RESUMEN
Galactinol synthase (GolS), which catalyses the synthesis of galactinol, is the first critical enzyme in the biosynthesis of raffinose family oligosaccharides (RFOs) and contributes to plant growth and development, and resistance mechanisms. However, its role in fruit development remains largely unknown. In this study, we used CRISPR/Cas9 gene-editing technology in tomato (Solanum lycopersicum) to create the gols2 mutant showing uniformly green fruits without dark-green shoulders, and promoting fruit ripening. Analysis indicated that galactinol was undetectable in the ovaries and fruits of the mutant, and the accumulation of chlorophyll and chloroplast development was suppressed in the fruits. RNA-sequencing analysis showed that genes related to chlorophyll accumulation and chloroplast development were down-regulated, including PROTOCHLOROPHYLLIDE OXIDOREDUCTASE, GOLDEN 2-LIKE 2, and CHLOROPHYLL A/B-BINDING PROTEINS. In addition, early color transformation and ethylene release was prompted in the gols2 lines by regulation of the expression of genes involved in carotenoid and ethylene metabolism (e.g. PHYTOENE SYNTHASE 1, CAROTENE CIS-TRANS ISOMERASE, and 1-AMINOCYCLOPROPANE-1-CARBOXYLIC ACID SYNTHASE2/4) and fruit ripening (e.g. RIPENING INHIBITOR, NON-RIPENING, and APETALA2a). Our results provide evidence for the involvement of GolS2 in pigment and ethylene metabolism of tomato fruits.
Asunto(s)
Carotenoides , Clorofila , Etilenos , Frutas , Proteínas de Plantas , Solanum lycopersicum , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Solanum lycopersicum/crecimiento & desarrollo , Solanum lycopersicum/enzimología , Carotenoides/metabolismo , Clorofila/metabolismo , Frutas/metabolismo , Frutas/genética , Frutas/crecimiento & desarrollo , Etilenos/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Galactosiltransferasas/metabolismo , Galactosiltransferasas/genética , Regulación de la Expresión Génica de las PlantasRESUMEN
The capture and separation of CF4 from CF4/N2 mixture gas is a crucial issue in the electronics industry, as CF4 is a commonly used etching gas and the ratio of CF4 to N2 directly affects process efficiency. Utilizing high-throughput computational screening techniques and grand canonical Monte Carlo (GCMC) simulations, we comprehensively screened and assessed 247 types of pure silicon zeolite materials to determine their adsorption and separation performance for CF4/N2 mixtures. Based on screening, the relationships between the structural parameters and adsorption and separation properties were meticulously investigated. Four indicators including adsorption selectivity, working capacity, adsorbent performance score (APS), and regenerability (R%) were used to evaluate the performance of adsorbents. Based on the evaluation, we selected the top three best-performing zeolite structures for vacuum swing adsorption (LEV, AWW and ESV) and pressure swing adsorption (AVL, ZON, and ERI) processes respectively. Also, we studied the preferable adsorption sites of CF4 and N2 in the selected zeolite structures through centroid density distributions at the molecule level. We expect the study may provide some valuable guidance for subsequent experimental investigations on adsorption and separation of CF4/N2.
RESUMEN
BACKGROUND: With rapid increase in the global use of various plastics, microplastics (MPs) and nanoplastics (NPs) pollution and their adverse health effects have attracted global attention. MPs have been detected out in human body and both MPs and NPs showed female reproductive toxicological effects in animal models. Miscarriage (abnormal early embryo loss), accounting for 15-25% pregnant women worldwide, greatly harms human reproduction. However, the adverse effects of NPs on miscarriage have never been explored. RESULTS: In this study, we identified that polystyrene (PS) plastics particles were present in women villous tissues. Their levels were higher in villous tissues of unexplained recurrent miscarriage (RM) patients vs. healthy control (HC) group. Furthermore, mouse assays further confirmed that exposure to polystyrene nanoplastics (PS-NPs, 50 nm in diameter, 50 or 100 mg/kg) indeed induced miscarriage. In mechanism, PS-NPs exposure (50, 100, 150, or 200 µg/mL) increased oxidative stress, decreased mitochondrial membrane potential, and increased apoptosis in human trophoblast cells by activating Bcl-2/Cleaved-caspase-2/Cleaved-caspase-3 signaling through mitochondrial pathway. The alteration in this signaling was consistent in placental tissues of PS-NPs-exposed mouse model and in villous tissues of unexplained RM patients. Supplement with Bcl-2 could efficiently suppress apoptosis in PS-NPs-exposed trophoblast cells and reduce apoptosis and alleviate miscarriage in PS-NPs-exposed pregnant mouse model. CONCLUSIONS: Exposure to PS-NPs activated Bcl-2/Cleaved-caspase-2/Cleaved-caspase-3, leading to excessive apoptosis in human trophoblast cells and in mice placental tissues, further inducing miscarriage.
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Aborto Espontáneo , Nanopartículas , Embarazo , Femenino , Humanos , Animales , Ratones , Aborto Espontáneo/inducido químicamente , Poliestirenos/toxicidad , Caspasa 3 , Microplásticos , Plásticos , Caspasa 2 , Placenta , Apoptosis , Modelos Animales de Enfermedad , Proteínas Proto-Oncogénicas c-bcl-2 , Nanopartículas/toxicidadRESUMEN
Environmental benzo(a)pyrene (BaP) and itsmetabolite benzo(a)pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE), classic endocrine disrupting chemical and persistent organic pollutant, could cause miscarriage. However, the detailed mechanisms are still largely unclear and should be further explored. In this study, we discovered that exposure of trophoblast cells with BPDE could suppressed cell invasion/migration by inhibiting MEST/VIM (Vimentin) pathway. Moreover, BPDE exposure also increased lnc-HZ01 expression level, which further inhibited MEST/VIM pathway and then suppressed invasion/migration. Knockdown of lnc-HZ01 or overexpression of MEST could efficiently rescue invasion/migration of BPDE-exposed Swan 71 cells. Furthermore, lnc-HZ01 was highly expressed and MEST/VIM were lowly expressed in recurrent miscarriage (RM) villous tissues compared with healthy control (HC) group. Finally, we also found that BaP exposure inhibited murine Mest/Vim pathway in placental tissues and induced miscarriage in BaP-exposed mice. Therefore, the regulatory mechanisms were similar in BPDE-exposed human trophoblast cells, RM villous tissues, and placental tissues of BaP-exposed mice with miscarriage, building a bridge to connect BaP/BPDE exposure, invasion/migration, and miscarriage. This study provided novel insights in the toxicological effects and molecular mechanisms of BaP/BPDE-induced miscarriage, which is helpful for better elucidating the toxicological risks of BaP/BPDE on female reproduction.
Asunto(s)
7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido , Benzo(a)pireno , Movimiento Celular , Regulación hacia Abajo , Trofoblastos , Trofoblastos/efectos de los fármacos , Femenino , Animales , Movimiento Celular/efectos de los fármacos , Benzo(a)pireno/toxicidad , Humanos , Ratones , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/toxicidad , Embarazo , Disruptores Endocrinos/toxicidad , Contaminantes Ambientales/toxicidad , Línea Celular , Aborto Espontáneo/inducido químicamenteRESUMEN
Copper pollution has attracted global environmental concern. Widespread Cu pollution results in excessive Cu accumulation in human. Epidemiological studies and animal experiments revealed that Cu exposure might have reproductive toxicity. Cuproptosis is a recently reported Cu-dependent and programmed cell death pattern. However, the mechanism by which copper exposure might cause cell cuproptosis is largely unknown. We chose trophoblast cells as cell model and found that copper exposure causes trophoblast cell cuproptosis. In mechanism, copper exposure up-regulates lnc-HZ11 expression levels, which increases intracellular Cu2+ levels and causes trophoblast cell cuproptosis. Knockdown of lnc-HZ11 efficiently reduces intracellular Cu2+ levels and alleviate trophoblast cell cuproptosis, which could be further alleviated by co-treatment with DC or TEPA. These results discover novel toxicological effects of copper exposure and also provide potential target for protection trophoblast cells from cuproptosis in the presence of excessive copper exposure.
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Cobre , Trofoblastos , Regulación hacia Arriba , Trofoblastos/efectos de los fármacos , Cobre/toxicidad , Humanos , Regulación hacia Arriba/efectos de los fármacos , Línea Celular , Contaminantes Ambientales/toxicidad , ARN Largo no Codificante/genéticaRESUMEN
Formamidinium lead iodide (FAPbI3) represents an optimal absorber material in perovskite solar cells (PSCs), while the application of FAPbI3 in inverted-structured PSCs has yet to be successful, mainly owing to its inferior film-forming on hydrophobic or defective hole-transporting substrates. Herein, we report a substantial improvement of FAPbI3-based inverted PSCs, which is realized by a multifunctional amphiphilic molecular hole-transporter, (2-(4-(10H-phenothiazin-10-yl)phenyl)-1-cyanovinyl)phosphonic acid (PTZ-CPA). The phenothiazine (PTZ) based PTZ-CPA, carrying a cyanovinyl phosphonic acid (CPA) group, forms a superwetting hole-selective underlayer that enables facile deposition of high-quality FAPbI3 thin films. Compared to a previously established carbazole-based hole-selective material (2-(3,6-dimethoxy-9H-carbazol-9-yl)ethyl)phosphonic acid (MeO-2PACz), the crystallinity of FAPbI3 is enhanced and the electronic defects are passivated by the PTZ-CPA more effectively, resulting in remarkable increases in photoluminescence quantum yield (four-fold) and Shockley-Read-Hall lifetime (eight-fold). Moreover, the PTZ-CPA shows a larger molecular dipole moment and improved energy level alignment with FAPbI3, benefiting the interfacial hole-collection. Consequently, FAPbI3-based inverted PSCs achieve an unprecedented efficiency of 25.35 % under simulated air mass 1.5 (AM1.5) sunlight. The PTZ-CPA based device shows commendable long-term stability, maintaining over 90 % of its initial efficiency after continuous operation at 40 °C for 2000â hours.
RESUMEN
Environmental mutagens lead to mutagenesis. However, the mechanisms are very complicated and not fully understood. Environmental mutagens produce various DNA lesions, including base-damaged or sugar-modified DNA lesions, as well as epigenetically modified DNA. DNA polymerases produce mutation spectra in translesion DNA synthesis (TLS) through misincorporation of incorrect nucleotides, frameshift deletions, blockage of DNA replication, imbalance of leading- and lagging-strand DNA synthesis, and genome instability. Motif or subunit in DNA polymerases further affects the mutations in TLS. Moreover, protein interactions and accessory proteins in DNA replisome also alter mutations in TLS, demonstrated by several representative DNA replisomes. Finally, in cells, multiple DNA polymerases or cellular proteins collaborate in TLS and reduce in vivo mutagenesis. Summaries and perspectives were listed. This review shows mechanisms of mutagenesis induced by DNA lesions and the effects of multiple factors on mutations in TLS in vitro and in vivo.
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Daño del ADN , ADN/biosíntesis , ADN/genética , Mutagénesis/genética , Mutación , Biosíntesis de Proteínas/genética , Animales , Reparación del ADN , Replicación del ADN , ADN Polimerasa Dirigida por ADN/metabolismo , Escherichia coli/enzimología , Inestabilidad Genómica , Humanos , MutágenosRESUMEN
Normal pregnancy is essential for human reproduction. However, BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) could cause dysfunctions of human trophoblast cells and might further induce miscarriage. Yet, the underlying mechanisms remain largely unknown. Herein, we identified a novel upregulated lnc-HZ04 and a novel downregulated miR-hz04 in villous tissues of unexplained recurrent miscarriage (RM) relative to those in healthy control tissues and also in BPDE-treated human trophoblast cells. Lnc-HZ04 directly and specifically bound with miR-hz04, diminished the reduction effects of miR-hz04 on IP3 R1 mRNA expression level and on IP3 R1 mRNA stability, and then activated the Ca2+ -mediated IP3 R1 /p-CaMKII/SGCB pathway, which further promoted trophoblast cell apoptosis. The miR-hz04 target site on lnc-HZ04 played crucial roles in these regulations. In normal trophoblast, relatively less lnc-HZ04 and more miR-hz04 suppressed this apoptosis pathway and gave normal pregnancy. After exposure to BPDE or in RM tissues, p53 was upregulated, which might promote p53-mediated lnc-HZ04 transcription. Relatively more lnc-HZ04 and less miR-hz04 activated this apoptosis pathway and might further induce miscarriage. BaP could also induce mice miscarriage by upregulating its corresponding murine apoptosis pathway. Therefore, BPDE-induced apoptosis of human trophoblast cells was associated with the occurrence of miscarriage. This work discovered the regulation roles of lnc-HZ04 and miR-hz04 and provided scientific and clinical understanding of the occurrence of unexplained miscarriage.
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Aborto Habitual/genética , Apoptosis/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Transducción de Señal/genética , Trofoblastos/metabolismo , Regulación hacia Arriba/genética , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/farmacología , Aborto Habitual/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Línea Celular , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Femenino , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Ratones , Ratones Endogámicos C57BL , Embarazo , Sarcoglicanos/genética , Transducción de Señal/efectos de los fármacos , Trofoblastos/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Strand displacement DNA synthesis (SDDS) is an essential step in DNA replication. With magnetic tweezers, we investigated SDDS kinetics of wild-type gp90 and its exonuclease-deficient polymerase gp90 exo- at single-molecule level. A novel binding state of gp90 to the fork flap was confirmed prior to SDDS, suggesting an intermediate in the initiation of SDDS. The rate and processivity of SDDS by gp90 exo- or wt-gp90 are increased with force and dNTP concentration. The rate and processivity of exonuclease by wt-gp90 are decreased with force. High GC content decreases SDDS and exonuclease processivity but increases exonuclease rate for wt-gp90. The high force and dNTP concentration and low GC content facilitate the successive SDDS but retard the successive exonuclease for wt-gp90. Furthermore, increasing GC content accelerates the transition from SDDS or exonuclease to exonuclease. This work reveals the kinetics of SDDS in detail and offers a broader cognition on the regulation of various factors on SDDS at single-polymerase level.
Asunto(s)
Bacteriófagos/fisiología , Replicación del ADN , ADN Viral/biosíntesis , ADN Polimerasa Dirigida por ADN/metabolismo , Pseudomonas aeruginosa/virología , Análisis de la Célula Individual/métodos , ADN Polimerasa Dirigida por ADN/genética , Recombinación GenéticaRESUMEN
Extracellular vesicles (EVs) derived from parental cells could communicate with neighboring or distant recipient cells. The components in EVs, especially non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, could regulate the functions of the recipient cells. Meanwhile, EVs could also be used as valuable biomarkers and drug delivery carriers. Moreover, environmental toxicants may alter EVs components and regulate EVs-mediated pathogenesis of various diseases. In this review, we mainly summarized the roles of EV-derived non-coding RNAs in the regulation of cell dysfunctions in various adverse pregnancy outcomes, such as preeclampsia (PE), gestational diabetes mellitus (GDM), and miscarriage. Moreover, the effects of environmental toxicants on the components and functions of EVs, as well as on their regulatory roles in these diseases, were also discussed.
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Vesículas Extracelulares , MicroARNs , ARN Largo no Codificante , Embarazo , Femenino , Humanos , Resultado del Embarazo , Vesículas Extracelulares/fisiología , MicroARNs/farmacología , Biomarcadores , ARN Largo no Codificante/farmacologíaRESUMEN
Adverse pregnancy outcomes, such as preeclampsia, gestational diabetes mellitus, fetal growth restriction, and recurrent miscarriage, occur frequently in pregnant women and might further induce morbidity and mortality for both mother and fetus. Increasing studies have shown that dysfunctions of human trophoblast are related to these adverse pregnancy outcomes. Recent studies also showed that environmental toxicants could induce trophoblast dysfunctions. Moreover, non-coding RNAs (ncRNAs) have been reported to play important regulatory roles in various cellular processes. However, the roles of ncRNAs in the regulation of trophoblast dysfunctions and the occurrence of adverse pregnancy outcomes still need to be further investigated, especially with exposure to environmental toxicants. In this review, we analyzed the regulatory mechanisms of ncRNAs and m6A methylation modification in the dysfunctions of trophoblast cells and the occurrence of adverse pregnancy outcomes and also summarized the harmful effects of environmental toxicants. In addition to DNA replication, mRNA transcription, and protein translation, ncRNAs and m6A modification might be considered as the fourth and fifth elements that regulate the genetic central dogma, respectively. Environmental toxicants might also affect these processes. In this review, we expect to provide a deeper scientific understanding of the occurrence of adverse pregnancy outcomes and to discover potential biomarkers for the diagnosis and treatment of these outcomes.
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Resultado del Embarazo , Trofoblastos , Embarazo , Femenino , Humanos , ARN no Traducido/genética , BiomarcadoresRESUMEN
Approximately 15-25% pregnant women end with miscarriage in the world. Environmental BaP (benzo(a)pyrene) and its terminal metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) may result in the dysfunctions of trophoblast cells, which might further lead to RM (recurrent miscarriage). However, potential mechanisms remain unelucidated. In this work, we identified a novel lnc-HZ05 highly expressed and a novel miR-hz05 lowly expressed in both trophoblast cells exposed to BPDE and human RM tissues. MiR-hz05 reduces FOXO3a mRNA level by weakening its mRNA stability. Lnc-HZ05 increases the expression of FOXO3a by acting as a ceRNA for miR-hz05, and then increases P21 level and reduces CDK2 level. Thus, cell cycle is arrested at G0/G1 phase and trophoblast proliferation is inhibited. Lnc-HZ05 harboring wild-type binding site for miR-hz05, but not its mutant site, could upregulate FOXO3a expression. In normal trophoblast cells, relatively less lnc-HZ05 and more miR-hz05 activate FOXO3a/P21/CDK2 pathway and promote trophoblast proliferation, giving normal pregnancy. In RM tissues and BPDE-treated human trophoblast cells, lnc-HZ05 is increased and miR-hz05 is reduced, both of which suppress this pathway and inhibit cell proliferation, and finally lead to miscarriage. Thus, lnc-HZ05 and miR-hz05 simultaneously regulate cell cycle and proliferation of BPDE-exposed trophoblast cells and miscarriage, providing new perspectives and clinical understandings in the occurrence of unexplained miscarriage.
Asunto(s)
7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido , Aborto Espontáneo , MicroARNs , ARN Largo no Codificante , Femenino , Humanos , Embarazo , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/toxicidad , Aborto Espontáneo/genética , Aborto Espontáneo/metabolismo , Benzo(a)pireno/toxicidad , Línea Celular , Movimiento Celular , Proliferación Celular/genética , MicroARNs/genética , MicroARNs/metabolismo , Trofoblastos/metabolismo , ARN Largo no Codificante/genéticaRESUMEN
Increasing evidences have shown that pregnant women might miscarry after exposure with environmental BaP (benzo(a)pyrene). Additionally, BPDE (benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide), the ultimate metabolite of BaP, could induce dysfunctions of human trophoblast cells. However, it is rarely correlated between miscarriage and trophoblast dysfunctions. Moreover, their underlying mechanisms are still largely unidentified. In this study, a novel lncRNA (long non-coding RNA), lnc-HZ08, was identified to be highly expressed in human recurrent miscarriage (RM) tissues and in BPDE-treated human trophoblast cells. Lnc-HZ08 acts as a RNA scaffold to interact with both PI3K and its ubiquitin ligase CBL (Cbl proto-oncogene), enhances their protein interactions, and promotes PI3K ubiquitin degradation. In RM tissues and BPDE-treated trophoblast cells, DNA methylation level in lnc-HZ08 promoter region was reduced, which promotes estrogen receptor 1 (ER)-mediated lnc-HZ08 transcription. Subsequently, this upregulated lnc-HZ08 downregulated PI3K level, suppressed PI3K/p-AKT/p-P21/CDK2 pathway, and thus weakened proliferation, migration, and invasion of human trophoblast cells, which further induces miscarriage. These results may provide novel scientific and clinical insights in the occurrence of unexplained miscarriage. A novel lncRNA (lnc-HZ08) regulates the functions of human trophoblast cells and affects miscarriage. Lnc-HZ08 promotes PI3K ubiquitin degradation by enhancing CBL and PI3K interactions, downregulates PI3K/p-AKT/p-P21/CDK2 pathway, and weakens proliferation, migration, and invasion of trophoblast cells. BPDE exposure reduces the DNA methylation level in lnc-HZ08 promoter region and promotes estrogen receptor 1 (ER)-mediated lnc-HZ08 transcription. The suppressed PI3K/p-AKT/p-P21/CDK2 pathway regulated by increased lnc-HZ08 is associated with miscarriage. These results provide novel insights in the occurrence of unexplained miscarriage. Graphical Headlights ⢠Lnc-HZ08 downregulates PI3K/p-AKT/p-P21/CDK2 pathway to suppress proliferation, migration, and invasion of human trophoblast cells, and affects miscarriage. ⢠Lnc-HZ08 acts as a RNA scaffold to enhance the protein interaction of PI3K and its ubiquitin ligase CBL, which increases PI3K ubiquitination and degradation. ⢠Lnc-HZ08 transcription is associated with DNA methylation on its promoter region and transcription factor ER.
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Aborto Espontáneo , ARN Largo no Codificante , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/metabolismo , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/farmacología , Aborto Espontáneo/genética , Aborto Espontáneo/metabolismo , Movimiento Celular , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Ligasas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Embarazo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Trofoblastos/metabolismo , Ubiquitina/metabolismoRESUMEN
The hexametric T7 helicase (gp4) adopts a spiral lock-washer form and encircles a coil-like DNA (tracking) strand with two nucleotides bound to each subunit. However, the chemo-mechanical coupling mechanism in unwinding has yet to be elucidated. Here, we utilized nanotensioner-enhanced Förster resonance energy transfer with one nucleotide precision to investigate gp4-induced unwinding of DNA that contains an abasic lesion. We observed that the DNA unwinding activity of gp4 is hindered but not completely blocked by abasic lesions. Gp4 moves back and forth repeatedly when it encounters an abasic lesion, whereas it steps back only occasionally when it unwinds normal DNA. We further observed that gp4 translocates on the tracking strand in step sizes of one to four nucleotides. We propose that a hypothetical intermediate conformation of the gp4-DNA complex during DNA unwinding can help explain how gp4 molecules pass lesions, providing insights into the unwinding dynamics of gp4.
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Bacteriófago T7/genética , ADN Helicasas/genética , ADN Primasa/genética , ADN/genética , Bacteriófago T7/química , ADN/química , ADN Primasa/química , Transferencia Resonante de Energía de Fluorescencia , Cinética , Conformación Molecular , Nucleótidos/química , Nucleótidos/genéticaRESUMEN
Human trophoblast cell apoptosis may induce miscarriage. Trophoblast cells are sensitive to environmental BaP-7,8-dihydrodiol-9,10-epoxide (BPDE). However, how BPDE induces human trophoblast cell apoptosis is still largely elusive. In this work, we used BPDE-treated human trophoblast cells and villous tissues collected from recurrent miscarriage and health control groups to explore the underlying mechanism of BPDE-induced human trophoblast cell apoptosis. Continued with our recent work, we found that lncRNA HZ01 (lnc-HZ01) could induce human trophoblast cell apoptosis. In mechanism, lnc-HZ01 up-regulated p53 expression level by suppressing its MDM2-mediated proteasomal degradation. Meanwhile, we found that p53 acted as lnc-HZ01 transcription factor and promoted lnc-HZ01 transcription. Thus, lnc-HZ01 and p53 composed a positive feedback loop in human trophoblast cells. In normal trophoblast cells, relatively low levels of lnc-HZ01 and p53 suppressed p53/caspase-3 apoptosis pathway, giving normal pregnancy. Upon BPDE exposure, BPDE up-regulated the expression levels of lnc-HZ01 and p53, triggered this positive feedback loop, activated the p53/caspase-3 apoptosis pathway, and then induced miscarriage. Collectively, we discovered new mechanism by which lnc-HZ01 regulated BPDE-induced human trophoblast cell apoptosis, providing scientific basis for the diagnosis and treatment of unexplained recurrent miscarriage.
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Aborto Habitual , ARN Largo no Codificante , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/metabolismo , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/toxicidad , Aborto Habitual/inducido químicamente , Aborto Habitual/metabolismo , Apoptosis , Caspasa 3/metabolismo , Retroalimentación , Femenino , Humanos , Embarazo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Trofoblastos/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Normal pregnancy is essential for human reproduction. However, environmental BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) induce dysfunctions of human trophoblastic cells, which could further result in miscarriage. Yet, the molecular mechanisms remain poorly understood. In this work, a novel lnc-HZ03 and a novel miR-hz03 were identified. Both lnc-HZ03 and miR-hz03 were highly expressed in human recurrent miscarriage villous tissues and in BPDE-exposed trophoblastic cells. Lnc-HZ03 and miR-hz03 upregulated each other, forming a positive feedback loop. MiR-hz03 could also upregulate p53 level by enhancing its mRNA stability. Both lnc-HZ03 and p53 mRNA contained the target site for miR-hz03 and could directly interact with miR-hz03. It was this target site instead of its mutant on lnc-HZ03 that regulated p53 expression. Subsequently, the upregulated p53 facilitated SAT1 transcription and enhanced SAT1-catalyzed spermine metabolism, which further resulted in trophoblastic cell apoptosis and induced miscarriage. All together, the p53/SAT1 pathway upregulated by lnc-HZ03 and miR-hz03 could promote BPDE-induced human trophoblastic cell apoptosis and the occurrence of miscarriage, shedding novel light on the causes of miscarriage. Graphical abstract Lnc-HZ03 and miR-hz03 regulate the occurrence of recurrent miscarriage (RM). In human trophoblastic cells, lnc-HZ03 upregulates miR-hz03 level. MiR-hz03 increases the RNA stability of lnc-HZ03 and p53 mRNA. P53 promotes SAT1 transcription and reduces its cellular spermine content, resulting in cell apoptosis. Under normal conditions, lnc-HZ03/miR-hz03 and p53/SAT1 pathways are downregulated, maintaining normal pregnancy. After exposure to BPDE, lnc-HZ03/miR-hz03 and p53/SAT1 pathways are upregulated and finally induce miscarriage.
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Aborto Espontáneo , MicroARNs , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido , Aborto Espontáneo/inducido químicamente , Aborto Espontáneo/genética , Apoptosis , Femenino , Humanos , MicroARNs/genética , Embarazo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BPDE (benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide), a metabolite of environmental carcinogenic BaP, weakens the migration and invasion of human villous trophoblast cells and may further induce miscarriage. However, the underlying mechanisms remain largely unknown. In this study, we identified that in trophoblast Swan 71 and HTR-8/SVneo cells, miR-hz02 upregulates the level of lnc-HZ02, which inhibits the expression of an RNA-binding protein HuR. HuR could interact with FAK mRNA and promote its mRNA stability, thus upregulating the FAK level and the FAK/SRC/PI3K/AKT pathway, and finally maintaining the normal migration and invasion of trophoblast cells. If trophoblast cells are exposed to BPDE, both miR-hz02 and lnc-HZ02 are upregulated, which reduce the level of HuR, weaken the interactions of HuR with FAK mRNA, downregulate FAK level and the FAK/SRC/PI3K/AKT pathway, and finally inhibit cell migration and invasion. This study provides a novel scientific understanding of the dysfunctions of human trophoblast cells.
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7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/toxicidad , Regulación hacia Abajo/efectos de los fármacos , Quinasa 1 de Adhesión Focal/metabolismo , MicroARNs/biosíntesis , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , ARN Largo no Codificante/biosíntesis , Trofoblastos/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Línea Celular Transformada , Humanos , Trofoblastos/patologíaRESUMEN
In this Chapter, we systematically and comprehensively described various environmental harmful factors. They were classified into four aspects: physical factors, chemical factors, biological factors, and physiological and psychological stress factors. Their classification, modes of presence, toxicity and carcinogenicity, routes of exposure to human and toxic effects on the female reproductive health were introduced. It is expected that the exposure routes could be controlled and eliminated, and the pathogenic mechanism of environmental harmful factors should be investigated and explained to protect female reproductive health.
Asunto(s)
Exposición a Riesgos Ambientales , Salud Reproductiva , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Reproducción , Salud de la MujerRESUMEN
Polycyclic aromatic hydrocarbons (PAHs) are widely spread persistent environmental toxicants. Its typical representative benzo[a]pyrene (BaP) is a human carcinogen. BaP can pass through the placental barrier and is finally metabolized into benzo[a]pyren-7, 8-dihydrodiol-9, 10-epoxide (BPDE). BPDE can form DNA adducts, which directly affect the female reproductive health. Based on the special physiological functions of trophoblast cells and its important effect on normal pregnancy, this chapter describes the toxicity and molecular mechanism of BPDE-induced dysfunctions of trophoblast cells. By affecting the invasion, migration, apoptosis, proliferation, inflammation, and hormone secretion of trophoblast cells, BPDE causes diseases such as choriocarcinoma, intrauterine growth restriction, eclampsia, and abortion. In the end, it is expected to provide a scientific basis and prevention approach for women's reproductive health and decision-making basis for the formulation of environmental health standards.
Asunto(s)
7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido , Trofoblastos , 7,8-Dihidro-7,8-dihidroxibenzo(a)pireno 9,10-óxido/farmacología , Benzo(a)pireno/farmacología , Carcinógenos/farmacología , Aductos de ADN , Femenino , Humanos , EmbarazoRESUMEN
Soluble carbohydrates not only directly affect plant growth and development but also act as signal molecules in processes that enhance tolerance to cold stress. Raffinose family oligosaccharides (RFOs) are an example and play an important role in abiotic stress tolerance. This study aimed to determine whether galactinol, a key limiting factor in RFO biosynthesis, functions as a signal molecule in triggering cold tolerance. Exposure to low temperatures induces the expression of galactinol synthase (AnGolS1) in Ammopiptanthus nanus, a desert plant that survives temperatures between -30 °C to 47 °C. AnGolS1 has a greater catalytic activity than tomato galactinol synthase (SlGolS2). Moreover, SlGolS2 is expressed only at low levels. Expression of AnGolS1 in tomato enhanced cold tolerance and led to changes in the sugar composition of the seeds and seedlings. AnGolS1 transgenic tomato lines exhibited an enhanced capacity for ethylene (ET) signaling. The application of galactinol abolished the repression of the ET signaling pathway by 1-methylcyclopropene during seed germination. In addition, the expression of ERF transcription factors was increased. Galactinol may therefore act as a signal molecule affecting the ET pathway.