| 1. |
- Hu, Min, et al.
(författare)
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Suppression of uterine and placental ferroptosis by N-acetylcysteine in a rat model of polycystic ovary syndrome. : Ferroptosis and N-acetylcysteine
- 2021
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Ingår i: Molecular human reproduction. - : Oxford University Press (OUP). - 1460-2407 .- 1360-9947. ; 27:12
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms that link hyperandrogenism and insulin resistance to the increased miscarriage rate in women with polycystic ovary syndrome (PCOS) remain elusive. Previous studies demonstrate that increased uterine and placental ferroptosis is associated with oxidative stress-induced fetal loss in a pre-clinical PCOS-like rat model. Here, we investigated the efficacy and molecular mechanism of action of the antioxidant N-acetylcysteine (NAC) in reversing gravid uterine and placental ferroptosis in pregnant rats exposed to 5α-dihydrotestosterone (DHT) and insulin. Molecular and histological analyses showed that NAC attenuated DHT and insulin-induced uterine ferroptosis, including dose-dependent increases in anti-ferroptosis gene content. Changes in other molecular factors after NAC treatment were also observed in the placenta exposed to DHT and insulin, such as increased glutathione peroxidase 4 protein level. Further, increased apoptosis inducing factor mitochondria associated 2 mRNA expression was seen in the placenta but not in the uterus. Additionally, NAC was not sufficient to rescue DHT+insulin-induced mitochondria-morphological abnormalities in the uterus, whereas the same treatment partially reversed such abnormalities in the placenta. Finally, we demonstrated that NAC selectively normalized uterine leukemia inhibitory factor, osteopontin/secreted phosphoprotein 1, progesterone receptor, and homeobox A11 mRNA expression and placental estrogen related receptor beta and trophoblast specific protein alpha mRNA expression. Collectively, our data provide insight into how NAC exerts beneficial effects on differentially attenuating gravid uterine and placental ferroptosis in a PCOS-like rat model with fetal loss. These results indicate that exogenous administration of NAC represents a potential therapeutic strategy in the treatment of hyperandrogenism and insulin resistance-induced uterine and placental dysfunction.
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| 2. |
- Hu, Min, et al.
(författare)
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Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant ROS production.
- 2019
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 316:5
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Tidskriftsartikel (refereegranskat)abstract
- Women with polycystic ovary syndrome (PCOS) are at increased risk of miscarriage, which often accompanies the hyperandrogenism and insulin resistance seen in these patients. However, neither the combinatorial interaction between these two PCOS-related etiological factors nor the mechanisms of their actions in the uterus during pregnancy are well understood. We hypothesised that hyperandrogensim and insulin resistance exert a causative role in miscarriage by inducing defects in uterine function that are accompanied by mitochondrial-mediated oxidative stress, inflammation and perturbed gene expression. Here we tested this hypothesis by studying the metabolic, endocrine and uterine abnormalities in pregnant rats after exposure to daily injection of 5α-dihydrotestosterone (DHT, 1.66 mg/kg body weight/day) and/or insulin (6.0 IU/day) from gestational day 7.5 to 13.5. We showed that while DHT-exposed and insulin-exposed pregnant rats presented impaired insulin sensitivity, DHT+insulin-exposed pregnant rats exhibited hyperandrogenism and peripheral insulin resistance, which mirrors pregnant PCOS patients. Compared to controls, hyperandrogenism and insulin resistance in the dam was associated with alterations in uterine morphology and aberrant expression of genes responsible for decidualization, placentation, angiogenesis and insulin signaling. Moreover, we observed changes in uterine mitochondrial function and homeostasis and suppression of both oxidative and antioxidative defenses in response to the hyperandrogenism and insulin resistance. These findings demonstrate that hyperandrogenism and insulin resistance induce mitochondria-mediated damage and a resulting imbalance between oxidative and antioxidative stress responses in the gravid uterus.
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| 3. |
- Hu, Min, et al.
(författare)
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Perturbed ovarian and uterine glucocorticoid receptor signaling accompanies the balanced regulation of mitochondrial function and NFκB-mediated inflammation under conditions of hyperandrogenism and insulin resistance.
- 2019
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Ingår i: Life sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 232
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to determine whether glucocorticoid receptor (GR) signaling, mitochondrial function, and local inflammation in the ovary and uterus are intrinsically different in rats with hyperandrogenism and insulin resistance compared to controls.Female Sprague Dawley rats were exposed to daily injections of human chorionic gonadotropin and/or insulin.In both the ovary and the uterus, decreased expression of the two GR isoforms was concurrent with increased expression of Fkbp51 but not Fkbp52 mRNA in hCG+insulin-treated rats. However, these rats exhibited contrasting regulation of Hsd11b1 and Hsd11b2 mRNAs in the two tissues. Further, the expression of several oxidative phosphorylation-related proteins decreased in the ovary and uterus following hCG and insulin stimulation, in contrast to increased expression of many genes involved in mitochondrial function and homeostasis. Additionally, hCG+insulin-treated rats showed increased expression of ovarian and uterine NFκB signaling proteins and Tnfaip3 mRNA. The mRNA expression of Il1b, Il6, and Mmp2 was decreased in both tissues, while the mRNA expression of Tnfa, Ccl2, Ccl5, and Mmp3 was increased in the uterus. Ovaries and uteri from animals co-treated with hCG and insulin showed increased collagen deposition compared to controls.Our observations suggest that hyperandrogenism and insulin resistance disrupt ovarian and uterine GR activation and trigger compensatory or adaptive effects for mitochondrial homeostasis, allowing tissue-level maintenance of mitochondrial function in order to limit ovarian and uterine dysfunction. Our study also suggests that hyperandrogenism and insulin resistance activate NFκB signaling resulting in aberrant regulation of inflammation-related gene expression.
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| 4. |
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| 5. |
- Ning, Tiao, et al.
(författare)
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Local origin or external input : modern horse origin in East Asia
- 2019
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Ingår i: BMC Evolutionary Biology. - : BMC. - 1471-2148. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Despite decades of research, the horse domestication scenario in East Asia remains poorly understood. Results The study identified 16 haplogroups with fine-scale phylogenetic resolution using mitochondrial genomes of 317 horse samples. The time to the most recent common ancestor of the 16 haplogroups ranges from [0.8-3.1] thousand years ago (KYA) to [7.9-27.1] KYA. With combined analyses of the mitochondrial control region for 35 extant Przewalski's horses, 3544 modern and 203 ancient horses across the world, researchers provide evidence for that East Asian prevalent haplogroups Q and R were indigenously domesticated or they were involved in numerous distinct genetic components from wild horses in the southern part of East Asia. These events of haplotypes Q and R occurred during 4.7 to 16.3 KYA and 2.1 to 11.5 KYA, respectively. The diffusion of preponderant European haplogroups L from west to East Asia is consistent with the external gene input. Furthermore, genetic differences were detected between northern East Asia and southern East Asia cohorts by Principal Component Analysis, Analysis of Molecular Variance test, the chi(2) test and phylogeographic analyses. Conclusions All results suggest a complex picture of horse domestication, as well as geographic pattern in East Asia. Both local origin and external input occurred in East Asia horse populations. And besides, there are at least two different domestication or hybridization centers in East Asia.
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| 6. |
- Sun, Mengtao, et al.
(författare)
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Intramolecular charge transfer and locally excited states of the fullerene-linked quarter-thiophenes dyad
- 2005
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Ingår i: Chemical Physics Letters. - : Elsevier BV. - 0009-2614. ; 413:1-3, s. 110-117
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Tidskriftsartikel (refereegranskat)abstract
- The ground and the excited state properties of the fullerene-linked quarter-thiophenes dyad were studied theoretically with the quantum chemistry method. To reveal the excited state properties of them in the vertical absorption process, the energies and densities of the HOMO and LUMO, the intramolecular charge transfer (ICT), locally excited (LE) are studied with transition density matrix, charge difference density and the off-resonant and resonant non-linear polarizabilities. The conclusion is drawn that there are also some intramolecular charge transfer (ICT) excited states, which result from large data of off-resonant and the resonant nonlinear polarizabilities in the vertical absorption process. (c) 2005 Elsevier B.V. All rights reserved.
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| 7. |
- Sun, Mengtao, et al.
(författare)
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Intramolecular charge transfer in the porphyrin-oligothiophene-fullerene triad
- 2005
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Ingår i: Chemical Physics Letters. - : Elsevier BV. - 0009-2614. ; 416:1-3, s. 94-99
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Tidskriftsartikel (refereegranskat)abstract
- Intramolecular charge transfer (ICT) in porphyrin-oligothiophene-fullerene triad was reported experimentally [J. Ikemoto, K. Takimiya, Y. Aso. T. Otsubo, M. Fujitsuka, O. Ito, Org. Lett. 4 (2002) 309], and the weak distance dependence of the oligothiophene spacer was found. In this Letter, ICT in this triad is theoretically investigated with quantum chemistry method as well as the 2D and 3D real space analysis methods. The calculated transition energies and oscillator strengths are consistent with the experimental data. The theoretical analysis with 2D and 3D real space analysis reveal that there are two ICT mechanisms. The experimental weak distance dependence of the oligothiophene spacer is benefitted from the superexchange mechanism. (c) 2005 Elsevier B.V. All rights reserved.
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| 8. |
- Wang, Dandan, et al.
(författare)
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Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
- 2021
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- ZBED6 (zinc finger BED domain containing protein 6) is a transcription factor unique to placental mammals and its interaction with the IGF2 (insulin-like growth factor 2) locus plays a prominent role in the regulation of postnatal skeletal muscle growth. Here, we generated lean Bama miniature pigs by generating ZBED6-knockout (ZBED6(-/-)) and investigated the mechanism underlying ZBED6 in growth of muscle and internal organs of placental mammals. ZBED6(-/-) pigs show markedly higher lean mass, lean mass rate, larger muscle fiber area and heavier internal organs (heart and liver) than wild-type (WT) pigs. The striking phenotypic changes of ZBED6(-/-) pigs coincided with remarkable upregulation of IGF2 mRNA and protein expression across three tissues (gastrocnemius muscle, longissimus dorsi, heart). Despite a significant increase in liver weight, ZBED6(-/-) pigs show comparable levels of IGF2 expression to those of WT controls. A mechanistic study revealed that elevated methylation in the liver abrogates ZBED6 binding at the IGF2 locus, explaining the unaltered hepatic IGF2 expression in ZBED6(-/-) pigs. These results indicate that a ZBED6-IGF2-independent regulatory pathway exists in the liver. Transcriptome analysis and ChIP-PCR revealed new ZBED6 target genes other than IGF2, including cyclin dependent kinase inhibitor 1A (CDKN1A) and tsukushi, small leucine rich proteoglycan (TSKU), that regulates growth of muscle and liver, respectively. Author summary The lean meat rate is an important economic trait for the swine industry and it is determined by muscle growth and development. A single base change in intron 3 of the insulin-like growth factor 2 (IGF2) gene increases meat production in pigs by disrupting a binding site for zinc finger BED domain containing protein 6 (ZBED6). Chinese indigenous pig breeds carrying the homozygous IGF2 wild-type allele produce low lean meat. We thus generate a lean pig model in Chinese Bama pig by knocking out ZBED6. In this model, we demonstrate that ZBED6 KO increases muscle and internal organ growth through ZBED6-IGF2 axis and other target genes. These results not only open new strategies for lean meat breeding in Chinese indigenous pigs, but also provide new insights to the global function of ZBED6 in organ growth and development.
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| 9. |
- Zhang, Yuehui, et al.
(författare)
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Increased uterine androgen receptor protein abundance results in implantation and mitochondrial defects in pregnant rats with hyperandrogenism and insulin resistance. : Deciphering the role of uterine AR in PCOS during early pregnancy
- 2021
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Ingår i: Journal of molecular medicine (Berlin, Germany). - : Springer Science and Business Media LLC. - 1432-1440 .- 0946-2716. ; 99, s. 1427-1446
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we show that during normal rat pregnancy, there is a gestational stage-dependent decrease in androgen receptor (AR) abundance in the gravid uterus and that this is correlated with the differential expression of endometrial receptivity and decidualization genes during early and mid-gestation. In contrast, exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) or DHT alone significantly increased AR protein levels in the uterus in association with the aberrant expression of endometrial receptivity and decidualization genes, as well as disrupted implantation. Next, we assessed the functional relevance of the androgen-AR axis in the uterus for reproductive outcomes by treating normal pregnant rats and pregnant rats exposed to DHT and INS with the anti-androgen flutamide. We found that AR blockage using flutamide largely attenuated the DHT and INS-induced maternal endocrine, metabolic, and fertility impairments in pregnant rats in association with suppressed induction of uterine AR protein abundance and androgen-regulated response protein and normalized expression of several endometrial receptivity and decidualization genes. Further, blockade of AR normalized the expression of the mitochondrial biogenesis marker Nrf1 and the mitochondrial functional proteins Complexes I and II, VDAC, and PHB1. However, flutamide treatment did not rescue the compromised mitochondrial structure resulting from co-exposure to DHT and INS. These results demonstrate that functional AR protein is an important factor for gravid uterine function. Impairments in the uterine androgen-AR axis are accompanied by decreased endometrial receptivity, decidualization, and mitochondrial dysfunction, which might contribute to abnormal implantation in pregnant PCOS patients with compromised pregnancy outcomes and subfertility. KEY MESSAGES: The proper regulation of uterine androgen receptor (AR) contributes to a normal pregnancy process, whereas the aberrant regulation of uterine AR might be linked to polycystic ovary syndrome (PCOS)-induced pregnancy-related complications. In the current study, we found that during normal rat pregnancy there is a stage-dependent decrease in AR abundance in the gravid uterus and that this is correlated with the differential expression of the endometrial receptivity and decidualization genes Spp1, Prl, Igfbp1, and Hbegf. Pregnant rats exposed to 5α-dihydrotestosterone (DHT) and insulin (INS) or to DHT alone show elevated uterine AR protein abundance and implantation failure related to the aberrant expression of genes involved in endometrial receptivity and decidualization in early to mid-gestation. Treatment with the anti-androgen flutamide, starting from pre-implantation, effectively prevents DHT + INS-induced defects in endometrial receptivity and decidualization gene expression, restores uterine mitochondrial homeostasis, and increases the pregnancy rate and the numbers of viable fetuses. This study adds to our understanding of the mechanisms underlying poor pregnancy outcomes in PCOS patients and the possible therapeutic use of anti-androgens, including flutamide, after spontaneous conception.
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