| 1. |
- Don-Doncow, Nicholas, et al.
(författare)
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Expression of STAT3 in Prostate Cancer Metastases
- 2017
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838. ; 71:3, s. 313-316
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Tidskriftsartikel (refereegranskat)abstract
- STAT3 and its upstream activator IL6R have been implicated in the progression of prostate cancer and are possible future therapeutic targets. We analyzed 223 metastatic samples from rapid autopsies of 71 patients who had died of castration-resistant prostate cancer (CRPC) to study protein and gene expression of pSTAT3 and IL6R. Immunohistochemical analysis revealed that 95% of metastases were positive for pSTAT3 and IL6R, with varying expression levels. Bone metastases showed significantly higher expression of both pSTAT3 and IL6R in comparison to lymph node and visceral metastases. STAT3 mRNA levels were significantly higher in bone than in lymph node and visceral metastases, whereas no significant difference in IL6R mRNA expression was observed. Our study strongly supports the suggested view of targeting STAT3 as a therapeutic option in patients with metastatic CRPC. Patient summary We studied the levels of two proteins (pSTAT3 and IL6R) in metastases from patients who died from castration-resistant prostate cancer. We found high levels of pSTAT3and IL6R in bone metastases, suggesting that these proteins could be used as targets for new anticancer drugs.
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| 2. |
- Don-Doncow, Nicholas, et al.
(författare)
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Galiellalactone is a Direct Inhibitor of STAT3 in Prostate Cancer Cells.
- 2014
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 289:23, s. 15969-15978
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor STAT3 is constitutively active in several malignancies including castration-resistant prostate cancer and has been identified as a promising therapeutic target. The fungal metabolite galiellalactone, a STAT3 signaling inhibitor, inhibits the growth, both in vitro and in vivo, of prostate cancer cells expressing active STAT3 and induces apoptosis of prostate cancer stem cell-like cells expressing pSTAT3. However, the molecular mechanism of this STAT3 inhibiting effect by galiellalactone has not been clarified. A biotinylated analogue of galiellalactone (GL-biot) was synthesized to be used for identification of galiellalactone target proteins. By adding streptavidin-sepharose beads to GL-biot treated DU145 cell lysates, STAT3 was isolated and identified as a target protein. Confocal microscopy revealed GL-biot in both the cytoplasm and nucleus of DU145 cells treated with GL-biot, appearing to co-localize with STAT3 in the nucleus. Galiellalactone inhibited STAT3 binding to DNA in DU145 cell lysates without affecting phosphorylation status of STAT3. Mass spectrometry analysis of recombinant STAT3 protein pretreated with galiellalactone revealed three modified cysteines (cys-367, cys-468 and cys-542). We here demonstrate with chemical and molecular pharmacological methods that galiellalactone is a cysteine reactive inhibitor that covalently binds to one or more cysteines in STAT3 and that this leads to inhibition of STAT3 binding to DNA and thus blocks STAT3 signaling without affecting phosphorylation. This further validates galiellalactone as a promising direct STAT3 inhibitor for treatment of castration-resistant prostate cancer.
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| 3. |
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| 4. |
- Don-Doncow, Nicholas, et al.
(författare)
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Simvastatin therapy attenuates memory deficits that associate with brain monocyte infiltration in chronic hypercholesterolemia
- 2021
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Ingår i: npj Aging and Mechanisms of Disease. - : Springer Science and Business Media LLC. - 2056-3973. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Evidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown. Here, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Chronic hypercholesterolemia that was accompanied by moderate blood pressure elevations associated with apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation that is associated with chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, and links to memory dysfunction. Therapeutic cholesterol-lowering through simvastatin reduced systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice with chronic hypercholesterolemia. BP-lowering therapy alone (i.e., hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. Our study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment and encourages cholesterol-lowering therapy as safe strategy to control hypercholesterolemia-associated memory decline during ageing.
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| 5. |
- Don-Doncow, Nicholas
(författare)
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STAT3 in Prostate Cancer
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer is the second most common diagnosed cancer among men. Currently there are no reliablebiomarkers to distinguish between indolent and aggressive disease. When men progress to advanced stages of the disease treatment options are limited and resistance to treatments available today is a growing problem. Recently the signal transducer and activator of transcription 3 (STAT3) has been suggested as both a potential target for treatment, and a biomarker in advanced prostate cancer.In this work we explored the potential of activated STAT3 (pSTAT3) as a tissue biomarker in two different cohorts. We also investigated the mechanism of action of the STAT3 inhibitor galiellalactone as well as its effect in combination treatments with chemotherapeutic agent docetaxel.In a rapid autopsy cohort of patients that have died of metastatic prostate cancer we found that expression of pSTAT3 was present in all metastases, with highest expression in the bone, likely an effect of the tumor microenvironment. A second cohort of hormone naïve patients with localized prostate cancer showed that pSTAT3 expression was higher in benign tissue compared with tumor tissue. Lower pSTAT3 expression in tumor cells was predictive of shorter time to recurrent disease. These two cohorts suggest that targeting pSTAT3 would be valuable at later stages of the disease.We also investigated galiellalactone, a natural fungal compound, and its mechanism of action in inhibiting STAT3. We found that galiellalactone binds directly to STAT3, thus blocking the ability of STAT3 to bind to DNA. When galiellalactone was used in combination with docetaxel it was able to produce a synergistic inhibitory effect, which was likely due to the observed downregulation of genes involved in docetaxel resistance.In conclusion, our results suggest that STAT3 is a promising treatment target in late stage prostate cancer and may lead to benefit when used in combination with docetaxel.
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| 6. |
- Don-Doncow, Nicholas, et al.
(författare)
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T-Cell Accumulation in the Hypertensive Brain: A Role for Sphingosine-1-Phosphate-Mediated Chemotaxis.
- 2019
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 20:3, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Hypertension is considered the major modifiable risk factor for the development of cognitive impairment. Because increased blood pressure is often accompanied by an activation of the immune system, the concept of neuro-inflammation gained increasing attention in the field of hypertension-associated neurodegeneration. Particularly, hypertension-associated elevated circulating T-lymphocyte populations and target organ damage spurred the interest to understanding mechanisms leading to inflammation-associated brain damage during hypertension. The present study describes sphingosine-1-phosphate (S1P) as major contributor to T-cell chemotaxis to the brain during hypertension-associated neuro-inflammation and cognitive impairment. Using Western blotting, flow cytometry and mass spectrometry approaches, we show that hypertension stimulates a sphingosine kinase 1 (SphK1)-dependent increase of cerebral S1P concentrations in a mouse model of angiotensin II (AngII)-induced hypertension. The development of a distinct S1P gradient between circulating blood and brain tissue associates to elevated CD3+ T-cell numbers in the brain. Inhibition of S1P1-guided T-cell chemotaxis with the S1P receptor modulator FTY720 protects from augmentation of brain CD3 expression and the development of memory deficits in hypertensive WT mice. In conclusion, our data highlight a new approach to the understanding of hypertension-associated inflammation in degenerative processes of the brain during disease progression.
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| 7. |
- Don-Doncow, Nicholas, et al.
(författare)
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The emerging alliance of sphingosine-1-phosphate signaling and immune cells: from basic mechanisms to implications in hypertension.
- 2019
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 176:12, s. 1989-2001
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Forskningsöversikt (refereegranskat)abstract
- The immune system plays a considerable role in hypertension. In particular, T-lymphocytes are recognized as important players in its pathogenesis. Despite substantial experimental efforts, the molecular mechanisms underlying the nature of T-cell activation contributing to an onset of hypertension or disease perpetuation are still elusive. Amongst other cell types, lymphocytes express distinct profiles of GPCRs for sphingosine-1-phosphate (S1P) – a bioactive phospholipid that is involved in many critical cell processes and most importantly majorly regulates T-cell development, lymphocyte recirculation, tissue-homing patterns and chemotactic responses. Recent findings have revealed a key role for S1P chemotaxis and T-cell mobilization for the onset of experimental hypertension, and elevated circulating S1P levels have been linked to several inflammation-associated diseases including hypertension in patients. In this article, we review the recent progress towards understanding how S1P and its receptors regulate immune cell trafficking and function and its potential relevance for the pathophysiology of hypertension. Linked Articles: This article is part of a themed section on Immune Targets in Hypertension.
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| 8. |
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| 9. |
- Krzyzanowska, Agnieszka, et al.
(författare)
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Expression of tSTAT3, pSTAT3 727 , and pSTAT3 705 in the epithelial cells of hormone-naïve prostate cancer
- 2019
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Ingår i: Prostate. - : Wiley. - 0270-4137. ; 79:7, s. 784-797
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Tidskriftsartikel (refereegranskat)abstract
- Background: The signal transducer and activator of transcription 3 (STAT3) pathway is observed to be constitutively activated in several malignancies including prostate cancer (PCa). In the present study, we investigated the expression of total STAT3 (tSTAT3) and two forms of activated phosphorylated STAT3 (pSTAT3 727 and pSTAT3 705 ) in tissue microarrays (TMA) of two cohorts of localized hormone-naïve PCa patients and analyzed associations between the expression and disease outcome. Methods: The expression of tSTAT3, pSTAT3 727 , and pSTAT3 705 was scored in the nuclei and cytoplasm of prostatic gland epithelial cells in two TMAs of paraffin-embedded prostatic tissue. The TMAs consisted of tissue originated from hormone-naïve radical prostatectomy patients from two different sites: Malmö, Sweden (n = 300) and Dublin, Ireland (n = 99). Results: The nuclear expression levels of tSTAT3, pSTAT3 727 , and pSTAT3 705 in the epithelial cells of benign glands were significantly higher than in the cancerous glands. Cytoplasmic tSTAT3 levels were also higher in benign glands. Patients with low pSTAT3 727 and pSTAT3 705 levels in the cancerous glands showed reduced times to biochemical recurrence, compared with those with higher levels. No significant trends in nuclear nor in cytoplasmic tSTAT3 were observed in relation to biochemical recurrence in the Malmö cohort. Higher cytoplasmic tSTAT3 was associated with reduced time to biochemical recurrence in the Dublin cohort. Adding the tSTAT3 and pSTAT3 expression data to Gleason score or pathological T stage did not improve their prognostic values. Conclusions: Low pSTAT3 727 and pSTAT3 705 expression in epithelial cells of cancerous prostatic glands in hormone-naïve PCa was associated with faster disease progression. However, pSTAT3 and tSTAT3 expression did not improve the prognostic value of Gleason score or pathological T stage and may not be a good biomarker in the early hormone naïve stages of PCa.
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| 10. |
- Meissner, Anja, et al.
(författare)
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Alterations to Cerebral Perfusion, Metabolite Profiles, and Neuronal Morphology in the Hippocampus and Cortex of Male and Female Mice during Chronic Exposure to a High-Salt Diet
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Excess dietary salt reduces resting cerebral blood flow (CBF) and vascular reactivity, which can limit the fueling of neuronal metabolism. It is hitherto unknown whether metabolic derangements induced by high-salt-diet (HSD) exposure during adulthood are reversed by reducing salt intake. In this study, male and female mice were fed an HSD from 9 to 16 months of age, followed by a normal-salt diet (ND) thereafter until 23 months of age. Controls were continuously fed either ND or HSD. CBF and metabolite profiles were determined longitudinally by arterial spin labeling magnetic resonance imaging and magnetic resonance spectroscopy, respectively. HSD reduced cortical and hippocampal CBF, which recovered after dietary salt normalization, and affected hippocampal but not cortical metabolite profiles. Compared to ND, HSD increased hippocampal glutamine and phosphocreatine levels and decreased creatine and choline levels. Dietary reversal only allowed recovery of glutamine levels. Histology analyses revealed that HSD reduced the dendritic arborization and spine density of cortical and hippocampal neurons, which were not recovered after dietary salt normalization. We conclude that sustained HSD exposure throughout adulthood causes permanent structural and metabolic alterations to the mouse brain that are not fully normalized by lowering dietary salt during aging.
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