| 51. |
- Nilsson, Johan, et al.
(författare)
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Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity
- 2021
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 213
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio.
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| 52. |
- Nilsson, Lisa M, 1976, et al.
(författare)
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Genetics and Therapeutic Responses to Tumor-Infiltrating Lymphocyte Therapy of Pancreatic Cancer Patient-Derived Xenograft Models
- 2022
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Ingår i: Gastro Hep Advances. - : Elsevier BV. - 2772-5723. ; 1:6, s. 1037-1048
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. Checkpoint immunotherapy has not yet shown encouraging results in pancreatic cancer possibly because of a poor immunogenicity and/or an immune suppressive microenvironment. The aim of this study was to develop patient-derived xenograft (PDX) models, compare their genetics to the original biopsies, and assess if autologous tumor-infiltrating lymphocytes (TILs) would have antitumoral activity in pancreatic cancer. Methods We subcutaneously transplanted tumors from 29 patients into NOG mice to generate PDX models. We established TIL cultures and injected them into PDX mice. We analyzed histology and genetics of biopsies and PDX tumors. Results Tumor growths were confirmed in 11 of 29 transplantations. The PDX tumors histologically resembled their original biopsies, but because stromal cells in the PDX model tumors were from mouse, their gene expression differed from the original biopsies. Immune checkpoint ligands other than programmed death ligand-1 (PD-L1) were expressed in pancreatic cancers, but PD-L1 was rarely expressed. When it was expressed, it correlated with tumor take in PDX models. One of the 3 tumors that expressed PD-L1 was an adenosquamous cancer, and another had a mismatch repair deficiency. TILs were expanded from 6 tumors and were injected into NOG or human interleukin-2 transgenic-NOG mice carrying PDX tumors. Regression of tumors could be verified in human interleukin-2 transgenic-NOG mice in 3 of the 6 PDX models treated with autologous TILs, including the adenosquamous PDX model. Conclusion PDX models of pancreatic cancer can be used to learn more about tumor characteristics and biomarkers and to evaluate responses to adoptive cell therapy and combination therapies. The major benefit of the model is that modifications of T cells can be tested in an autologous humanized mouse model to gain preclinical data to support the initiation of a clinical trial.
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| 53. |
- Nilsson, Sigrid, 1997-
(författare)
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Vasomotor Symptoms, Cardiovascular Risk and the Role of Physical Activity in Midlife Women
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The menopausal transition is, for most women, accompanied by hot flushes and night sweats (i.e., vasomotor symptoms, VMS). VMS has been associated with a worsened cardiovascular risk profile, but whether VMS constitutes an independent risk marker for developing subclinical atherosclerotic cardiovascular disease (ASCVD) is still uncertain. Visceral adipose tissue (VAT) contributes more to systemic low-grade inflammation than abdominal subcutaneous adipose tissue (ASAT), enhancing atherosclerosis development. Physical activity is an effective behavioral strategy to maintain and improve cardiovascular health. Whether a resistance training intervention (RTI) could reduce low-grade inflammation and VAT volume in postmenopausal women with VMS remains unclear, and whether the RTI-associated effects could be maintained over time requires further investigation.Material and Methods: This thesis is based on three studies. Study 1 was conducted on a subset of participants from the cross-sectional population-based Swedish CArdioPulmonary BioImage Study (SCAPIS), including women 50-64 years of age. The women underwent comprehensive cardiovascular assessments and completed an extensive female-specific questionnaire. VMS was assessed on a 4-point scale. Subclinical ASCVD was detected via coronary computed tomography angiography (CCTA), computed tomography (CT), and carotid ultrasound. Study 2 is a sub-study of 65 postmenopausal women with VMS and low physical activity, randomized to either three days/week of an RTI or unchanged physical activity for 15 weeks. Women underwent anthropometric measurements, magnetic resonance imaging (MRI), and blood sampling at baseline and after 15 weeks. During the last followup contact in Study 2 after two years, 35 women agreed to attend an additional clinic visit to reevaluate cardiovascular risk markers, marking the inception of Study 3.Results: Of 2995 women included in Study 1, 14.2% reported severe VMS (n = 425), 18.1% moderate VMS (n = 543), and 67.7% no or mild VMS (n = 2027). Current or previous severe VMS, but not moderate VMS, was significantly associated with CCTA-detected coronary atherosclerosis, with odds ratio (OR) before and after multivariable adjustment 1.36, 95% confidence interval (CI) 1.08 – 1.72 and 1.33, 95% CI 1.02 – 1.72, respectively. This association was only present for >5 years durations of severe VMS or when the onset of severe VMS occurred before menopause. Adjustment for menopausal hormone therapy strengthened the association for women with severe VMS >5 years (OR 1.67, 95% CI 1.16 – 2.40). Women compliant with an RTI had compared to a control group (CG), decreased adiponectin (p < 0.01), ASAT (p < 0.01), VAT (p < 0.01), total abdominal adipose tissue (TAAT) (p < 0.01) and fat ratio (p <0.001). Furthermore, an RTI reduced moderate to severe VMS frequency to six months post-intervention compared to a CG, but did neither contribute to preserved cardiovascular health markers nor improved health-related quality of life (HRQoL) after two years compared to a CG.Conclusions: There is a need for extra vigilance regarding cardiovascular risk factors in the group of women suffering from severe VMS. Implementing a 15-week RTI in these women could counteract the VAT redistribution and alter the frequency of moderate to severe VMS with maintained effects up to six months.
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| 54. |
- Nilsson Wadström, Benjamin, et al.
(författare)
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Aortic Stiffness, Inflammation, and Incidence of Cardiovascular Events in Elderly Participants From the General Population
- 2022
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Ingår i: Angiology. - : SAGE Publications. - 0003-3197 .- 1940-1574. ; 73:1, s. 51-59
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Tidskriftsartikel (refereegranskat)abstract
- Low-grade inflammation and arterial stiffness are key factors in the development of vascular aging. However, the interplay between arterial stiffness and inflammation for cardiovascular (CV) disease is unclear. Aortic pulse wave velocity (aPWV) and the inflammatory markers, high-sensitivity C-reactive protein (CRP) and orosomucoid, were measured in 2710 participants (median age: 72 years). These participants were followed up for a mean of 7.6 years for a composite CV disease end point. Per 1 interquartile range increment of CRP and orosomucoid, respectively, aPWV increased by 0.19 m/s (95% CI: 0.07-0.32) and 0.19 m/s (0.11-0.27), after multifactorial adjustment. Mediation analysis showed that aPWV, after multifactorial adjustment, mediated 8% (−4, 20) of the CV disease risk associated with CRP and 8% (−4, 18) of orosomucoid risk. The associated risk increased with combinations of high aPWV and high CRP or orosomucoid. We found no evidence that arterial PWV acted as an important mediator of the relationship between systemic inflammation and CV disease risk in this elderly population. The results instead indicate an additive effect. Our study supports the view that arterial stiffness and chronic inflammation affects CV risk mainly through separate causal pathways.
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| 55. |
- Nilsson Wadström, Benjamin, et al.
(författare)
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Exploring and comparing definitions of healthy vascular ageing in the population : characteristics and prospective cardiovascular risk
- 2021
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Ingår i: Journal of Human Hypertension. - : Springer Science and Business Media LLC. - 0950-9240 .- 1476-5527. ; 35:5, s. 428-436
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Tidskriftsartikel (refereegranskat)abstract
- Different methods can be used to define healthy vascular ageing (HVA). In this prospective cohort study, we explored three different definitions in order to provide guidance for which to use. 2718 subjects were included from the Cardiovascular (CV) arm of the Malmö Diet Cancer Study (MDCS; median age 71.9 years, 62.2% females). Three different definitions of HVA were used: HVA-1 (<15th percentile of aortic pulse wave velocity (aPWV) distribution from age-quintiles); HVA-2 (<35th percentile of aPWV+ <35th percentile of carotid Intima-Media Thickness. cIMT); and HVA-3 (aPWV < 7.6 m/s + no hypertension). The HVA-1 and HVA-2 groups were compared with the HVA-3, and to the corresponding groups without HVA (non-HVA), in cross-sectional analyses for baseline characteristics and using Cox regressions for prospective risk, yielding hazard ratios (HRs) adjusted for conventional risk factors. A composite CVD endpoint was used, consisting of myocardial infarctions, ischemic heart disease mortality, and coronary artery procedures. The baseline characteristics were, with minor exceptions, similar across HVA groups. In the fully adjusted model, the HRs (95%CI) were 0.62 (0.41–0.93), 0.45 (0.26–0.76), and 0.56 (0.34–0.91) for HVA-1, HVA-2, and HVA-3, respectively. In summary, this observational study of elderly subjects provides examples of integrating hypertension and cIMT in the definition of HVA, as compared with only using aPWV. As aPWV itself is such a robust marker of HVA, it is demanding to find additional markers which improve the definition. There is a need to create a generally accepted definition of HVA.
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| 56. |
- Pape Møller, Anders, et al.
(författare)
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Interaction of climate change with effects of conspecific and heterospecific density on reproduction
- 2020
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Ingår i: Oikos. - : Wiley. - 0030-1299 .- 1600-0706. ; 129:12, s. 1807-1819
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Tidskriftsartikel (refereegranskat)abstract
- We studied the relationship between temperature and the coexistence of great tit Parus major and blue tit Cyanistes caeruleus, breeding in 75 study plots across Europe and North Africa. We expected an advance in laying date and a reduction in clutch size during warmer springs as a general response to climate warming and a delay in laying date and a reduction in clutch size during warmer winters due to density‐dependent effects. As expected, as spring temperature increases laying date advances and as winter temperature increases clutch size is reduced in both species. Density of great tit affected the relationship between winter temperature and laying date in great and blue tit. Specifically, as density of great tit increased and temperature in winter increased both species started to reproduce later. Density of blue tit affected the relationship between spring temperature and blue and great tit laying date. Thus, both species start to reproduce earlier with increasing spring temperature as density of blue tit increases, which was not an expected outcome, since we expected that increasing spring temperature should advance laying date, while increasing density should delay it cancelling each other out. Climate warming and its interaction with density affects clutch size of great tits but not of blue tits. As predicted, great tit clutch size is reduced more with density of blue tits as temperature in winter increases. The relationship between spring temperature and density on clutch size of great tits depends on whether the increase is in density of great tit or blue tit. Therefore, an increase in temperature negatively affected the coexistence of blue and great tits differently in both species. Thus, blue tit clutch size was unaffected by the interaction effect of density with temperature, while great tit clutch size was affected in multiple ways by these interactions terms.
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| 57. |
- Parvin, Farjana, et al.
(författare)
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Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and AppNL-F Mice
- 2024
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Ingår i: ACS Chemical Neuroscience. - : AMER CHEMICAL SOC. - 1948-7193. ; 15:10, s. 2058-2069
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid plaques composed of fibrils of misfolded A beta peptides are pathological hallmarks of Alzheimer's disease (AD). A beta fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of A beta fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how A beta fibril structures in situ differ in A beta plaque of different mouse models expressing familial mutations in the A beta PP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and A beta-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and App(NL-F) have different fibril structures within A beta-amyloid plaques depending on the A beta PP-processing genotype. Co-staining with A beta-specific antibodies showed that individual plaques from APP23 mice expressing A beta PP Swedish mutation have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact A beta 40 fibrils, and the corona region is dominated by diffusely packed A beta 40 fibrils. Conversely, the A beta PP knock-in mouse App(NL-F), expressing the A beta PP Iberian mutation along with Swedish mutation has tiny, cored plaques consisting mainly of compact A beta 42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age-dependent polymorph rearrangement of plaque cores observed for APP23 and APPPS1 mice >12 months, appears strongly promoted by A beta 40 and was hence minuscule in App(NL-F). These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.
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| 58. |
- Reyes, Juan, et al.
(författare)
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Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinsons disease
- 2021
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-synuclein (alpha-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinsons disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that alpha-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that alpha-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric alpha-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of alpha-syn within the liver of three different transgenic (tg) mouse models expressing human alpha-syn under CNS-specific promoters, despite the lack of alpha-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of alpha-syn pathology within the liver of wild type mice one month after a single striatal alpha-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Ass) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed alpha-syn pathology containing alpha-syn within hepatocellular structures to a higher degree (75%) than control subjects without alpha-syn accumulation in the brain (57%). Our results reveal that alpha-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.
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| 59. |
- Stepanchuk, Anastasiia, et al.
(författare)
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Early detection of prion protein aggregation with a fluorescent pentameric oligothiophene probe using spectral confocal microscopy
- 2021
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Ingår i: Journal of Neurochemistry. - : WILEY. - 0022-3042 .- 1471-4159. ; 156:6, s. 1033-1048
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Tidskriftsartikel (refereegranskat)abstract
- Misfolding of the prion protein (PrP) and templating of its pathological conformation onto cognate proteins causes a number of lethal disorders of central nervous system in humans and animals, such as Creutzfeldt-Jacob disease, chronic wasting disease and bovine spongiform encephalopathy. Structural rearrangement of PrP (c) into PrP(Sc)promotes aggregation of misfolded proteins into beta-sheet-rich fibrils, which can be visualized by conformationally sensitive fluorescent probes. Early detection of prion misfolding and deposition might provide useful insights into its pathophysiology. Pentameric formyl thiophene acetic acid (pFTAA) is a novel amyloid probe that was shown to sensitively detect various misfolded proteins, including PrP. Here, we compared sensitivity of pFTAA staining and spectral microscopy with conventional methods of prion detection in mouse brains infected with mouse-adapted 22L prions. pFTAA bound to prion deposits in mouse brain sections exhibited a red-shifted fluorescence emission spectrum, which quantitatively increased with disease progression. Small prion deposits were detected as early as 50 days post-inoculation, well before appearance of clinical signs. Moreover, we detected significant spectral shifts in the greater brain parenchyma as early as 25 days post-inoculation, rivaling the most sensitive conventional method (real-time quaking-induced conversion). These results showcase the potential of pFTAA staining combined with spectral imaging for screening of prion-infected tissue. Not only does this method have comparable sensitivity to established techniques, it is faster and technically simpler. Finally, this readout provides valuable information about the spatial distribution of prion aggregates across tissue in the earliest stages of infection, potentially providing valuable pathophysiological insight into prion transmission.
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| 60. |
- Sulheim, Einar, et al.
(författare)
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Contrast Enhanced Magnetic Resonance Imaging of Amyloid-beta Plaques in a Murine Alzheimers Disease Model
- 2023
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Ingår i: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 93:2, s. 411-419
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early detection of amyloid-beta(A beta) aggregates is a critical step to improve the treatment of Alzheimers disease (AD) because neuronal damage by the A beta aggregates occurs before clinical symptoms are apparent. We have previously shown that luminescent conjugated oligothiophenes (LCOs), which are highly specific towards protein aggregates of A beta, can be used to fluorescently label amyloid plaque in living rodents. Objective: We hypothesize that the LCO can be used to target gadolinium to the amyloid plaque and hence make the plaque detectable by T-1-weighted magnetic resonance imaging (MRI). Methods: A novel LCO-gadolinium construct was synthesized to selectively bind to A beta plaques and give contrast in conventional T-1-weighted MR images after intravenous injection in Tg-APPSwe mice. Results: We found that mice with high plaque-burden could be identified using the LCO-Gd constructs by conventional MRI. Conclusion: Our study shows that MR imaging of amyloid plaques is challenging but feasible, and hence contrast-mediated MR imaging could be a valuable tool for early AD detection.
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