Recurrent spontaneous abortion (RSA), is a dangerous pregnancy-related condition and is a subject of debate in the gynaecology and obstetrics communities. The objective of this study was to determine ...the function of DNA Topoisomerase II Alpha (TOP2A) in RSA and elucidate the underlying molecular mechanisms.
In vitro models of TOP2A-knockdown and -overexpression were generated by transfecting specific sh-RNA lentivirus and overexpression plasmid, respectively. An in vitro TOP2A inhibition model was established by culturing mouse embryos at the two-cell stage in a medium containing PluriSIn2, a TOP2A inhibitor. Immunohistochemical staining was used to analyse expression of TOP2A in villi tissues of patients with RSA. Western blotting and qRT-PCR were used to analyse the expression of TOP2A and proteins involved in trophoblast functions, the FOXO signalling pathway, and the development of pre-implantation embryos. 5-Ethynyl-2'-deoxyuridine staining, TUNEL assay and flow cytometry were used to further evaluate the effect of TOP2A on cell proliferation and apoptosis. Transwell and wound healing assays were used to evaluate migration and invasion. Moreover, the effect of TOP2A inhibitor on embryos was determined by immunofluorescence and mitochondrial-related dyes.
Evaluation of clinical samples revealed that the villi tissues of patients that have experienced RSA had lower TOP2A expression compared with that from women who have experienced normal pregnancy (P < 0.01). In vitro, TOP2A knockdown decreased the proliferation, migration, and invasion of trophoblast cell lines, and increased apoptosis and activation of the FOXO signalling pathway (P < 0.05). Conversely, TOP2A overexpression reversed these effects. Moreover, in vivo experiments confirmed that inhibition of TOP2A impairs trophectoderm differentiation, embryonic mitochondrial function as well as the developmental rate; however, no differences were noted in the expression of zygotic genome activation-related genes.
Collectively, our data suggest that lower TOP2A expression is related to RSA as it inhibits trophoblast cell proliferation, migration, and invasion by activation of the FOXO signalling pathway. Additionally, TOP2A inhibition resulted in impaired development of pre-implantation embryos in mice, which could be attributed to excessive oxidative stress.
The remarkable advancements related to cerebral organoids have provided unprecedented opportunities to model human brain development and diseases. However, despite their potential significance in ...neurodegenerative diseases such as Parkinson's disease (PD), the role of exosomes from cerebral organoids (OExo) has been largely unknown. In this study, we compared the effects of OExo to those of mesenchymal stem cell (MSC)-derived exosomes (CExo) and found that OExo shared similar neuroprotective effects to CExo. Our findings showed that OExo mitigated H
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-induced oxidative stress and apoptosis in rat midbrain astrocytes by reducing excess ROS production, antioxidant depletion, lipid peroxidation, mitochondrial dysfunction, and the expression of pro-apoptotic genes. Notably, OExo demonstrated superiority over CExo in promoting the differentiation of human-induced pluripotent stem cells (iPSCs) into dopaminergic (DA) neurons. This was attributed to the higher abundance of neurotrophic factors, including neurotrophin-4 (NT-4) and glial-cell-derived neurotrophic factor (GDNF), in OExo, which facilitated the iPSCs' differentiation into DA neurons in an LIM homeobox transcription factor 1 alpha (LMX1A)-dependent manner. Our study provides novel insight into the biological properties of cerebral organoids and highlights the potential of OExo in the treatment of neurodegenerative diseases such as PD.
The dual-wavelength UV photodetector (PD) with sandwich structure of ZnO/Au/MgZnO/SiO
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was fabricated and investigated with an emphasis on the effects of the Ag nanoparticles localized surface ...plasmons (LSPs). The results demonstrated that the modification in Ag nanoparticle (NP) position played a remarkable influence on the performance of dual-wavelength UV photodetectors. In comparison with decorating Ag NPs on the surface of the PDs, embedding Ag NPs between the MgZnO and ZnO films could improve two peak responsivities (caused by MgZnO and ZnO layers) significantly. By calculating the responsivities enhancement ratio of double layers (MgZnO and ZnO), the results indicated that the enhancement ratio of MgZnO is higher than that of ZnO. This was ascribed to LSPs of energy match with MgZnO which was superior to ZnO. This work described a creative method for increasing the performance of dual-wavelength UV PDs.
Abstract
Background
Successful implantation is a complex process that is influenced by embryo quality, endometrial receptivity, immune factors, and the specific type of in vitro fertilization ...protocol used. DNA topoisomerase IIα (TOP2A) is a well-known protein involved in cell proliferation; however, its expression and effect on the endometrium in recurrent implantation failure (RIF) have not been fully elucidated.
Methods
The human endometrial tissues of healthy controls and patients with RIF were collected. A proteomic analysis was performed to evaluate the differentially expressed proteins between the RIF group and the fertile control group. The expression patterns of TOP2A in the human preimplantation endometrium of the patients with RIF were determined by immunohistochemical staining, Western blotting and qRT-PCR. TOP2A knockdown (sh-TOP2A) T-HESCs were generated using lentiviruses. The expression of TOP2A in T-HESCs was manipulated to investigate its role in decidualization. The TOP2A-related changes in decidualization were screened by mRNA sequencing in decidualized TOP2A knockdown and control T-HESCs and then confirmed by Western blotting and immunofluorescence staining. TOP2A-deficient mice were generated by injection of TOP2A-interfering adenovirus on GD2.5 and GD3.5.
Results
We performed a proteomic analysis of endometrial tissues to investigate the potential pathogenesis of RIF by comparing the patients with RIF and the matched controls and found that TOP2A might be a key protein in RIF. TOP2A is ubiquitously expressed in both stromal and glandular epithelial cells of the endometrium. The data indicate that TOP2A expression is significantly lower in the mid-secretory endometrium of women with RIF. TOP2A expression was downregulated under stimulation by 8-bromo-cAMP and MPA. Ablation of TOP2A resulted in upregulated expression of decidual biomarkers and morphological changes in the cells. Mechanistic analysis revealed that TOP2A regulates the NF-κB signaling pathway in decidualized T-HESCs. The TOP2A-deficient mice exhibited lower fetal weights.
Conclusions
Our findings revealed that abnormal expression of TOP2A affects decidualization and changes the “window of implantation”, leading to RIF. TOP2A participates in the processes of decidualization and embryo implantation, functioning at least in part through the NF-κB pathway. Regulating the expression of TOP2A in the endometrium may become a new strategy for the prevention and treatment of RIF.
Tetraaminoporphyrin (TAPP) sensitized ZIF-8 was successfully prepared by one-pot method as an efficient visible light photocatalyst. The prepared photocatalyst TAPP/ZIF-8 was characterized by XRD and ...SEM. The combination of TAPP and ZIF-8 enhances the absorption of visible light, effectively improves the electron-hole separation, and improves the photocatalytic activity under visible light. In the photocatalytic experiment, TAPP/ZIF-8 showed good photocatalytic performance for the removal of Rhodamine B (RhB) under visible light. Therefore, our work provides an efficient green photocatalyst for water treatment.
In this study, 3-hydroxyethoxyphenyl-9(10), 16(17), 23 (24)-decyloxy-zinc phthalocyanine (HDPcZn) was first prepared by liquid phase catalysis, and then it was esterified with ...Poly-(N-isopropylacrylamide) which have two carboxyl groups (TRIT-PNIPAM) at the end to obtain a linear thermoresponsive polymer (PcZn-PNIPAM-PcZn) with two phthalocyanines at the end. The polymer was characterized by FT-IR,
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H NMR, EDS and UV-vis, and the photocatalytic performance of the polymer was tested with 1,5-dihydroxynaphthalene (DHN) as a model pollutant. The results showed that PcZn-PNIPAM-PcZn exhibited excellent photocatalytic oxidation ability for DHN under visible light irradiation (2h, 78.1 %).
Metal-semiconductor-metal (MSM) ultraviolet photodetector is fabricated on ZnO films, prepared by radio frequency magnetron sputtering technique on quartz substrates. The ZnO photodetector shows low ...dark current and external quantum efficiency (EQE) due to the gain effect. The device also exhibits a near linear responsivity dependence on voltage, which gradually rise to the peak first, then fall sharply, and then slightly rise again. A physical mechanism primarily focused on the relationship between carrier (electron-hole pairs) transport and barrier height at Schottky metal-semiconductor contact is given to explain the above phenomena. It is demonstrated as a straightforward and convenient way to enhance the internal gain of the simple ZnO-based Schottky photodetectors for application in the future.
Graphical abstract
We proposed and demonstrated MgZnO metal-semiconductor-metal (MSM) ultraviolet photodetectors (UV) assisted with surface plasmons (SPs) prepared by the radio frequency magnetron sputtering deposition ...method. After the decoration of their surface with Pt nanoparticles (NPs), the responsivity of all the electrode spacing (3, 5, and 8 μm) photodetectors were enhanced dramatically; to our surprise, comparing with them the responsivity of larger spacing sample, more SPs were gathered which are smaller than others in turn. A physical mechanism focused on SPs and depletion width is given to explain the above results.
The current diagnosis method for Creutzfeldt-Jakob disease (CJD) is post-mortem examination, so early detection of CJD has been historically problematic. Auxiliary detection of CJD based on changes ...in levels of components of the cerebrospinal fluid (CSF) has become a focus of research. In other neurodegenerative diseases such as Alzheimer's disease (AD), cell-free mitochondrial DNA (mtDNA) in the CSF of patients may serve as a biomarker that could facilitate early diagnosis and studies of the mechanisms underlying the disease.
In this study, the cell-free mitochondrial DNA in the CSF of patients with sCJD and control patients was compared by digital droplet PCR.
The cell-free mitochondrial DNA copy number in the CSF of sCJD patients was significantly increased in comparison with that of the control group, and this difference was pathologically related to CJD.
Therefore, we speculate that changes in cerebrospinal fluid mitochondrial DNA copy number play an important role in the study of CJD mechanism and diagnosis.
Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells' (NFAT) ...suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, minocycline, in the pre-symptomatic stage of prion infection in hamsters. Here we used for the first time, a combinatory FK506+minocycline treatment to test its transcriptional modulating effects in the symptomatic stage of prion infection. Our results indicate that prolonged treatment with FK506+minocycline was effective in alleviating astrogliosis and neuronal death triggered by misfolded prions. Specifically, the combinatory therapy with FK506+minocycline lowered the expression of the astrocytes activation marker GFAP and of the microglial activation marker IBA-1, subsequently reducing the level of pro-inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and increasing the levels of anti-inflammatory cytokines IL-10 and IL-27. We further found that FK506+minocycline treatment inhibited mitogen-activated protein kinase (MAPK) p38 phosphorylation, NF-kB nuclear translocation, caspase expression, and enhanced phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD) levels to reduce cognitive impairment and apoptosis. Interestingly, FK506+minocycline reduced mitochondrial fragmentation and promoted nuclear factor⁻erythroid2-related factor-2 (NRF2)-heme oxygenase 1 (HO-1) pathway to enhance survival. Taken together, our results show that a therapeutic cocktail of FK506+minocycline is an attractive candidate for prolonged use in prion diseases and we encourage its further clinical development as a possible treatment for this disease.
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