is uncertainty about the relevance of animal foods to the etiology of ischemic heart disease (IHD). We examined meat, fish, dairy products and eggs and risk for IHD in the pan-European EPIC cohort.METHODS: A prospective study of 409,885 men and women in nine European countries. Diet was assessed using validated questionnaires, calibrated using 24-hour recalls. Lipids and blood pressure were measured in a subsample. During 12.6 years mean follow up, 7198 participants had a myocardial infarction or died from IHD. The relationships of animal foods with risk were examined using Cox regression with adjustment for other animal foods and relevant covariates.RESULTS: The hazard ratio (HR) for IHD was 1.19 (95% CI 1.06-1.33) for a 100 g/d increment in intake of red and processed meat, and this remained significant after excluding the first 4 years of follow-up (HR 1.25 [1.09-1.42]). Risk was inversely associated with intakes of yogurt (HR 0.93 [0.89-0.98] per 100 g/d increment), cheese (HR 0.92 [0.86-0.98] per 30 g/d increment) and eggs (HR 0.93 [0.88-0.99] per 20 g/d increment); the associations with yogurt and eggs were attenuated and non-significant after excluding the first 4 years of follow-up. Risk was not significantly associated with intakes of poultry, fish or milk. In analyses modelling dietary substitutions, replacement of 100 kcal/d from red and processed meat with 100 kcal/d from fatty fish, yogurt, cheese or eggs was associated with approximately 20% lower risk of IHD. Consumption of red and processed meat was positively associated with serum non-HDL cholesterol concentration and systolic blood pressure, and consumption of cheese was inversely associated with serum non-HDL cholesterol.CONCLUSIONS: Risk for IHD was positively associated with consumption of red and processed meat, and inversely associated with consumption of yogurt, cheese and eggs, although the associations with yogurt and eggs may be influenced by reverse causation bias. It is not clear whether the associations with red and processed meat and cheese reflect causality, but they were consistent with the associations of these foods with plasma non-HDL cholesterol, and for red and processed meat with systolic blood pressure, which could mediate such effects.
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| 4. |
- Pattanaik, Bagmi, 1977, et al.
(författare)
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Polymorphisms in alpha 7 nicotinic acetylcholine receptor gene, CHRNA7, and its partially duplicated gene, CHRFAM7A, associate with increased inflammatory response in human peripheral mononuclear cells
- 2022
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Ingår i: Faseb Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 36:5
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Tidskriftsartikel (refereegranskat)abstract
- The vagus nerve can, via the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR), regulate inflammation. The gene coding for the alpha 7nAChR, CHRNA7, can be partially duplicated, that is, CHRFAM7A, which is reported to impair the anti-inflammatory effect mediated via the alpha 7nAChR. Several single nucleotide polymorphisms (SNPs) have been described in both CHRNA7 and CHRFAM7A, however, the functional role of these SNPs for immune responses remains to be investigated. In the current study, we set out to investigate whether genetic variants of CHRNA7 and CHRFAM7A can influence immune responses. By investigating data available from the Swedish SciLifeLab SCAPIS Wellness Profiling (S3WP) study, in combination with droplet digital PCR and freshly isolated PBMCs from the S3WP participants, challenged with lipopolysaccharide (LPS), we show that CHRNA7 and CHRFAM7A are expressed in human PBMCs, with approximately four times higher expression of CHRFAM7A compared with CHRNA7. One SNP in CHRFAM7A, rs34007223, is positively associated with hsCRP in healthy individuals. Furthermore, gene ontology (GO)-terms analysis of plasma proteins associated with gene expression of CHRNA7 and CHRFAM7A demonstrated an involvement for these genes in immune responses. This was further supported by in vitro data showing that several SNPs in both CHRNA7 and CHRFAM7A are significantly associated with cytokine response. In conclusion, genetic variants of CHRNA7 and CHRFAM7A alters cytokine responses. Furthermore, given that CHRFAM7A SNP rs34007223 is associated with inflammatory marker hsCRY in healthy individuals suggests that CHRFAM7A may have a more pronounced role in regulating inflammatory processes in humans than previously been recognized.
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| 5. |
- Svahn, Sara L, et al.
(författare)
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Spleen proteomics data from high fat diet fed mice
- 2020
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Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 32
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Tidskriftsartikel (refereegranskat)abstract
- The composition of the diet affects many processes in the body, including body weight and endocrine system. We have previously shown that dietary fat also affects the immune system. Mice fed high fat diet rich in polyunsaturated fatty acids survive S. aureus infection to a much greater extent than mice fed high fat diet rich in saturated fatty acids. Here we present data regarding the dietary effects on protein expression in spleen from mice fed three different diets, I) low fat/chow diet (LFD, n = 4), II) high fat diet rich in saturated fatty acids (HFD-S, n = 4) and III) high fat diet rich in polyunsaturated fatty acids (HFD-P, n = 4). We performed mass spectrophotometry based quantitative proteomics analysis of isolated spleen by implementing the isobaric tags for relative and absolute quantification (iTRAQ) approach. Mass spectrometry data were analyzed using Proteome Discoverer 2.4 software using the search engine mascot against Mus musculus in SwissProt. 924 proteins are identified in all sets (n = 4) for different dietary effects taken for statistical analysis using Qlucore Omics Explorer software. Only 20 proteins were found to be differentially expressed with a cut-off value of false discovery rate < 0.1 (q-value) when comparing HFD-S and HFD-P but no differentially expressed proteins were found when LFD was compared with HFD-P or HFD-S. The identified proteins and statistical analysis comparing HFD-S and HFD-P diets are available as a supplementary file S1. We identified a subset of proteins that showed an inverse expression pattern between two high fat diets. These differentially expressed proteins were further classified by gene ontology for their role in biological processes and molecular functions. Mass spectrometry raw data are also available via ProteomeXchange with identifier PXD020365.
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| 6. |
- Adermark, Louise, 1974, et al.
(författare)
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Weight gain and neuroadaptations elicited by high fat diet depend on fatty acid composition.
- 2021
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 126
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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.
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| 7. |
- Andersson, Irene, 1978, et al.
(författare)
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Endothelial dysfunction in growth hormone transgenic mice
- 2006
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 110:2, s. 217-25
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Tidskriftsartikel (refereegranskat)abstract
- Acromegaly [overproduction of GH (growth hormone)] is associated with cardiovascular disease. Transgenic mice overexpressing bGH (bovine GH) develop hypertension and hypercholesterolaemia and could be a model for cardiovascular disease in acromegaly. The aims of the present study were to investigate the effects of excess GH on vascular function and to test whether oxidative stress affects endothelial function in bGH transgenic mice. We studied the ACh (acetylcholine)-induced relaxation response in aortic and carotid rings of young (9-11 weeks) and aged (22-24 weeks) female bGH transgenic mice and littermate control mice, without and with the addition of a free radical scavenger {MnTBAP [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride]}. We also measured mRNA levels of eNOS (endothelial nitric oxide synthase) and EC-SOD (extracellular superoxide dismutase). Intracellular superoxide anion production in the vascular wall was estimated using a dihydroethidium probe. Carotid arteries from bGH transgenic mice had an impaired ACh-induced relaxation response (young, 46 +/- 7% compared with 69 +/- 8%; aged, 52 +/- 5% compared with 80 +/- 3%; P < 0.05), whereas endothelial function in aorta was intact in young but impaired in aged bGH transgenic mice. Endothelial dysfunction was corrected by addition of MnTBAP in carotid arteries from young mice and in aortas from aged mice; however, MnTBAP did not correct endothelial dysfunction in carotid arteries from aged bGH transgenic mice. There was no difference in intracellular superoxide anion production between bGH transgenic mice and control mice, whereas mRNA expression of EC-SOD and eNOS was increased in aortas from young bGH transgenic mice compared with control mice (P < 0.05). We interpret these data to suggest that bGH overexpression is associated with a time- and vessel-specific deterioration in endothelial function, initially caused by increased oxidative stress and later by other alterations in vascular function.
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| 8. |
- Bernberg, Evelina, 1981, et al.
(författare)
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Effects of social isolation and environmental enrichment on atherosclerosis in ApoE-/- mice
- 2008
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Ingår i: Stress. - 1607-8888 .- 1025-3890. ; 11:5, s. 381-9
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Tidskriftsartikel (refereegranskat)abstract
- Social support and a stimulating environment have been suggested to reduce stress reactions and cardiovascular risk. The aim of this study was to assess the role of environmental enrichment and social interaction for development of atherosclerosis in atherosclerosis prone mice. Male ApoE-/- mice were divided into four groups and followed during 20 weeks: (i) enriched environment (E, n=12), (ii) deprived environment (ED, n=12), (iii) enriched environment with exercise (E-Ex, n=12) and (iv) socially deprived by individual housing (SD, n=10). Plasma lipid and cytokine concentrations were measured. Atherosclerosis was quantified in cross-sections of innominate artery and en face in thoracic aorta. Plaque area was significantly increased in SD mice in the innominate artery (P<0.05 vs. all other groups), but not in the thoracic aorta. Plasma lipids were increased in SD mice (P<0.001 vs. all for total cholesterol, P<0.05 vs. E and P<0.01 vs. ED for triglycerides). Plasma concentration of granulocyte-colony stimulating factor (G-CSF) was decreased in SD mice compared to E mice (P<0.05). Thus, social isolation increased atherosclerosis and plasma lipids in ApoE-/- mice. Reduction in plasma G-CSF levels may hamper endothelial regeneration in the atherosclerotic process. While environmental enrichment did not affect atherosclerosis, social isolation accelerated atherosclerosis.
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| 9. |
- Engstrom, G., et al.
(författare)
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Cardiovagal Function Measured by the Deep Breathing Test: Relationships With Coronary Atherosclerosis
- 2022
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Ingår i: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Background The cardiovagal function can be assessed by quantification of respiratory sinus arrhythmia (RSA) during a deep breathing test. However, population studies of RSA and coronary atherosclerosis are lacking. This population-based study examined the relationship between RSA during deep breathing and coronary atherosclerosis, assessed by coronary artery calcium score (CACS). Methods and Results SCAPIS (Swedish Cardiopulmonary Bioimage Study) randomly invited men and women aged 50 to 64 years from the general population. CACS was obtained from computed tomography scanning, and deep breathing tests were performed in 4654 individuals. Expiration-inspiration differences (E-Is) of heart rates were calculated, and reduced RSA was defined as E-I in the lowest decile of the population. The relationship between reduced RSA and CACS (CACS >= 100 or CACS >= 300) was calculated using multivariable-adjusted logistic regression. The proportion of CACS >= 100 was 24% in the lowest decile of E-I and 12% in individuals with E-I above the lowest decile (P<0.001), and the proportion of CACS >= 300 was 12% and 4.8%, respectively (P<0.001). The adjusted odds ratio (OR) for CACS >= 100 was 1.42 (95% CI, 1.10-1.84) and the adjusted OR for CACS >= 300 was 1.62 (95% CI, 1.15-2.28), when comparing the lowest E-I decile with deciles 2 to 10. Adjusted ORs per 1 SD lower E-I were 1.17 (P=0.001) for CACS >= 100 and 1.28 (P=0.001) for CACS >= 300. Conclusions Low RSA during deep breathing is associated with increased coronary atherosclerosis as assessed by CACS, independently of traditional cardiovascular risk factors. Cardiovagal dysfunction could be a prevalent and modifiable risk factor for coronary atherosclerosis in the general population.
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| 10. |
- Hägg Samuelsson, Ulrika, 1973, et al.
(författare)
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Gene expression profile and aortic vessel distensibility in voluntarily exercised spontaneously hypertensive rats: potential role of heat shock proteins
- 2005
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Ingår i: Physiol Genomics. - 1531-2267 .- 1094-8341. ; 22:3, s. 319-26
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Tidskriftsartikel (refereegranskat)abstract
- Physical exercise is considered to be beneficial for cardiovascular health. Nevertheless, the underlying specific molecular mechanisms still remain unexplored. In this study, we aimed to investigate the effects of voluntary exercise on vascular mechanical properties and gene regulation patterns in spontaneously hypertensive rats. By using ultrasound biomicroscopy in an ex vivo perfusion chamber, we studied the distensibility of the thoracic aorta. Furthermore, exercise-induced gene regulation was studied in aortae, using microarray analysis and validated with real-time PCR. We found that distensibility was significantly improved in aortas from exercising compared with control rats (P < 0.0001). Exercising rats demonstrated a striking pattern of coordinated downregulation of genes belonging to the heat shock protein family. In conclusion, voluntary exercise leads to improved vessel wall distensibility and reduced gene expression of heat shock protein 60 and 70, which may indicate decreased oxidative stress in the aortic vascular wall.
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