Biology subjects

Wang, Q.

Publications and source records attributed to Wang, Q..

At least 271 records · Page 15Linked to original sources

bioRxiv2024

Proteolysis-targeting vaccines (PROTAVs) for robust tumor combination immunotherapy

Protein/peptide subunit vaccines are promising to promote the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of melanoma. PROTAVs are modular conjugates of protein/peptide antigens, E3 ligase-binding ligands, and linkers. In antigen-presenting cells (APCs), PROTAVs bind to E3 ligases to rapidly ubiquitinate PROTAV antigens, facilitating antigen proteolytic processing by proteasome, and thereby promoting antigen cross-presentation to T cells and potentiating CD8+ T cell responses. We developed a melanoma PROTAV using a tandem peptide of trivalent melanoma-associated antigens. Co-delivered by lipid nanoparticles (LNPs) with bivalent immunostimulant adjuvants, this PROTAV promotes the quantity and quality of melanoma-specific CD8+ T cells in mice. Further, combining PROTAV and ICB ameliorates the immunosuppressive melanoma microenvironment. As a result, PROTAV and ICB combination enhances melanoma complete regression rates and eradicated 100% large BrafV600E melanoma without recurrence in syngeneic mice. PROTAVs hold the potential for robust tumor combination immunotherapy.

bioengineering↗

bioRxiv2024

Environmental polysulfides promote protein disulfide bond formation of microorganisms growing under anaerobic condition

Polysulfides are rich in anaerobic and microbial metabolism active environments. Anaerobic survival of microorganisms requires the formation of protein disulfide bond (DSB). The relation between environmental polysulfides and anaerobic DSB formation has not been studied so far. Herein, we discovered that environmental polysulfides can efficiently mediate protein DSB formation of microorganisms under anaerobic condition. We used polysulfides to treat proteins including roGFP2, Trx1, and DsbA under anaerobic condition and found that all three proteins formed intramolecular DSB in vitro. The growth of E. coli {Delta}dsbB was reduced and the amount of its intracellular protein DSB was decreased under anaerobic condition. However, treating the mutant strain with polysulfides recovered the growth and reversed DSB decrease. Treating E. coli {Delta}dsbA with polysulfides promoted DSB formation of its periplasmic roGFP2 and recovered its growth under anaerobic condition. In addition, treating Schizosaccharomyces pombe with polysulfides led to increase of the intracellular protein DSB content. Thus, our study reveals that environmental polysulfides can promote DSB formation independent of the enzymatic DSB mediating system and oxygen. In this aspect, environmental polysulfides are beneficial for the survival of microorganisms in anaerobic habitats. IMPORTANCEHow polysulfides benefit adaption of microorganisms to anaerobic environments are unclear. Our study reveals that environmental polysulfides efficiently facilitate protein DSB formation under anaerobic condition. Polysulfides contain zero valent sulfur atoms (S0), which can be transferred to the thiol group of cysteine residue. This S0 atom gets two electrons from two cysteine residues and becomes reduced H2S, leaving two cysteine residues in disulfide bond form. Anaerobic growth of microorganisms was benefited from the formation of DSB. This finding paves the way for a deeper understanding of the intricate relationship between polysulfides and microorganisms in environmental contexts.

molecular biology↗

bioRxiv2024

Engineering Human ARMMs as Therapeutic Non-Viral Vehicles for in vivo Delivery of Genome Editing Payloads

The ability to edit the human genome to treat previously incurable diseases or to modify previously undruggable targets has the potential to transform the lives of patients. However, delivery of genome editing machineries in vivo, and in a transient manner, continues to be a major challenge. We engineered human cell-derived ARRDC1-mediated microvesicles (ARMMs) as non-viral vehicles that mediate intracellular delivery of proteins, including DNA-modifying enzymes such as Cre recombinase and Cas9/guide RNA ribonucleoproteins (RNPs). ARMMs packaged multiple payloads per vesicle in our production system, yielding dose-dependent functional delivery of Cre or Cas9/gRNA RNP to a variety of cell types, including primary mouse and human cells. Oropharyngeal aspiration of ARMMs loaded with Cre led to biodistribution to alveolar macrophages (AMs), whereas intravenous administration predominantly to Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and splenocytes. Suprisingly, one administration of ARMMs loaded with Cas9 RNPs by oropharyngeal aspiration or intravenously resulted in efficient knockout of multiple genes in AMs or KCs, suggesting potential therapeutic utility. Through intravenous administration of ARMMs loaded with Cas9/NLRP3 gRNA we showed amelioration of drug-induced liver injury in a mouse model, supporting the use of ARMMs as human cell-derived therapeutic vehicles for genome editor delivery in vivo.

bioengineering↗

bioRxiv2024

OPUS-DSD2: Disentangling Dynamics and Compositional Heterogeneity for Cryo-EM Single Particle Analysis

Cryo-electron microscopy and tomography (cryo-EM/ET) capture structural heterogeneities in macromolecules, ranging from dynamic motions to compositional changes-- key to understanding biological mechanisms. While the deep learning framework, OPUS-DSD, advanced heterogeneity analysis for cryo-EM, it conflates different types of heterogeneities, and remains incompatible with cryo-ET which can elucidate macromolecular functions in their native cellular environments. Here, we present OPUS-DSD2, a unified framework for disentangling structural heterogeneity in both cryo-EM and cryo-ET data. OPUS-DSD2 augments a 3D convolutional neural network with a multi-layer perceptron based rigid-body dynamics model, advocating the separation of subunit level rigid-body dynamics from other heterogeneities. Tests on real datasets demonstrate that OPUS-DSD2 effectively captures large-scale subunit motions while isolating spatially localized structural variations into distinct principal components of the composition latent space. Critically, OPUS-DSD2 enables direct analysis of noisy cryo-ET template-matching results, bypassing labor-intensive subtomogram classification and averaging and unlocking high-throughput visual proteomics. Backward-compatible with OPUS-DSD, OPUS-DSD2 is available at https://github.com/alncat/opusDSD.

biophysics↗

bioRxiv2024

Why do we have so many excitatory neurons?

The emerging electron microscopy connectome datasets provides connectivity maps of the brains at single cell resolution, enabling us to estimate various network statistics, such as connectedness. We desire the ability to assess how the functional complexity of these networks depends on these network statistics. To this end, we developed an analysis pipeline and a statistic, XORness, which quantifies the functional complexity of these networks with varying network statistics. We illustrate that actual connectomes have high XORness, as do generated connectomes with the same network statistics, suggesting a normative role for functional complexity in guiding the evolution of connectomes, and providing clues to guide the development of artificial neural networks.

neuroscience↗

bioRxiv2024

Microglia replacement by ER-Hoxb8 conditionally immortalized macrophages provides insight into Aicardi-Goutieres Syndrome neuropathology

Microglia, the brains resident macrophages, can be reconstituted by surrogate cells - a process termed "microglia replacement." To expand the microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized macrophages, a cell model for generation of immune cells from murine bone marrow, as a versatile model for microglia replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary bone marrow-derived (BMD) macrophages in vitro, and, when transplanted into a microglia-free brain, engraft the parenchyma and differentiate into microglia-like cells. Furthermore, ER-Hoxb8 progenitors are readily transducible by virus and easily stored as stable, genetically manipulated cell lines. As a demonstration of this systems power for studying the effects of disease mutations on microglia in vivo, we created stable, Adar1-mutated ER-Hoxb8 lines using CRISPR-Cas9 to study the intrinsic contribution of macrophages to Aicardi-Goutieres Syndrome (AGS), an inherited interferonopathy that primarily affects the brain and immune system. We find that Adar1 knockout elicited interferon secretion and impaired macrophage production in vitro, while preventing brain macrophage engraftment in vivo - phenotypes that can be rescued with concurrent mutation of Ifih1 (MDA5) in vitro, but not in vivo. Lastly, we extended these findings by generating ER-Hoxb8 progenitors from mice harboring a patient-specific Adar1 mutation (D1113H). We demonstrated the ability of microglia-specific D1113H mutation to drive interferon production in vivo, suggesting microglia drive AGS neuropathology. In sum, we introduce the ER-Hoxb8 approach to model microglia replacement and use it to clarify macrophage contributions to AGS.

neuroscience↗

bioRxiv2024

YTHDF1 Facilitates Lung Adenocarcinoma Progression via Promotion of EEF1G Translation in a m6A-Dependent Manner

Lung adenocarcinoma (LUAD) is a malignant tumor with high morbidity and mortality worldwide, and overall survival rates for LUAD patients remain unimproved. RNA modification is a key process in post-transcriptional gene regulation in epigenetics, with N6-methyladenosine (m6A) being a common RNA modification. The molecular mechanisms of LUAD are unclear, but evidence suggests that m6A RNA methylation plays a significant role. This study aimed to clarify the role of YTHDF1 in LUAD development and pathogenesis. These findings confirmed that YTHDF1, a m6A reader protein, is highly expressed in LUAD tissues and is correlated with tumor differentiation and TNM stage. The results of functional loss experiments in LUAD cell lines revealed that downregulating YTHDF1 inhibits proliferation, migration, and invasion and induces apoptosis, with opposite effects observed upon YTHDF1 upregulation. In vivo, YTHDF1 knockout suppressed LUAD xenograft growth. RNA-seq, MeRIP-seq, RIP-seq, and bioinformatics analyses identified EEF1G as a downstream target of YTHDF1 in LUAD, and high expression of EEF1G was confirmed. The interaction between YTHDF1 and EEF1G was validated through RIP-qPCR, Co-IP and Co-IF assays. The overexpression of EEF1G in LUAD cells partially counteracts the tumor suppression induced by YTHDF1 silencing, and the knockdown of EEF1G has the opposite effect, further confirming the regulatory relationship. In summary, this study describes a novel YTHDF1/EEF1G regulatory pathway in which YTHDF1 promotes LUAD progression by recognizing and binding to the m6A-modified mRNA of EEF1G, accelerating its translation, suggesting that YTHDF1 may be a potential biomarker and therapeutic target.

cancer biology↗

bioRxiv2024

Bird Name-a-thon: Categorizing English bird names using crowdsourcing

Common names of species are important for communicating with the general public. In principle, these names should provide an accessible way to engage with and identify species. The common names of species have historically been labile without standard guidelines, even within a language. Currently, there is no systematic assessment of how often common names communicate identifiable and biologically relevant characteristics about species. This is a salient issue in ornithology, where common names are used more often than scientific names for species of birds in written and spoken English, even by professional researchers. To gain a better understanding of the types of terminology used in the English-language common names of bird species, a group of 85 professional ornithologists and non-professional contributors classified unique descriptors in the common names of all recognized species of birds. In the AvianLexiconAtlas database produced by this work, each species common name is assigned to one of ten categories associated with aspects of avian biology, ecology, or human culture. Across 10,906 species of birds, 89% have names describing the biology of the species, while the remaining 11% of species have names derived from human cultural references, human names, or local non-English languages. Species with common names based on features of avian biology are more likely to be related to each other or be from the same geographic region. The crowdsourced data collection also revealed that many common names contain specialized or historic terminology unknown to many of the data collectors, and we include these terms in a glossary and gazetteer alongside the dataset. The AvianLexiconAtlas can be used as a quantitative resource to assess the state of terminology in English-language common names of birds. Future research using the database can shed light on historical approaches to nomenclature and how people engage with species through their names.

zoology↗

bioRxiv2024

Monovalent XBB.1.5 mRNA Vaccine Recalls a More Durable and Coordinated Antibody Response to SARS-CoV-2 Spike than the Bivalent WT/BA.5 mRNA Vaccine

In the fall of 2023, the monovalent XBB.1.5 mRNA vaccine for COVID-19 became available. However, the comparative magnitude, durability, and functionality of antibody responses induced by the XBB.1.5 vaccine compared with the 2022-2023 bivalent wildtype (WT) + Omicron BA.5 vaccine remains to be fully determined. In this study, we compared antibody profiles generated by these two vaccines in healthcare workers. We show that the monovalent XBB.1.5 vaccine induced higher magnitude binding, neutralizing, and Fc-gamma receptor (Fc{gamma}R) binding antibodies to the XBB.1.5 spike compared with the bivalent vaccine against the WT and BA.5 spikes, both at both peak immunogenicity and at 6 months post-vaccination. Moreover, antibody interaction architectures and correlations remained more robust at 6 months post-vaccination with the XBB.1.5 vaccine, whereas these correlations were largely lost at 6 months with the bivalent vaccine. Our results suggest that the XBB.1.5 vaccine led to a more durable and functionally coordinated antibody response compared to the bivalent vaccine.

immunology↗

bioRxiv2024

Dynamic epigenomic landscape of carbon-concentrating mechanisms in the model industrial oleaginous microalga Nannochloropsis oceanica

Despite their ecological and physiological significance, how carbon-concentrating mechanisms (CCM) are regulated in microalgae remains elusive. Here in the model industrial microalga Nannochloropsis oceanica, we uncovered an epigenetic regulatory mechanism for CCM via comprehensive, multi-dimensional epigenomic analyses. Our integrated study reveals the complex interplay among histone modifications, dynamic nucleosome positioning, and 3D chromatin structure in regulating gene expression during low CO2 adaptation, despite minimal DNA methylation. Histone modifications, including lysine acetylation (H3K9ac and H3K27ac), crotonylation (Kcr), and methylation (H3K4me2), were associated with active chromatin states. Significantly altered ChIP-Seq peaks were linked to 43.1% of the differentially expressed genes (DEGs). Notably, H3K4me2 exhibited a distinct dual-peak profile around the transcription start site (TSS), which is unique among microalgae and plants. Chromatin compartment dynamics were correlated with gene expression and histone modifications, particularly H3K4me2, while differentially positioned nucleosomes were associated with key CCM-related genes and transcription factors. To further elucidate the role of H3K4me2, we knocked out its methyltransferase, resulting in genome-wide H3K4me2 peak shifts, slower growth, and reduced photosynthesis. These changes were accompanied by differential expression of key genes of NoHINT and NoPMA2, whose subsequent deletion and overexpression revealed their subtle yet significant impacts on growth and photosynthetic efficiency under low CO2 conditions, with NoHINT regulating growth and NoPMA2 influencing photosynthesis. Finally, we proposed a comprehensive model for epigenetic regulation of CCM in N. oceanica, which established a foundation for enhancing microalgal productivity through targeted epigenetic modifications. HighlightsO_LIMulti-layered epigenetic modifications contribute to the regulation of CCM and its adaptation to low CO2 in N. oceanica. C_LIO_LIThe histone modification H3K4me2 regulates the growth and photosynthesis of N. oceanica under low CO2 conditions. C_LIO_LIH3K4me2 targets NoHINT and NoPMA2 in N. oceanica, with NoHINT influencing growth dynamics and NoPMA2 modulating photosynthetic efficiency under low CO2 conditions. C_LI

genomics↗

bioRxiv2024

Single-cell analysis of the somatic mutational landscape in human chondrocytes during aging and in osteoarthritis

Somatic mutation is now recognized as a cause of multiple human diseases other than cancer. Osteoarthritis (OA), a highly prevalent age-related disease, has been associated with increased chromosomal abnormalities in articular cartilage of OA patients. Thus far no systematic attempt has been made to characterize the somatic mutational landscape of chondrocytes during normal aging and in affected cartilage of OA patients. Here we used single-cell whole genome sequencing to quantitatively analyze single-nucleotide variants (SNVs) and small insertions and deletions (InDels) in 100 single chondrocytes isolated from the cartilage of hip femoral heads of 17 subjects aged from 26 to 90 years, including 9 OA patients and 8 non-OA donors. Both SNVs and InDels were found to accumulate with age in chondrocytes with a clock-like mutational signature. Surprisingly, the age-related accumulation rate of these mutations was found to be lower in OA chondrocytes compared with chondrocytes from non-OA control subjects.

genomics↗

bioRxiv2024

OPUS-Design: Designing Protein Sequence from Backbone Structure with 3DCNN and Protein Language Model

Protein sequence design, also known as protein inverse folding, is a crucial task in protein engineering and design. Despite the recent advancements in this field, which have facilitated the identification of amino acid sequences based on backbone structures, achieving higher levels of accuracy in sequence recovery rates remains challenging. It this study, we introduce a two-stage protein sequence design method named OPUS-Design. Our evaluation on recently released targets from CAMEO and CASP15 shows that OPUS-Design significantly surpasses several other leading methods on both monomer and oligomer targets in terms of sequence recovery rate. Furthermore, by utilizing its finetune version OPUS-Design-ft and our previous work OPUS-Mut, we have successfully designed a thermal-tolerant double-point mutant of T4 lysozyme that demonstrates a residual enzyme activity exceeding that of the wild-type T4 by more than twofold when both are subjected to extreme heat treatment at 70{degrees}C. Importantly, this accomplishment is achieved through the experimental verification of less than 10 mutant candidates, thus significantly alleviating the burden of experimental verification process.

bioengineering↗

bioRxiv2024

Genetic differentiation and adaptive evolution of buff-tailed bumblebees in Asia

Bumblebees are ecologically and economically important pollinating insects, so their declines resulting from environmental changes have received intensive attention. Understanding how environmental factors shape the genetic differentiation of natural populations and identifying the genetic basis of local adaptation will provide insights into how species may cope with environmental changes. The buff-tailed bumblebee (Bombus terrestris) has a wide natural distribution range and has been successfully domesticated to produce commercial colonies for greenhouse pollination. Previous population genetics studies on B. terrestris have mainly focused on populations in Europe; however, populations in Asia, representing the eastern side of its natural distribution, have been less thoroughly sampled. To fill this gap, we collected wild B. terrestris samples from Asia, as well as wild B. terrestris from Europe and samples from domesticated colonies. We conducted whole-genome resequencing for 77 collected B. terrestris workers and performed population genomics analysis. Our results revealed significant genetic differentiation (FST= 0.076) between buff-tailed bumblebees in Europe and Asia, along with notable morphological and physiological differences. Consequently, B. terrestris in Asia represents a distinct new genetic resource. Demographic analysis suggested that the population size of buff-tailed bumblebees had increased during historic cold periods, confirming their cold-adapted characteristics. Selective sweep analysis identified 331 genes under selection in the genomes of Asian B. terrestris, likely involved in their adaptation to high ultraviolet radiation, low temperature, and low precipitation in their habitats. Our research provides insights into the population genetic structure and genetic basis of local adaptation in the buff-tailed bumblebee, which will be useful for its conservation and management.

bioinformatics↗

bioRxiv2024

Pemivibart is less active against recent SARS-CoV-2 JN.1 sublineages

Protection from COVID-19 vaccination is suboptimal in many immunocompromised individuals. In March 2024, the Food and Drug Administration issued an Emergency Use Authorization for pemivibart (Permagard/VYD222), an engineered human monoclonal antibody, for pre-exposure prophylaxis in this vulnerable population. However, SARS-CoV-2 has since evolved extensively, resulting in multiple Omicron JN.1 sublineages. We therefore evaluated the in vitro neutralizing activity of pemivibart against the prevalent forms of JN.1, including KP.2, KP.3, KP.2.3, LB.1, and, importantly, KP.3.1.1, which is now expanding most rapidly. A panel of VSV-based pseudoviruses representing major JN.1 sublineages was generated to assess their susceptibility to pemivibart neutralization in vitro. Structural analyses were then conducted to understand the impact of specific spike mutations on the virus-neutralization results. Pemivibart neutralized both JN.1 and KP.2 in vitro with comparable activity, whereas its potency was decreased slightly against LB.1, KP.2.3, and KP.3 but substantially against KP.3.1.1. Critically, the 50% inhibitory concentration of pemivibart against KP.3.1.1 was [~]6 {micro}g/mL, or [~]32.7 fold higher than that of JN.1 in our study. Structural analyses suggest that Q493E and the S31-deletion mutations in viral spike contribute to the antibody evasion, with the latter having a more pronounced effect. Our findings show that pemivibart has lost substantial neutralizing activity in vitro against KP.3.1.1, the most rapidly expanding lineage of SARS-CoV-2 today. Close monitoring of its clinical efficacy is therefore warranted. These results also highlight the imperative to expand our arsenal of preventive agents to protect millions of immunocompromised individuals who could not respond robustly to COVID-19 vaccines.

immunology↗

bioRxiv2024

Two TAL effectors of Xanthomonas citri pv. malvacearum target GhSWEET15 as the susceptibility genes for bacterial blight of cotton

Bacterial Blight of Cotton (BBC) caused by Xanthomonas citri pv. malvacearum (Xcm) is an important and destructive disease affecting cotton plants. Transcription activator-like effectors (TALEs) released by the pathogen regulate cotton resistance to the susceptibility. In this study, we sequenced the whole genome of Xcm Xss-V2-18 and identified eight tal genes; seven on the plasmids and one on the chromosome. Deletion and complementation experiments of Xss-V2-18 tal genes demonstrated that Tal1b is required for full virulence on cotton. Transcriptome profiling coupled with TALE-binding element prediction revealed that Tal1b targets GhSWEET15A04/D04 and GhSWEET15D02 simultaneously. Expression analysis confirmed the independent inducibility of GhSWEET15A04/D04 and GhSWEET15D02 by Tal1b, whereas GhSWEET15A04/D04 is additionally targeted by Tal1. Moreover, GUS ({beta}-glucuronidase) and Xa10-mediated HR (hypersensitive response) assays indicated that the EBEs are required for the direct and specific activation of the candidate targets by Tal1 and Ta1b. These findings may advance our understanding of the dynamics between TALEs and EBEs, and decipher a simple and effective DNA-binding mechanism that could lead to the development of more efficient methods for gene editing and transgenic research.

pathology↗

bioRxiv2024

Gene Expression Prediction from Histology Images via Hypergraph Neural Networks

Spatial transcriptomics reveals the spatial distribution of genes in complex tissues, providing crucial insights into biological processes, disease mechanisms, and drug development. The prediction of gene expression based on cost-effective histology images is a promising yet challenging field of research. Existing methods for gene prediction from histology images exhibit two major limitations. First, they ignore the intricate relationship between cell morphological information and gene expression. Second, these methods do not fully utilize the different latent stages of features extracted from the images. To address these limitations, we propose a novel hypergraph neural network model, HGGEP, to predict gene expressions from histology images. HGGEP includes a gradient enhancement module to enhance the models perception of cell morphological information. A lightweight backbone network extracts multiple latent stage features from the image, followed by attention mechanisms to refine the representation of features at each latent stage and capture their relations with nearby features. To explore higher-order associations among multiple latent stage features, we stack them and feed into the hypergraph to establish associations among features at different scales. Experimental results on multiple datasets from disease samples including cancers and tumor disease, demonstrate the superior performance of our HGGEP model than existing methods. Key PointsWe develop a novel histology image-based gene prediction model named HGGEP, which demonstrates high accuracy and robust performance. To reveal the intricate relationship between cell morphology and gene expression in images, we propose a gradient enhancement module, which effectively improves the models capability in perceiving cell morphology in images. HGGEP includes a hypergraph module that efficiently models higher-order associations among features across multiple latent stages, resulting in significant performance improvement.

bioinformatics↗

bioRxiv2024

A biodegradable and restorative peripheral neural interface for the interrogation of neuropathic injuries

Monitoring the early-stage healing of severe traumatic nerve injuries is essential to gather physiological and pathological information for timely interventions and optimal clinical outcomes. While implantable peripheral nerve interfaces provide direct access to nerve fibers for precise interrogation and modulation, conventional non-degradable designs pose limited utilization in nerve injury rehabilitation. Here, we introduce a biodegradable and restorative neural interface for wireless real-time tracking and recovery of long-gap nerve injuries. Leveraging machine learning techniques, this electronic platform deciphers nerve recovery status and identifies traumatic neuroma formation at the early phase, enabling timely intervention and significantly improved therapeutic outcomes. The biodegradable nature of the device eliminates the need for retrieval procedures, reducing infection risks and secondary tissue damage. This research sheds light on bioresorbable multifunctional peripheral nerve interfaces for probing neuropathic injuries, offering vital information for early diagnosis and therapeutic intervention.

bioengineering↗

bioRxiv2024

The effect of norepinephrine on ovarian dysfunction by mediating ferroptosis in mice model

Studies shows that stress is associated with ovarian dysfunction. Norepinephrine (NE), a classic stress hormone in the stress response, is less recognized for its role in ovarian function. A NE-treated mouse model is induced by intraperitoneal injection of NE for 4 weeks. Compared with the normal control, we find that NE-treated mice show disturbances in the estrous cycle, decreased levels of anti-Mullerian hormone (AMH) and estradiol (E2), and increased levels of follicle-stimulating hormone (FSH). Additionally, the number of primordial follicles, primary follicles, secondary follicles, and antral follicles decreased, while the number of atretic follicles increased in NE-treated mice, indicating NE-induced ovarian dysfunction. RNA sequencing further reveals that genes associated with ferroptosis are significantly enriched in NE-treated ovarian tissues. Concurrently, the content of reactive oxygen species (ROS), ferrous ion, and malondialdehyde (MDA) increased, while the expression level of glutathione peroxidase 4 (GPX4) decreased. To elucidate the mechanism of NE-induced ferroptosis in ovaries and the potential reversal by Coenzyme Q10 (CoQ10), an antioxidant, we conduct both in vitro and in vivo experiments. In vitro, we observe that the granulosa cell line KGN, when treated with NE, shows decreased cell viability, reduced expression of GPX4, elevated ferrous ion and ROS content, and increased MDA levels. However, these NE-induced changes are rescued by the addition of CoQ10. In the mouse model, we find that NE-treated mice supplemented with CoQ10 increased GPX4 levels and decreased the contents of iron, ROS, and MDA compared with the NE group. Moreover, the differential expression of genes associated with ferroptosis induced by NE is ameliorated by CoQ10 in NE-treated mice. Additionally, CoQ10 improved ovarian function, as evidenced by increased ovarian weight, more regular estrous cycles, and an increase in follicles at various stages of growth in NE-treated mice. In conclusion, NE induces ovarian dysfunction by triggering ferroptosis in ovarian tissues, and CoQ10 represents a promising approach for protecting reproductive function by inhibiting ferroptosis.

molecular biology↗