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Benzo(a)pyrene (BaP) or benzo (a) pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE) exposure causes trophoblast cell dysfunctions and induces miscarriage, which is generally epigenetically regulated. Homologous recombination (HR) repair of DNA double strand break (DSB) plays a crucial role in maintenance of genetic stability and cell normal functions. However, whether BaP/BPDE might suppress HR repair in human trophoblast cells to induce miscarriage, as well as its epigenetic regulatory mechanism, is largely unclear. In this study, we find that BaP/BPDE suppresses HR repair of DSB in trophoblast cells and eventually induces miscarriage by up-regulating lnc-HZ08. In mechanism, lnc-HZ08 (1) down-regulates the expression levels of FOXA1 (forkhead box A1) and thus suppresses FOXA1-mediated mRNA transcription of BRCA1 (Breast cancer susceptibility gene 1) and CtIP (CtBP-interacting protein), (2) impairs BRCA1 and CtIP protein interactions by competitive binding with CtIP through lnc-HZ08-1 fragment, and also (3) suppresses BRCA1-mediated CtIP ubiquitination without affecting CtIP stability, three of which eventually suppress HR repair in human trophoblast cells. Supplement with murine Ctip could efficiently restore (i.e. increase) HR repair and alleviate miscarriage in BaP-exposed mouse model. Collectively, this study not only reveals the association and causality among BaP/BPDE exposure, the defective HR repair, and miscarriage, but also discovers novel mechanism in lnc-HZ08-regulated BRCA1/CtIP-mediated HR repair, bridging epigenetic regulation and genetic instability and also providing an efficient approach for treatment against BaP/BPDE-induced unexplained miscarriage.
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The microstructure, corrosion resistance and mechanical properties of extruded pure Mg, Mg-2Y and Mg-2Gd were studied by means of scanning electron microscope (SEM), X-ray diffraction (XRD), electron backscatter diffraction (EBSD), scanning probe microscope (SPM), immersion test, electrochemical test and tensile test. The results demonstrated that Mg-2Y and Mg-2Gd were composed of Mg, Mg24Y5, and Mg5Gd phases with the addition of Y and Gd. The addition of Y and Gd to pure Mg noticeably reduced the grain size and textural strength of the alloy. Mg-2Gd alloy had the smallest grain size and the lowest textural strength. The corrosion rate of Mg-2Gd was the slowest due to the influence of grain size. Y slowed the corrosion of pure Mg in the early stages due to the grain refinement, but speeded up the corrosion because of the galvanic corrosion produced by the precipitation of the second phase in the latter stages. The elongation of pure Mg, Mg-2Y, and Mg-2Gd were 16.5 %, 38.67 %, and 48.67 %, respectively. The inclusion of Y and Gd refined the grain, softened the texture strength, and activated basal slip, which improved the elasticity of alloys. Gd was more significant than Y in improving the corrosion resistance and mechanical properties of pure Mg.
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Since 2019, Coronavirus Disease 2019(COVID-19) has affected millions of people worldwide. Except for acute respiratory distress syndrome, dysgeusis is also a common symptom of COVID-19 that burdens patients for weeks or permanently. However, the mechanisms underlying taste dysfunctions remain unclear. Here, we performed complete autopsies of five patients who died of COVID-19. Integrated tongue samples, including numerous taste buds, salivary glands, vessels, and nerves were collected to map the pathology, distribution, cell tropism, and receptor distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the tongue. Our results revealed that all patients had moderate lymphocyte infiltration around the salivary glands and in the lamina propria adjacent to the mucosa, and pyknosis in the epithelia of taste buds and salivary glands. This may be because the serous acini, salivary gland ducts, and taste buds are the primary sites of SARS-CoV-2 infection. Multicolor immunofluorescence showed that SARS-CoV-2 readily infects Keratin (KRT)7+ taste receptor cells in taste buds, secretory cells in serous acini, and inner epithelial cells in the ducts. The major receptors, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), were both abundantly expressed in these cells. Viral antigens and receptor were both rarely detected in vessels and nerves. This indicates that SARS-CoV-2 infection triggers pathological injury in the tongue, and that dysgeusis may be directly related to viral infection and cellular damage.
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Enzima Convertidora de Angiotensina 2 , Autopsia , COVID-19 , SARS-CoV-2 , Serina Endopeptidasas , Lengua , Tropismo Viral , Humanos , COVID-19/patología , COVID-19/virología , SARS-CoV-2/patogenicidad , Lengua/virología , Lengua/patología , Masculino , Enzima Convertidora de Angiotensina 2/metabolismo , Femenino , Persona de Mediana Edad , Serina Endopeptidasas/metabolismo , Glándulas Salivales/virología , Glándulas Salivales/patología , Anciano , Papilas Gustativas/virología , Papilas Gustativas/patología , Receptores Virales/metabolismoRESUMEN
As a novel electrochemical energy conversion device, direct ethanol fuel cells are currently encountering two significant challenges: CO poisoning and the difficulty of C-C bond cleavage in ethanol. In this work, an amorphous PdS nanowires/ultrafine IrMnOx bimetallic oxides (denoted as a-PdS/IrMnOx NWs) catalyst with abundant oxide/metal (crystalline/amorphous) inverse heterogeneous interfaces was synthesized via a hydrothermal process succeeded by a nonthermal air-plasma treatment. This unique interfacial electronic structure along with the incorporation of oxyphilic metal has resulted in a significant enhancement in the electrocatalytic performance of a-PdS/IrMnOx NWs toward the ethanol oxidation reaction, achieving current densities of 12.45 mA·cm-2 and 3.68 A·mgPd-1. Moreover, the C1 pathway selectivity for ethanol oxidation has been elevated to 47%, exceeding that of other as-prepared Pd-based counterparts and commercial Pd/C catalysts. Density functional theory calculations have validated the findings that the decoration of IrMn species onto the amorphous PdS surface has induced a charge redistribution in the interface region. The redistribution of surface charges on the a-PdS/IrMnOx NWs catalyst results in a significant decrease in the activation energy required for C-C bond cleavage and a notable weakening of the CO binding strength at the Pd active sites. Consequently, it enhanced both the EOR C1 pathway selectivity and CO poisoning resistance to the a-PdS/IrMnOx NWs catalyst.
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Programmed death ligand-1 (PD-L1)-expressing exosomes are considered a potential marker for diagnosis and classification of lung adenocarcinoma (LUAD). There is an urgent need to develop highly sensitive and accurate chemiluminescence (CL) immunosensors for the detection of PD-L1-expressing exosomes. Herein, N-(4-aminobutyl)-N-ethylisopropanol-functionalized nickel-cobalt hydroxide (NiCo-DH-AA) with a hollow nanoflower structure as a highly efficient CL nanoprobe was synthesized using gold nanoparticles as a "bridge". The resulting NiCo-DH-AA exhibited a strong and stable CL emission, which was ascribed to the exceptional catalytic capability and large specific surface area of NiCo-DH, along with the capacity of AuNPs to facilitate free radical generation. On this basis, an ultrasensitive sandwich CL immunosensor for the detection of PD-L1-expressing exosomes was constructed by using PD-L1 antibody-modified NiCo-DH-AA as an effective signal probe and rabbit anti-CD63 protein polyclonal antibody-modified carboxylated magnetic bead as a capture platform. The immunosensor demonstrated outstanding analytical performance with a wide detection range of 4.75 × 103-4.75 × 108 particles/mL and a low detection limit of 7.76 × 102 particles/mL, which was over 2 orders of magnitude lower than the reported CL method for detecting PD-L1-expressing exosomes. Importantly, it was able to differentiate well not only between healthy persons and LUAD patients (100% specificity and 87.5% sensitivity) but also between patients with minimally invasive adenocarcinoma and invasive adenocarcinoma (92.3% specificity and 52.6% sensitivity). Therefore, this study not only presents an ultrasensitive and accurate diagnostic method for LUAD but also offers a novel, simple, and noninvasive approach for the classification of LUAD.
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Adenocarcinoma del Pulmón , Antígeno B7-H1 , Cobalto , Exosomas , Neoplasias Pulmonares , Níquel , Humanos , Níquel/química , Cobalto/química , Antígeno B7-H1/análisis , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/inmunología , Neoplasias Pulmonares/diagnóstico , Exosomas/química , Inmunoensayo/métodos , Hidróxidos/química , Nanopartículas del Metal/química , Técnicas Biosensibles/métodos , Oro/química , Mediciones Luminiscentes/métodos , Límite de DetecciónRESUMEN
Eugenol (Eug) holds potential as a treatment for bacterial rhinosinusitis by nasal powder drug delivery. To stabilization and solidification of volatile Eug, herein, nasal inhalable γ-cyclodextrin metal-organic framework (γ-CD-MOF) was investigated as a carrier by gas-solid adsorption method. The results showed that the particle size of Eug loaded by γ-CD-MOF (Eug@γ-CD-MOF) distributed in the range of 10-150 µm well. In comparison to γ-CD and ß-CD-MOF, γ-CD-MOF has higher thermal stability to Eug. And the intermolecular interactions between Eug and the carriers were verified by characterizations and molecular docking. Based on the bionic human nasal cavity model, Eug@γ-CD-MOF had a high deposition distribution (90.07 ± 1.58%). Compared with free Eug, the retention time Eug@γ-CD-MOF in the nasal cavity was prolonged from 5 min to 60 min. In addition, the cell viability showed that Eug@γ-CD-MOF (Eug content range 3.125-200 µg/mL) was non-cytotoxic. And the encapsulation of γ-CD-MOF could not reduce the bacteriostatic effect of Eug. Therefore, the biocompatible γ-CD-MOF could be a potential and valuable carrier for nasal drug delivery to realize solidification and nasal therapeutic effects of volatile oils.
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Administración Intranasal , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Eugenol , Estructuras Metalorgánicas , Polvos , Estructuras Metalorgánicas/química , Polvos/química , Humanos , Eugenol/química , Eugenol/administración & dosificación , Eugenol/farmacología , Administración Intranasal/métodos , Sistemas de Liberación de Medicamentos/métodos , Portadores de Fármacos/química , Tamaño de la Partícula , Supervivencia Celular/efectos de los fármacos , Simulación del Acoplamiento Molecular/métodos , gamma-Ciclodextrinas/química , Estabilidad de Medicamentos , Antibacterianos/administración & dosificación , Antibacterianos/química , Antibacterianos/farmacología , Ciclodextrinas/química , Cavidad Nasal/metabolismoRESUMEN
Sepsis is an infection-triggered, rapidly progressive systemic inflammatory syndrome with a high mortality rate. Currently, there are no promising therapeutic strategies for managing this disease in the clinic. Heparanase plays a crucial role in the pathology of sepsis, and its inhibition can significantly relieve related symptoms. Here, a novel heparanase inhibitor CV122 is rationally designed and synthesized, and its therapeutic potential for sepsis with Lipopolysaccharide (LPS) and Cecal Ligation and Puncture (CLP)-induced sepsis mouse models are evaluated. It is found that CV122 potently inhibits heparanase activity in vitro, protects cell surface glycocalyx structure, and reduces the expression of adhesion molecules. In vivo, CV122 significantly reduces the systemic levels of proinflammatory cytokines, prevents organ damage, improves vitality, and efficiently protects mice from sepsis-induced death. Mechanistically, CV122 inhibits the activity of heparanase, reduces its expression in the lungs, and protects glycocalyx structure of lung tissue. It is also found that CV122 provides effective protection from organ damage and death caused by Crimean-Congo hemorrhagic fever virus (CCHFV) infection. These results suggest that CV122 is a potential drug candidate for sepsis therapy targeting heparanase by inhibiting cytokine storm.
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Síndrome de Liberación de Citoquinas , Modelos Animales de Enfermedad , Glucuronidasa , Sepsis , Animales , Sepsis/tratamiento farmacológico , Ratones , Glucuronidasa/metabolismo , Glucuronidasa/antagonistas & inhibidores , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Ratones Endogámicos C57BL , Masculino , Citocinas/metabolismoRESUMEN
Baculoviruses enter insect midgut epithelial cells via a set of occlusion-derived virion (ODV) envelope proteins called per os infectivity factors (PIFs). P74 of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), which was the first identified PIF, is cleaved by an endogenous proteinase embedded within the occlusion body during per os infection, but the target site(s) and function of the cleavage have not yet been ascertained. Here, based on bioinformatics analyses, we report that cleavage was predicted at an arginine and lysine-rich region in the middle of P74. A series of recombinant viruses with site-directed mutants in this region of P74 were generated. R325 or R334 was identified as primary cleavage site. In addition, we showed that P74 is also cleaved by brush border membrane vesicles (BBMV) of the host insect at R325 or R334, instead of R195, R196, and R199, as previously reported. Simultaneous mutations in R195, R196, and R199 lead to instability of P74 during ODV release. Bioassays showed that mutations at both R325 and R334 significantly affected oral infectivity. Taken together, our data show that both R325 and R334 of AcMNPV P74 are the primary cleavage site for both occlusion body endogenous proteinase and BBMV proteinase during ODV release and are critical for oral infection. IMPORTANCE: Cleavage of viral envelope proteins is usually an important trigger for viral entry into host cells. Baculoviruses are insect-specific viruses that infect host insects via the oral route. P74, a per os infectivity factor of baculoviruses, is cleaved during viral entry. However, the function and precise cleavage sites of P74 remain unknown. In this study, we found that R325 or R334 between the N- and C-conserved domains of P74 was the primary cleavage site by proteinase either from the occlusion body or host midgut. The biological significance of cleavage seems to be the release of the potential fusion peptide at the N-terminus of the cleaved C-terminal P74. Our results shed light on the cleavage model of P74 and imply its role in membrane fusion in baculovirus per os infection.
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Microvellosidades , Nucleopoliedrovirus , Cuerpos de Oclusión Viral , Péptido Hidrolasas , Proteínas del Envoltorio Viral , Animales , Microvellosidades/enzimología , Microvellosidades/metabolismo , Nucleopoliedrovirus/genética , Nucleopoliedrovirus/metabolismo , Nucleopoliedrovirus/fisiología , Cuerpos de Oclusión Viral/enzimología , Cuerpos de Oclusión Viral/metabolismo , Cuerpos de Oclusión Viral/virología , Péptido Hidrolasas/metabolismo , Péptido Hidrolasas/genética , Células Sf9 , Spodoptera/citología , Spodoptera/virología , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismo , Virión/química , Virión/genética , Virión/metabolismo , Internalización del Virus , Mutación , Boca/virología , Especificidad por Sustrato , Liberación del VirusRESUMEN
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.
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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
The spread of upper respiratory tract (URT) infections harms people's health and causes social burdens. Developing targeted treatment strategies for URT infections that exhibit good biocompatibility, stability, and strong antimicrobial effects remains challenging. The dual antimicrobial and antiviral effects of iodine (I2) in combination with the cooling sensation of l-menthol in the respiratory tract can simultaneously alleviate URT inflammation symptoms. However, as both I2 and l-menthol are volatile, addressing stability issues is crucial. In this study, a potassium iodide ß-cyclodextrin metal-organic framework [ß-CD-POF(I)] with appropriate particle size was used to coload and deliver I2 and l-menthol. Primarily, ß-CD-POF(I) was employed as the most efficient carrier to significantly enhance the stability of I2, surpassing any other known protection strategies in the pharmaceutical field (CD complexations, PVP conjugations, and cadexomer iodine). The mechanism underlying the improvement in stability of I2 by ß-CD-POF(I) was investigated through scanning electron microscopy with energy-dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and molecular docking. The results revealed that the key processes involved in improving stability were the inclusion of I2 by ß-CD cavities in ß-CD-POF(I) and the formation of polyiodide anion between iodine ions and I2. Furthermore, the potential of ß-CD-POF(I) to load and deliver drugs was validated, and coloading of l-menthol and I2 demonstrated reliable stability. ß-CD-POF(I) achieved a rate of URT deposition ≥95% in vitro, and the combined antibacterial effects of coloaded I2 and l-menthol was better than I2 or PVP-I alone, with no irritation noted following URT administration in rabbits. Therefore, the stable coloading of drugs by ß-CD-POF(I), leading to enhanced antimicrobial effects, provides a new strategy for treating URT infections.
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Antibacterianos , Yodo , Estructuras Metalorgánicas , beta-Ciclodextrinas , Yodo/química , Yodo/farmacología , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , beta-Ciclodextrinas/química , Antibacterianos/química , Antibacterianos/farmacología , Animales , Pruebas de Sensibilidad Microbiana , Conejos , Portadores de Fármacos/química , Staphylococcus aureus/efectos de los fármacos , Simulación del Acoplamiento MolecularRESUMEN
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic bunyavirus with a fatality rate of up to 40%. Currently, there are no licensed antiviral drugs for the treatment of CCHF; thus, the World Health Organization (WHO) listed the disease as a priority. A unique viral transcription initiation mechanism called "cap-snatching" is shared by influenza viruses and bunyaviruses. Thus, we tested whether baloxavir (an FDA-approved anti-influenza drug that targets the "cap-snatching" mechanism) could inhibit CCHFV infection. In cell culture, baloxavir acid effectively inhibited CCHFV infection and targeted CCHFV RNA transcription/replication. However, it has weak oral bioavailability. Baloxavir marboxil (the oral prodrug of baloxavir) failed to protect mice against a lethal dose challenge of CCHFV. To solve this problem, baloxavir sodium was synthesized owing to its enhanced aqueous solubility and pharmacokinetic properties. It consistently and significantly improved survival rates and decreased tissue viral loads. This study identified baloxavir sodium as a novel scaffold structure and mechanism of anti-CCHF compound, providing a promising new strategy for clinical treatment of CCHF after further optimization.
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Antivirales , Dibenzotiepinas , Morfolinas , Piridinas , Piridonas , Triazinas , Replicación Viral , Animales , Morfolinas/farmacología , Morfolinas/farmacocinética , Morfolinas/química , Antivirales/farmacología , Antivirales/farmacocinética , Antivirales/química , Dibenzotiepinas/farmacología , Dibenzotiepinas/farmacocinética , Ratones , Piridinas/farmacología , Piridinas/farmacocinética , Piridinas/química , Replicación Viral/efectos de los fármacos , Triazinas/farmacología , Triazinas/farmacocinética , Triazinas/química , Triazinas/uso terapéutico , Piridonas/farmacología , Piridonas/farmacocinética , Piridonas/química , Tiepinas/farmacología , Tiepinas/uso terapéutico , Tiepinas/farmacocinética , Tiepinas/química , Carga Viral/efectos de los fármacos , Chlorocebus aethiops , Células Vero , Femenino , Oxazinas/farmacología , Oxazinas/farmacocinética , Oxazinas/uso terapéutico , Ratones Endogámicos BALB C , Humanos , Tiazoles/farmacología , Tiazoles/farmacocinética , Tiazoles/químicaRESUMEN
Copper pollution has become global environmental concern. Widespread Cu pollution results in excessive Cu exposure in human. Epidemiological studies and animal experiments revealed that Cu exposure might have reproductive toxicity. Cuproptosis is a newly reported Cu-dependent and programmed cell death formTsvetkov et al., 2022. However, whether copper exposure at real environmental exposure dose might cause placental cuproptosis and induce miscarriage was completely unexplored. In this study, we found that Cu exposure during pregnancy induced miscarriage or complete pregnancy loss by inducing placenta cuproptosis in CuCl2-exposed pregnant mice. Notably, Cu exposure at 1.3 mg/kg/d (a real environmental exposure dose) was enough to cause placenta cuproptosis. CuCl2 exposure disrupts the TCA cycle, causes proteotoxic stress, increases Cu2+ ion import/decreases Cu2+ export, and results in the loss of Fe-S cluster proteins in mouse placenta, which induces placenta cuproptosis. Moreover, we also identified that Cu exposure down-regulates the expression levels of mmu-miR-3473b, which interacts with Dlst or Rtel1 mRNA and simultaneously positively regulates Dlst or Rtel1 expression, thereby disrupting the TCA cycle and resulting in the loss of Fe-S cluster proteins, and thus epigenetically regulates placental cuproptosis. Treatment with TTM (a cuproptosis inhibitor) suppressed placental cuproptosis and alleviated miscarriage in CuCl2-exposed mice. This work provides novel reproductive toxicity of Cu exposure in miscarriage or complete pregnancy loss by causing placental cuproptosis. This study also provides new ways for further studies on other toxicological effects of Cu and proposes a new approach for protection against Cu-induced reproductive diseases.
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Aborto Espontáneo , Embarazo , Humanos , Femenino , Animales , Ratones , Aborto Espontáneo/inducido químicamente , Cobre/toxicidad , Placenta , Exposición a Riesgos Ambientales , Contaminación Ambiental , ApoptosisRESUMEN
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
The high risk of SARS-CoV-2 infection and reinfection and the occurrence of post-acute pulmonary sequelae have highlighted the importance of understanding the mechanism underlying lung repair after injury. To address this concern, comparative and systematic analyses of SARS-CoV-2 infection in COVID-19 patients and animals were conducted. In the lungs of nine patients who died of COVID-19 and one recovered from COVID-19 but died of unrelated disease in early 2020, damage-related transient progenitor (DATP) cells expressing CK8 marker proliferated significantly. These CK8+ DATP cells were derived from bronchial CK5+ basal cells. However, they showed different cell fate toward differentiation into type I alveolar cells in the deceased and convalescent patients, respectively. By using a self-limiting hamster infection model mimicking the dynamic process of lung injury remodeling in mild COVID-19 patients, the accumulation and regression of CK8+ cell marker were found to be closely associated with the disease course. Finally, we examined the autopsied lungs of two patients who died of infection by the recent Omicron variant and found that they only exhibited mild pathological injury with no CK8+ cell proliferation. These results indicate a clear pulmonary cell remodeling route and suggest that CK8+ DATP cells play a primary role in mediating alveolar remodeling, highlighting their potential applications as diagnostic markers and therapeutic targets.
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COVID-19 , SARS-CoV-2 , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Humanos , Animales , Masculino , Persona de Mediana Edad , Femenino , Cricetinae , Pulmón/patología , Pulmón/virología , Pulmón/inmunología , Adulto , Alveolos Pulmonares/patología , Alveolos Pulmonares/virología , Alveolos Pulmonares/inmunología , Anciano , Modelos Animales de Enfermedad , Lesión Pulmonar/virología , Lesión Pulmonar/patología , Lesión Pulmonar/inmunología , Proliferación Celular , Diferenciación CelularRESUMEN
Defects of human trophoblast cells may induce miscarriage (abnormal early embryo loss), which is generally regulated by lncRNAs. Ferroptosis is a newly identified iron-dependent programmed cell death. Hypoxia is an important and unavoidable feature in mammalian cells. However, whether hypoxia might induce trophoblast cell ferroptosis and then induce miscarriage, as well as regulated by a lncRNA, was completely unknown. In this work, we discovered at the first time that hypoxia could result in ferroptosis of human trophoblast cells and then induce miscarriage. We also identified a novel lncRNA (lnc-HZ06) that simultaneously regulated hypoxia (indicated by HIF1α protein), ferroptosis, and miscarriage. In mechanism, HIF1α-SUMO, instead of HIF1α itself, primarily acted as a transcription factor to promote the transcription of NCOA4 (ferroptosis indicator) in hypoxic trophoblast cells. Lnc-HZ06 promoted the SUMOylation of HIF1α by suppressing SENP1-mediated deSUMOylation. HIF1α-SUMO also acted as a transcription factor to promote lnc-HZ06 transcription. Thus, both lnc-HZ06 and HIF1α-SUMO formed a positive auto-regulatory feedback loop. This loop was up-regulated in hypoxic trophoblast cells, in RM villous tissues, and in placental tissues of hypoxia-treated mice, which further induced ferroptosis and miscarriage by up-regulating HIF1α-SUMO-mediated NCOA4 transcription. Furthermore, knockdown of either murine lnc-hz06 or Ncoa4 could efficiently suppress ferroptosis and alleviate miscarriage in hypoxic mouse model. Taken together, this study provided new insights in understanding the regulatory roles of lnc-HZ06/HIF1α-SUMO/NCOA4 axis among hypoxia, ferroptosis, and miscarriage, and also offered an effective approach for treatment against miscarriage.
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Aborto Espontáneo , Ferroptosis , ARN Largo no Codificante , Ratones , Femenino , Humanos , Embarazo , Animales , Ferroptosis/genética , ARN Largo no Codificante/genética , Placenta , Hipoxia de la Célula , Hipoxia/genética , Factores de Transcripción , Trofoblastos , Mamíferos , Coactivadores de Receptor NuclearRESUMEN
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus, prevalent in more than 30 countries worldwide. Human infection by this virus leads to severe illness, with an average case fatality of 40%. There is currently no approved vaccine or drug to treat the disease. Neutralizing antibodies are a promising approach to treat virus infectious diseases. This study generated 37 mouse-derived specific monoclonal antibodies against CCHFV Gc subunit. Neutralization assays using pseudotyped virus and authentic CCHFV identified Gc8, Gc13, and Gc35 as neutralizing antibodies. Among them, Gc13 had the highest neutralizing activity and binding affinity with CCHFV Gc. Consistently, Gc13, but not Gc8 or Gc35, showed in vivo protective efficacy (62.5% survival rate) against CCHFV infection in a lethal mouse infection model. Further characterization studies suggested that Gc8 and Gc13 may recognize a similar, linear epitope in domain II of CCHFV Gc, while Gc35 may recognize a different epitope in Gc. Cryo-electron microscopy of Gc-Fab complexes indicated that both Gc8 and Gc13 bind to the conserved fusion loop region and Gc13 had stronger interactions with sGc-trimers. This was supported by the ability of Gc13 to block CCHFV GP-mediated membrane fusion. Overall, this study provides new therapeutic strategies to treat CCHF and new insights into the interaction between antibodies with CCHFV Gc proteins.
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Virus de la Fiebre Hemorrágica de Crimea-Congo , Fiebre Hemorrágica de Crimea , Animales , Ratones , Humanos , Virus de la Fiebre Hemorrágica de Crimea-Congo/genética , Anticuerpos Monoclonales , Microscopía por Crioelectrón , Anticuerpos Neutralizantes , EpítoposRESUMEN
Human trophoblast cells are crucial for healthy pregnancy. However, whether the defective homologous recombination (HR) repair of dsDNA break (DSB) in trophoblast cells may induce miscarriage is completely unknown. Moreover, the abundance of BRCA1 (a crucial protein for HR repair), its recruitment to DSB foci, and its epigenetic regulatory mechanisms, are also fully unexplored. In this work, it is identified that a novel lnc-HZ10, which is highly experssed in villous tissues of recurrent miscarriage (RM) vs their healthy control group, suppresses HR repair of DSB in trophoblast cell. Lnc-HZ10 and AhR (aryl hydrocarbon receptor) form a positive feedback loop. AhR acts as a transcription factor to promote lnc-HZ10 transcription. Meanwhile, lnc-HZ10 also increases AhR levels by suppressing its CUL4B-mediated ubiquitination degradation. Subsequently, AhR suppresses BRCA1 transcription; and lnc-HZ10 (mainly 1-447 nt) interacts with γ-H2AX; and thus, impairs its interactions with BRCA1. BPDE exposure may trigger this loop to suppress HR repair in trophoblast cells, possibly inducing miscarriage. Knockdown of murine Ahr efficiently recovers HR repair in placental tissues and alleviates miscarriage in a mouse miscarriage model. Therefore, it is suggested that AhR/lnc-HZ10/BRCA1 axis may be a promising target for alleviation of unexplained miscarriage.
Asunto(s)
Aborto Espontáneo , Reparación del ADN por Recombinación , Humanos , Femenino , Ratones , Embarazo , Animales , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Aborto Espontáneo/genética , Placenta/metabolismo , Trofoblastos/metabolismo , Proteínas Cullin/genéticaRESUMEN
Nanoplastics (NPs), as emerging pollutants, have attracted global attention. Nevertheless, the adverse effects of NPs on female reproductive health, especially unexplained miscarriage, are poorly understood. Defects of trophoblast cell migration and invasion are associated with miscarriage. Migrasomes were identified as cellular organelles with largely unidentified functions. Whether NPs might affect migration, invasion, and migrasome formation and induce miscarriage has been completely unexplored. In this study, we selected polystyrene nanoplastics (PS-NPs, 50 nm) as a model of plastic particles and treated human trophoblast cells and pregnant mice with PS-NPs at doses near the actual environmental exposure doses of plastic particles in humans. We found that exposure to PS-NPs induced a pregnant mouse miscarriage. PS-NPs suppressed ROCK1-mediated migration/invasion and migrasome formation. SOX2 was identified as the transcription factor of ROCK1. PS-NPs activated autophagy and promoted the autophagy degradation of SOX2, thus suppressing SOX2-mediated ROCK1 transcription. Supplementing with murine SOX2 or ROCK1 could efficiently rescue migration/invasion and migrasome formation and alleviate miscarriage. Analysis of the protein levels of SOX2, ROCK1, TSPAN4, NDST1, P62, and LC-3BII/I in PS-NP-exposed trophoblast cells, villous tissues of unexplained miscarriage patients, and placental tissues of PS-NP-exposed mice gave consistent results. Collectively, this study revealed the reproductive toxicity of nanoplastics and their potential regulatory mechanism, indicating that NP exposure is a risk factor for female reproductive health.
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Aborto Espontáneo , Nanopartículas , Contaminantes Químicos del Agua , Embarazo , Humanos , Femenino , Animales , Ratones , Microplásticos , Poliestirenos , Placenta , Autofagia , Trofoblastos , Quinasas Asociadas a rhoRESUMEN
Urban vegetation can effectively filter and adsorb particulate matter (PM). However, limited studies have been conducted on the PM retention capacity of tree barks. This study investigated the ability of five common urban tree species in the Yangtze River Delta region to retain PM through their barks and leaves by conducting a 14-day tree PM retention experiment on the five tree species during autumn and winter. The results showed that (1) the PM retention per unit area of bark was 6.9 times and 11.8 times higher than that of leaves during autumn and winter, respectively; (2) when considering total surface area, bark and leaves exhibited comparable PM retention capacities at the whole-plant scale; (3) the ability of bark to retain PM is species-specific, which can be attributed to different bark morphology among different tree species; and (4) bark and leaves exhibited distinct preferences for retaining PM of different particle sizes, even when exposed to similar environmental conditions. This study highlights the remarkable ability of tree bark to PM removal and provides valuable insights into the role of urban trees in mitigating PM pollution. Furthermore, these findings can provide valuable insights into studies on dry deposition modelling, urban planning, and green space management strategies.
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Contaminantes Atmosféricos , Material Particulado , Material Particulado/análisis , Árboles , Contaminantes Atmosféricos/análisis , Corteza de la Planta/química , Monitoreo del Ambiente/métodos , Hojas de la Planta/químicaRESUMEN
Severe fever with thrombocytopenia syndrome (SFTS) caused by the SFTS virus (SFTSV) is an emerging disease in East Asia with a fatality rate of up to 30%. However, the viral-host interaction of SFTSV remains largely unknown. The heat-shock protein 90 (Hsp90) family consists of highly conserved chaperones that fold and remodel proteins and has a broad impact on the infection of many viruses. Here, we showed that Hsp90 is an important host factor involved in SFTSV infection. Hsp90 inhibitors significantly reduced SFTSV replication, viral protein expression, and the formation of inclusion bodies consisting of nonstructural proteins (NSs). Among viral proteins, NSs appeared to be the most reduced when Hsp90 inhibitors were used, and further analysis showed that their translation was affected. Co-immunoprecipitation of NSs with four isomers of Hsp90 showed that Hsp90 ß specifically interacted with them. Knockdown of Hsp90 ß expression also inhibited replication of SFTSV. These results suggest that Hsp90 ß plays a critical role during SFTSV infection and could be a potential target for the development of drugs against SFTS.