Brilliant quantum dots' photoluminescence from a dual-resonance plasmonic grating.

Semiconductor quantum dots (QDs) have recently caused a stir as a promising and powerful lighting material applied in real-time fluorescence detection, display, and imaging. Photonic nanostructures are well suited for enhancing photoluminescence (PL) due to their ability to tailor the electromagnetic field, which raises both radiative and nonradiative decay rate of QDs nearby. However, several proposed structures with a complicated manufacturing process or low PL enhancement hinder their application and commercialization. Here, we present two kinds of dual-resonance gratings to effectively improve PL enhancement and propose a facile fabrication method based on holographic lithography. A maximum of 220-fold PL enhancement from CdSe/CdS/ZnS QDs are realized on 1D Al-coated photoresist (PR) gratings, where dual resonance bands are excited to simultaneously overlap the absorption and emission bands of QDs, much larger than those of some reported structures. Giant PL enhancement realized by cost-effective method further suggests the potential of better developing the nanostructure to QD-based optical and optoelectronic devices.

Inherited disease-linked arginine76/75 mutants in Cx50 and Cx45 showed impaired homotypic and heterotypic gap junction function, but not Cx43.

Connexins form intercellular communication channels, known as gap junctions (GJs), in many tissues/organs. Mutations in connexin genes are found to be linked to various inherited diseases, but the mechanisms are not fully clear. The Arg76 (R76) in Cx50 is fully conserved across the entire connexin family and is a hotspot for five connexin-linked inherited diseases, including Cx50 and Cx46-linked congenital cataract, Cx43-linked oculodentodigital dysplasia, and Cx45-linked cardiac arrhythmias. To better understand the molecular and cellular mechanism of dysfunction caused by R76/75 mutations, we examined the functional status and properties of GJs containing R76 mutations in Cx50 (R76H/C), Cx43 (R76H/S/C), and Cx45 (R75H) with an emphasis on heterotypic GJs in connexin-deficient model cells. All tested mutants showed an impairment of homotypic GJ function reflected by a decreased coupling% and conductance, except for Cx43 R76H/S. These connexin mutants also showed impaired GJ function when paired with a docking-compatible connexin, such as Cx50/Cx46 or Cx45/Cx43, except for all mutants on Cx43 which formed functional heterotypic GJs with Cx45. Localization studies on fluorescent protein tagged connexin mutants revealed that Cx45 R75H and Cx43 R76C showed impaired localization. Our homology structure models indicated that mutations of R76/75 in these GJs led to a loss of intra- and/or inter-connexin non-covalent interactions (salt bridges) at the sidechain of this residue, which could contribute to the observed GJ impairments underlying diseases. It is interesting that unlike those disease-linked variants in Cx50 and Cx45, Cx43 can tolerate some variations at R76.

Gut microbiota disorder induces liver dysfunction in polycystic ovary syndrome rats' model by regulating metabolite rosmarinic acid.

AIMS: The present study aims to investigate the impact of the gut microbiota and serum metabolites on the regulation of liver dysfunction in PCOS. MATERIALS AND METHODS: PCOS rat models were established by treating Sprague Dawley (SD) rats with DHEA (an androgen, 60 mg/kg) and LET (a nonsteroidal aromatase inhibitor, 1 mg/kg) for 90 days. Hematoxylin and eosin staining (H&E), Western blotting, and radioimmunoassay were employed to test ovarian and liver functions. Gut microbiome and serum metabolites were assessed using 16S rRNA amplicon sequencing and non-targeted metabolomics, respectively. The association between gut microbiota and serum metabolites was examined using Spearman analysis. Finally, using HepG2 cells to investigate the function of the serum metabolite rosmarinic acid (RA). KEY FINDINGS: Both Dehydroepiandrosterone (DHEA) and letrozole (LET) treatments induced a PCOS phenotype and liver dysfunction. However, LET resulted in more severe lipid accumulation and liver cell apoptosis than DHEA. 16S rRNA sequencing and non-targeted metabolomics analysis revealed significant differences in beta diversity and serum metabolite profiles among the three groups. Furthermore, among the significantly changed metabolites, RA was found to have a significant correlation with the levels of serum aspartate transaminase (AST) and lactate dehydrogenase (LDH) and could promote HepG2 cell apoptosis. SIGNIFICANCE: Restoring gut microbiota, altering serum metabolites and/or decreasing RA may provide a new insight to treat this complication.

Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors.

ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium, including ovarian and uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). Loss-of-function mutations in ARID1A alter epigenetic regulation of transcription, cell-cycle checkpoint control, and DNA damage repair. We report here that mammalian cells with ARID1A deficiency harbor accumulated DNA base lesions and increased abasic (AP) sites, products of glycosylase in the first step of base excision repair (BER). ARID1A mutations also delayed recruitment kinetics of BER long-patch repair effectors. Although ARID1A-deficient tumors were not sensitive to monotherapy with DNA-methylating temozolomide (TMZ), the combination of TMZ with PARP inhibitors (PARPi) potently elicited double-strand DNA breaks, replication stress, and replication fork instability in ARID1A-deficient cells. The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A-mutated cancers to PARP inhibition, which warrants further experimental exploration and clinical trial validation. SIGNIFICANCE: The combination of temozolomide and PARP inhibitor exploits the specific DNA damage repair status of ARID1A-inactivated ovarian cancers to suppress tumor growth.

Pregnancy Outcomes of Freeze-All versus Fresh Embryo Transfer in Women with Adenomyosis: A Retrospective Study.

Adenomyosis has been associated with adverse fertility and pregnancy outcomes, and its impact on the outcomes of in vitro fertilization (IVF) has received much attention. It is controversial whether the freeze-all strategy is better than fresh embryo transfer (ET) in women with adenomyosis. Women with adenomyosis were enrolled in this retrospective study from January 2018 to December 2021 and were divided into two groups: freeze-all (n = 98) and fresh ET (n = 91). Data analysis showed that freeze-all ET was associated with a lower rate of premature rupture of membranes (PROM) compared with fresh ET (1.0% vs. 6.6%, p = 0.042; adjusted OR 0.17 (0.01-2.50), p = 0.194). Freeze-all ET also had a lower risk of low birth weight compared with fresh ET (1.1% vs. 7.0%, p = 0.049; adjusted OR 0.54 (0.04-7.47), p = 0.642). There was a nonsignificant trend toward a lower miscarriage rate in freeze-all ET (8.9% vs. 11.6%; p = 0.549). The live birth rate was comparable in the two groups (19.1% vs. 27.1%; p = 0.212). The freeze-all ET strategy does not improve pregnancy outcomes for all patients with adenomyosis and may be more appropriate for certain patients. Further large-scale prospective studies are needed to confirm this result.

Tempol modulates lncRNA-miRNA-mRNA ceRNA networks in ovaries of DHEA induced PCOS rats.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in reproductive age women. Our previous results demonstrated that tempol was able to ameliorate PCOS phenotype in rats. However, the exact pathophysiological effect of tempol on PCOS remains largely unknown. To extend this research, deep RNA-sequencing was performed to investigate the long noncoding RNA (lncRNA) associated ceRNA mechanisms in the ovarian tissues of control rats, dehydropiandrosterone (DHEA) induced PCOS rats and tempol treated PCOS rats. Our results identified total 164, 79, and 914 significantly dysregulated lncRNAs, miRNAs, and mRNAs in three groups, respectively. The total of 7 lncRNAs, 8 mRNAs and 5 miRNAs were involved in lncRNA-associated ceRNA networks were constructed. Among them, mRNAs including C1qtnf1, Dipk2a, IL4r and lncRNAs including MSTRG.16751.2, MSTRG.8065.2 had high RNA connectivity in the ceRNA network, which also showed significant alterations in these three groups by using qPCR validation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the involvement of the identified ceRNA networks in regulating the development of PCOS from distinct origins, such as metabolic pathway, immune cell differentiation. The study presents the first systematic dissection of lncRNA-associated ceRNA profiles in tempol treated PCOS rats. The identified ceRNA networks could provide insights that help facilitate PCOS diagnosis and treatment.

The ADMA-DDAH1 axis in ovarian apoptosis of polycystic ovary syndrome.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) mainly degrades asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor. Emerging evidence suggested that plasma ADMA is accumulated in patients with polycystic ovary syndrome (PCOS). However, ADMA-DDAH1 involvement in PCOS pathogenesis is unclear. Here, we used dehydroepiandrosterone (DHEA)-induced PCOS rats and the ovarian granulosa cell line KGN to investigate the effect of the ADMA-DDAH1 pathway on ovarian apoptosis. Moreover, we also quantified the ADMA levels and redox status in human serum specimens, Sprague Dawley rats and KGN cells to investigate the effect of ADMA-DDAH1 on redox status and ovarian apoptosis in PCOS. We enrolled 19 women with PCOS and 17 healthy women (controls) in this study. The women with PCOS had increased serum ADMA levels and decreased glutathione peroxidase (GSH-PX) compared with the controls. In Sprague Dawley rats, 21-day DHEA treatment established PCOS and the rat contained higher ADMA levels in serum and lower DDAH1 expression in ovaries. Moreover, the PCOS rat serum and ovaries exhibited increased levels of the oxidative stress marker malondialdehyde (MDA). ADMA treatment of the KGN cells induced reactive oxygen species accumulation and led to apoptosis. Contrastingly, overexpressing DDAH1 in the KGN cells significantly decreased ADMA levels, enhanced cell viability, and inhibited oxidative stress, while the effect was inverse in DDAH1 knockdown cells. Overall, our results demonstrated that PCOS involves elevated ADMA levels and redox imbalance. The ADMA-DDAH1 pathway exerted a marked effect on oxidative stress and ovarian apoptosis in PCOS. Our findings suggested that strategies for increasing DDAH1 activity in ovarian cells may provide a novel approach for ameliorating PCOS.

Dynamics of gut microbiota during pregnancy in women with TPOAb-positive subclinical hypothyroidism: a prospective cohort study.

BACKGROUND: Anti-thyroid peroxidase antibody (TPOAb) positivity can contribute to inhibit thyroxine synthesis. Gut microbiota can interact with metabolic or immune diseases. However, dynamics of gut microbiota from the second (T2) to the third trimester (T3) in women with TPOAb-positive/negative subclinical hypothyroidism (TPOAb+/TPOAb- SCH) have not been reported. Therefore, we aimed to evaluate whether gut microbiota can be potential therapeutic targets for managing TPOAb+ SCH. METHODS: In this single-center prospective cohort study, we observed gut microbiota dynamics by sequencing 16S rRNA from fecal samples collected in T2 (20-23+ 6 weeks) and T3 (28-33+ 6 weeks). TPOAb+/TPOAb- SCH were stratified depending on whether or not they used levothyroxine (LT4) during the pregnancy (LT4+/LT4-). Microbiome bioinformatics analyses were performed using QIIME2. The linear discriminant analysis effect size (LEfSe) was used for the quantitative analysis of biomarkers. Functional profiling was performed with PICRUSt2. RESULTS: Distinct gut microbiota dynamics from T2 to T3 were noted in the TPOAb- (n = 68) and TPOAb+ (n = 64) SCH groups. The TPOAb+ LT4- group was characterized by enriched bacterial amplicon sequence variants (ASVs) of Prevotella in T2 and Bacteria, Lachnospirales, Lachnospiraceae, Blautia, and Agathobacter in T3 and by depleted ASVs of Gammaproteobacteria, Enterobacterales, and Enterobacteriaceae in T2 and Actinobacteriota, Coriobacteriia, Actinobacteria, Coriobacteriales, Bifidobacteriales, Bifidobacteriaceae, Bifidobacterium, Dorea formicigenerans, and Bifidobacterium longum in T3. The TPOAb+ LT4+ group was characterized by enriched bacterial ASVs of Blautia, Streptococcus salivarius, and Bifidobacterium longum in T3 and by depleted ASVs of Bacteroidota, Bacteroidia, Bacteroidales, and Prevotella in T2 and Agathobacter in T3. Moreover, we identified 53 kinds of metabolic functions that were mainly involved in sugar, lipid, and amino acid metabolism. CONCLUSIONS: Our results indicated that low dynamics of gut microbiota composition and high dynamics of its metabolic function from T2 to T3 were associated with TPOAb+ SCH. We concluded that gut microbiota could be new targets for treatment of TPOAb+ SCH during pregnancy. TRIAL REGISTRATION: This study was retrospectively registered at the Chinese Clinical Trial Registry (registration number ChiCTR2100047175 ) on June 10, 2021.

Characteristics of the Intestinal Flora of TPOAb-Positive Women With Subclinical Hypothyroidism in the Second Trimester of Pregnancy: A Single-Center Prospective Cohort Study.

Pregnant women are at high risk of developing subclinical hypothyroidism (SCH), and anti-thyroid peroxidase antibody (TPOAb) positivity can further inhibit thyroxine synthesis. Emerging evidence indicates that intestinal flora can modulate metabolic and immune homeostasis. The characteristics of intestinal flora of TPOAb-positive women with SCH in their second trimester of pregnancy have not been reported. This single-center prospective observational cohort study investigated gut microbial composition and metabolic function using sequencing of the 16S rRNA gene in fecal samples from 75 TPOAb-positive women with SCH and 90 TPOAb-negative women with SCH during their second trimester of pregnancy. Women were treated with no levothyroxine (LT4), low-dose LT4 (≤50ug/d), or high-dose LT4 (>50ug/d). Taxonomic analysis showed Firmicutes and Bacteroidetes were the dominant phyla, followed by Actinobacteria and Proteobacteria. Faecalibacterium, Bacteroides, Prevotella 9, Bifidobacterium, Subdoligranulum, Lachnospira, and Megamonas were the predominant genera. The intestinal flora of TPOAb-positive women with SCH who received no LT4 was characterized by bacterial amplicon sequence variants (ASVs)/operational taxonomic units (OTUs) enriched in the genus Subdoligranulum. The intestinal flora of TPOAb-positive women with SCH who received low-dose or high-dose LT4 were characterized by bacterial ASVs/OTUs depleted of the species Ruminococcus sp._or Bacteroides massiliensis, respectively. A total of 19 metabolic functions of intestinal flora, mainly involving lipid and amino acid metabolism, discriminated TPOAb-positive and TPOAb-negative women with SCH. Our study suggests that there are differences in the composition and metabolic function of intestinal flora of TPOAb-positive and TPOAb-negative women with SCH treated with different doses of LT4 in the second trimester of pregnancy. The findings provide insight into intestinal flora as novel targets for the treatment of TPOAb-positive women with SCH during pregnancy.

Effect on the cardiovascular independent risk factor lipoprotein(a) in overweight or obese PCOS patients with ethinyl-estradiol/drospirenone alone or plus orlistat.

OBJECTIVE: This study aimed to assess the effect on the cardiovascular independent risk factor Lipoprotein(a) [Lp(a)] in overweight or obese polycystic ovary syndrome (PCOS) patients with ethinyl-estradiol/drospirenone (EE/DRSP) alone or plus orlistat. METHODS: In this randomized controlled prospective study, 66 PCOS patients with overweight or obesity were matched according to age and BMI. All participants were randomly divided into two groups to receive EE/DRSP plus Orlistat (n = 33) or EE/DRSP alone (n = 33) for 3 months. Changes in cardiovascular risk factors including Lp(a), CRP, LDL-C, anthropometric assessments, variations in sex hormones related parameters, and in glucolipid metabolic index were evaluated after the intervention. RESULTS: Lp(a) and CRP were significantly decreased at 3 months only in the EE/DRSP plus Orlistat group. There were significant reductions in LDL-C, weight, BMI, waist circumference (WC), body fat percentage (BFP), FT in both groups compared to baseline. However, these reductions were significantly greater in EE/DRSP plus Orlistat group. The levels of HDL-C, TG, and SHBG significantly increased, while TT and LH significantly decreased in both groups over time. TC, FINS, FPG were not significantly changed in both groups after the intervention. CONCLUSIONS: This is the first study found that EE/DRSP plus Orlistat could significantly decrease Lp(a) in overweight or obese PCOS patients. This result can be assessed as particularly important, because Lp(a) is well-known as an independent risk factor predicting an increased risk of cardiovascular diseases (CVDs).

Bound states at partial dislocation defects in multipole higher-order topological insulators.

The bulk-boundary correspondence, which links a bulk topological property of a material to the existence of robust boundary states, is a hallmark of topological insulators. However, in crystalline topological materials the presence of boundary states in the insulating gap is not always necessary since they can be hidden in the bulk energy bands, obscured by boundary artifacts of non-topological origin, or, in the case of higher-order topology, they can be gapped altogether. Recently, exotic defects of translation symmetry called partial dislocations have been proposed to trap gapless topological modes in some materials. Here we present experimental observations of partial-dislocation-induced topological modes in 2D and 3D insulators. We particularly focus on multipole higher-order topological insulators built from circuit-based resonator arrays, since crucially they are not sensitive to full dislocation defects, and they have a sublattice structure allowing for stacking faults and partial dislocations.

Benchmark Examination of Blood Amino Acids Patterns in Phenylketonuria Neonates and Young Children on Phenylalanine-Restricted Dietary Treatment.

Background: Phenylalanine-restricted diets have been the basis of therapy for phenylketonuria; however, little is known how this treatment effects homeostasis of other amino acids. This study aimed to assess blood amino acid alterations in phenylketonuric neonates before and after treatment to identify any residual amino acid alterations with phenylalanine restriction in these treated children. Methods: Concentrations of 11 amino acids were measured using liquid chromatography-tandem mass spectrometry performed on dried blood spots. Results: Elevated blood phenylalanine, arginine, citrulline, valine, methionine concentrations and decreased tyrosine, proline concentrations were observed in phenylketonuria neonates relative to controls, of which phenylalanine, arginine, methionine, tyrosine, and proline levels could be either partially or completely restored with dietary intervention, whereas citrulline and valine were not restored and remained higher. Conclusions: Blood amino acid homeostasis is disrupted in phenylketonuria. Although dietary intervention adjusts amino acid homeostasis in the direction of a healthy equilibrium, complete restoration is not achieved.

Early Gut Microbiota Colonisation of Premature Infants Fed with Breastmilk or Formula with or without Probiotics: A Cohort Study.

Premature infants have a fragile ecology of the gut microbiota, which is associated with many health problems and may be influenced by formula versus breast feeding. The present study investigated differences in the process of gut microbiota colonisation in preterm infants fed with breastmilk or formula with or without probiotics before 12 weeks. This cohort study recruited 138 premature infants; 31 in the breastmilk (BM) group, 59 in the probiotics formula (PF) group and 48 in the non-probiotics formula (NPF) group, according to the feeding practice they received at birth. Gut bacterial composition was identified with 16S rRNA gene sequencing in faecal samples collected at 1 week, 6 weeks and 12 weeks after birth. The alpha diversity was higher in the PF group compared to the other groups at week 1 and 6 (both p < 0.01) but showed no difference at week 12. The beta diversity of the three groups showed a trend towards similarity at the first two stages (p < 0.001 and p = 0.009, respectively) and finally showed no difference at week 12. Canonical redundancy analysis showed that feeding type could explain the difference in gut microbiota composition at week one and six (both p < 0.01). At genus level, Bifidobacterium was enriched in the PF group, while the Enterococcus and Streptococcus was enriched in the NPF group. In summary, formula with probiotics feeding after birth can affect gut microbiota colonisation and lead to a bacterial community with less potential pathogens.

Differential Domain Distribution of gnomAD- and Disease-Linked Connexin Missense Variants.

Twenty-one human genes encode connexins, a family of homologous proteins making gap junction (GJ) channels, which mediate direct intercellular communication to synchronize tissue/organ activities. Genetic variants in more than half of the connexin genes are associated with dozens of different Mendelian inherited diseases. With rapid advances in DNA sequencing technology, more variants are being identified not only in families and individuals with diseases but also in people in the general population without any apparent linkage to Mendelian inherited diseases. Nevertheless, it remains challenging to classify the pathogenicity of a newly identified connexin variant. Here, we analyzed the disease- and Genome Aggregation Database (gnomAD, as a proxy of the general population)-linked variants in the coding region of the four disease-linked α connexin genes. We found that the most abundant and position-sensitive missense variants showed distinct domain distribution preference between disease- and gnomAD-linked variants. Plotting missense variants on topological and structural models revealed that disease-linked missense variants are highly enriched on the structurally stable/resolved domains, especially the pore-lining domains, while the gnomAD-linked missense variants are highly enriched in the structurally unstable/unresolved domains, especially the carboxyl terminus. In addition, disease-linked variants tend to be on highly conserved residues and those positions show evolutionary co-variation, while the gnomAD-linked missense variants are likely on less conserved residue positions and on positions without co-variation. Collectively, the revealed distribution patterns of disease- and gnomAD-linked missense variants further our understanding of the GJ structure-biological function relationship, which is valuable for classifying the pathogenicity of newly identified connexin variants.

Tempol ameliorates polycystic ovary syndrome through attenuating intestinal oxidative stress and modulating of gut microbiota composition-serum metabolites interaction.

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, which is often accompanied by oxidative stress. Tempol, a superoxide dismutase mimetic, protects against several diseases caused by oxidative stress. However, the effect of tempol on PCOS has not been investigated. The present study demonstrated the alleviation of ovarian dysfunction and glucose tolerance in dehydroepiandrosterone (DHEA)-induced PCOS rats treated with tempol. Tempol significantly reduced the intestinal oxidative stress in PCOS rats without affecting the ovarian redox rate. The 16S rDNA sequencing of the intestinal microbiome and non-targeted metabolomics analysis indicated significant differences in gut microbiota composition and serum metabolite profiles between the control and PCOS rats, and most of these differences were reduced after tempol intervention. Tempol alters the gut microbiome by increasing the abundance of genus Ruminococcus_1 and by decreasing the abundance of Ruminococcus_2, Staphylococcus, Ideonella, and Corynebnacterium genera. Tempol also attenuates the reduction of serum bile acid and stachyose levels in PCOS rats, and the serum stachyose level was significantly correlated with the abundance of 15 genera, particularly Ruminococcus_1 and Ruminococcus_2. Moreover, stachyose administration improved ovarian dysfunction in PCOS rats. Thus, our data indicate that tempol ameliorates PCOS phenotype by reducing intestinal oxidative stress, restoring gut dysbiosis, and modulating the interaction between gut microbiota and host metabolite. Therefore, tempol intervention is a potential therapeutic approach for PCOS.

Trapped fractional charges at bulk defects in topological insulators.

Topological crystalline insulators (TCIs) can exhibit unusual, quantized electric phenomena such as fractional electric polarization and boundary-localized fractional charge1-6. This quantized fractional charge is the generic observable for identification of TCIs that lack clear spectral features5-7, including ones with higher-order topology8-11. It has been predicted that fractional charges can also manifest where crystallographic defects disrupt the lattice structure of TCIs, potentially providing a bulk probe of crystalline topology10,12-14. However, this capability has not yet been confirmed in experiments, given that measurements of charge distributions in TCIs have not been accessible until recently11. Here we experimentally demonstrate that disclination defects can robustly trap fractional charges in TCI metamaterials, and show that this trapped charge can indicate non-trivial, higher-order crystalline topology even in the absence of any spectral signatures. Furthermore, we uncover a connection between the trapped charge and the existence of topological bound states localized at these defects. We test the robustness of these topological features when the protective crystalline symmetry is broken, and find that a single robust bound state can be localized at each disclination alongside the fractional charge. Our results conclusively show that disclination defects in TCIs can strongly trap fractional charges as well as topological bound states, and demonstrate the primacy of fractional charge as a probe of crystalline topology.

The Effect and Mechanism of Asymmetric Dimethylarginine Regulating Trophoblastic Autophagy on Fetal Growth Restriction.

Fetal growth restriction (FGR) is an important cause of perinatal death and adverse pregnancy outcomes. Asymmetric dimethylarginine (ADMA) is associated with FGR, but the mechanisms have not been thoroughly studied. Here, we determined the levels of ADMA and autophagy-related molecules in human blood samples and placental tissues. And we also used the human chorionic carcinoma cell line BeWo to investigate the mechanism of ADMA-induced FGR in vitro. Compared with the control group, ADMA levels in maternal blood and placenta were increased in patients with FGR, and the birth weight (BW) percentile was negatively correlated with maternal serum ADMA concentration in the FGR group. The expression of mammalian target of rapamycin (mTOR) in the placenta of the FGR group was lower than the control group, while the expression of Beclin-1 and microtubule-associated protein 1 light chain 3-II (LC3-II)/LC3-I was significantly increased in the FGR group. And the expression of matrix metalloproteinase 9 (MMP9) was decreased in the placenta of patients with FGR. In in vitro cell experiments, compared with the control group, the expression of mTOR and MMP9 in BeWo cells was decreased and the expression of Beclin-1 and LC3-II/LC3-I was increased in the ADMA-treated group. Moreover, ADMA had favorable effects on the formation of autophagic vacuoles, and the autophagy inhibitor 3-Methyladenine (3-MA) could reduce the autophagy-induction effect of ADMA on BeWo cells. This study found that ADMA could participate in the occurrence of FGR through inducing autophagy in trophoblasts.

Involvement of endogenous testosterone in hepatic steatosis in women with polycystic ovarian syndrome.

AIMS: The prevalence of nonalcoholic fatty liver disease (NAFLD) is higher in women with polycystic ovarian syndrome (PCOS) than that in healthy women. This association can be explained in part by the resistance to insulin and the prevalence of obesity, which are fueled by high androgen levels. However, there is little evidence of the involvement of endogenous testosterone in hepatic steatosis in women with PCOS. Here, we treated Sprague Dawley rats with the aromatase inhibitor, letrozole, to increase the endogenous testosterone level and to decrease the estradiol levels. We also quantified the testosterone levels in human serum specimens and HepG2 cells to investigate the effects of androgens on hepatic steatosis and liver dysfunction. RESULTS: Twenty-nine PCOS patients and twenty healthy women were enrolled. Alanine transaminase and aspartate transaminase (AST) levels were increased in women with PCOS, and a strong correlation between testosterone and AST levels was observed. After letrozole treatment for 90 days, rats were significantly more obese, with animals developing hepatic steatosis and moderate insulin resistance. Additional experiments revealed that excess androgen inhibited the AMP-activated protein kinase alpha pathway in letrozole-treated livers and dihydrotestosterone (DHT)-treated HepG2 cells, thereby causing steatosis. INNOVATION AND CONCLUSION: Our results show that an elevated endogenous testosterone level can induce hepatic steatosis. Decreasing the endogenous testosterone level in hepatocytes may represent a new approach in the treatment of NAFLD in PCOS patients.