| 1. |
- Casares, L., et al.
(författare)
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The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity
- 2022
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Ingår i: Redox Biology. - : Elsevier BV. - 2213-2317. ; 51
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these compounds have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.
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| 2. |
- Hjaeresen, S., et al.
(författare)
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MIF in the cerebrospinal fluid is decreased during relapsing-remitting while increased in secondary progressive multiple sclerosis
- 2022
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Ingår i: Journal of the Neurological Sciences. - : Elsevier BV. - 0022-510X. ; 439
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Tidskriftsartikel (refereegranskat)abstract
- Background: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS). Objectives: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue. Methods: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database. Results: MIF was significantly decreased in treatmentnaive CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly higher in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia. Conclusion: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails.
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| 3. |
- Hjaeresen, S., et al.
(författare)
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The levels of the serine protease HTRA1 in cerebrospinal fluid correlate with progression and disability in multiple sclerosis
- 2021
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Ingår i: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 268, s. 3316-3324
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Tidskriftsartikel (refereegranskat)abstract
- Background High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease. Objective Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue. Methods Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map. Results HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons. Conclusion HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.
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| 4. |
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| 5. |
- Holdø, B., et al.
(författare)
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Surgeon’s experience and clinical outcome after retropubic tension-free vaginal tape—A case series
- 2020
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 99:8, s. 1071-1077
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The retropubic tension-free vaginal tape procedure has been the preferred method for primary surgical treatment of stress and stress-dominant mixed urinary incontinence in women for more than 20years. In this study, we assessed associations between surgeon's experience with the primary tension-free vaginal tape procedure and both perioperative complications and recurrence rates. Material and methods: Using a consecutive case-series design, we assessed 596 patients treated with primary retropubic tension-free vaginal tape surgery performed by 18 surgeons from 1998 through 2012, with follow up through 2015 (maximum follow-up time: 10years per patient). Data on perioperative complications and recurrence of stress urinary incontinence from medical records was transferred to a case report form. Surgeon's experience with the tension-free vaginal tape procedure was defined as number of such procedures performed as lead surgeon (1-19 [“beginners”], 20-49 and ≥50 procedures). All analyses were done with a 5% level of statistical significance. We applied the Chi-square test in the assessment of perioperative complications. The regression analyses of recurrence rate by number of tension-free vaginal tape procedures performed were restricted to the three surgeons who performed ≥50 procedures. Results: We found a significantly higher rate of bladder perforations (P=.03) and a higher rate of urinary retentions among patients whose tension-free vaginal tape procedures were performed by “beginners” (P=.06). We observed a significant reduction in recurrence rates with increasing number of tension-free vaginal tape procedures for one surgeon (P=.03). Conclusions: Surgeon's experience with the tension-free vaginal tape procedure is associated with the risk of bladder perforation and urinary retention, and may be associated with the long-term effectiveness of the procedure. © 2020 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG)
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| 6. |
- Holdø, B., et al.
(författare)
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The retropubic tension-free vaginal tape procedure—Efficacy, risk factors for recurrence and long-term safety
- 2019
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 98:6, s. 722-728
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The retropubic tension-free vaginal tape has been the preferred method for primary surgical treatment of stress urinary incontinence and stress-dominated mixed urinary incontinence in women for more than 20years. This study presents long-term safety and efficacy data and assesses risk factors for long-term recurrence. Material and methods: In a case-series design we assessed a historical cohort of primary surgeries performed with the tension-free vaginal tape procedure in 596 women from 1998 to 2012 with follow up through 2015. Information from the medical records was transferred to a case report form comprising data on early and late complications and recurrence of urinary incontinence defined as bothersome stress urinary incontinence symptoms. All analyses were performed with SPSS using Pearson chi-square, survival and Cox regression analyses. Results: After a 10-year follow up, mixed urinary incontinent women (hazard ratio 2.1, 95% confidence interval [CI] 1.4-3.0) had a significantly increased risk of recurrence of stress urinary incontinence symptoms compared with women with pure stress urinary incontinence as the indication for surgery. Overall cumulative cure rates after 1, 5 and 10years were 92% (95% CI; 90%-94%), 79% (95% CI; 75%-83%) and 69% (95% CI; 63%-75%), respectively. Recurrent surgery (0.3%) and serious tape complications needing major surgical treatment (0.3%) were rare. Six patients (1.0%) had the tape cut due to urinary retention, and 9 patients (1.5%) reported urinary retention more than 3months after surgery. Conclusions: The tension-free vaginal tape procedure has a high long-term durability. Mixed urinary incontinence as an indication for surgery predicted long-term recurrence. Long-term complications were rare. © 2019 Nordic Federation of Societies of Obstetrics and Gynecology
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