| 1. |
- Andersson, Karin, et al.
(författare)
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A two-year clinical lifestyle intervention program for weight loss in obesity
- 2008
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Ingår i: Food & nutrition research. - : Co-Action Publishing. - 1654-661X .- 1654-6628. ; 52, s. 1656-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In recent randomised prospective studies, lifestyle intervention induced a weight loss of approximately 5%. OBJECTIVE: To describe and evaluate a 2-year on-going group intervention program in clinical practice in terms of weight loss and changes in metabolic risk factors, i.e. sagital abdominal diameter (SAD), triglycerides, fasting blood glucose and blood pressure. DESIGN: The aim of the intervention program was to motivate lifestyle changes concerning food intake and physical activity. The emphasis was on lifestyle modification, followed up at regular visits during 2 years. Subjects evaluated were 100 women with mean BMI 37.6 kg/m(2) and 26 men with mean BMI 36.5 kg/m(2). RESULTS: One hundred of 151 enrolled women and 26 of 36 men completed the program. Mean weight decreased by 3.8 kg in women (from 103.5 to 99.7, p<0.001) and 4.4 kg in men (from 116.5 to 112.1, p<0.05), respectively. SAD decreased by 5% (p=0.001 in women, p=0.01 in men), and triglycerides by 16% in women (p=0.01) and 24% in men (p=0.001), however systolic and diastolic blood pressure increased slightly but significantly. CONCLUSION: It is possible to perform a clinical lifestyle intervention program for outpatients on an ongoing basis with weight loss, lowered SAD and triglycerides, and a similar or lower dropout rate compared to clinical trials.
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| 2. |
- Bergendahl, Sandra, et al.
(författare)
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Lateral episiotomy versus no episiotomy to reduce obstetric anal sphincter injury in vacuum-assisted delivery in nulliparous women : Study protocol on a randomised controlled trial
- 2019
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Obstetric anal sphincter injury (OASIS) occurs in 5%-7% of normal deliveries and increases with vacuum extraction (VE) to 12%-14% in nulliparous women in Sweden. Lateral/mediolateral episiotomy may reduce the prevalence of OASIS at VE in nulliparous women. The current use of episiotomy is restrictive. The protective effect and consequences are uncertain. This trial will investigate if lateral episiotomy can reduce the prevalence of OASIS and assess short-term and long-term effects. Methods and analysis This is a multicentre randomised controlled trial of lateral episiotomy versus no episiotomy in nulliparous women with a singleton, live fetus, after gestational week 34+0 with indication for VE. A lateral episiotomy of 4 cm is cut at crowning, 1-3 cm from the midline, at a 60° angle. The primary outcome is OASIS by clinical diagnosis analysed according to intention to treat. To demonstrate a 50% reduction in OASIS prevalence (from 12.4% to 6.2%), 710 women will be randomised at a 1:1 ratio. Secondary outcomes are pain, blood loss, other perineal injuries, perineal complications, Apgar score, cord pH and neonatal complications. Web-based questionnaires at baseline, 2 months, 1 and 5 years will be used to assess pain, incontinence, prolapse, sexual function, quality of life and childbirth experience. A subset of women will receive follow-up by pelvic floor sonography and pelvic examination. Mode of delivery and recurrence of OASIS/episiotomy in subsequent pregnancies will be assessed at 5 and 10 years using register data. Ethics and dissemination The trial is open for enrolment. The trial has received ethical approval from the Regional Ethical Review Board of Stockholm and full funding from the Swedish Research Council. Women are interested in participation. The predominant restrictive view on episiotomy may limit recruitment. Results are of global interest and will be disseminated in peer-reviewed journals and at international congresses.
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| 3. |
- Borgegård, Tomas, et al.
(författare)
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Alzheimer's Disease : Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.
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| 4. |
- Chavez Karlström, Anna, et al.
(författare)
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Medical Defibulation as a Possibility-the Experiences of Young Swedish-Somali Women.
- 2020
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Ingår i: International journal of qualitative studies on health and well-being. - : Informa UK Limited. - 1748-2631. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Infibulation is the most pervasive form of female genital cutting. Infibulated women face difficulties such as obstruction of urine and menstrual blood flow, sexual problems, and birth complications, and may therefore need medical defibulation. This study explores the lived experiences of young migrant women from Somalia and their views on undergoing medical defibulation in Sweden. Methods: A qualitative study was conducted using phenomenological lifeworld research. Data were collected through in-depth interviews with nine young women originating from Somalia, now resident in Sweden. The interviews were analysed to reveal the meaning of the phenomenon of infibulation. Results: The essential meaning of the phenomenon is characterized by a limbo regarding both infibulation and defibulation. There is a strong desire both to handle the Swedish perspective on infibulation and to stay with the Somalian cultural values. These women are being exposed to a tacit tradition that makes it hard to relate to the possibility of medical defibulation. As a result, the women perceive the possibility to undergo medical defibulation as limited or non-existent. Conclusions: Healthcare professionals can be a support to encourage women in need of medical defibulation to reflect on traditional ideals concerning infibulation and defibulation.
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| 5. |
- Hildingsson, Ingegerd, et al.
(författare)
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African midwifery students’ self-assessed confidence in antenatal care : a multi-country study
- 2019
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Ingår i: Global Health Action. - : Informa UK Limited. - 1654-9716 .- 1654-9880. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence-based antenatal care is one cornerstone in Safe Motherhood and educated and confident midwives remain to be optimal caregivers in Africa. Confidence in antenatal midwifery skills is important and could differ depending on the provision of education among the training institutions across Africa. Objective: The aim of the study was to describe and compare midwifery students’ confidence in basic antenatal skills, in relation to age, sex, program type and level of program. Methods: A survey in seven sub-Saharan African countries was conducted. Enrolled midwifery students from selected midwifery institutions in each country presented selfreported data on confidence to provide antenatal care. Data were collected using a selfadministered questionnaire. The questionnaire consisted of 22 antenatal skills based on the competency framework from the International Confederation of Midwives. The skills were grouped into three domains; Identify fetal and maternal risk factors and educate parents; Manage and document emergent complications and Physical assessment and nutrition. Results: In total, 1407 midwifery students from seven Sub-Saharan countries responded. Almost one third (25-32%) of the students reported high levels of confidence in all three domains. Direct entry programs were associated with higher levels of confidence in all three domains, compared to post-nursing and double degree programs. Students enrolled at education with diploma level presented with high levels of confidence in two out of three domains. Conclusions: A significant proportion of student midwives rated themselves low on confidence to provide ANC. Midwifery students enrolled in direct entry programs reported higher levels of confidence in all domains. It is important that local governments develop education standards, based on recommendations from the International Confederation of midwives. Further research is needed for the evaluation of actual competence.
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| 6. |
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| 7. |
- Karlström, Annika, et al.
(författare)
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Maternal and infant outcome after caesarean section without recorded medical indication: findings from a Swedish casecontrol study
- 2013
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Ingår i: Bjog-an International Journal of Obstetrics and Gynaecology. - : Wiley. - 1470-0328 .- 1471-0528. ; 120:4, s. 479-486
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To compare maternal complications and infant outcomes for women undergoing elective caesarean sections based on a maternal request and without recorded medical indication with those of women who underwent spontaneous onset of labour with the intention to have a vaginal birth. DESIGN: Retrospective register study. SETTING: Sweden; Medical Birth Register used for data collection. METHODS: A case-control study of 5877 birth records of women undergoing caesarean sections without medical indication and a control group of 13 774 women undergoing births through spontaneous onset of labour. The control group was further divided into women who actually had a vaginal birth and women who ended up with an emergency caesarean section. RESULTS: Maternal complications occurred more frequently among women undergoing caesarean section with odds ratios (OR) for bleeding complications of 2.5 (95% CI 2.1-3.0) in the elective caesarean group and 2.0 (95% CI 1.5-2.6) in the emergency caesarean group. The OR for infections was 2.6 in both groups. Breastfeeding complications were most common in women having an elective caesarean section: 6.8 (95% CI 3.2-14.5). Infant outcomes showed a higher incidence of respiratory distress with an OR of 2.7 (95% CI 1.8-3.9) in the elective caesarean section group compared with infants born by emergency caesarean section. The risk of hypoglycaemia was at least twice as high for infants in the caesarean group. CONCLUSIONS: Caesarean sections without medical indication as well as emergency caesarean sections were associated with higher risks for maternal and infant morbidity.
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| 8. |
- Karlström, Hanna, et al.
(författare)
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Kompetensöverföring i småföretag : En övervägande informell process
- 2009
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Denna rapport är resultatet av ett forsknings- och utvecklingsprojekt inom HELIX VINN Excellence Centre i samarbete med IUC Öst AB och Industrikompetens AB. Syftet med projektet är att studera kompetensförsörjning i små och medelstora företag (SMF). Närmare bestämt presenteras här resultat som rör synen på, och arbetet, med kompetensöverföring i fyra företag. Det empiriska underlaget samlades in under våren 2009 och har tidigare redovisats i en magisteruppsats på PA-programmet vid Linköpings universitet (Karlström & Schyldt, 2009). Vi vill speciellt tacka de personer i de inblandade företagen som ställt upp på intervjuer, samt Karolina Hallstedt som medverkat i datainsamlingen. Ett stort tack även till Sune Karlsson vid IUC Öst och till Gunilla Åberg och Katarina Nyhammar vid Industrikompetens. Vidare vill vi också tacka Bodil Ekholm och Dan Rönnqvist vid Institutionen för beteendevetenskap och lärande, Linköpings universitet, för deras stöd och givande synpunkter.
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| 9. |
- Karlström, Helena
(författare)
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Notch receptor processing and CNS disease
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- We have studied the relationship of Notch receptor processing and two diseases of the central nervous system: Alzheimer's disease (AD) and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). The Notch receptor signalling pathway plays a crucial role during development in many different species for directing adjacent cells to adopt different fates. During maturation and ligand activation the Notch receptor undergoes a series of complex proteolytic cleavages before the intracellular domain is released and translocated to the nucleus where it affects transcription. The first cleavage (S 1) occurs during the transport out to the plasma membrane in the trans-Golgi compartment by a furin-like convertase. This cleavage is constitutive and generates a bipartite receptor, where the two Notch fragments are held together through non-covalent forces. The second cleavage (S2) occurs near the transmembrane region at the extracellular side when Notch is ligand- activated. The S2 cleavage is immediately followed by the third cleavage (S3) at the border of the transmembrane region and the intracellular side. The metalloprotease TACE (TNFalpha converting enzyme) has been shown to be responsible for the S2 cleavage, while the S3 cleavage is dependent on presenilins (PSs). The PSs have been genetically linked to familial AD and are involved in the gamma-secretase cleavage of the betaamyloid precursor protein (APP) and the production of the neurotoxic Abeta peptide, which causes senile plaques in the brain. There are four known mammalian Notch receptors (Notch 1-Notch 4) with overlapping patterns of expression, but the role of the different Notch receptors is not that well understood. Mutations in the Notch 3 gene cause the genetic disorder CADASIL. CADASIL is an inherited form of stroke and dementia and the histopathological hallmarks are degeneration of vascular smooth muscle cells and deposits of granular osmiophilic material between the vascular smooth muscle cells. The mutations in the Notch 3 gene always affect a cysteine residue in the epidermal growth factor-like- repeats in the extracellular domain, but how this leads to CADASIL is poorly understood. There is an obvious need to produce therapeutical drugs that prevent the formation of Abeta peptide, in order to reduce plaque formation in AD, and inhibitors of PSs and the gamma-secretase cleavage would be useful. The fact that not only APP, but also Notch cleavage is controlled by PSs, however complicates the issue, and it will be important to find drugs that act differentially on Notch and APP. We show in a cell-based assay that PSs are absolutely required for S3/gamma-secretase processing of Notch and APP (paper I and II). The assay was further developed and gamma-secreatse cleavage of Notch and APP could be measured by adding different gamma-secretase inhibitors and PS active site mutants. We demonstrate that the assay is specific and sensitive and can record small differences in the gamma-secretase processing of Notch and APP (paper II). Furthermore, in an in vitro assay, we show that PSs are not the direct executors of Notch processing, but that the enzymatic activity is absolutely dependent on PSs. This notion is based on the observation that there is a specific Notch-processing activity in PS-containing cells, which is absent in PS-deficient cells, but the activity does not comigrate with PSs in protein purification (paper II). To learn more in detail which parts of the PSI protein are crucial and responsible for gamma-secretase cleavage of Notch and APP we set out to narrow down the PSI protein by deletions and mutations (paper III). We show that a five amino acid motif in the N-terminal fragment of PS I is necessary for gamma-secretase cleavage of both Notch and APP. Moreover, a tyrosine residue in position 288 is critical and the activity is restored when substituting this amino acid with hydrophobic or bulky, but not with charged residues. The endoproteolysis of PS I is in some but not all cases affected when different residues occupy the 288 position, indicating a more direct role of the Tyrosine 288 in the gamma-secretase activity. To address the cellular and biochemical mechanisms behind CADASIL, we have used a very prevalent mutation in the Notch 3 gene (R142C), which cause CADASIL in humans (paper IV). Using coculture experiments, western blot analysis and immunocytochemistry of stable cell lines expressing the CADASIL-mutated or wild type receptor, we show that the S I cleavage is impaired and less amount of the mutated receptor is expressed at the cell surface compared to wild type receptor. Furthermore, the mutated receptor is more prone to form intracellular aggregates, which are found in close vicinity to the Golgi network, but do not share the characteristics of an aggresome. In coculture experiments together with cells expressing the ligands, Serrate and Delta, we find that the Notch 3 receptor can respond to ligand activation but that there are no differences in signalling between the mutated and wild type receptor. In conclusion, we show that PSs are absolutely required for gamma-secretase cleavage of Notch and APP but that PSs are not the direct executors for Notch cleavage. The cell-based assay allows screening and detection of compounds that differentially affect processing of Notch and APP, which is crucial in the attempt to prevent AD without affecting Notch signalling. We find a critical motif in the PS I gene, tyrosine 288, which seems to affect gamma-secretase cleavage directly for both Notch and APP. Finally, cells expressing as CADASIL-mutated Notch 3 receptor show impaired S I cleavage and decreased expression at the cell surface, more intracellular aggregates but with normal ligand-induced signalling as compared to wild type Notch 3 receptor. These differences can be one of the reasons underlying the cellular mechanisms of CADASIL.
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| 10. |
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| 11. |
- Malm, Dan, 1954-, et al.
(författare)
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Effects of brief mindfulness-based cognitive behavioural therapy on health-related quality of life and sense of coherence in atrial fibrillation patients
- 2018
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Ingår i: European Journal of Cardiovascular Nursing. - : Sage Publications. - 1474-5151 .- 1873-1953. ; 17:7, s. 589-597
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to evaluate the effects of a brief dyadic cognitive behavioural therapy (CBT) programme on the health-related quality of life (HRQoL), as well as the sense of coherence in atrial fibrillation patients, up to 12 months post atrial fibrillation.Methods: A longitudinal randomised controlled trial with a pre and 12-month post-test recruitment of 163 persons and their spouses, at a county hospital in southern Sweden. In all, 104 persons were randomly assigned to either a CBT (n=56) or a treatment as usual (TAU) group (n=55). The primary outcome was changes in the HRQoL (Euroqol questionnaire; EQ-5D), and the secondary outcomes were changes in psychological distress (hospital anxiety and depression scale; HADS) and sense of coherence (sense of coherence scale; SOC-13).Results: At the 12-month follow-up, the CBT group experienced a higher HRQoL than the TAU group (mean changes in the CBT group 0.062 vs. mean changes in the TAU group −0.015; P=0.02). The sense of coherence improved in the CBT group after the 12-month follow-up, compared to the TAU group (mean changes in the CBT group 0.062 vs. mean changes in the TAU group −0.16; P=0.04). The association between the intervention effect and the HRQoL was totally mediated by the sense of coherence (z=2.07, P=0.04).Conclusions: A dyadic mindfulness-based CBT programme improved HRQoL and reduced psychological distress up to 12 months post atrial fibrillation. The sense of coherence strongly mediated the HRQoL; consequently, the sense of coherence is an important determinant to consider when designing programmes for atrial fibrillation patients.
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| 12. |
- Oliveira, Daniel V, et al.
(författare)
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Active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model.
- 2022
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Ingår i: EMBO molecular medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial small vessel disease; no preventive or curative therapy is available. CADASIL is caused by mutations in the NOTCH3 gene, resulting in a mutated NOTCH3 receptor, with aggregation of the NOTCH3 extracellular domain (ECD) around vascular smooth muscle cells. In this study, we have developed a novel active immunization therapy specifically targeting CADASIL-like aggregated NOTCH3 ECD. Immunizing CADASIL TgN3R182C150 mice with aggregates composed of CADASIL-R133C mutated and wild-type EGF1-5 repeats for a total of 4months resulted in a marked reduction (38-48%) in NOTCH3 deposition around brain capillaries, increased microglia activation and lowered serum levels of NOTCH3 ECD. Active immunization did not impact body weight, general behavior, the number and integrity of vascular smooth muscle cells in the retina, neuronal survival, or inflammation or the renal system, suggesting that the therapy is tolerable. This is the first therapeutic study reporting a successful reduction of NOTCH3 accumulation in a CADASIL mouse model supporting further development towards clinical application for the benefit of CADASIL patients.
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| 13. |
- Pietilä, Riikka, et al.
(författare)
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Molecular anatomy of adult mouse leptomeninges
- 2023
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Ingår i: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 111:23
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Tidskriftsartikel (refereegranskat)abstract
- Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we iden-tify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arach-noid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.
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| 14. |
- Sharma, Bharati, et al.
(författare)
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African midwifery students' self-assessed confidence in postnatal and newborn care : A multi-country survey
- 2021
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Ingår i: Midwifery. - : Elsevier. - 0266-6138 .- 1532-3099. ; 101
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Tidskriftsartikel (refereegranskat)abstract
- Background: Majority of maternal and new-born deaths occur within 28 hours and one week after birth. These can be prevented by well-educated midwives. Confidence in postnatal and newborn care skills depend on the quality of midwifery education. Objective: To assess confidence and its associated factors for basic postnatal and new-born care skills of final year midwifery students , from seven African countries. Methods: A multi-country cross-sectional study where final year midwifery students answered a questionnaire consisting of basic skills of postnatal and newborn care listed by the International Confederation of Midwives. The postnatal care area had 16 and newborn care area had 19 skill statements. The 16 skills of postnatal care were grouped into three domains through principle component analysis (PCA); Basic postnatal care; postnatal complications and educating parents and documentation . The 19 skills under the newborn care area were grouped into three domains; Basic care and care for newborn complications; Support parents for newborn care ; and Care for newborns of HIV positive mothers and documentation. Results: In total 1408 midwifery students from seven Sub-Saharan countries participated in the study namely; Kenya, Malawi, Tanzania, Uganda, Zambia, Zimbabwe, and Somaliland Overall high confidence for all domains under Post Natal Care ranged from 30%-50% and for Newborn care from 39-55%. High confidence for postnatal skills was not found to be associated with any background variables (Age, sex, type and level of educational programme). High confidence for newborn care was associated with being female students, those aged 26-35 years, students from the direct entry programmes and those enrolled in diploma programmes. Conclusions: Almost half of the study participants expressed lack of confidence for skills under postnatal and newborn care. No association was found between high confidence for domains of postnatal care and background variables. High confidence was associated with being a female, between 26-35 years of age, from direct entry or diploma programmes for newborn care area. The results of the study indicate gaps in midwifery education. Countries could use the ICM list of competencies to develop country specific standards for midwifery education. However, actual competence remains to be measured.
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| 15. |
- Wanngren, Johanna, et al.
(författare)
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Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations.
- 2014
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Ingår i: FEBS Open Bio. - : Wiley. - 2211-5463. ; 4, s. 393-406
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Tidskriftsartikel (refereegranskat)abstract
- The enzyme complex γ-secretase generates amyloid β-peptide (Aβ), a 37-43-residue peptide associated with Alzheimer disease (AD). Mutations in presenilin 1 (PS1), the catalytical subunit of γ-secretase, result in familial AD (FAD). A unifying theme among FAD mutations is an alteration in the ratio Aβ species produced (the Aβ42/Aβ40 ratio), but the molecular mechanisms responsible remain elusive. In this report we have studied the impact of several different PS1 FAD mutations on the integration of selected PS1 transmembrane domains and on PS1 active site conformation, and whether any effects translate to a particular amyloid precursor protein (APP) processing phenotype. Most mutations studied caused an increase in the Aβ42/Aβ40 ratio, but via different mechanisms. The mutations that caused a particular large increase in the Aβ42/Aβ40 ratio did also display an impaired APP intracellular domain (AICD) formation and a lower total Aβ production. Interestingly, seven mutations close to the catalytic site caused a severely impaired integration of proximal transmembrane/hydrophobic sequences into the membrane. This structural defect did not correlate to a particular APP processing phenotype. Six selected FAD mutations, all of which exhibited different APP processing profiles and impact on PS1 transmembrane domain integration, were found to display an altered active site conformation. Combined, our data suggest that FAD mutations affect the PS1 structure and active site differently, resulting in several complex APP processing phenotypes, where the most aggressive mutations in terms of increased Aβ42/Aβ40 ratio are associated with a decrease in total γ-secretase activity.
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| 16. |
- Wanngren, Johanna, et al.
(författare)
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Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production.
- 2012
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Ingår i: The Journal of biological chemistry. - 1083-351X. ; 287:39, s. 32640-50
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Tidskriftsartikel (refereegranskat)abstract
- The γ-secretase complex is an appealing drug target when the therapeutic strategy is to alter amyloid-β peptide (Aβ) aggregation in Alzheimer disease. γ-Secretase is directly involved in Aβ formation and determines the pathogenic potential of Aβ by generating the aggregation-prone Aβ42 peptide. Because γ-secretase mediates cleavage of many substrates involved in cell signaling, such as the Notch receptor, it is crucial to sustain these pathways while altering the Aβ secretion. A way of avoiding interference with the physiological function of γ-secretase is to use γ-secretase modulators (GSMs) instead of inhibitors of the enzyme. GSMs modify the Aβ formation from producing the amyloid-prone Aβ42 variant to shorter and less amyloidogenic Aβ species. The modes of action of GSMs are not fully understood, and even though the pharmacology of GSMs has been thoroughly studied regarding Aβ generation, knowledge is lacking about their effects on other substrates, such as Notch. Here, using immunoprecipitation followed by MALDI-TOF MS analysis, we found that two novel, second generation GSMs modulate both Notch β and Aβ production. Moreover, by correlating S3-specific Val-1744 cleavage of Notch intracellular domain (Notch intracellular domain) to total Notch intracellular domain levels using immunocytochemistry, we also demonstrated that Notch intracellular domain is not modulated by the compounds. Interestingly, two well characterized, nonsteroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drug), R-flurbiprofen and sulindac sulfide, affect only Aβ and not Notch β formation, indicating that second generation GSMs and nonsteroidal anti-inflammatory drug-based GSMs have different modes of action regarding Notch processing.
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| 17. |
- Weber, Tobias A, et al.
(författare)
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γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.
- 2022
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Ingår i: Journal of cellular and molecular medicine. - : Wiley. - 1582-4934 .- 1582-1838. ; 26:3, s. 880-892
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Tidskriftsartikel (refereegranskat)abstract
- The aggregation of β-amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 that are produced as a result of γ-secretase-mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ-Secretase modulators (GSMs) represent a promising class of Aβ42-lowering anti-amyloidogenic compounds for the treatment of AD. Gamma-secretase modulators change the relative proportion of secreted Aβ peptides, while sparing the γ-secretase-mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ-secretase cleavage of three γ-secretase substrates, E-cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ-secretase-dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ-secretase processing of EphA4 and EphB2 results in the release of several Aβ-like peptides, but that only the production of Aβ-like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ-secretase-mediated Aβ production.
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| 18. |
- Wu, Dan, et al.
(författare)
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The infantile myofibromatosis NOTCH3 L1519P mutation leads to hyperactivated ligand-independent Notch signaling and increased PDGFRB expression
- 2021
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Ingår i: Disease Models and Mechanisms. - : COMPANY BIOLOGISTS LTD. - 1754-8403 .- 1754-8411. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Infantile myofibromatosis (IMF) is a benign tumor form characterized by the development of nonmetastatic tumors in skin, bone, muscle and sometimes viscera. Autosomal-dominant forms of IMF are caused by mutations in the PDGFRB gene, but a family carrying a L1519P mutation in the NOTCH3 gene has also recently been identified. In this study, we address the molecular consequences of the NOTCH3L1519P mutation and the relationship between Notch and PDGFRB signaling in IMF. The NOTCH3L1519P receptor generates enhanced downstream signaling in a ligand-independent manner. Despite the enhanced signaling, the NOTCH3L1519P receptor is absent from the cell surface and instead accumulates in the endoplasmic reticulum. Furthermore, the localization of the NOTCH3L1519P receptor in the bipartite, heterodimeric state is altered, combined with avid secretion of the mutated extracellular domain from the cell. Chloroquine treatment strongly reduces the amount of secreted NOTCH3L1519P extracellular domain and decreases signaling. Finally, NOTCH3L1519P upregulates PDGFRB expression in fibroblasts, supporting a functional link between Notch and PDGF dysregulation in IMF. Collectively, our data define a NOTCH3-PDGFRB axis in IMF, in which an IMF-mutated NOTCH3 receptor elevates PDGFRB expression. The functional characterization of a ligand-independent gain-of-function NOTCH3 mutation is important for Notch therapy considerations for IMF, including strategies aimed at altering lysosome function.
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