| 1. |
- Dillner, Karin, 1974, et al.
(författare)
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Gene expression analysis of prostate hyperplasia in mice overexpressing the prolactin gene specifically in the prostate.
- 2003
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 144:11, s. 4955-66
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Tidskriftsartikel (refereegranskat)abstract
- The probasin (Pb)-PRL transgenic mice that overexpress the rat PRL gene specifically in the prostate develop a dramatic enlargement of the prostate gland. The objective of this study was to characterize the molecular mechanisms involved in the prostate hyperplasia seen in the Pb-PRL transgenic mice. cDNA microarray analysis was used to identify differentially expressed transcripts in the hyperplastic prostates of 6-month-old transgenic mice compared with age-matched controls. We report the identification of 266 genes (175 up-regulated and 91 down-regulated) that were differentially expressed in the enlarged transgenic prostates compared with controls. Subsequential real-time RT-PCR was used to verify a set of differentially regulated transcripts. The hyperplastic prostates of Pb-PRL transgenic mice demonstrate a molecular pattern supporting the importance of reduced degree of apoptosis for the development of the phenotype. Immunohistochemical analysis of apoptotic activity using two different markers of apoptosis (single-stranded DNA and activated caspase-3) were performed, and the results showed diminished apoptosis activity in the prostate of Pb-PRL transgenic mice compared with control prostates. The increased stromal/epithelial ratio of the Pb-PRL transgenic prostate together with up-regulation of a significant fraction of genes involved in tissue remodeling activity, including the synthesis and degradation of the extracellular matrix and changes in protease activity, suggest that activation of the stroma is involved in the development of prostate hyperplasia. Overall, the differentially expressed transcripts identified in this study show many molecular similarities between the prostate hyperplasia of PRL-transgenic mice and human prostate pathology, including both benign prostatic hyperplasia and prostate cancer.
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| 2. |
- Feng, Ruizhi, et al.
(författare)
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MiRNA-320 in the human follicular fluid is associated with embryo quality in vivo and affects mouse embryonic development in vitro.
- 2015
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Previous work from our laboratory demonstrated the existence of miRNAs in human follicular fluid. In the current study, we have sought to identify miRNAs that might affect oocyte/embryo quality in patients undergoing intracytoplasmic sperm injection and to investigate their roles in in vitro fertilization outcomes in mouse oocytes. 53 samples were classified as Group 1 (high quality) if the day-3 embryos had seven and more cells or as Group 2 (low quality) if the embryos had six and fewer cells. TaqMan Human microRNAs cards and qRT-PCR were performed to verify differently expressed miRNAs. The function of the corresponding miRNA was investigated in mouse oocytes by injecting them with miRNA-inhibitor oligonucleotides. We found that hsa-miR-320a and hsa-miR-197 had significantly higher expression levels in the Group 1 follicular fluids than in Group 2 (p = 0.0073 and p = 0.008, respectively). Knockdown of mmu-miR-320 in mouse oocytes strongly decreased the proportions of MII oocytes that developed into two-cell and blastocyst stage embryos (p = 0.0048 and p = 0.0069, respectively). Wnt signaling pathway components had abnormal expression level in miR-320 inhibitor-injected oocytes. This study provides the first evidence that miRNAs in human follicular fluid are indicative of and can influence embryo quality.
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| 3. |
- Feng, Ruizhi, et al.
(författare)
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Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
- 2016
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Ingår i: The New England journal of medicine. - 1533-4406. ; 374:3, s. 223-232
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Tidskriftsartikel (refereegranskat)abstract
- Background Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. Methods We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other β-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one β-tubulin polypeptide (α/β-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. Results We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed β-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/β-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. Conclusions TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.).
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| 4. |
- Feng, Yi, et al.
(författare)
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Effects of androgen and leptin on behavioral and cellular responses in female rats.
- 2011
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Ingår i: Hormones and behavior. - : Elsevier BV. - 1095-6867 .- 0018-506X. ; 60:4, s. 427-38
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Tidskriftsartikel (refereegranskat)abstract
- The causes of anxiety and depression in women with polycystic ovary syndrome (PCOS) remain elusive. To identify steps linking androgen signaling to the regulation of affective symptoms in vivo, we compared behavioral responses in female rats continuously exposed to DHT from puberty (a model of DHT-induced PCOS) and in rats exposed to DHT for 1week. Continuous and 1week of DHT exposure resulted in a general decrease in locomotor activity and time spent on the open arms in the elevated plus maze, indicating anxiety-like behavior. Rats with DHT-induced PCOS have increases in adiposity and circulating leptin levels accompanied by leptin resistance. One week of DHT exposure decreased androgen receptor (AR) expression in the hypothalamus and leptin synthesis and function in adipocytes; it also inhibited signal transducer and activator of transcription 3 (STAT3) and attenuated leptin activity by increasing levels of soluble leptin receptor, a leptin-binding protein, in the hypothalamus. This may affect the androgen-induced anxiety-related behavior in female rats. In conclusion, our results highlight the central role of androgens in behavioral function in female rats and suggest that androgens directly regulate the AR by decreasing its hypothalamic expression. Androgens also increase leptin synthesis in adipocytes, which drives central leptin signaling, and may regulate anxiety-related behaviors. Elucidating mechanisms by which androgens modulate female anxiety-like behavior may uncover useful approaches for treating women with PCOS who have symptoms of anxiety.
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| 5. |
- Feng, Yi, et al.
(författare)
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Electrical and manual acupuncture stimulation affect oestrous cyclicity and neuroendocrine function in an 5α-dihydrotestosterone-induced rat polycystic ovary syndrome model.
- 2012
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Ingår i: Experimental physiology. - : Wiley. - 1469-445X .- 0958-0670. ; 97:5, s. 651-62
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Tidskriftsartikel (refereegranskat)abstract
- Both low-frequency electro-acupuncture (EA) and manual acupuncture improve menstrual frequency and decrease circulating androgens in women with polycystic ovary syndrome (PCOS). We sought to determine whether low-frequency EA is more effective than manual stimulation in regulating disturbed oestrous cyclicity in rats with PCOS induced by 5α-dihydrotestosterone. To identify the central mechanisms of the effects of stimulation, we assessed hypothalamic mRNA expression of molecules that regulate reproductive and neuroendocrine function. From age 70 days, rats received 2 Hz EA or manual stimulation with the needles five times per week for 4-5 weeks; untreated rats served as control animals. Specific hypothalamic nuclei were obtained by laser microdissection, and mRNA expression was measured with TaqMan low-density arrays. Untreated rats were acyclic. During the last 2 weeks of treatment, seven of eight (88%) rats in the EA group had epithelial keratinocytes, demonstrating oestrous cycle change (P = 0.034 versus control rats). In the manual group, five of eight (62%) rats had oestrous cycle changes (n.s. versus control animals). The mRNA expression of the opioid receptors Oprk1 and Oprm1 in the hypothalamic arcuate nucleus was lower in the EA group than in untreated control rats. The mRNA expression of the steroid hormone receptors Esr2, Pgr and Kiss1r was lower in the manual group than in the control animals. In rats with 5α-dihydrotestosterone-induced PCOS, low-frequency EA restored disturbed oestrous cyclicity but did not differ from the manual stimulation group, although electrical stimulation lowered serum testosterone in responders, those with restored oestrus cyclicity, and differed from both control animals and the manual stimulation group. Thus, EA cannot in all aspects be considered superior to manual stimulation. The effects of low-frequency EA may be mediated by central opioid receptors, while manual stimulation may involve regulation of steroid hormone/peptide receptors.
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| 6. |
- Feng, Yi, et al.
(författare)
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Hypothalamic neuroendocrine functions in rats with dihydrotestosterone-induced polycystic ovary syndrome: effects of low-frequency electro-acupuncture.
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:8
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Tidskriftsartikel (refereegranskat)abstract
- Adult female rats continuously exposed to androgens from prepuberty have reproductive and metabolic features of polycystic ovary syndrome (PCOS). We investigated whether such exposure adversely affects estrous cyclicity and the expression and distribution of gonadotropin-releasing hormone (GnRH), GnRH receptors, and corticotrophin-releasing hormone (CRH) in the hypothalamus and whether the effects are mediated by the androgen receptor (AR). We also assessed the effect of low-frequency electro-acupuncture (EA) on those variables. At 21 days of age, rats were randomly divided into three groups (control, PCOS, and PCOS EA; n = 12/group) and implanted subcutaneously with 90-day continuous-release pellets containing vehicle or 5alpha-dihydrostestosterone (DHT). From age 70 days, PCOS EA rats received 2-Hz EA (evoking muscle twitches) five times/week for 4-5 weeks. Hypothalamic protein expression was measured by immunohistochemistry and western blot. DHT-treated rats were acyclic, but controls had regular estrous cycles. In PCOS rats, hypothalamic medial preoptic AR protein expression and the number of AR- and GnRH-immunoreactive cells were increased, but CRH was not affected; however, GnRH receptor expression was decreased in both the pituitary and hypothalamus. Low-frequency EA restored estrous cyclicity within 1 week and reduced the elevated hypothalamic GnRH and AR expression levels. EA did not affect GnRH receptor or CRH expression. Interestingly, nuclear AR co-localized with GnRH in the hypothalamus. Thus, rats with DHT-induced PCOS have disrupted estrous cyclicity and an increased number of hypothalamic cells expressing GnRH, most likely mediated by AR activation. Repeated low-frequency EA normalized estrous cyclicity and restored GnRH and AR protein expression. These results may help explain the beneficial neuroendocrine effects of low-frequency EA in women with PCOS.
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| 7. |
- Feng, Yi, et al.
(författare)
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Spatiotemporal expression of androgen receptors in the female rat brain during the oestrous cycle and the impact of exogenous androgen administration: a comparison with gonadally intact males.
- 2010
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Ingår i: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 321:2, s. 161-74
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the regulation and cellular distribution of androgen receptors (ARs) in female rodent brains at various stages of the oestrous cycle. This information is critical for further studies of androgen signalling in the regulation of brain function under physiological and pathophysiological conditions. In this report, we show that the distribution of AR immunoreactivity in the female rat brain is consistent with reported AR mRNA hybridisation signals in the male brain, except for the dentate gyrus of the hippocampus. Immunohistochemical and Western blot analyses performed herein revealed that the onset of region-specific changes in AR proteins was strongly correlated with circulating and ovarian levels of estradiol and testosterone across the oestrous cycle. During the metestrus and diestrus stages, however, the highest levels of AR expression were abolished by chronic dihydrotestosterone (DHT) treatment. This demonstrates that fluctuations in endogenous androgens are required for the regulation of AR expression in the female rat brain. Colocalisation studies revealed that: (1) anatomical variations in AR protein localisation existed between female and male brains, (2) AR immunoreactivity was both neuronal and non-neuronal, and (3) AR protein expression was lower in female rat brains at all stages of the oestrous cycle compared to age-matched males. Our results indicate the presence of regional sex differences in AR expression and changes in the proportion of AR between different subcellular compartments. Furthermore, DHT was found to down-regulate the level of AR in the subcellular compartment in females in a region-specific manner. As a whole, the present study provides the first step toward understanding the dynamics of AR expression and regulation in the brain during normal physiological conditions and for differences in neuronal androgen effects based on sex.
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| 8. |
- Johansson, Julia, 1982, et al.
(författare)
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Electrical vs Manual Acupuncture Stimulation in a Rat Model of Polycystic Ovary Syndrome: Different Effects on Muscle and Fat Tissue Insulin Signaling
- 2013
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- In rats with dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS), repeated low-frequency electrical stimulation of acupuncture needles restores whole-body insulin sensitivity measured by euglycemic hyperinsulinemic clamp. We hypothesized that electrical stimulation causing muscle contractions and manual stimulation causing needle sensation have different effects on insulin sensitivity and related signaling pathways in skeletal muscle and adipose tissue, with electrical stimulation being more effective in DHT-induced PCOS rats. From age 70 days, rats received manual or low-frequency electrical stimulation of needles in abdominal and hind limb muscle five times/wk for 4–5 wks; controls were handled but untreated rats. Low-frequency electrical stimulation modified gene expression (decreased Tbc1d1 in soleus, increased Nr4a3 in mesenteric fat) and protein expression (increased pAS160/AS160, Nr4a3 and decreased GLUT4) by western blot and increased GLUT4 expression by immunohistochemistry in soleus muscle; glucose clearance during oral glucose tolerance tests was unaffected. Manual stimulation led to faster glucose clearance and modified mainly gene expression in mesenteric adipose tissue (increased Nr4a3, Mapk3/Erk, Adcy3, Gsk3b), but not protein expression to the same extent; however, Nr4a3 was reduced in soleus muscle. The novel finding is that electrical and manual muscle stimulation affect glucose homeostasis in DHT-induced PCOS rats through different mechanisms. Repeated electrical stimulation regulated key functional molecular pathways important for insulin sensitivity in soleus muscle and mesenteric adipose tissue to a larger extent than manual stimulation. Manual stimulation improved whole-body glucose tolerance, an effect not observed after electrical stimulation, but did not affect molecular signaling pathways to the same extent as electrical stimulation. Although more functional signaling pathways related to insulin sensitivity were affected by electrical stimulation, our findings suggest that manual stimulation of acupuncture needles has a greater effect on glucose tolerance. The underlying mechanism of the differential effects of the intermittent manual and the continuous electrical stimulation remains to be elucidated.
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| 9. |
- Johansson, Julia, 1982, et al.
(författare)
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Intense electroacupuncture normalizes insulin sensitivity, increases muscle GLUT4 content, and improves lipid profile in a rat model of polycystic ovary syndrome.
- 2010
-
Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 299:4
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Tidskriftsartikel (refereegranskat)abstract
- Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance, possibly reflecting defects in skeletal muscle and adipocyte insulin signaling. Low-frequency (2 Hz) electroacupuncture (EA) increases insulin sensitivity in female rats with dihydrotestosterone (DHT)-induced PCOS, but the mechanism is unclear. We hypothesized that low-frequency EA regulates mediators involved in skeletal muscle glucose uptake and metabolism and alters the lipid profile in rats with DHT-induced PCOS. To test this hypothesis, we implanted in prepubescent female rats 90-day continuous-release pellets containing DHT (PCOS). At 70 days of age, the rats were randomly subdivided into two groups: one received low-frequency EA (evoking muscle twitches) for 20-25 min five times/wk for 4-5 wk; the other did not. Controls were implanted with pellets containing vehicle only. All three groups were otherwise handled similarly. Lipid profile was measured in fasting blood samples. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp, soleus muscle protein expression of glucose transporter 4 (GLUT4), and phosphorylated and nonphosphorylated Akt, and Akt substrate of 160 kDa was determined by Western blot analysis and GLUT4 location by immunofluorescence staining. PCOS EA rats had normalized insulin sensitivity, lower levels of total high-density lipoprotein and low-density lipoprotein cholesterol, and increased expression of GLUT4 in different compartments of skeletal muscle compared with PCOS rats. Total weight and body composition did not differ in the groups. Thus, in rats with DHT-induced PCOS, low-frequency EA has systemic and local effects involving intracellular signaling pathways in muscle that may, at least in part, account for the marked improved insulin sensitivity.
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| 10. |
- Niu, Xianzhi, et al.
(författare)
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Suppression of apoptosis occurs in the cochlea by sound conditioning.
- 2003
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Ingår i: Neuroreport. - : Ovid Technologies (Wolters Kluwer Health). - 0959-4965. ; 14:7, s. 1025-9
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Tidskriftsartikel (refereegranskat)abstract
- Apoptosis plays a critical role in the pathogenesis of noise-induced hearing loss. The goal of this study was to determine if apoptotic pathways are suppressed by sound conditioning. Sound conditioning is a pretreatment to low-level non-damaging sound that protects against a subsequent damaging acoustic trauma. Sound conditioning protects against hair cell death and thereby preserves hearing after a subsequent acoustic trauma. Using a combination of immunocytochemical and Western blotting techniques we show that acoustic trauma causes the release of cytochrome c from the mitochondria into the cytoplasm, and a decrease in bcl-2 immunoreactivity in the outer hair cells. Sound conditioning was found to trigger a protection against these detrimental changes. These data suggest that bcl-2 plays an important role in the regulation of hair cell death, and provides evidence that bcl-2 acts as an inducible neuroprotective gene that is upregulated by sound conditioning.
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| 11. |
- Nutu, Magdalena, 1967, et al.
(författare)
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Stromal cell-specific apoptotic and antiestrogenic mechanisms may explain uterine defects in humans after clomiphene citrate therapy.
- 2010
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Ingår i: American journal of obstetrics and gynecology. - : Elsevier BV. - 1097-6868 .- 0002-9378. ; 203:1
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The purpose of this study was to investigate clomiphene citrate (CC)-induced modulation of uterine cell function in vivo. STUDY DESIGN: Prepubertal female Sprague-Dawley rats were treated intraperitoneally with CC for 6 or 24 hours or with a combination of CC and/or 17-beta-estradiol (E2) for 4 days. RESULTS: Chronic CC treatment induced apoptosis in a fraction of uterine stromal cells by activating the caspase-3-mediated apoptotic pathway. The damage was prevented by successive E2 treatment; however, pretreatment or concomitant treatment with E2 did not protect against CC-induced uterine apoptosis. CC decreased the protein expression of estrogen receptor alpha and increased its phosphorylation but did not affect estrogen receptor beta expression or phosphorylation. Furthermore, changes in Hoxa11, p27, and progesterone receptor protein levels and localization were associated with CC treatment. CONCLUSION: We provide novel mechanistic insights into cellular and molecular events by which CC regulates uterine stromal cell function and hence the implantation process and pregnancy outcome.
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| 12. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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Ciliated epithelial-specific and regional-specific expression and regulation of the estrogen receptor-beta2 in the fallopian tubes of immature rats: a possible mechanism for estrogen-mediated transport process in vivo
- 2007
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Ingår i: American journal of physiology. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 293:1
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Tidskriftsartikel (refereegranskat)abstract
- Several ERbeta isoforms have been identified in human and rodent tissues, but it is unclear whether each isoform has distinctly different cellular targeting characteristics and physiological functions. We have investigated the intracellular localization and regulatory patterns for ERbeta isoforms in rat fallopian tubes. Western blot analysis reveals that two ERbeta isoforms corresponding to ERbeta1 and ERbeta2 are expressed in rat fallopian tubes. However, ERbeta2 is the predominant form of ERbeta in this tissue. High-resolution confocal imaging and immunohistochemical analysis provide ample evidence that ERbeta expression is limited almost exclusively to the ciliated epithelial cells, in contrast to ERalpha, which is widely distributed. Furthermore, within the ciliated epithelial cells, ERbeta is colocalized with beta-tubulin IV at stem portion of the cilia. We show that ERbeta2 protein expression is tightly regulated by E(2) or DPN in a time-dependent manner without changes in ERbeta1 expression. These estrogenic effects are inhibited by an ER antagonist, ICI 182,780. In addition, significant alteration of ERbeta immunoreactivity is detected only histologically in the ampullary region. Since the cilia are considered an essential determinant of tubal transport, we further demonstrate that E(2)- or DPN-induced ERbeta2 activation is associated with alterations in tubal protein expression crucial for the regulation of calcium-dependent ciliary beating. Given the coordinated regulation and interaction of ER and progesterone receptor in the cilia, we hypothesize that tubal ERbeta2 may facilitate the estrogen-mediated transport process by processing protein-protein interaction under physiological and/or pathological conditions. We show for the first time that a previously unrecognized localization of ERbeta isoform in rat fallopian tubes can combine with estrogen to individually control the expression of ER beta-isoforms in normal target tissues.
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| 13. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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Clomiphene citrate causes aberrant tubal apoptosis and estrogen receptor activation in rat fallopian tube: implications for tubal ectopic pregnancy.
- 2009
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Ingår i: Biology of reproduction. - : Oxford University Press (OUP). - 0006-3363 .- 1529-7268. ; 80:6, s. 1262-71
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Tidskriftsartikel (refereegranskat)abstract
- Clomiphene citrate (CC) therapy for disorders of anovulatory infertility has been linked to an increased frequency of tubal ectopic pregnancy. Although CC enhances apoptotic processes in the ovaries, villi, and decidual tissues, its effect on apoptosis in the fallopian tube is unknown. Here, we show that chronic treatment with CC induces tubal apoptosis, but not necrosis, through an intrinsic mitochondria-dependent signaling pathway in vivo. The apoptosis was specific to epithelial cells in the isthmus, and the damage was reversed with 17beta-estradiol (E2); however, pretreatment or concomitant treatment with E2 did not protect against tubal apoptosis induced by chronic treatment with CC. Chronic treatment activated estrogen receptors (ESRs), particularly cilia-localized ESR2A (formerly ERbeta2). In contrast to E2, acute treatment of superovulating rats with a high dose of CC or the ESR2-selective agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) significantly delayed the transport of oocyte-cumulus complexes through the fallopian tube. Our findings suggest that in response to chronic CC therapy, isthmus-specific apoptosis of epithelial cells and activation of cilia-ESR2A act in parallel to block gamete and embryo passage through the fallopian tube, eventually resulting in tubal ectopic pregnancy.
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| 14. |
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| 15. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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Down-Regulation of Cilia-Localized IL-6R{alpha} by 17{beta}-Estradiol in Mouse and Human Fallopian Tubes.
- 2009
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Ingår i: American journal of physiology. Cell physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 297:1
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Tidskriftsartikel (refereegranskat)abstract
- The action of Interleukin-6 (IL-6) impacts female reproduction. Although IL-6 was recently shown to inhibit cilia activity in human fallopian tubes in vitro, the molecular mechanisms underlying IL-6 signaling to tubal function remain elusive. Here, we investigate the cellular localization, regulation, and possible function of two IL-6 receptors (IL-6Ralpha and gp130) in mouse and human fallopian tubes in vivo. We show that IL-6Ralpha is restricted to the cilia of epithelial cells in both mouse and human fallopian tubes. Exogenous 17beta-estradiol (E2), but not progesterone (P4), causes a time-dependent decrease in IL-6Ralpha expression which is blocked by the estrogen receptor (ER) antagonist ICI 182,780. Exposure of different ER-selective agonists, PTT or DPN, demonstrated an ER subtype-specific regulation of IL-6Ralphaalpha in mouse fallopian tubes. In contrast to IL-6Ralpha, gp130 was detected in tubal epithelial cells in mice but not in humans. In humans, gp130 was found in the muscle cells and was decreased in the periovulatory and luteal phases during the reproductive cycles, indicating a species-specific expression and regulation of gp130 in the fallopian tube. Expression of tubal IL-6Ralpha and gp130 in IL-6 knockout mice was found to be normal; however, E2 treatment increased IL-6Ralpha, but not gp130, in IL-6 knockout mice compared to wild-type mice. Furthermore, expression levels of IL-6Ralpha, but not gp130, decreased in parallel with estrogenic accelerated oocyte-cumulus complex (OCC) transport in mouse fallopian tubes. Our findings unveil a potential role for cilia-specific IL-6Ralpha in the regulation of OCC transport and suggest an estrogen-regulatory pathway of IL-6Ralpha in the fallopian tube. Key words: estrogen, IL-6R, cilia, fallopian tube.
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| 16. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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From mice to women and back again: Causalities and clues for Chlamydia-induced tubal ectopic pregnancy.
- 2012
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Ingår i: Fertility and sterility. - : Elsevier BV. - 1556-5653 .- 0015-0282. ; 98:5, s. 1175-85
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Tidskriftsartikel (refereegranskat)abstract
- To provide an overview of knockout mouse models that have pathological tubal phenotypes after Chlamydia muridarum infection, discuss factors and pathological processes that contribute to inflammation, summarize data on tubal transport and progression of tubal implantation from studies in humans and animal models, and highlight research questions in the field.
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| 17. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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Increase of SUMO-1 expression in response to hypoxia: direct interaction with HIF-1alpha in adult mouse brain and heart in vivo
- 2004
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Ingår i: FEBS letters. - : Wiley. - 0014-5793. ; 569:1-3, s. 293-300
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Tidskriftsartikel (refereegranskat)abstract
- The present study investigates the regulation of small ubiquitin-related modifier-1 (SUMO-1) expression in response to hypoxia in adult mouse brain and heart. We observed a significant increase in SUMO-1 mRNAs and proteins after hypoxic stimulation in vivo. Because SUMO-1 interacts with various transcription factors, including hypoxia-inducible factor-1beta (HIF-1beta) in vitro, we not only demonstrated that the HIF-1alpha expression is increased by hypoxia in brain and heart, but also provided evidence that SUMO-1 co-localizes in vivo with HIF-1alpha in response to hypoxia by demonstrating the co-expression of these two proteins in neurons and cardiomyocytes. The specific interaction between SUMO-1 and HIF-1alpha was additionally demonstrated with co-immunoprecipitation. These results indicate that the increased levels of SUMO-1 participate in the modulation of HIF-1alpha function through sumoylation in brain and heart.
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| 18. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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Nuclear progesterone receptor A and B isoforms in mouse fallopian tube and uterus: implications for expression, regulation, and cellular function
- 2006
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Ingår i: American journal of physiology. - : American Physiological Society. - 0193-1849. ; 291:1
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Tidskriftsartikel (refereegranskat)abstract
- Progesterone and its interaction with nuclear progesterone receptors (PR) PR-A and PR-B play a critical role in the regulation of female reproductive function in all mammals. However, our knowledge of the regulation and possible cellular function of PR protein isoforms in the fallopian tube and uterus in vivo is still very limited. In the present study, we revealed that equine chorionic gonadotropin (eCG) treatment resulted in a time-dependent increase in expression of both isoforms, reaching a maximal level at 48 h in the fallopian tube. Regulation of PR-A protein expression paralleled that of PR-B protein expression. However, in the uterus PR-B protein levels increased and peaked earlier than PR-A protein levels after eCG treatment. With prolonged exposure to eCG, PR-B protein levels decreased, whereas PR-A protein levels continued to increase. Furthermore, subsequent treatment with human (h)CG decreased the levels of PR protein isoforms in both tissues in parallel with increased endogenous serum progesterone levels. To further elucidate whether progesterone regulates PR protein isoforms, we demonstrated that a time-dependent treatment with progesterone (P(4)) decreased the expression of PR protein isoforms in both tissues, whereas decreases in p27, cyclin D(2), and proliferating cell nuclear antigen protein levels were observed only in the uterus. To define the potential PR-mediated effects on apoptosis, we demonstrated that the PR antagonist treatment increased the levels of PR protein isoforms, induced mitochondrial-associated apoptosis, and decreased in epidermal growth factor (EGF) and EGF receptor protein expression in both tissues. Interestingly, immunohistochemistry indicated that the induction of apoptosis by PR antagonists was predominant in the epithelium, whereas increase in PR protein expression was observed in stromal cells of both tissues. Taken together, these observations suggest that 1) the tissue-specific and hormonal regulation of PR isoform expression in mouse fallopian tube and uterus, where they are potentially involved in regulation of mitochondrial-mediated apoptosis depending on the cellular compartment; and 2) a possible interaction between functional PR protein and growth factor signaling may have a coordinated role for regulating apoptotic process in both tissues in vivo.
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| 19. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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Revealing the Hidden Mechanisms of Smoke-Induced Fallopian Tubal Implantation.
- 2012
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Ingår i: Biology of reproduction. - : Oxford University Press (OUP). - 1529-7268 .- 0006-3363. ; 86:4
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Tidskriftsartikel (refereegranskat)abstract
- Ectopic pregnancy (EP) is an enigmatic reproductive disorder. Although tubal EP is difficult to predict, several hypotheses about its etiology have been proposed. In retrospective case-control studies, smoking is associated with an increased rate of EPs in the Fallopian tube. Studies of experimental animals in vivo and human Fallopian tubal tissues in vitro have suggested mechanisms of Fallopian tubal damage and dysfunction induced by nicotine and other smoking-related chemicals that may explain this association. However, the pathogenesis of smoking-induced modulation of implantation leading to tubal EP is largely unknown. Since cigarette/tobacco smoke adversely affects the success of intrauterine implantation, there is a great need to determine how embryo implantation occurs in the Fallopian tube in female smokers of reproductive age.
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| 20. |
- Sun, Miao, et al.
(författare)
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Maternal androgen excess reduce placental and fetal weights, increase placental steroidogenesis and leads to long-term health effects in their female offspring.
- 2012
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 303:11
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Tidskriftsartikel (refereegranskat)abstract
- Here we tested the hypothesis that excess maternal androgen in late pregnancy reduces placental and fetal growth, increases placental steroidogenesis, and adversely affects glucose and lipid metabolism in adult female offspring. Pregnant Wistar rats were randomly assigned to treatment with testosterone (daily injections of 5 mg free testosterone from gestational day 16 to 19) or vehicle alone. In experiment 1, fetal and placental weights, circulating maternal testosterone, estradiol, and corticosterone levels, and placental protein expression and distribution of estrogen receptors α and ß, androgen receptor, and 17 beta-hydroxysteroid dehydrogenase 2 were determined. In experiment 2, birth weights, postnatal growth rates, circulating testosterone, estradiol, and corticosterone levels, insulin sensitivity, adipocyte size, lipid profiles, and the presence of non-alcoholic fatty liver were assessed in female adult offspring. Treatment with testosterone reduced placental and fetal weights and increased placental expression of all four proteins. The offspring of testosterone-treated dams were born with intrauterine growth restriction, however at 6 weeks of age there was no difference in body weight between the offspring of testosterone-, and control-treated rats. At 10-11 weeks of age, the offspring of the testosterone-treated dams had less fat mass and smaller adipocyte size than those born to control rats and had no difference in insulin sensitivity. Circulating triglyceride levels were higher in the offspring of testosterone-treated dams and they developed non-alcoholic fatty liver as adults. We demonstrate for the first time that prenatal testosterone exposure alters placental steroidogenesis and leads to dysregulation of lipid metabolism in their adult female offspring.
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| 21. |
- Svensson, Johan, 1964, et al.
(författare)
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Liver-derived IGF1 enhances the androgenic response in prostate.
- 2008
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 199:3, s. 489-97
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Tidskriftsartikel (refereegranskat)abstract
- Both IGF1 and androgens are major enhancers of prostate growth and are implicated in the development of prostate hyperplasia and cancer. The aim of the present study was to investigate whether liver-derived endocrine IGF1 modulates the androgenic response in prostate. Mice with adult, liver-specific inactivation of IGF1 (LI-IGF1(-/-) mice) displayed an approximately 80% reduction in serum IGF1 levels associated with decreased prostate weight compared with control mice (anterior prostate lobe -19%, P<0.05; dorsolateral prostate (DLP) lobe -35%, P<0.01; ventral prostate (VP) lobe -47%, P<0.01). Reduced androgen receptor (Ar) mRNA and protein levels were observed in the VP lobe (-34% and -30% respectively, both P<0.05 versus control mice). Analysis of prostate morphology showed reductions in both the glandular and fibromuscular compartments of the VP and DLP lobes that were proportional to the reductions in the weights of these lobes. Immunohistochemistry revealed reduced intracellular AR immunoreactivity in the VP and DLP lobes. The non-aromatizable androgen dihydrotestosterone increased VP weight to a lesser extent in orchidectomized (ORX) LI-IGF1(-/-) mice than in ORX controls (-40%, P<0.05 versus control mice). In conclusion, deficiency of liver-derived IGF1 reduces both the glandular and fibromuscular compartments of the prostate, decreases AR expression in prostate, and reduces the stimulatory effect of androgens on VP weight. These findings may explain, at least in part, the well-known clinical association between serum IGF1 levels and conditions with abnormal prostate growth.
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| 22. |
- Windahl, Sara H, 1971, et al.
(författare)
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Reduced bone mass and muscle strength in male 5α-reductase type 1 inactivated mice.
- 2011
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Androgens are important regulators of bone mass but the relative importance of testosterone (T) versus dihydrotestosterone (DHT) for the activation of the androgen receptor (AR) in bone is unknown. 5α-reductase is responsible for the irreversible conversion of T to the more potent AR activator DHT. There are two well established isoenzymes of 5α-reductase (type 1 and type 2), encoded by separate genes (Srd5a1 and Srd5a2). 5α-reductase type 2 is predominantly expressed in male reproductive tissues whereas 5α-reductase type 1 is highly expressed in liver and moderately expressed in several other tissues including bone. The aim of the present study was to investigate the role of 5α-reductase type 1 for bone mass using Srd5a1⁻/⁻ mice. Four-month-old male Srd5a1⁻/⁻ mice had reduced trabecular bone mineral density (-36%, p<0.05) and cortical bone mineral content (-15%, p<0.05) but unchanged serum androgen levels compared with wild type (WT) mice. The cortical bone dimensions were reduced in the male Srd5a1⁻/⁻ mice as a result of a reduced cortical periosteal circumference compared with WT mice. T treatment increased the cortical periosteal circumference (p<0.05) in orchidectomized WT mice but not in orchidectomized Srd5a1⁻/⁻ mice. Male Srd5a1⁻/⁻ mice demonstrated a reduced forelimb muscle grip strength compared with WT mice (p<0.05). Female Srd5a1⁻/⁻ mice had slightly increased cortical bone mass associated with elevated circulating levels of androgens. In conclusion, 5α-reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength and we propose that these effects are due to lack of 5α-reductase type 1 expression in bone and muscle. In contrast, the increased cortical bone mass in female Srd5a1⁻/⁻ mice, is an indirect effect mediated by elevated circulating androgen levels.
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| 23. |
- Xu, Yiran, 1988, et al.
(författare)
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Cranial irradiation alters neuroinflammation and neural proliferation in the pituitary gland and induces late-onset hormone deficiency.
- 2020
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Ingår i: Journal of cellular and molecular medicine. - : Wiley. - 1582-4934 .- 1582-1838. ; 24:24, s. 14571-14582
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Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy induces endocrine disorders and reproductive abnormalities, particularly in long-term female cancer survivors, and this might in part be caused by injury to the pituitary gland, but the underlying mechanisms are unknown. The aim of this study was to investigate the influence of cranial irradiation on the pituitary gland and related endocrine function. Female Wistar rat pups on postnatal day 11 were subjected to a single dose of 6Gy whole-head irradiation, and hormone levels and organ structure in the reproductive system were examined at 20weeks after irradiation. We found that brain irradiation reduced cell proliferation and induced persistent inflammation in the pituitary gland. The whole transcriptome analysis of the pituitary gland revealed that apoptosis and inflammation-related pathways were up-regulated after irradiation. In addition, irradiation led to significantly decreased levels of the pituitary hormones, growth hormone, adrenocorticotropic hormone, thyroid-stimulating hormone and the reproductive hormones testosterone and progesterone. To conclude, brain radiation induces reduction of pituitary and reproduction-related hormone secretion, this may due to reduced cell proliferation and increased pituitary inflammation after irradiation. Our results thus provide additional insight into the molecular mechanisms underlying complications after head irradiation and contribute to the discovery of preventive and therapeutic strategies related to brain injury following irradiation.
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| 24. |
- Xu, Yiran, 1988, et al.
(författare)
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Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats.
- 2018
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Ingår i: Developmental Neuroscience. - : S. Karger AG. - 0378-5866 .- 1421-9859. ; 40:2, s. 120-33
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Tidskriftsartikel (refereegranskat)abstract
- Cranial radiotherapy is one of the most effective tools for treating children with brain tumors. However, radiotherapy-induced late-onset side effects have a significant impact on patients' quality of life. The purpose of this study was to investigate the effects of irradiation on metabolism and the possible molecular and cellular mechanisms behind such effects. Female Wistar rats were subjected to a single dose of 6-Gy whole-brain irradiation on postnatal day 11. The animals were sacrificed 6 h or 20 weeks after irradiation. Cell death and proliferation, microglial activation, and inflammation were analyzed and RNA sequencing was performed. We found that irradiation led to a significantly increased body weight from 15 weeks (p < 0.05) along with white adipose tissue accumulation and adipocyte hypertrophy at 20 weeks, and these changes were accompanied by glucose and lipid metabolic disturbances as indicated by reduced glucose tolerance, increased insulin resistance, increased serum triglycerides, and an increased leptin/adiponectin ratio. Furthermore, irradiation induced cell death, microglial activation, inflammation, and persistent astrocyte reactivity in the hypothalamus. Hypothalamic transcriptome analysis showed that 865 genes were downregulated and 290 genes were upregulated in the irradiated group 20 weeks after irradiation, and further pathway analysis showed that the insulin resistance-related PI3K-Akt signaling pathway and the energy expenditure-related adipocytokine signaling pathway were downregulated. Gene Ontology enrichment analysis showed that the expression of fatty acid metabolism-related proteins and effector proteins was significantly different in the irradiation group. This study demonstrates that ionizing radiation to the juvenile female brain induces hypothalamic damage that is likely to be associated with delayed metabolic abnormalities, and this critical vulnerability of the hypothalamus to irradiation should be taken into consideration in the development of future protective strategies for radiotherapy.
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| 25. |
- Billig, Håkan, 1955, et al.
(författare)
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Follicular development and apoptosis.
- 2002
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Ingår i: Ernst Schering Research Foundation workshop. - 0947-6075. ; :41, s. 23-41
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Tidskriftsartikel (refereegranskat)
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