| 1. |
- Hu, Min, et al.
(författare)
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Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats.
- 2018
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 237:2, s. 123-137
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Tidskriftsartikel (refereegranskat)abstract
- Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions.
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| 2. |
- Lagström, Oona, et al.
(författare)
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Subregion specific neuroadaptations in the female rat striatum during acute and protracted withdrawal from nicotine
- 2024
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Ingår i: Journal of Neural Transmission. - 0300-9564. ; 131:1, s. 83-94
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies and clinical observations suggest that nicotine, a major contributor of the global burden of disease, acts in a partially sex specific manner. Still, preclinical research has primarily been conducted in males. More research is thus required to define the effects displayed by nicotine on the female brain. To this end, female rats received 15 injections of either nicotine (0.36mg/kg) or saline, over a 3-week period and were then followed for up to 3 months. Behavioral effects of nicotine were assessed using locomotor activity measurements and elevated plus maze, while neurophysiological changes were monitored using ex vivo electrophysiological field potential recordings conducted in subregions of the dorsal and ventral striatum. Behavioral assessments demonstrated a robust sensitization to the locomotor stimulatory properties of nicotine, but monitored behaviors on the elevated plus maze were not affected during acute (24 h) or protracted (3 months) withdrawal. Electrophysiological recordings revealed a selective increase in excitatory neurotransmission in the nucleus accumbens shell and dorsomedial striatum during acute withdrawal. Importantly, accumbal neuroadaptations in nicotine-treated rats correlated with locomotor behavior, supporting a role for the nucleus accumbens in behavioral sensitization. While no sustained neuroadaptations were observed following 3 months withdrawal, there was an overall trend towards reduced inhibitory tone. Together, these findings suggest that nicotine produces selective transformations of striatal brain circuits that may drive specific behaviors associated with nicotine exposure. Furthermore, our observations suggest that sex-specificity should be considered when evaluating long-term effects by nicotine on the brain.
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| 3. |
- Vestin, Edvin, et al.
(författare)
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Differential and long-lasting changes in neurotransmission in the amygdala of male Wistar rats during extended amphetamine abstinence
- 2022
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 210
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Tidskriftsartikel (refereegranskat)abstract
- Amphetamine addiction is associated with maladaptive actions that promotes continued use despite negative consequences, and a high risk of relapse even after protracted abstinence. Considering the role of the amygdala in regulating incentive motivation and reward-based behavior, the aim of this study was to assess neuroadaptations in subregions of the amygdala elicited by a brief period of discontinuous amphetamine exposure (2.0 mg/kg/day, 5 days) followed by abstinence (2 weeks, 1 month, 3 months) in male Wistar rats. Electrophysiological field potential recordings demonstrated that repeated amphetamine exposure significantly depressed evoked populations spikes in the basolateral amygdala (BLA). Evoked populations spikes were normalized after three months abstinence, but one challenge dose of amphetamine (0.5 mg/kg) was sufficient to reinstate synaptic depression in animals previously receiving amphetamine. In the central nucleus of the amygdala (CeA), amphetamine produced a long-lasting hyperexcitability that sustained even after three months abstinence. In the CeA, there were no significant differences between treatment groups following bath perfusion of the GABAA receptor antagonist bicuculline, indicating that amphetamine acts by reducing the inhibitory tone. Recordings performed in brain subregions interlinked with the amygdala, including medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens shell (nAc), revealed no significant neuroadaptations after two weeks abstinence. However, synaptic output was significantly depressed in the nAc after one-and three-month abstinence. In conclusion, the data presented here shows that five days of discontinuous exposure to amphetamine is sufficient to produce long-lasting neuroadaptations, which may contribute to compulsive drug taking and increase the risk for relapse.
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| 4. |
- Wang, Tao, et al.
(författare)
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Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia, an Early Hallmark of Endometrial Cancer, In Vivo and the Impact of Metformin In Vitro.
- 2019
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Ingår i: International journal of biological sciences. - : Ivyspring International Publisher. - 1449-2288. ; 15:3, s. 714-725
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Tidskriftsartikel (refereegranskat)abstract
- The underlying mechanisms of polycystic ovarian syndrome (PCOS)-induced endometrial dysfunction are not fully understood, and although accumulating evidence shows that the use of metformin has beneficial effects in PCOS patients, the precise regulatory mechanisms of metformin on endometrial function under PCOS conditions have only been partially explored. To address these clinical challenges, this study aimed to assess the protein expression patterns of glycolytic enzymes, estrogen receptor (ER), and androgen receptor (AR) along with differences in mitochondria-dependent apoptosis in PCOS patients with and without endometrial hyperplasia in vivo and to investigate the effects of metformin in PCOS patients with endometrial hyperplasia in vitro. Here, we showed that compared to non-PCOS patients and PCOS patients without hyperplasia, the endometria from PCOS patients with hyperplasia had a distinct protein expression pattern of glycolytic enzymes, including pyruvate kinase isozyme M2 isoform (PKM2) and pyruvate dehydrogenase (PDH), and mitochondrial transcription factor A (TFAM). In PCOS patients with endometrial hyperplasia, increased glandular epithelial cell secretion and infiltrated stromal cells in the glands were associated with decreased PDH immunoreactivity in the epithelial cells. Using endometrial tissues from PCOS patients with hyperplasia, we found that in response to metformin treatment in vitro, hexokinase 2 (HK2) expression was decreased, whereas phosphofructokinase (PFK), PKM2, and lactate dehydrogenase A (LDHA) expression was increased compared to controls. Although there was no change in PDH expression, metformin treatment increased the expression of TFAM and cleaved caspase-3. Moreover, our in vivo study showed that while endometrial ERβ expression was no different between non-PCOS and PCOS patients regardless of whether or not hyperplasia was present, ERα and AR protein expression was gradually increased in women with PCOS following the onset of endometrial hyperplasia. Our in vitro study showed that treatment with metformin inhibited ERα expression without affecting ERβ expression. Our findings suggest that decreased glycolysis and increased mitochondrial activity might contribute to the onset of ERα-dependent endometrial hyperplasia and that metformin might directly reverse impaired glycolysis and normalize mitochondrial function in PCOS patients with endometrial hyperplasia.
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| 5. |
- Zhang, Yuehui, et al.
(författare)
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Hyperandrogenism and insulin resistance contribute to hepatic steatosis and inflammation in female rat liver.
- 2018
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:26, s. 18180-18197
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Tidskriftsartikel (refereegranskat)abstract
- Women with polycystic ovary syndrome (PCOS) are at high risk for nonalcoholic fatty liver disease (NAFLD). While insulin resistance is a common trait for both PCOS and NAFLD, hyperandrogenism is also considered to be a key factor contributing to PCOS, and the molecular mechanisms behind the interactions between insulin resistance and hyperandrogenism in the female liver remain largely unexplored. Using chronic treatment with insulin and/or human chorionic gonadotropin (hCG), we showed that all female rats with different treatments induced imbalance between de novo lipogenesis and mitochondrial β-oxidation via the Pparα/β-Srebp1/2-Acc1 axis, resulting in varying degrees of hepatic steatosis. Given the fact that hepatic lipid metabolism and inflammation are tightly linked processes, we found that hCG-induced hyperandrogenic rats had strongly aggravated hepatic inflammation. Further mechanistic investigations revealed that dysregulation of the IRS-PI3K-Akt signaling axis that integrated aberrant inflammatory, apoptotic and autophagic responses in the liver was strongly associated with hyperandrogenism itself or combined with insulin resistance. Additionally, we found that hCG-treated and insulin+hCG-induced rats developed visceral adipose tissue inflammation characterized by the presence of "crown like" structure and increased inflammatory gene expression. Because a more pronounced hepatic steatosis, inflammatory responses, and hepatocyte cell damage were observed in insulin+hCG-induced PCOS-like rats, our finding suggest that NAFLD seen in PCOS patients is dependent of hyperandrogenism and insulin resistance.
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