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Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.
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Ferroptosis , Interleucina-6 , Pulmón , Poli I-C , Receptores Citoplasmáticos y Nucleares , Ferroptosis/efectos de los fármacos , Animales , Poli I-C/farmacología , Interleucina-6/metabolismo , Ratones , Receptores Citoplasmáticos y Nucleares/metabolismo , Pulmón/patología , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Ratones Endogámicos C57BL , Masculino , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Lesión Pulmonar/tratamiento farmacológico , Humanos , Transducción de Señal/efectos de los fármacosRESUMEN
NORSF is a nuclear long noncoding RNA (lncRNA) that contributes to the follicular atresia and restrains 17ß-estradiol (E2) release by granulosa cells (GCs). Importantly, it is also a potential candidate gene in the quantitative trait locus (QTLs) for sow fertility traits. We identified NORSF as a candidate (causal) gene affecting sow fertility traits. A novel G-A variant was discovered at -478 nt of the NORSF promoter and termed as g.-478G>A. Association analysis revealed that this variant was associated with sow fertility traits (e.g., the total number of piglets born, the total number of piglets born alive, and the number of healthy piglets). Mechanistically, the g.-478G>A variant reduced the binding activity of the NORSF promoter to its transcription activator regulatory factor X7 (RFX7), leading to decreased NORSF promoter activity and transcription levels in sow GCs (sGCs), and weakened inhibitory effects on the transcription of CYP19A1, which encodes a rate-limiting enzyme for E2 synthesis and E2 release by sGCs. In addition, RFX7 is transcriptionally activated by P53, which restrains E2 release from sGCs via the RFX7/NORSF/CYP19A1 pathway. These findings indicate that the lncRNA NORSF is a causal gene in QTLs for sow fertility traits and define the P53/NORSF/CYP19A1 pathway as a new signaling pathway affecting sow reproduction, which provides a new target for improving female fertility.
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In this paper, we present the bit error rate (BER) performance of the underwater wireless optical communication (UWOC) systems using the optical space shift keying (OSSK) on the gamma-gamma turbulent fading channel, which also considers pointing errors and channel estimation errors. Firstly, we develop the new expressions for the probability density function (PDF) based on the Gamma-Gamma distribution with error factors. Subsequently, we analyze the statistical characteristic of the difference in attenuation coefficients between two channels in the OSSK system, by which we provide analytical results for evaluating the average BER performance. The results show that the effective improvement of spectral efficiency (SE) and BER performance is achieved by rationally allocating the number of lasers and detectors in the system. The OSSK-UWOC system performs better when a narrow beam waist is used. Furthermore, the presence of channel estimation error brings the BER performance advantage to the system, and the system with a high channel estimation error (ρ = 0.7) shows a 4â dB improvement in signal-to-noise ratio (SNR) gain compared to the system with a low channel estimation error (ρ = 0.95). The findings in this paper can be used for the UWOC system design.
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This paper investigates the propagation of Gaussian array beams (GABs) through seawater-to-air in the presence of oceanic turbulence, atmospheric turbulence, and wave foams. Specifically, we focus on the intensity distribution of diverse typical GAB structures (ring, multi-ring, and rectangle). Then, an innovative intensity analysis model to calculate the average intensity in each medium is proposed. Moreover, we experimentally verify the proposed method by examining the intensity fading characteristic of Gaussian beams in the seawater-to-air path. Our results show that the peak intensity is primarily affected by the refraction in the ocean and foam layer, rather than air layer. The difference of theoretical and experimental values are less than 0.13 for the peak intensity. Moreover, the intensity distributions are more significantly affected by ocean turbulence but less influenced by wind speed.
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OBJECTIVES: As a GABAB receptor agonist, baclofen has demonstrated efficacy in alleviating symptoms of refractory gastroesophageal reflux disease (r-GERD). This meta-analysis aims to evaluate the safety and effectiveness of baclofen as an add-on therapy for this condition. METHOD: We conducted a comprehensive search of the PubMed, Embase, and Web of Science databases for studies published up until October 2023. Subsequently, we performed a meta-analysis encompassing all eligible trials. RESULTS: From 719 records, 10 studies were included, most of these studies were moderate risk. The findings demonstrated that the addition of baclofen as a supplementary treatment effectively improves symptoms (GERD Q score) in r-GERD (standardized mean difference=-0.78, 95% CI: -1.06 to -0.51, I2=0%). The addition of this treatment also resulted in a decrease in the frequency of nonacidic reflux episodes (standardized mean difference=-0.93, 95% CI: -1.49 to -0.37, I2=63%) and an improvement in DeMeester scores (standardized mean difference=-0.82, 95% CI: -1.61 to -0.04, I2=81%) among patients with r-GERD when compared with the use of proton pump inhibitor (PPI) drugs alone. However, no significant disparity was observed in terms of reducing acid reflux episodes (standardized mean difference=-0.12, 95% CI: -0.49 to 0.19, I2=0%) and proximal reflux (standardized mean difference=-0.47, 95% CI: -1.08 to 0.14, I2=60%). CONCLUSION: Baclofen as an add-on treatment can effectively improve the symptoms of patients with r-GERD and reduce the incidence of nonacidic reflux and improve DeMeester score. However, long-term use of baclofen leads to an increased incidence of side effects and is not effective in reducing the occurrence of acid reflux.
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Mutations in PIK3CA, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in PTEN, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers1,2. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis3. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy3-6. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K-mTOR signalling axis in tumours, thereby compromising treatment effectiveness7,8. Here we show, in several model tumours in mice, that systemic glucose-insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.
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Retroalimentación Fisiológica/efectos de los fármacos , Insulina/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Animales , Glucemia/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/metabolismo , Neoplasias/patología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
In this Letter, author Xing Du was incorrectly listed as Du Xing; this has been corrected online.
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Di-hexyl phthalate (2-ethylhexyl) (DEHP) has been confirmed to cause female reproductive toxicity in humans and model animals by affecting the survival of ovarian granulosa cells (GCs), but the interrelationships between DEHP's on autophagy, apoptosis, and inflammation in GCs are not clear. Our previous study demonstrated that DEHP exposure resulted in the disturbance of intestinal flora associated with serum LPS release, which in turn led to impaired ovarian function. LPS has also been shown to determine cell fate by modulating cellular autophagy, apoptosis, and inflammation. Therefore, this study investigated the role and link between LPS and autophagy, apoptosis, and inflammation of GCs in DEHP-induced ovarian injury. Here, we constructed an in vivo injury model by continuous gavage of 0-1500â¯mg/kg of DEHP in female mice for 30 days and an in vitro injury model by treatment of human ovarian granulosa cells (KGN) cells with mono-2- ethylhexyl ester (MEHP, an active metabolite of DEHP in vivo). In addition, the expression of relevant pathway molecules was detected by immunohistochemistry, immunofluorescence, qRT-PCR, and Western blotting after the addition of the autophagy inhibitor 3-methyladenine (3-MA), the apoptosis inhibitor Z-VAD- FMK and the NF-κB inhibitor BAY11-7082. The current study found that autophagy and apoptosis were significantly activated in GCs of DEHP-induced atretic follicles in vivo and found that MEHP-induced KGN cells autophagy and apoptosis were independent and potentially cytotoxic of each other in vitro. Further studies confirmed that DEHP exposure resulted in LPS release from the intestinal tract and entering the ovary, thereby participating in DEHP-induced inflammation of GCs. In addition, we found that exogenous LPS synergized with MEHP could activate the NF-κB signaling pathway to induce inflammation and apoptosis of GCs in a relatively prolonged exposure condition. Meanwhile, inhibition of inflammatory activation could rescue apoptosis and estrogen secretion function of GCs induced by MEHP combined with LPS. These results indicated that the increased LPS influenced by DEHP might cooperate with MEHP to induce inflammatory apoptosis of GCs, an important cause of ovarian injury in mice.
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Apoptosis , Autofagia , Dietilhexil Ftalato , Dietilhexil Ftalato/análogos & derivados , Células de la Granulosa , Inflamación , Lipopolisacáridos , Femenino , Animales , Dietilhexil Ftalato/toxicidad , Autofagia/efectos de los fármacos , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/patología , Lipopolisacáridos/toxicidad , Apoptosis/efectos de los fármacos , Ratones , Inflamación/inducido químicamente , Inflamación/patología , Reproducción/efectos de los fármacos , HumanosRESUMEN
BACKGROUND: Functioning as a competing endogenous RNA (ceRNA) is the main action mechanism of most cytoplasmic lncRNAs. However, it is not known whether this mechanism of action also exists in the nucleus. RESULTS: We identified four nuclear lncRNAs that are presented in granulosa cells (GCs) and were differentially expressed during sow follicular atresia. Notably, similar to cytoplasmic lncRNAs, these nuclear lncRNAs also sponge miRNAs in the nucleus of GCs through direct interactions. Furthermore, NORSF (non-coding RNA involved in sow fertility), one of the nuclear lncRNA acts as a ceRNA of miR-339. Thereby, it relieves the regulatory effect of miR-339 on CYP19A1 encoding P450arom, a rate-limiting enzyme for E2 synthesis in GCs. Interestingly, miR-339 acts as a saRNA that activates CYP19A1 transcription and enhances E2 release by GCs through altering histone modifications in the promoter by directly binding to the CYP19A1 promoter. Functionally, NORSF inhibited E2 release by GCs via the miR-339 and CYP19A1 axis. CONCLUSIONS: Our findings highlight an unappreciated mechanism of nuclear lncRNAs and show it acts as a ceRNA, which may be a common lncRNA function in the cytoplasm and nucleus. We also identified a potential endogenous saRNA for improving female fertility and treating female infertility.
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MicroARNs , ARN Largo no Codificante , Femenino , Porcinos , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Atresia Folicular/genética , Células de la Granulosa/metabolismo , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
The identification of biofilm growth footprints influencing on the biofilm detachment and breakup can advance research into how biofilms form. Thus, a gravity-driven ceramic membrane bioreactor (GDCMBR) was used to investigate the growth, detachment and breakup of biofilm using rainwater pretreated by electrocoagulation under 70-days continuous operation. The in-situ ultrasonic time-domain reflectometry (UTDR) technique was applied to non-invasively determine the biofilm thickness. Initially, the biofilm was slowly thickening, but it would collapse and became thinner after accumulating to a certain level, and then it thickened again in a later period, following a cyclic pattern of 'thickening - collapsing - thickening'. This is because the biofilm growth is related with the accumulation of flocs, however, excessive floc formation results in the biofilm being overweight till reaching the thickness limit and thus collapsing. Subsequently, the biofilm gradually thickens again due to the floc production and continuous deposition. Although the biofilm was dynamically changing, the water quality of treatment of the biofilm always remained stable. Ammonia nitrogen and total phosphorus have been almost completely removed, while CODMn removal efficiency was around 25%. And total bacteria amount in the membrane concentrate was obviously higher than that in the influent with the greater microbial activity, demonstrating the remarkable enrichment effect on bacteria. The understanding of biofilm growth characteristic and footprint identification enables us to develop rational approaches to control biofilm structure for efficient GDCMBR performance and operation lifespan.
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Biopelículas , Reactores Biológicos , Cerámica , Purificación del Agua/métodos , Lluvia , Membranas Artificiales , FósforoRESUMEN
The daily discharge of rural sewage in China occupies 30 % of the national wastewater discharge, and developing an energy-efficient, easy to operate, and decentralized rural sewage treatment technology becomes an important task. In this work, a novel rural sewage treatment technology, Electrocoagulation enhanced Gravity-Driven Membrane Bioreactor (EC-GDMBR) was exploited for the rural sewage treatment under long-term operation (160 days). Two EC-GDMBRs with various module structures of ceramic membrane (horizontal module and side module) not only displayed the desirable effluent quality, but also sustained the stable flux (8-13 LMH). The electrocoagulation, electrooxidation, biodegradation, and separation in EC-GDMBRs were able to synergistically remove the particle matter, organic (CODCr effluent <11.6 ± 1.2 mg/L) and nutrients (NH3-N effluent <0.1 mg/L, TN effluent <8.5 mg/L, TP effluent <0.05 mg/L). Besides, the high permeability of ceramic membrane and large porosity of biofilm on its surface improved the sustainability of stable flux during the long-term operation. Moreover, by analyzing bacterial abundance, Extracellular Polymeric Substances, Adenosine Tri-Phosphate and Confocal Laser Scanning Microscopy, a large number of microorganisms grew and accumulated on the carrier, as well as formed the biofilm (23.46-659.9 µm), while Nitrobacteria (1.6-4.1 %) and Nitrate (0.01-0.06 %) exited in the carrier biofilms, promoting the nitrogen removal. Compared with EC-GDMBR with side module of ceramic membrane, EC-GDMBR with horizontal module of ceramic membrane has advantages in flux behavior, organic/nutrient removal, microbial abundance/activity, abundance of nitrogen removal functional bacteria and water permeability of biofilm, because the ceramic membrane of horizontal module can promote the uniform growth of biofilm and improve the uniformity of flow penetration distribution. In general, the findings of this work verify the reliability of EC-GDMBR for the sustainable operation of wastewater treatment and improve its application value of rural sewage treatment.
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Aguas del Alcantarillado , Eliminación de Residuos Líquidos , Aguas del Alcantarillado/química , Reproducibilidad de los Resultados , Membranas Artificiales , Reactores Biológicos , Nitrógeno/metabolismo , Bacterias/metabolismoRESUMEN
Li-N2 batteries have received widespread attention for their potential to integrate N2 fixation, energy storage, and conversion. However, because of the low activity and poor stability of cathode catalysts, the electrochemical performance of Li-N2 batteries is suboptimal, and their electrochemical reversibility has rarely been proven. In this study, a novel bifunctional photo-assisted Li-N2 battery system was established by employing a plasmonic Au nanoparticles (NPs)-modified defective carbon nitride (Au-Nv -C3 N4 ) photocathode. The Au-Nv -C3 N4 exhibits strong light-harvesting, N2 adsorption, and N2 activation abilities, and the photogenerated electrons and hot electrons are remarkably beneficial for accelerating the discharge and charge reaction kinetics. These advantages enable the photo-assisted Li-N2 battery to achieve a low overpotential of 1.32â V, which is the lowest overpotential reported to date, as well as superior rate capability and prolonged cycle stability (≈500â h). Remarkably, a combination of theoretical and experimental results demonstrates the high reversibility of the photo-assisted Li-N2 battery. The proposed novel strategy for developing efficient cathode catalysts and fabricating photo-assisted battery systems breaks through the overpotential bottleneck of Li-N2 batteries, providing important insights into the mechanism underlying N2 fixation and storage.
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Chemically self-recharging zinc ion batteries (ZIBs), which are capable of auto-recharging in ambient air, are promising in self-powered battery systems. Nevertheless, the exclusive reliance on chemical energy from oxygen for ZIBs charging often would bring some obstacles in charging efficiency. Herein, we develop photo-assisted chemically self-recharging aqueous ZIBs with a heterojunction of MoS2/SnO2 cathode, which are favorable to enhancing both the charging and discharging efficiency as well as the chemical self-charging capabilities under illumination. The photo-assisted process promotes the electron transfer from MoS2/SnO2 to oxygen, accelerating the occurrence of the oxidation reaction during chemical self-charging. Furthermore, the electrons within the MoS2/SnO2 cathode exhibit a low transfer impedance under illumination, which is beneficial to reducing the migration barrier of Zn2+ within the cathode and thereby facilitating the uniform inserting of Zn2+ into MoS2/SnO2 cathode during discharging. This photo-assisted chemical self-recharging mechanism enables ZIBs to attain a maximum self-charging potential of 0.95 V within 3 hours, a considerable self-charging capacity of 202.5 mAh g-1 and excellent cycling performance in a self-charging mode. This work not only provides a route for optimizing chemical self-charging energy storage, but also broadens the potential application of aqueous ZIBs.
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Since the linkages structured in covalent organic frameworks (COFs) usually impact the charge transfer behavior during photocatalytic hydrogen evolution reaction (pc-HER), linkage dependence on charge transfer kinetics should be further claimed. Herein, COFs with N-based linkages and pyrene-based building nodes are constructed to enable us to obtain new clues about the charge transfer behavior and evolution tendency relevant to linkages at a molecular level for pc-HER. It is demonstrated that photo-excited electrons preferably move to the N sites in C=N linkage for pc-HER and are trapped around NN linkage as well. A high electron transfer rate does not point to high photocatalytic activity directly, while a small difference between the electron transfer rate and electron recombination rate ΔkCT - CR predicts the inefficiency of charge transfer in Azod-COFs. Contrarily, large value of ΔkCT - CR in the case of Benzd-COFs, demonstrats an unimpeded charge transfer process to result in boosted pc-HER rate (2027.3 µmol h-1 g-1 ). This work offers a prominent strategy for the reasonable design of efficient photocatalysts at the molecular level for structural regulation and achieves an efficient charge transfer process for the pc-HER process.
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Ferroptosis is a non-apoptotic cell death regulated by iron-dependent lipid peroxidation. Glutathione (GSH), a key antioxidant against oxidative damage, is involved in one of the most important metabolic pathways of ferroptosis. Herein, an excellent plasmonic nanoprobe was developed for highly sensitive, in situ, dynamic real-time monitoring of intracellular GSH levels during ferroptosis. A nanoprobe was prepared by functionalizing gold nanoparticles (AuNPs) with the probe molecule crystal violet (CV). The fluctuation in the SERS signal intensity of CV via the competitive displacement reaction can be used to detect GSH. The advantages of the plasmonic nanoprobe including low-cost production techniques, outstanding stability and biocompatibility, high specificity and sensitivity towards GSH with a detection limit of 0.05 µM. It enables real-time dynamic monitoring of GSH levels in living cells during erastin-induced ferroptosis. This approach is expected to provide important theoretical support for elucidating the GSH-related ferroptosis metabolic mechanism and advancing our understanding of ferroptosis-based cancer therapy. Overview of the workflow of sensing principle for highly sensitive, in situ and dynamic tracking of intracellular GSH levels during drug-triggered ferroptosis process.
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Ferroptosis , Nanopartículas del Metal , Oro/química , Nanopartículas del Metal/química , Peroxidación de Lípido/fisiología , Glutatión/metabolismoRESUMEN
Harmful algal blooms pose an emerging threat to freshwater ecological security and human health, necessitating further study in offshore areas. In this work, boron-doped diamond electro-oxidation (BDD/EO) coupled with a ceramic membrane filtration was employed aiming to assess the salt tide affecting algae-laden water treatment involving with various natural organic matters (e.g., HA, SA, and BSA). The results have demonstrated that BDD/EO remove chlorophyll from the algae-laden water effectively due to the inactivation of algal cells. Moreover, considering the influence of salt tide, NH3-N would be mainly oxidized through the in-situ generated active chlorine at the electrode-liquid interface. In addition, in three kinds of salt tide affecting algae-laden water, TOC content in BSA group was decreasing remarkably after BDD/EO with TOC removal efficiency above 80%; while those in HA and SA groups had no obvious reducing due to the more algae cells breakage synchronous with HA and SA removal. Based on the fluorescent characteristics and particle size distribution, the generated small molecular organics after electro-oxidation might raise the pore blockage probability and the hydrophobic organic and fluorescent substances were preferentially oxidized in BDD/EO process being beneficial to reducing membrane fouling. Besides, the membrane special flux in three groups were decreasing significantly and the irreversible fouling resistance in SA group accounted for a larger proportion of the total resistance than those of HA and BSA. At last, in BDD/EO-CM process, macromolecular substances degradation rate was greater than that of small molecules based on the molecular weight distribution in three groups of salt tide affected algae-laden water treatment. In a word, this work provides effective and innovative strategies for the harmful algal bloom control and contributes interesting insights of membrane fouling performance of electrochemical coupled ultrafiltration membrane process.
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microRNAs (miRNAs) are well known to be important in mammalian female fertility. However, the genetic regulation of miRNAs associated with female fertility remains largely unknown. Here, we report that two single-nucleotide variants (SNVs) in the miR-23a promoter strongly influence miR-23a transcription and function in granulosa cell (GC) apoptosis. Two novel SNVs, g.-283G>C and g.-271C>T, were detected in the porcine miR-23a promoter by pooled-DNA sequencing. Furthermore, SNVs in the promoter region influenced miR-23a transcription in porcine GCs by altering its promoter activity. Functionally, SNVs in the promoter strongly influenced miR-23a regulation of early apoptosis in porcine GCs cultured in vitro. In addition, a preliminary association analysis showed that the combined genotypes of the two SNVs, rather than a single SNV, were tentatively associated with sow fertility traits in a Large White population. Overall, our findings suggest that the SNVs g.-283G>C and g.-271C>T in the miR-23a promoter are causal variants affecting GC apoptosis and miR-23a may be a potential small-molecule nonhormonal drug for regulating female fertility.
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MicroARNs , Femenino , Animales , Porcinos/genética , MicroARNs/genética , Apoptosis/genética , Regiones Promotoras Genéticas , Células de la Granulosa , Nucleótidos , Mamíferos/genéticaRESUMEN
Di-(2-ethylhexyl) phthalate (DEHP) is widely used in various plastics but has been demonstrated to cause female reproductive toxicity. However, the exact mechanism underlying the ovarian damage induced by DEHP remains unclear. In this study, DEHP was administered orally to 5-week-old female mice for 30 days at doses of 0, 250, 500, and 1000 mg/kg/day. The findings demonstrated that DEHP exposure disrupted ovarian function and follicular development as well as induced oxidative stress and autophagy in ovarian granulosa cells (GCs). Further, 200 µM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP in vivo, induced autophagy in both human ovarian granulosa cells line (KGN) and mouse primary GCs within 24 h in vitro. However, it did not affect the p62-dependent autophagy flux. Furthermore, MEHP-induced autophagy was inhibited by the autophagy inhibitor 3-MA and exacerbated by the autophagy activator rapamycin, indicating that MEHP induces excessive autophagy in GCs. Subsequently, we found that MEHP-induced autophagic cell death was primarily attributed to oxidative damage from elevated intracellular ROS levels. Meanwhile, MEHP exposure induced nuclear translocation of erythroid-derived factor 2-related factor (Nrf2), a key regulator of antioxidant activity resulting in activating antioxidant effects. Interestingly, we also found that MEHP-induced increase in p62 competitively binds Keap1, thereby facilitating nuclear translocation of Nrf2 and establishing a positive feedback loop in antioxidant regulation. Therefore, this study demonstrated that inhibition of Nrf2 could aggravate oxidative damage and enhance excessive autophagy caused by MEHP, while activation of Nrf2 could reverse the trend. These findings have also been reinforced in studies of cultured ovaries in vitro. Our study suggests that the p62-Keap1-Nrf2 pathway may serve as a potential protective mechanism against DEHP-induced oxidative stress and excessive autophagy in mouse GCs.
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Microplastics (MPs) and nanoplastics (NPs) are novel environmental pollutants that are ubiquitous in the environment and everyday life. NPs can easily enter the tissues and have more significant potential health risks due to their smaller diameter. Previous studies have shown that NPs can induce male reproductive toxicity, but the detailed mechanisms remain uncertain. In this study, intragastric administration treated mice with polystyrene NPs (PS-NPs, 50, and 90 nm) at 3 and 15 mg/mL/day doses for 30 days. Then, the fresh fecal samples were collected from those mice that the exposure doses of 50 nm PS-NPs at 3 mg/mL/day and 90 nm at 15 mg/mL/day for subsequent investigations of 16S rRNA and metabolomics according to significant toxicological effects (Sperm number, viability, abnormality, and testosterone level). The conjoint analysis findings indicated that PS-NPs disrupted the homeostasis of the gut microbiota, metabolism, and male reproduction, suggesting that abnormal gut microbiota-metabolite pathways may be important in PS-NPs-induced male reproductive toxicity. Meanwhile, the common differential metabolites such as 4-deoxy-Erythronic acid, 8-iso-15-keto-PGE2, apo-10'-violaxanthin, beta-D-glucosamine, isokobusone, oleamide, oxoadipic acid, sphingosine induced by 50 and 90 nm PS-NPs might be used as biomarkers to explore PS-NPs-induced male reproductive toxicity. In addition, this study systematically demonstrated that nano-scale PS-NPs induced male reproductive toxicity via the crosstalk of gut microbiota and metabolites. It also provided valuable insights into the toxicity of PS-NPs, which was conducive to reproductive health risk assessment for public health prevention and treatment.
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Microbiota , Contaminantes Químicos del Agua , Masculino , Animales , Ratones , Microplásticos , Poliestirenos/toxicidad , Plásticos/toxicidad , ARN Ribosómico 16S , Semen , MetabolomaRESUMEN
MicroRNA-23a (miR-23a) is an endogenous small activating RNA (saRNA) involved in ovarian granulosa cell (GC) apoptosis and sow fertility by activating lncRNA NORHA transcription. Here, we reported that both miR-23a and NORHA were repressed by a common transcription factor MEIS1, which forms a small network regulating sow GC apoptosis. We characterized the pig miR-23a core promoter, and the putative binding sites of 26 common transcription factors were detected in the core promoters of both miR-23a and NORHA. Of them, transcription factor MEIS1 expression was the highest in the ovary, and widely distributed in various ovarian cells, including GCs. Functionally, MEIS1 is involved in follicular atresia by inhibiting GC apoptosis. Luciferase reporter and ChIP assays showed that transcription factor MEIS1 represses the transcription activity of miR-23a and NORHA through direct binding to their core promoters. Furthermore, MEIS1 represses miR-23a and NORHA expression in GCs. Additionally, MEIS1 inhibits the expression of FoxO1, a downstream of the miR-23a/NORHA axis, and GC apoptosis by repressing the miR-23a/NORHA axis. Overall, our findings point to MEIS1 as a common transcription repressor of miR-23a and NORHA, and develop the miR-23a/NORHA axis into a small regulatory network regulating GC apoptosis and female fertility.