Connecting the dots: the role of fatigue in female infertility.

Fatigue, an increasingly acknowledged symptom in various chronic diseases, has garnered heightened attention, during the medical era of bio-psycho-social model. Its persistence not only significantly compromises an individual's quality of life but also correlates with chronic organ damage. Surprisingly, the intricate relationship between fatigue and female reproductive health, specifically infertility, remains largely unexplored. Our exploration into the existing body of evidence establishes a compelling link between fatigue with uterine and ovarian diseases, as well as conditions associated with infertility, such as rheumatism. This observation suggests a potentially pivotal role of fatigue in influencing overall female fertility. Furthermore, we propose a hypothetical mechanism elucidating the impact of fatigue on infertility from multiple perspectives, postulating that neuroendocrine, neurotransmitter, inflammatory immune, and mitochondrial dysfunction resulting from fatigue and its co-factors may further contribute to endocrine disorders, menstrual irregularities, and sexual dysfunction, ultimately leading to infertility. In addition to providing this comprehensive theoretical framework, we summarize anti-fatigue strategies and accentuate current knowledge gaps. By doing so, our aim is to offer novel insights, stimulate further research, and advance our understanding of the crucial interplay between fatigue and female reproductive health.

Characterisation and critical processes identification for production of herbal preparations using 1H-NMR and chemometrics: A case study of Trichosanthis Pericarpium injection.

INTRODUCTION: Herbal preparations are extensively utilised for the treatment of diseases in Asian countries. However, the variations in origin, climate, and production processes can lead to inconsistencies in the quality of herbal preparations. Existing quality control methods only target a few components in the finished product but ignore the control in the pharmaceutical process. Therefore, this study intends to develop a comprehensive component analysis method for intermediates in the pharmaceutical process to reveal the change patterns of substances and deepen the process understanding. OBJECTIVE: This study aims to develop a rapid and comprehensive process characterisation and critical process identification method for herbal preparations. METHODS: Six batches of Trichosanthis Pericarpium injection (TPI) intermediates were collected from the production process. Proton nuclear magnetic resonance (1H-NMR) spectra were acquired for qualitative and quantitative analysis of the se intermediates. Subsequently, chemometrics were used to identify critical processes and potential chemical markers. RESULTS: A total of 39 components in intermediates were identified, and the transfer of 25 components during the production process was investigated. Column chromatography was determined as the critical process. Nine components were identified as chemical markers. CONCLUSION: The application of 1H-NMR facilitated a comprehensive reflection of the chemical composition information of process intermediates, enabling investigations into the transfer of multi-component substances and accurate identification of critical processes and chemical markers.

Mutant U2AF1-Induced Mis-Splicing of mRNA Translation Genes Confers Resistance to Chemotherapy in Acute Myeloid Leukemia.

Patients with primary refractory acute myeloid leukemia (AML) have a dismal long-term prognosis. Elucidating the resistance mechanisms to induction chemotherapy could help identify strategies to improve AML patient outcomes. Herein, we retrospectively analyzed the multiomics data of more than 1,500 AML cases and found that patients with spliceosome mutations had a higher risk of developing refractory disease. RNA splicing analysis revealed that the mis-spliced genes in refractory patients converged on translation-associated pathways, promoted mainly by U2AF1 mutations. Integrative analyses of binding and splicing in AML cell lines substantiated that the splicing perturbations of mRNA translation genes originated from both the loss and gain of mutant U2AF1 binding. In particular, the U2AF1S34F and U2AF1Q157R mutants orchestrated the inclusion of exon 11 (encoding a premature termination codon) in the eukaryotic translation initiation factor 4A2 (EIF4A2). This aberrant inclusion led to reduced eIF4A2 protein expression via nonsense-mediated mRNA decay. Consequently, U2AF1 mutations caused a net decrease in global mRNA translation that induced the integrated stress response (ISR) in AML cells, which was confirmed by single-cell RNA sequencing. The induction of ISR enhanced the ability of AML cells to respond and adapt to stress, contributing to chemoresistance. A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway. SIGNIFICANCE: U2AF1 mutations induce the integrated stress response by disrupting splicing of mRNA translation genes that improves AML cell fitness to enable resistance to chemotherapy, which can be targeted to improve AML treatment.

Application of the Analytical Procedure Lifecycle Concept to a Quantitative 1H NMR Method for Total Dammarane-Type Saponins.

Dammarane-type saponins (DTSs) exist in various medicinal plants, which are a class of active ingredients with effects on improving myocardial ischemia and immunomodulation. In this study, a quantitative 1H NMR method of total DTSs in herbal medicines was developed based on the analytical procedure lifecycle. In the first stage (analytical procedure design), the Ishikawa diagram and failure mode effects and criticality analysis were used to conduct risk identification and risk ranking. Plackett-Burman design and central composite design were used to screen and optimize critical analytical procedure parameter. Then, the method operable design region was obtained through modeling. In the second stage (analytical procedure performance qualification), the performance of methodological indexes was investigated based on analytical quality by design. As examples of continued procedure performance verification, the method was successfully applied to determine the total DTSs in herbal pharmaceutical preparations and botanical extracts. As a general analytical method to quantify total DTSs in medicinal plants or pharmaceutical preparations, the developed method provides a new quality control strategy for various products containing dammarane-type saponin.

Downregulation of SEPTIN11 inhibits endometrial epithelial cell adhesive function in patients with elevated peripheral blood natural killer cell counts.

RESEARCH QUESTION: What is the underlying mechanism of IVF and embryo transfer (IVF-ET) failure in patients with elevated peripheral blood natural killer cell (pNK) counts? DESIGN: Patients undergoing IVF-ET cycles for tubal obstruction or pelvic adhesion (n = 486) were assigned to three groups: high (CD56+CD16+pNK >30% [n = 49]); medium (15< CD56+CD16+pNK ≤30% [n = 211]); and normal pNK groups (5≤ CD56+CD16+pNK ≤15% [n = 226]). Their general condition, previous pregnancy history and IVF outcomes were compared. Uterine fluid and endometrial tissue from patients in the high and normal pNK groups were collected during the mid-secretory phase and studied to elucidate the molecular mechanism underlying impaired endometrial receptivity. RESULTS: The highest incidence of IVF-ET cycles (P < 0.0001) and biochemical pregnancy losses (P < 0.0001), and lowest implantation and clinical pregnancy rates (both P < 0.0001), were observed in patients with pNK over 30%. No significant difference was found in the number of previous miscarriages and rate of spontaneous miscarriage in IVF outcomes. Lower Septin11 (SEPT11) expression in the uterine fluid and endometrial epithelial cells (EEC), and higher endometrial IFN-γ, was observed in patients with high pNK. Ishikawa cell and human endometrial epithelial cell (HEEC) adhesion was inhibited after SEPT11 knock-down. Elevated IFN-γ decreased the SEPT11 protein levels in Ishikawa cells and HEECs. CONCLUSIONS: CD56+CD16+pNK above 30% may be a threshold for adverse IVF-ET outcomes. Low SEPT11 expression in EEC inhibits cell adhesion, which may cause impaired endometrial receptivity in patients with elevated pNK. The level of SEPT11 in mid-secretory uterine fluid could serve as a non-invasive marker to assess endometrial receptivity in these patients.

Assessing carbon reduction benefits of teleworking: A case study of Beijing.

Teleworking can efficiently decrease the energy consumption and carbon emissions related to physical commuting. Previous studies on assessing the carbon reduction benefits of teleworking were customarily performed according to hypotheses or qualitative methods, and disregarded different potentials of different industries for teleworking implementation. In this study, a quantitative approach was proposed to assess the carbon reduction benefits of teleworking in different industries, which was illustrated via the case study of Beijing, China. The teleworking penetrations of different industries were first estimated. Then, the carbon reduction of teleworking was assessed through the decreased commuting distance using the large-scale travel survey data. Finally, the study samples were extended to a citywide scale and the uncertainty of carbon reduction benefits was evaluated with Monte Carlo simulation. The results showed that (1) teleworking can lead to an average of 1.32 (95 % confidence interval (CI): 0.70-2.05) million tons of carbon reduction, accounting for 7.05 % (95 % CI: 3.74 %-10.95 %) of the total carbon emissions by road transport in Beijing; and (2) information and communication, and professional, scientific and technical service industries had higher carbon reduction potential. Additionally, the rebound effect slightly weakened the carbon reduction benefit of teleworking, which was necessary to be considered and mitigated through relevant policies. The proposed method can be also applied to other regions worldwide, helping to exploit future work patterns and realize global carbon neutrality targets.

Bioactive Injectable and Self-Healing Hydrogel Via Cell-Free Fat Extract for Endometrial Regeneration.

The damaged endometrium and the formation of fibrosis are key barriers to pregnancy and further lead to infertility. However, how to promote endometrium repair is always a challenge. Here, a bioactive injectable and self-healing hydrogel is developed by physically combination of thiolated polyethylene (PEG), Cu2+ and cell-free fat extract (CEFFE, CF) for endometrial regeneration and fertility. By inheriting the advantages of various active proteins contained in CEFFE, it could induce the overall repair of endometrial microenvironment for intrauterine adhesion (IUA). In vitro, CF@Cu-PEG reduces endometrial cell apoptosis by more than 50%, and increases angiogenesis by 92.8%. In the IUA mouse, injection of CF@Cu-PEG significantly reduces the rate of uterine hydrometra and prevents the formation of endometrial fibrosis. Remarkably, CF@Cu-PEG contributes to the repair of endometrial microstructure, especially increases the number of endometrial pinopodes, significantly improves endometrial receptivity, and increases the pregnancy rate of IUA mice from 7.14% to 66.67%. In summary, through the physically combination of CEFFE and Cu-PEG, the construction of loaded bioactive injectable hydrogel not only inhibits the IUA, but also induces the self-repair of endometrial cells in situ and improves fertility, providing a new strategy for IUA repair in clinical application.

Fabrication of Phytic Acid/Urea Co-Modified Bamboo Biochar and Its Application as Green Flame Retardant for Polylactic Acid Resins.

It is of great significance to develop green, sustainable additives to improve the thermal stability and flame retardancy of biopolymers. In this work, a synergistic modification of P/N elements to bamboo biochar (mBC) was successfully achieved by grafting a reaction of phytic acid and urea with preoxidized bamboo biochar. Fourier transform infrared spectroscopy, X-ray diffraction, nuclear magnetic resonance and scanning electron microscope determinations of the mBC demonstrated a successive grafting of phytic acid and urea to the originally porous surface. The ground mBC was blended with polylactic acid (PLA) to prepare mBC/PLA composites by extrusion and hot pressing. Mechanical strength studies showed a compromise in rigidity, which might originate from the mBC overdose and its limited miscibility with the resin. The thermogravimetric results supported the fact that the enhancement of thermal stability and flame retardancy of the composites with the mBC dosage, which showed that the mBC dosage in the PLA composites was not only lower than that of the conventional flame retardants, but also outperformed the counterparts using BC modified by inorganic phosphoric acid and urea. The mBC was prone to accelerate the earlier decomposition of the composites (30 °C lower in decomposition) and generate a continuous, dense residual carbon layer, which provides an effective shield resisting the mass and heat transfer between the combustion area and the underlying composite matrix. Only 10 wt% of mBC dosage could achieve a V-0 rating (UL94) for the composite, with a higher limiting oxygen index up to 28.3% compared to 20.7% for that of the virgin PLA; the cone colorimetric results also suggested that the flame retardancy had been greatly improved for all composites. In this work, biobased P-/N-containing bamboo biochar would be expected as a nontoxic biochar-based flame retardant that serves as green filler in polymer composites.

A multivariate curve resolution-alternating least squares (MCR-ALS) technology assisted 1 H-NMR methodology for multi-component quantitation of Trichosanthis Pericarpium injection.

INTRODUCTION: Trichosanthis Pericarpium injection (TPI) is a traditional Chinese medicine preparation obtained from Trichosanthis Pericarpium by extraction, purification and sterilisation. It contains amino acids, alkaloids, nucleotides and other components. Existing quantitative methods only analyse a few components in injections, so this study intends to develop a method for comprehensive analysis of TPI components. OBJECTIVE: To develop a method for quantification of components in TPI by multivariate curve resolution-alternating least squares (MCR-ALS) assisted proton nuclear magnetic resonance (1 H-NMR). METHODS: A 1 H-NMR method was developed for the quantification of components in TPI. For components with independent signals, 3-(trimethylsilyl) propionic-2,2,3,3-d4 acid sodium salt (TSP) was used as an internal standard to calculate the component contents. For components with overlapping signals, the method of MCR-ALS was used. RESULTS: A total of 36 components were identified in TPI, of which 33 were quantified. Methodological validation results showed that the developed 1 H-NMR method has good linearity, accuracy, precision, robustness and specificity. CONCLUSION: The use of 1 H-NMR provides a reliable and universal method for the TPI components identification and quantification. Also, it can be used as a powerful tool for analysing the contents in a complex mixture as a quality control measure.

Effects of different composting methods on antibiotic-resistant bacteria, antibiotic resistance genes, and microbial diversity in dairy cattle manures.

Composting is a common practice used for treating animal manures before they are used as organic fertilizers for crop production. Whether composting can effectively reduce microbial pathogens and antibiotic resistance genes remain poorly understood. In this study, we compared 3 different dairy manure composting methods-anaerobic fermentation (AF), static compost (SC), and organic fertilizer production (OFP)-for their effects on antibiotic-resistant bacteria, antibiotic resistance genes, and microbial community diversity in the treated manures. The 3 composting methods produced variable and distinct effects on antibiotic-resistant bacteria, zoonotic bacteria, and resistance genes, some of which were decreased and others of which showed no significant changes during composting. Particularly, SC and OFP reduced chloramphenicol resistance gene fexA and opportunistic pathogen Vibrio fluvialis, whereas AF significantly reduced tetracycline resistance gene tetB and opportunistic pathogens Enterococcus faecium and Escherichia fergusonii. The compositions of microbial communities varied significantly during the composting processes, and there were significant differences between the 3 composting methods. In all 3 composts, the dominant phyla were Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria. Interestingly, Firmicutes, Proteobacteria, and Bacteroidetes remained stable in the entire AF process, whereas they were dominated at the beginning, decreased at the early stage of composting, and rebounded at the later stage during SC and OFP. In general, SC and OFP produced a more profound effect than AF on microbial community diversities, pathogens, and dominant species. Additionally, Enterococcus aquimarinus was isolated from AF for the first time. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States function prediction analysis indicated that the genes related to membrane transport and amino acid metabolism were abundant in the 3 composts. The metabolism of amino acids, lipids, and carbohydrates increased as composting progressed. The biosynthesis of antibiotics was enhanced after fermentation in the 3 composting methods, and the increase in the SC was the most obvious. These results reveal dynamic changes in antibiotic-resistant bacteria, antibiotic resistance genes, microbial community composition, and function succession in different dairy manure composts and provide useful information for further optimization of composting practices.

Case report: A case of duodenal adenocarcinoma achieving significantly long survival treating with immune checkpoint inhibitors and chemotherapy without positive biomarkers.

Small bowel adenocarcinoma (SBA), particularly duodenal adenocarcinoma (DA), is a rare gastrointestinal cancer with a dismal prognosis. Data on SBA treatments are limited, and the therapeutic strategy remains uncertain. Currently, chemotherapy is the most used treatment; however, it has a poor median progression-free survival (mPFS) of no more than five months in the second-line setting. We report a case with DA that responded well to the immune checkpoint inhibitor (ICI) tislelizumab plus irinotecan in the second-line treatment. To our knowledge, this is the first report of administering ICIs plus chemotherapy to SBA. Despite the absence of microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB), the patient with TP53/KRAS mutation achieved a significantly long PFS of 17 months, and the benefit is still ongoing. The mechanism of this remarkable efficacy might be associated with an increase in tumor immunogenicity after chemotherapy. The current study presents a promising effect of ICIs plus chemotherapy on SBA, affirming the need to investigate the clinical value of this combination in SBA and the underlying mechanism behind it.

Dynamic contrast-enhanced magnetic resonance imaging-based radiomics for the prediction of progression-free survival in advanced nasopharyngeal carcinoma.

To establish a multidimensional nomogram model for predicting progression-free survival (PFS) and risk stratification in patients with advanced nasopharyngeal carcinoma (NPC). This retrospective cross-sectional study included 156 patients with advanced NPC who underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Radiomic features were extracted from the efflux rate constant (Ktrans ) and extracellular extravascular volume (Ve ) mapping derived from DCE-MRI. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied for feature selection. The Radscore was constructed using the selected features with their respective weights in the LASSO Cox regression analysis. A nomogram model combining the Radscore and clinical factors was built using multivariate Cox regression analysis. The C-index was used to assess the discrimination power of the Radscore and nomogram. The Kaplan-Meier method was used for survival analysis. Of the 360 radiomic features, 28 were selected (7, 6, and 15 features extracted from Ktrans , Ve, and Ktrans +Ve images, respectively). The combined Radscore k trans +Ve (C-index, 0.703, 95% confidence interval [CI]: 0.571-0.836) showed higher efficacy in predicting the prognosis of advanced NPC than Radscore k trans (C-index, 0.693; 95% CI, 0.560-0.826) and Radscore Ve (C-index, 0.614; 95% CI, 0.481-0.746) did. Multivariable Cox regression analysis revealed clinical stage, T stage, and treatment with nimotuzumab as risk factors for PFS. The nomogram established by Radscore k trans +Ve and risk factors (C-index, 0.732; 95% CI: 0.599-0.864) was better than Radscore k trans +Ve in predicting PFS in patients with advanced NPC. A lower Radscore k trans +Ve (HR 3.5584, 95% CI 2.1341-5.933), lower clinical stage (hazard ratio [HR] 1.5982, 95% CI 0.5262-4.854), lower T stage (HR 1.4365, 95% CI 0.6745-3.060), and nimotuzumab (NTZ) treatment (HR 0.7879, 95% CI 0.4899-1.267) were associated with longer PFS. Kaplan-Meier analysis showed a lower PFS in the high-risk group than in the low-risk group (p<0.0001). The nomogram based on combined pretreatment DCE-MRI radiomics features, NTZ, and clinicopathological risk factors may be considered as a noninvasive imaging marker for predicting individual PFS in patients with advanced NPC.

Potential blood biomarkers for chronic traumatic encephalopathy: The multi-omics landscape of an observational cohort.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, which is susceptible in elderly people with declined mobility, athletes of full contact sports, military personnel and victims of domestic violence. It has been pathologically diagnosed in brain donors with a history of repetitive mild traumatic brain injury (rmTBI), but cannot be clinically diagnosed for a long time. By the continuous efforts by neuropathologists, neurologists and neuroscientists in recent 10 years, an expert consensus for the diagnostic framework of CTE was proposed in 2021 funded by the National Institute of Neurological Disorders and Stroke. The new consensus contributes to facilitating research in the field. However, it still needs to incorporate in vivo biomarkers to further refine and validate the clinical diagnostic criteria. From this, a single-center, observational cohort study has been being conducted by Tianjin Medical University General Hospital since 2021. As a pilot study of this clinical trial, the present research recruited 12 pairs of gender- and age-matched rmTBI patients with healthy subjects. Their blood samples were collected for exosome isolation, and multi-omics screening to explore potential diagnostic biomarkers in blood and its exosomes. The expression level of CHL1 protein, KIF2A mRNA, LIN7C mRNA, miR-297, and miR-1183 in serum and exosomes were found to be differentially expressed between groups. Besides, serum and exosomal CHL1, KIF2A, and miR-1183, as well as exosomal miR-297 were further verified as potential biomarkers for CTE by low-throughput assays. They are expected to contribute to establishing a novel set of CTE diagnostic signatures with classic neurodegenerative indicators in our future study, thereby updating the consensus diagnostic criteria for CTE by incorporating new evidence of the in vivo biomarkers.

Synthesis of P-/N-Containing Bamboo-Activated Carbon toward Enhanced Thermal Stability and Flame Retardancy of Polylactic Acid.

A P-/N-containing bamboo-activated carbon (BACm) was successfully synthesized by steam activation of bamboo charcoal and chemical grafting to as-prepared activated carbon using the reaction of phosphoric acid and urea. Characterizations of BACm presented a synergistic grafting of P and N elements to the BAC surface. The BACm was further loaded in a polylactic acid (PLA) matrix to prepare BACm/PLA composites. Mechanical strength study showed tensile strength dropped from 75.19 MPa to 61.30 MPa, and tensile modulus from 602.49 MPa to 375.56 MPa, suggesting a rigidity reduction and deformation resistance enhancement owing to the roughened surface of BACm that interlocked with the polymer. The thermogravimetric analysis showed that the carbon residue rate of BACm dramatically fell to 49.25 wt.% in contrast to 88.28% for the control BAC, and cone calorimeter measurements confirmed the enhancement of flame retardancy of the composites with BACm loading, and the carbon residue rate increased progressively with BACm loading in the composites, notably up to 8.60 wt.% for the BAC/PLA9 composite, which outweighed the theoretical residue rate by more than 50%. The elemental analysis also confirmed rich P/N levels of the dense carbon residue layer that could perform synergistically and effectively in fire suppression. The BACm tended to stimulate the earlier decomposition of the composites and formed a continuous residual carbon layer which functioned as an effective barrier hindering the mass and heat transfer between the combustion zone and the underlying matrix. Moreover, 9 wt.% of BACm loading could attain a V-0 rating (UL94) for the composite with an improved limiting oxygen index up to 31.7%. The biomass-based modified activated carbon in this work could be considered as an alternative flame retardant in polymer applications.

Differential Paralog-Specific Expression of Multiple Small Subunit Proteins Cause Variations in Rpl42/eL42 Incorporation in Ribosome in Fission Yeast.

Ribosomes within a cell are commonly viewed as biochemically homogenous RNA-protein super-complexes performing identical functions of protein synthesis. However, recent evidence suggests that ribosomes may be a more dynamic macromolecular complex with specialized roles. Here, we present extensive genetic and molecular evidence in the fission yeast S. pombe that the paralogous genes for many ribosomal proteins (RPs) are functionally different, despite that they encode the same ribosomal component, often with only subtle differences in the sequences. Focusing on the rps8 paralog gene deletions rps801d and rps802d, we showed that the mutant cells differ in the level of Rpl42p in actively translating ribosomes and that their phenotypic differences reside in the Rpl42p level variation instead of the subtle protein sequence difference between Rps801p and Rps802p. Additional 40S ribosomal protein paralog pairs also exhibit similar phenotypic differences via differential Rpl42p levels in actively translating ribosomes. Together, our work identifies variations in the Rpl42p level as a potential form of ribosome heterogeneity in biochemical compositions and suggests a possible connection between large and small subunits during ribosome biogenesis that may cause such heterogeneity. Additionally, it illustrates the complexity of the underlying mechanisms for the genetic specificity of ribosome paralogs.

Cell-Free Fat Extract Improves Ovarian Function and Fertility in Mice With Advanced Age.

The reduction in the quantity and quality of oocytes is the major factor affecting fertility in women with advanced age, who tend to experience delayed childbearing and declined fertility rate. However, effective therapeutic strategies to combat this decrease in ovarian function are lacking in clinical practice. Thus, identifying a new method to rescue ovarian function and improve reproduction in natural age-related decline in fertility is necessary. Cell-free fat extract (CEFFE) has been verified to possess diverse active proteins exerting anti-aging and proliferation-promoting effects. Nonetheless, whether CEFFE can rescue the decline in aged-related ovarian function and improve the fertility of females with advanced age remains unclear. In this study, a natural aging mouse model, exhibiting similarities to the physiological changes of ovarian senescence, was used to observe the anti-aging effect of CEFFE on ovarian functions. We found that CEFFE, injected via the veins, could recover the levels of the sex hormone, increase angiogenesis and the number of growth follicles in the natural aging mice model. Moreover, CEFFE promoted the development of embryos and increased the litter size of aged mice. Transcriptome analysis of the aged mouse ovaries revealed that CEFFE treatment upregulated the expression of genes involved in the repair of DNA damage. And both in vivo and in vitro experiment proved that CEFFE improved the function of granulosa cells, including promoting proliferation, alleviating senescence, and rescuing DNA damage in aged granulosa cells. Collectively, our study implied that CEFFE improved the ovarian function and fertility of naturally aging mice by ameliorating the overall microenvironment of ovary, which provided a theoretical basis for new anti-aging therapeutic strategies for cell-free therapy in ovaries.