| 1. |
|
|
| 2. |
- Huhtaniemi, R., et al.
(author)
-
Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts
- 2018
-
In: American Journal of Pathology. - : Elsevier BV. - 0002-9440. ; 188:12, s. 2890-2901
-
Journal article (peer-reviewed)abstract
- The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P4) and moderate levels of androgens, such as androstenedione, testosterone, and dihydrotestosterone, in the adrenal glands of both intact and orchectomized (ORX) mice. ORX alone had no effect on serum P4 concentration, whereas orchectomized and adrenalectomized (ORX + ADX) resulted in a significant decrease in serum P4 and in a further reduction in the low levels of serum androgens (androstenedione, testosterone, and dihydrotestosterone), measured by mass spectrometry. In line with this, the serum prostate-specific antigen and growth of VCaP xenografts in mice after ORX + ADX were markedly reduced compared with ORX alone, and the growth difference was not abolished by a glucocorticoid treatment. Moreover, ORX + ADX altered the androgen-dependent gene expression in the tumors, similar to that recently shown for the enzalutamide treatment. These data indicate that in contrast to the current view, and similar to humans, mouse adrenals synthesize significant amounts of steroids that contribute to the androgen receptor–dependent growth of CRPC. © 2018 American Society for Investigative Pathology
|
|
| 3. |
- Huhtaniemi, R., et al.
(author)
-
High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice
- 2022
-
In: iScience. - : Elsevier BV. - 2589-0042. ; 25:5
-
Journal article (peer-reviewed)abstract
- Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.
|
|
| 4. |
- Muus, Christoph, et al.
(author)
-
Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics
- 2021
-
In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:3, s. 546-559
-
Journal article (peer-reviewed)abstract
- Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2(+)TMPRSS2(+) cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.
|
|
| 5. |
- Parikka, V, et al.
(author)
-
Estrogen responsiveness of bone formation in vitro and altered bone phenotype in aged estrogen receptor-alpha-deficient male and female mice
- 2005
-
In: European Journal of Endocrinology. - : Oxford University Press (OUP). - 1479-683X .- 0804-4643. ; 152:2, s. 301-314
-
Journal article (peer-reviewed)abstract
- Objective: Although the beneficial effects of estrogen on bone are well known, the roles of estrogen receptors (ERs) in mediating these effects are not fully understood. Methods: To study the effects of long-term ERalpha deficiency, bone phenotype was studied in aged ERalpha knockout (ERKO) mice. In addition, ERKO osteoclasts and osteoblasts were cultured in vitro. Design and results: Histomorphometric analysis showed that the trabecular bone volume and thickness were significantly increased and the rate of bone formation enhanced in both male and female ERKO mice in comparison to the witd-type animals. In ERKO males, however, the bones were thinner and their maximal bending strengths decreased. Consistent with previous reports, the bones of knockout mice, especially of female mice, were shorter than those of wild-type mice. In addition, the growth plates were totally absent in the tibiae of aged ERKO females, whereas the growth plate cartilages were detectable in wild-type females as well as in all the males. Analysis of cultured bone marrow cells from 10- to 12-week-old mice demonstrated that 17beta-estradiol could stimulate osteoblastic differentiation of bone marrow cells derived from ERKO mice relatively to the same extent as those derived from wild-type mice. This was demonstrated by increases in synthesis of type I collagen, activity of alkaline phosphatase and accumulation of calcium in cultures. Total protein content was, however, reduced in ERKO osteoblast cultures. Conclusions: These results show altered bone phenotype in ERKO mice and demonstrate the stimulatory effect of estrogen on ostcoblasts even in the absence of full-length ERalpha.
|
|
| 6. |
- Vehmas, A. P., et al.
(author)
-
Liver lipid metabolism is altered by increased circulating estrogen to androgen ratio in male mouse
- 2016
-
In: Journal of Proteomics. - : Elsevier BV. - 1874-3919. ; 133, s. 66-75
-
Journal article (peer-reviewed)abstract
- Estrogens are suggested to lower the risk of developing metabolic syndrome in both sexes. In this study, we investigated how the increased circulating estrogen-to-androgen ratio (E/A) alters liver lipid metabolism in males. The cytochrome P450 aromatase (P450arom) is an enzyme converting androgens to estrogens. Male mice overexpressing human aromatase enzyme (AROM + mice), and thus have high circulating E/A, were used as a model in this study. Proteomics and gene expression analyses indicated an increase in the peroxisomal beta-oxidation in the liver of AROM + mice as compared with their wild type littermates. Correspondingly, metabolomic analysis revealed a decrease in the amount of phosphatidylcholines with long-chain fatty acids in the plasma. With interest we noted that the expression of Cyp4a12a enzyme, which specifically metabolizes arachidonic acid (AA) to 20-hydroxy AA, was dramatically decreased in the AROM + liver. As a consequence, increased amounts of phospholipids having AA as a fatty acid tail were detected in the plasma of the AROM + mice. Overall, these observations demonstrate that high circulating E/A in males is linked to indicators of higher peroxisomal beta-oxidation and lower AA metabolism in the liver. Furthermore, the plasma phospholipid profile reflects the changes in the liver lipid metabolism. (C) 2015 Elsevier B.V. All rights reserved.
|
|
| 7. |
- Zhang, F. P., et al.
(author)
-
Lack of androgen receptor SUMOylation results in male infertility due to epididymal dysfunction
- 2019
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
-
Journal article (peer-reviewed)abstract
- Androgen receptor (AR) is regulated by SUMOylation at its transactivation domain. In vitro, the SUMOylation is linked to transcriptional repression and/or target gene-selective regulation. Here, we generated a mouse model (ArKl) in which the conserved SUMO acceptor lysines of AR are permanently abolished (Ar-K381R, (K500R)) ArKl males develop normally, without apparent defects in their systemic androgen action in reproductive tissues. However, the ArKl males are infertile. Their spermatogenesis appears unaffected, but their epididymal sperm maturation is defective, shown by severely compromised motility and fertilization capacity of the sperm. Fittingly, their epididymal AR chromatin-binding and gene expression associated with sperm maturation and function are misregulated. AR is SUMOylated in the wild-type epididymis but not in the testis, which could explain the tissue-specific response to the lack of AR SUMOylation. Our studies thus indicate that epididymal AR SUMOylation is essential for the post-testicular sperm maturation and normal reproductive capability of male mice.
|
|
| 8. |
- Adam, M., et al.
(author)
-
Hydroxysteroid (17 beta) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice
- 2018
-
In: Faseb Journal. - 0892-6638. ; 32:6, s. 3434-3447
-
Journal article (peer-reviewed)abstract
- Hydroxysteroid (17(3) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13-knockout (HSD17B13KO) mice deficient in Hsd1 7b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcamitines, suggesting impaired mitochondrial beta-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsdl7b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.
|
|
| 9. |
- Deshpande, Prasannakumar, et al.
(author)
-
Protein synthesis is suppressed in sporadic and familial Parkinson’s disease by LRRK2
- 2020
-
In: FASEB Journal. - 0892-6638. ; 34:11, s. 14217-14233
-
Journal article (peer-reviewed)abstract
- Gain of function LRRK2-G2019S is the most frequent mutation found in familial and sporadic Parkinson's disease. It is expected therefore that understanding the cellular function of LRRK2 will provide insight on the pathological mechanism not only of inherited Parkinson's, but also of sporadic Parkinson's, the more common form. Here, we show that constitutive LRRK2 activity controls nascent protein synthesis in rodent neurons. Specifically, pharmacological inhibition of LRRK2, Lrrk2 knockdown or Lrrk2 knockout, all lead to increased translation. In the rotenone model for sporadic Parkinson's, LRRK2 activity increases, dopaminergic neuron translation decreases, and the neurites atrophy. All are prevented by LRRK2 inhibitors. Moreover, in striatum and substantia nigra of rotenone treated rats, phosphorylation changes are observed on eIF2α-S52(↑), eIF2s2-S2(↓), and eEF2-T57(↑) in directions that signify protein synthesis arrest. Significantly, translation is reduced by 40% in fibroblasts from Parkinson's patients (G2019S and sporadic cases alike) and this is reversed upon LRRK2 inhibitor treatment. In cells from multiple system atrophy patients, translation is unchanged suggesting that repression of translation is specific to Parkinson's disease. These findings indicate that repression of translation is a proximal function of LRRK2 in Parkinson's pathology.
|
|
| 10. |
- Elo, Irma T., et al.
(author)
-
Children's educational attainment, occupation, and income and their parents' mortality
- 2018
-
In: Population Studies. - : Informa UK Limited. - 0032-4728 .- 1477-4747. ; 72:1, s. 53-73
-
Journal article (peer-reviewed)abstract
- Using data from Finland, this paper contributes to a small but growing body of research regarding adult children's education, occupation, and income and their parents' mortality at ages 50+ in 1970-2007. Higher levels of children's education are associated with 30-36 per cent lower parental mortality at ages 50-75, controlling for parents' education, occupation, and income. This association is fully mediated by children's occupation and income, except for cancer mortality. Having at least one child educated in healthcare is associated with 11-16 per cent lower all-cause mortality at ages 50-75, an association that is largely driven by mortality from cardiovascular diseases. Children's higher white-collar occupation and higher income is associated with 39-46 per cent lower mortality in the fully adjusted models. At ages 75+, these associations are much smaller overall and children's schooling remains more strongly associated with mortality than children's occupation or income.
|
|
