Ectopic pregnancy is a common reproductive disorder of unknown etiology and is a leading cause of... more Ectopic pregnancy is a common reproductive disorder of unknown etiology and is a leading cause of maternal and fetal mortality. Because of the asymptomatic nature of early tubal ectopic pregnancy and the lack of specific biomarkers for early diagnosis, a better understanding of the complex cellular and molecular interactions that contribute to tubal ectopic pregnancy is required. DNA methylation is the most studied epigenetic process in various tissues and cells, and the goal of this article is to provide a brief review of recent work describing the potential mechanisms of DNA methylation and the biological function of such methylation in normal intrauterine pregnancy. Further, novel findings from our laboratory highlight the possible role of DNA methylation in human Fallopian tube dysfunction and suggest a possible correlation between methylation of estrogen receptor α in women and the occurrence of tubal ectopic pregnancies.
Journal of experimental & clinical cancer research : CR, Jan 11, 2014
Although a number of in vitro studies have demonstrated the antiproliferative, anti-invasive, and... more Although a number of in vitro studies have demonstrated the antiproliferative, anti-invasive, and antimetastatic effects of metformin in multiple cancer cell types, its cellular and molecular mechanisms of anti-cancer action in the endometrium of women with polycystic ovary syndrome (PCOS) have not yet been fully elucidated. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are known to be involved in metformin uptake and excretion in cells. In this article, we discuss the novel therapeutic possibilities for early-stage endometrial carcinoma (EC) in women with PCOS focusing on metformin, which might have a direct effect in the endometrium through the OCTs and MATEs. We then review the molecular mechanism(s) of the action of metformin in the endometrium and highlight possible mechanistic insights into the inhibition of cell proliferation and tumor growth and, ultimately, the reversal of early-stage EC into normal endometria in women with PCOS.
International journal of molecular sciences, Jan 23, 2015
Nitric oxide (NO) is highly unstable and has a half-life of seconds in buffer solutions. It is sy... more Nitric oxide (NO) is highly unstable and has a half-life of seconds in buffer solutions. It is synthesized by NO-synthase (NOS), which has been found to exist in the following three isoforms: neuro nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS). NOS activity is localized in the reproductive tracts of many species, although direct evidence for NOS isoforms in the Fallopian tubes of mice is still lacking. In the present study, we investigated the expression and regulation of NOS isoforms in the mouse and human Fallopian tubes during the estrous and menstrual cycles, respectively. We also measured isoform expression in humans with ectopic pregnancy and in mice treated with lipopolysaccharide (LPS). Our results confirmed the presence of different NOS isoforms in the mouse and human Fallopian tubes during different stages of the estrous and menstrual cycles and showed that iNOS expression increased in the Fallopian tubes...
Background The controlled beating of cilia of the fallopian tube plays an important role in facil... more Background The controlled beating of cilia of the fallopian tube plays an important role in facilitating the meeting of gametes and subsequently transporting the fertilized egg to its implantation site. Rapid effects of progesterone on ciliary beat frequency have been reported in the fallopian tubes of cows, but the identity of the receptors mediating this non-genomic action of progesterone is not known. We recently identified a member of the non-genomic membrane progesterone receptor family, mPR gamma, as a candidate for mediating these actions of progesterone. Here, we investigated the possible presence of a related receptor, mPR beta, in the fallopian tubes of mice and women as well as the possible hormonal regulation of mPR beta and gamma. Methods Western blot and immunohistochemistry with specific antibodies were used to characterize the expression and cellular localization of the mPRs in mouse and human tissues. Taqman (Quantitative Polymerase Chain Reaction) assays were used ...
Background The physiological regulation of ciliary beat frequency (CBF) within the fallopian tube... more Background The physiological regulation of ciliary beat frequency (CBF) within the fallopian tube is important for controlling the transport of gametes and the fertilized ovum. Progesterone influences gamete transport in the fallopian tube of several mammalian species. In fallopian tubes isolated from cows, treatment with 20 micromolar progesterone caused a rapid reduction of the tubal CBF. The aims of this study were to establish methodology for studying fallopian tube CBF in the mouse, as it is an important model species, and to investigate if progesterone rapidly affects the CBF of mice at nM concentrations. Methods A method to assess tubal CBF of mice was developed. Fallopian tubes were dissected and the tissue was cut in small pieces. Tissue samples with moving cilia were located under an inverted bright field microscope and held still against the bottom of a petri dish by a motorized needle system. Images were acquired over 90 minutes at 35 degrees C with a high-speed camera a...
Only a minute fraction of the ovarian follicles present in a fetal ovary will complete the path t... more Only a minute fraction of the ovarian follicles present in a fetal ovary will complete the path to ovulation. Most of the follicles will undergo atresia, a hormonally controlled apoptotic process. Apoptosis occurs at each stage of follicular development and there is a marked reduction in the number of follicles present at birth. Stage-dependent mechanisms of follicle survival can be postulated to achieve co-ordinated development, leading to ovulation of a small fraction of follicles. Indeed, hormone and growth factor regulation of follicular atresia is stage-specific. This short review considers the factors that promote survival of ovarian follicles throughout development, including endocrine, locally produced and intracellular mediators, as exemplified mainly by follicular development in rodents. In primordial follicles, oocyte apoptosis is considered to be the cause of subsequent follicle degeneration. In slow-growing preantral follicles, FSH is not a survival factor, but some loc...
The aim of this study was to investigate the regulation of resistin, a recently identified adipoc... more The aim of this study was to investigate the regulation of resistin, a recently identified adipocyte‐secreted peptide, in the adipose tissue of prolactin (PRL)‐transgenic (tg) mice using ribonuclease protection assay. The level of resistin mRNA increased 3.5‐fold in the adipose tissue of untreated male PRL‐tg mice compared to controls. However, there was no difference in resistin expression in the adipose tissue of female PRL‐tg mice compared to control mice. PRL‐tg male mice have elevated serum testosterone levels and we therefore analyzed the effects of testosterone alone on resistin mRNA expression. Furthermore, the effects of elevated androgen levels on PRL receptor (PRLR) mRNA expression in the adipose tissue were investigated. Resistin mRNA increased 2.6‐fold in the adipose tissue of control male mice with elevated serum androgen levels. In addition, PRLR mRNA expression was increased in the adipose tissue of male mice with elevated testosterone. These results suggest testoste...
Both low‐frequency electro‐acupuncture (EA) and manual acupuncture improve menstrual frequency an... more 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...
Ectopic pregnancy is a common reproductive disorder of unknown etiology and is a leading cause of... more Ectopic pregnancy is a common reproductive disorder of unknown etiology and is a leading cause of maternal and fetal mortality. Because of the asymptomatic nature of early tubal ectopic pregnancy and the lack of specific biomarkers for early diagnosis, a better understanding of the complex cellular and molecular interactions that contribute to tubal ectopic pregnancy is required. DNA methylation is the most studied epigenetic process in various tissues and cells, and the goal of this article is to provide a brief review of recent work describing the potential mechanisms of DNA methylation and the biological function of such methylation in normal intrauterine pregnancy. Further, novel findings from our laboratory highlight the possible role of DNA methylation in human Fallopian tube dysfunction and suggest a possible correlation between methylation of estrogen receptor α in women and the occurrence of tubal ectopic pregnancies.
Journal of experimental & clinical cancer research : CR, Jan 11, 2014
Although a number of in vitro studies have demonstrated the antiproliferative, anti-invasive, and... more Although a number of in vitro studies have demonstrated the antiproliferative, anti-invasive, and antimetastatic effects of metformin in multiple cancer cell types, its cellular and molecular mechanisms of anti-cancer action in the endometrium of women with polycystic ovary syndrome (PCOS) have not yet been fully elucidated. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are known to be involved in metformin uptake and excretion in cells. In this article, we discuss the novel therapeutic possibilities for early-stage endometrial carcinoma (EC) in women with PCOS focusing on metformin, which might have a direct effect in the endometrium through the OCTs and MATEs. We then review the molecular mechanism(s) of the action of metformin in the endometrium and highlight possible mechanistic insights into the inhibition of cell proliferation and tumor growth and, ultimately, the reversal of early-stage EC into normal endometria in women with PCOS.
International journal of molecular sciences, Jan 23, 2015
Nitric oxide (NO) is highly unstable and has a half-life of seconds in buffer solutions. It is sy... more Nitric oxide (NO) is highly unstable and has a half-life of seconds in buffer solutions. It is synthesized by NO-synthase (NOS), which has been found to exist in the following three isoforms: neuro nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS). NOS activity is localized in the reproductive tracts of many species, although direct evidence for NOS isoforms in the Fallopian tubes of mice is still lacking. In the present study, we investigated the expression and regulation of NOS isoforms in the mouse and human Fallopian tubes during the estrous and menstrual cycles, respectively. We also measured isoform expression in humans with ectopic pregnancy and in mice treated with lipopolysaccharide (LPS). Our results confirmed the presence of different NOS isoforms in the mouse and human Fallopian tubes during different stages of the estrous and menstrual cycles and showed that iNOS expression increased in the Fallopian tubes...
Background The controlled beating of cilia of the fallopian tube plays an important role in facil... more Background The controlled beating of cilia of the fallopian tube plays an important role in facilitating the meeting of gametes and subsequently transporting the fertilized egg to its implantation site. Rapid effects of progesterone on ciliary beat frequency have been reported in the fallopian tubes of cows, but the identity of the receptors mediating this non-genomic action of progesterone is not known. We recently identified a member of the non-genomic membrane progesterone receptor family, mPR gamma, as a candidate for mediating these actions of progesterone. Here, we investigated the possible presence of a related receptor, mPR beta, in the fallopian tubes of mice and women as well as the possible hormonal regulation of mPR beta and gamma. Methods Western blot and immunohistochemistry with specific antibodies were used to characterize the expression and cellular localization of the mPRs in mouse and human tissues. Taqman (Quantitative Polymerase Chain Reaction) assays were used ...
Background The physiological regulation of ciliary beat frequency (CBF) within the fallopian tube... more Background The physiological regulation of ciliary beat frequency (CBF) within the fallopian tube is important for controlling the transport of gametes and the fertilized ovum. Progesterone influences gamete transport in the fallopian tube of several mammalian species. In fallopian tubes isolated from cows, treatment with 20 micromolar progesterone caused a rapid reduction of the tubal CBF. The aims of this study were to establish methodology for studying fallopian tube CBF in the mouse, as it is an important model species, and to investigate if progesterone rapidly affects the CBF of mice at nM concentrations. Methods A method to assess tubal CBF of mice was developed. Fallopian tubes were dissected and the tissue was cut in small pieces. Tissue samples with moving cilia were located under an inverted bright field microscope and held still against the bottom of a petri dish by a motorized needle system. Images were acquired over 90 minutes at 35 degrees C with a high-speed camera a...
Only a minute fraction of the ovarian follicles present in a fetal ovary will complete the path t... more Only a minute fraction of the ovarian follicles present in a fetal ovary will complete the path to ovulation. Most of the follicles will undergo atresia, a hormonally controlled apoptotic process. Apoptosis occurs at each stage of follicular development and there is a marked reduction in the number of follicles present at birth. Stage-dependent mechanisms of follicle survival can be postulated to achieve co-ordinated development, leading to ovulation of a small fraction of follicles. Indeed, hormone and growth factor regulation of follicular atresia is stage-specific. This short review considers the factors that promote survival of ovarian follicles throughout development, including endocrine, locally produced and intracellular mediators, as exemplified mainly by follicular development in rodents. In primordial follicles, oocyte apoptosis is considered to be the cause of subsequent follicle degeneration. In slow-growing preantral follicles, FSH is not a survival factor, but some loc...
The aim of this study was to investigate the regulation of resistin, a recently identified adipoc... more The aim of this study was to investigate the regulation of resistin, a recently identified adipocyte‐secreted peptide, in the adipose tissue of prolactin (PRL)‐transgenic (tg) mice using ribonuclease protection assay. The level of resistin mRNA increased 3.5‐fold in the adipose tissue of untreated male PRL‐tg mice compared to controls. However, there was no difference in resistin expression in the adipose tissue of female PRL‐tg mice compared to control mice. PRL‐tg male mice have elevated serum testosterone levels and we therefore analyzed the effects of testosterone alone on resistin mRNA expression. Furthermore, the effects of elevated androgen levels on PRL receptor (PRLR) mRNA expression in the adipose tissue were investigated. Resistin mRNA increased 2.6‐fold in the adipose tissue of control male mice with elevated serum androgen levels. In addition, PRLR mRNA expression was increased in the adipose tissue of male mice with elevated testosterone. These results suggest testoste...
Both low‐frequency electro‐acupuncture (EA) and manual acupuncture improve menstrual frequency an... more 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...
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