| 1. |
- Hammarlund, Maria, et al.
(författare)
-
The Alpha 7 Nicotinic Acetylcholine Receptor Does Not Affect Neonatal Brain Injury
- 2022
-
Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:8
-
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.
|
|
| 2. |
- Hammarlund, Maria, et al.
(författare)
-
The selectivealpha7 nicotinic acetylcholine receptor agonist AR‑R17779 does not affect ischemia-reperfusion brain injury in mice.
- 2021
-
Ingår i: Bioscience reports. - 1573-4935. ; 41:6
-
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.
|
|
| 3. |
- Pattanaik, Bagmi, 1977, et al.
(författare)
-
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
-
Ingår i: Faseb Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 36:5
-
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.
|
|
| 4. |
- Svahn, Sara L, et al.
(författare)
-
Spleen proteomics data from high fat diet fed mice
- 2020
-
Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 32
-
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.
|
|
| 5. |
- 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.
|
|
| 6. |
- Engstrom, G., et al.
(författare)
-
Cardiovagal Function Measured by the Deep Breathing Test: Relationships With Coronary Atherosclerosis
- 2022
-
Ingår i: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 11:7
-
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.
|
|
| 7. |
- Rodrigues Silva, Vagner Ramon, 1985, et al.
(författare)
-
Somatic ablation of IKKβ in liver and leukocytes is not tolerated in obese mice but hepatic IKKβ deletion improves fatty liver and insulin sensitivity.
- 2022
-
Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - 1530-6860. ; 36:9
-
Tidskriftsartikel (refereegranskat)abstract
- The kinase IKKβ controls pro-inflammatory gene expression, and its activity in the liver and leukocytes was shown to drive metabolic inflammation and insulin resistance in obesity. However, it was also proposed that liver IKKβ signaling protects obese mice from insulin resistance and endoplasmic reticulum (ER) stress by increasing XBP1s protein stability. Furthermore, mice lacking IKKβ in leukocytes display increased lethality to lipopolysaccharides. This study aims at improving our understanding of the role of IKKβ signaling in obesity. We induced IKKβ deletion in hematopoietic cells and liver of obese mice by Cre-LoxP recombination, using an INF-inducible system, or a liver-specific IKKβ deletion in obese mice by adenovirus delivery of the Cre recombinase. The histopathological, immune, and metabolic phenotype of the mice was characterized. IKKβ deletion in the liver and hematopoietic cells was not tolerated in mice with established obesity exposed to the TLR3 agonist poly(I:C) and exacerbated liver damage and ER-stress despite elevated XBP1s. By contrast, liver-specific ablation of IKKβ in obese mice reduced steatosis and improved insulin sensitivity in association with increased XBP1s protein abundance and reduced expression of de-novo lipogenesis genes. We conclude that IKKβ blockage in liver and leukocytes is not tolerated in obese mice exposed to TLR3 agonists. However, selective hepatic IKKβ ablation improves fatty liver and insulin sensitivity in association with increased XBP1s protein abundance and reduced expression of lipogenic genes.
|
|
| 8. |
- Ulleryd, Marcus A, et al.
(författare)
-
RNA sequencing data describing transcriptional changes in aorta of ApoE-/mice after alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) stimulation
- 2020
-
Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 30
-
Tidskriftsartikel (refereegranskat)abstract
- This manuscript is a companion paper to Ulleryd M.U. et al., "Stimulation of alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) inhibits atherosclerosis via immunomodulatory effects on myeloid cells" Atherosclerosis, 2019 [1]. Data shown here include RNA sequencing data from whole aorta of ApoE-/- mice fed high fat diet and treated with the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) agonist AZ6983 for 8 weeks using subcutaneously implanted osmotic minipumps. Here we present the top gene networks affected by treatment with AZ6983, as well as the up- and down-regulated genes in aorta after treatment. Further, a URL link to the RNA sequencing datasets submitted to GEO is included. (C) 2020 The Authors. Published by Elsevier Inc.
|
|
| 9. |
- Parma, L., et al.
(författare)
-
Bis(maltolato)oxovanadium(IV) Induces Angiogenesis via Phosphorylation of VEGFR2
- 2020
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 21:13
-
Tidskriftsartikel (refereegranskat)abstract
- VEGFR2 and VEGF-A play a pivotal role in the process of angiogenesis. VEGFR2 activation is regulated by protein tyrosine phosphatases (PTPs), enzymes that dephosphorylate the receptor and reduce angiogenesis. We aim to study the effect of PTPs blockade using bis(maltolato)oxovanadium(IV) (BMOV) on in vivo wound healing and in vitro angiogenesis. BMOV significantly improves in vivo wound closure by 45% in C57BL/6JRj mice. We found that upon VEGFR2 phosphorylation induced by endogenously produced VEGF-A, the addition of BMOV results in increased cell migration (45%), proliferation (40%) and tube formation (27%) in HUVECs compared to control. In a mouse ex vivo, aortic ring assay BMOV increased the number of sprouts by 3 folds when compared to control. However, BMOV coadministered with exogenous VEGF-A increased ECs migration, proliferation and tube formation by only 41%, 18% and 12% respectively and aortic ring sprouting by only 1-fold. We also found that BMOV enhances VEGFR2 Y951 and p38MAPK phosphorylation, but not ERK1/2. The level of phosphorylation of these residues was the same in the groups treated with BMOV supplemented with exogenous VEGF-A and exogenous VEGF-A only. Our study demonstrates that BMOV is able to enhance wound closure in vivo. Moreover, in the presence of endogenous VEGF-A, BMOV is able to stimulate in vitro angiogenesis by increasing the phosphorylation of VEGFR2 and its downstream proangiogenic enzymes. Importantly, BMOV had a stronger proangiogenic effect compared to its effect in coadministration with exogenous VEGF-A.
|
|
