Reactive oxygen species-scavenging nanomaterials for the prevention and treatment of age-related diseases.

With increasing proportion of the elderly in the population, age-related diseases (ARD) lead to a considerable healthcare burden to society. Prevention and treatment of ARD can decrease the negative impact of aging and the burden of disease. The aging rate is closely associated with the production of high levels of reactive oxygen species (ROS). ROS-mediated oxidative stress in aging triggers aging-related changes through lipid peroxidation, protein oxidation, and DNA oxidation. Antioxidants can control autoxidation by scavenging free radicals or inhibiting their formation, thereby reducing oxidative stress. Benefiting from significant advances in nanotechnology, a large number of nanomaterials with ROS-scavenging capabilities have been developed. ROS-scavenging nanomaterials can be divided into two categories: nanomaterials as carriers for delivering ROS-scavenging drugs, and nanomaterials themselves with ROS-scavenging activity. This study summarizes the current advances in ROS-scavenging nanomaterials for prevention and treatment of ARD, highlights the potential mechanisms of the nanomaterials used and discusses the challenges and prospects for their applications.

Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1.

Limited understanding exists regarding how aging impacts the cellular and molecular aspects of the human ovary. This study combines single-cell RNA sequencing and spatial transcriptomics to systematically characterize human ovarian aging. Spatiotemporal molecular signatures of the eight types of ovarian cells during aging are observed. An analysis of age-associated changes in gene expression reveals that DNA damage response may be a key biological pathway in oocyte aging. Three granulosa cells subtypes and five theca and stromal cells subtypes, as well as their spatiotemporal transcriptomics changes during aging, are identified. FOXP1 emerges as a regulator of ovarian aging, declining with age and inhibiting CDKN1A transcription. Silencing FOXP1 results in premature ovarian insufficiency in mice. These findings offer a comprehensive understanding of spatiotemporal variability in human ovarian aging, aiding the prioritization of potential diagnostic biomarkers and therapeutic strategies.

Towards prolonging ovarian reproductive life: Insights into trace elements homeostasis.

Ovarian aging is marked by a reduction in the quantity and quality of ovarian follicles, leading to a decline in female fertility and ovarian endocrine function. While the biological characteristics of ovarian aging are well-established, the exact mechanisms underlying this process remain elusive. Recent studies underscore the vital role of trace elements (TEs) in maintaining ovarian function. Imbalances in TEs can lead to ovarian aging, characterized by reduced enzyme activity, hormonal imbalances, ovulatory disorders, and decreased fertility. A comprehensive understanding of the relationship between systemic and cellular TEs balance and ovarian aging is critical for developing treatments to delay aging and manage age-related conditions. This review consolidates current insights into TEs homeostasis and its impact on ovarian aging, assesses how altered TEs metabolism affects ovarian aging, and suggests future research directions to prolong ovarian reproductive life. These studies are expected to offer novel approaches for mitigating ovarian aging.

Multiomics insights into the female reproductive aging.

The human female reproductive lifespan significantly diminishes with age, leading to decreased fertility, reduced fertility quality and endocrine function disorders. While many aspects of aging in general have been extensively documented, the precise mechanisms governing programmed aging in the female reproductive system remain elusive. Recent advancements in omics technologies and computational capabilities have facilitated the emergence of multiomics deep phenotyping. Through the application and refinement of various high-throughput omics methods, a substantial volume of omics data has been generated, deepening our comprehension of the pathogenesis and molecular underpinnings of reproductive aging. This review highlights current and emerging multiomics approaches for investigating female reproductive aging, encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics. We elucidate their influence on fundamental cell biology and translational research in the context of reproductive aging, address the limitations and current challenges associated with multiomics studies, and offer a glimpse into future prospects.

Inhibition of checkpoint kinase prevents human oocyte apoptosis induced by chemotherapy and allows enhanced tumour chemotherapeutic efficacy.

STUDY QUESTION: Could inhibition of the checkpoint kinase (CHEK) pathway protect human oocytes and even enhance the anti-tumour effects, during chemotherapy? SUMMARY ANSWER: CHEK inhibitors prevented apoptosis of human oocytes induced by chemotherapy and even enhanced the anti-tumour effects. WHAT IS KNOWN ALREADY: CHEK inhibitors showed ovarian protective effects in mice during chemotherapy, while their role in human oocytes is unclear. STUDY DESIGN, SIZE, DURATION: This experimental study evaluated the ovarian reserve of young patients (120 patients) with cancer, exposed or not exposed to taxane and platinum (TP)-combined chemotherapy. Single RNA-sequencing analysis of human primordial oocytes from 10 patients was performed to explore the mechanism of oocyte apoptosis induced by TP chemotherapy. The damaging effects of paclitaxel (PTX) and cisplatin on human oocytes were also evaluated by culturing human ovaries in vitro. A new mouse model that combines human ovarian xenotransplantation and patient-derived tumour xenografts was developed to explore adjuvant therapies for ovarian protection. The mice were randomly allocated to four groups (10 mice for each group): control, cisplatin, cisplatin + CK1 (CHEK1 inhibitor, SCH 900776), and cisplatin + CK2 (CHEK2 inhibitor, BML277). PARTICIPANTS/MATERIALS, SETTING, METHODS: In the prospective cohort study, human ovarian follicles were counted and serum AMH levels were evaluated. RNA-sequencing analysis was conducted, and staining for follicular damage (phosphorylated H2AX histone; γH2AX), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) assays and assessments of apoptotic biomarkers (western blot and immunofluorescence) were conducted in human ovaries. After the treatments, histological analysis was performed on human ovarian samples to investigate follicular populations, and oocyte damage was measured by γH2AX staining, BAX staining, and TUNEL assays. At the same time, the tumours were evaluated for volume, weight, and apoptosis levels. MAIN RESULTS AND THE ROLE OF CHANCE: Patients who received TP chemotherapy showed decreased ovarian reserves. Single RNA-sequencing analysis of human primordial oocytes indicated that TP chemotherapy induced apoptosis of human primordial oocytes by causing CHEK-mediated TAp63α phosphorylation. In vitro culture of human ovaries showed greater damaging effects on oocytes after cisplatin treatment compared with that after PTX treatment. Using the new animal model, CHEK1/2 inhibitors prevented the apoptosis of human oocytes induced by cisplatin and even enhanced its anti-tumour effects. This protective effect appeared to be mediated by inhibiting DNA damage via the CHEK-TAp63α pathway and by generation of anti-apoptotic signals in the oocytes. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This was a preclinical study performed with human ovarian samples, and clinical research is required for validation. WIDER IMPLICATIONS OF THE FINDINGS: These findings highlight the therapeutic potential of CHEK1/2 inhibitors as a complementary strategy for preserving fertility in female cancer patients. STUDY FUNDING/COMPETING INTEREST(S): This work was financially supported by the National Natural Science Foundation of China (nos. 82001514 and 81902669) and the Fundamental Research Funds for the Central Universities (2021yjsCXCY087). The authors declare no conflict of interest.

Tumor microenvironment promotes lymphatic metastasis of cervical cancer: its mechanisms and clinical implications.

Although previous studies have shed light on the etiology of cervical cancer, metastasis of advanced cervical cancer remains the main reason for the poor outcome and high cancer-related mortality rate. Cervical cancer cells closely communicate with immune cells recruited to the tumor microenvironment (TME), such as lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells. The crosstalk between tumors and immune cells has been clearly shown to foster metastatic dissemination. Therefore, unraveling the mechanisms of tumor metastasis is crucial to develop more effective therapies. In this review, we interpret several characteristics of the TME that promote the lymphatic metastasis of cervical cancer, such as immune suppression and premetastatic niche formation. Furthermore, we summarize the complex interactions between tumor cells and immune cells within the TME, as well as potential therapeutic strategies to target the TME.

Semaphorin 4C regulates ovarian steroidogenesis through RHOA/ROCK1-mediated actin cytoskeleton rearrangement.

Semaphorins are a family of evolutionarily conserved morphogenetic molecules that were initially found to be associated with axonal guidance. Semaphorin 4C (Sema4C), a member of the fourth subfamily of semaphorins, has been demonstrated to play multifaceted and important roles in organ development, immune regulation, tumor growth, and metastasis. However, it is completely unknown whether Sema4C is involved in the regulation of ovarian function. We found that Sema4C was widely expressed in the stroma, follicles, and corpus luteum of mouse ovaries, and its expression was decreased at distinct foci in ovaries of mice of mid-to-advanced reproductive age. Inhibition of Sema4C by the ovarian intrabursal administration of recombinant adeno-associated virus-shRNA significantly reduced oestradiol, progesterone, and testosterone levels in vivo. Transcriptome sequencing analysis showed changes in pathways related to ovarian steroidogenesis and the actin cytoskeleton. Similarly, knockdown of Sema4C by siRNA interference in mouse primary ovarian granulosa cells or thecal interstitial cells significantly suppressed ovarian steroidogenesis and led to actin cytoskeleton disorganization. Importantly, the cytoskeleton-related pathway RHOA/ROCK1 was simultaneously inhibited after the downregulation of Sema4C. Furthermore, treatment with a ROCK1 agonist after siRNA interference stabilized the actin cytoskeleton and reversed the inhibitory effect on steroid hormones described above. In conclusion, Sema4C may play an important role in ovarian steroidogenesis through regulation of the actin cytoskeleton via the RHOA/ROCK1 signaling pathway. These findings shed new light on the identification of dominant factors involved in the endocrine physiology of female reproduction.

Microenvironmentally Responsive Chemotherapeutic Prodrugs and CHEK2 Inhibitors Self-Assembled Micelles: Protecting Fertility and Enhancing Chemotherapy.

Chemotherapy is a widely used and effective adjuvant treatment for cancer, and it has unavoidable damage to female fertility, with statistics showing 38% of women who have received chemotherapy are infertile. How to reduce fertility toxicity while enhancing the oncologic chemotherapy is a clinical challenge. Herein, co-delivery micelles (BML@PMP) are developed, which are composed of a reduction-sensitive paclitaxel prodrug (PMP) for chemotherapy and a CHEK2 inhibitor (BML277) for both fertility protection and chemotherapy enhancement. BML@PMP achieves fertility protection through three actions: (1) Due to the enhanced permeability and retention (EPR) effect, BML@PMP is more enriched in the tumor, while very little in the ovary (about 1/10th of the tumor). (2) Glutathione (GSH) triggers the release of PTX, and with low levels of GSH in the ovary, the amount of PTX released in the ovary is correspondingly reduced. (3) BML277 inhibits oocyte apoptosis by inhibiting the CHEK2-TAp63α pathway. Because of the different downstream targets of CHEK2 in tumor cells and oocytes, BML277 also enhances chemotherapeutic efficacy by reducing DNA damage repair which is activated through the CHEK2 pathway. This bidirectional effect of CHEK2 inhibitor-based co-delivery system represents a promising strategy for improving oncology treatment indices and preventing chemotherapy-associated fertility damage.

The effects and mechanism of taxanes on chemotherapy-associated ovarian damage: A review of current evidence.

Chemotherapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to the effects of chemotherapeutic agents. Different chemotherapeutic agents with varying mechanisms of action may damage ovarian function differently. Taxanes are widely used in clinical cancer treatment, but the specific reproductive toxicological information is still controversial. This review described the impact and duration of taxanes on ovarian function in women and analyzed the possible reasons for different conclusions. Furthermore, the toxicity of taxanes on ovarian function and its possible mechanisms were discussed. The potential protective strategies and agents against ovarian damage induced by taxanes are also reviewed.

Global burden and trends of pelvic organ prolapse associated with aging women: An observational trend study from 1990 to 2019.

Purpose: Worldwide, about 40% of women will experience pelvic organ prolapse (POP), and this proportion is expected to increase with the aging of the population. We investigated the global, regional and national influenza burden in the past 30 years through the age and sociodemographic index (SDI). Patients and methods: Data were extracted from the Global Burden of Disease (GBD) 2019 database for 195 countries and territories between 1990 and 2019. Estimated annual percentage changes (EAPCs) were used to explore the age-standardized incidence rate (ASIR) and age-standardized disability adjusted life years (AS-DALYs) trends, and the corresponding 95% uncertainty intervals (UI). In addition, the time cut-off points of 1990 and 2019 were used to separately analyze the incidence rate and DALYs. Results: In 2019, the global ASIR and AS-DALYs for POP were 316.19 (95%UI: 259.84-381.84) and 10.37 (95%UI: 5.79-17.99) per 100,000 population, respectively. Moreover, from 1990 to 2019, the ASR of both showed a downward trend, and EAPCs were -0.46 (95%CI: -0.52 to -0.4) and -0.53 (95%CI: -0.58 to -0.47), respectively. In addition, DALYs of POP also showed a downward trend in most regions and countries with high SDI. From 1990 to 2019, the global incidence rate and DALYs rate were highest in the 65-75 and ≥60 age groups, respectively. Conclusion: Over the past three decades, the incidence and DALY of POP have been decreasing from 1990 to 2019. However, POP remains a major health problem, especially among females in less developed countries. Primary and secondary prevention measures of POP should be integrated into the practice of healthcare professionals dealing with aging women.

Biomaterials and advanced technologies for the evaluation and treatment of ovarian aging.

Ovarian aging is characterized by a progressive decline in ovarian function. With the increase in life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Over the years, various strategies have been developed to preserve fertility in women, while there are currently no clinical treatments to delay ovarian aging. Recently, advances in biomaterials and technologies, such as three-dimensional (3D) printing and microfluidics for the encapsulation of follicles and nanoparticles as delivery systems for drugs, have shown potential to be translational strategies for ovarian aging. This review introduces the research progress on the mechanisms underlying ovarian aging, and summarizes the current state of biomaterials in the evaluation and treatment of ovarian aging, including safety, potential applications, future directions and difficulties in translation.

Carbon tetrachloride exposure induces ovarian damage through oxidative stress and inflammatory mediated ovarian fibrosis.

Carbon tetrachloride (CCL4) is widely used as a chemical intermediate and as a feedstock in the production of chlorofluorocarbons. CCL4 is highly toxic in the liver, kidney, testicle, brain and other tissues. However, the effect of CCL4 on ovarian function has not been reported. In this study, we found that the mice treated with CCL4 showed decreased ovarian function with disturbed estrus cycle, decreased serum level of 17ß-estradiol and the reduced number of healthy follicles. Ovarian damage was accompanied by oxidative stress and the production of proinflammatory cytokines, especially interleukins. The indicators of oxidative stress, 4-Hydroxynonenal (4-HNE), 8-hydroxy-2´-deoxyguanosine (8-OHdG), 3-Nitrotyrosine (3-NT) and malondialdehyde (MDA), and the levels of proinflammatory cytokines IL-1α, IL-1ß, IL-6 and IL-11 were increased, while the antioxidants, including superoxide dismutase (SOD), nuclear factor erythroid2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), were decreased in the CCL4 group. In the CCL4 treated group, the results of Sirius Red staining, immunohistochemistry and qPCR indicated that proinflammatory cytokines caused further ovarian fibrosis. And CCL4 could also promote ovarian thecal cells to secrete inflammatory cytokines, resulting in fibrosis in vitro. In addition, CCL4 inhibited oocyte development and triggered oocyte apoptosis. In conclusion, CCL4 exposure causes ovarian damage by strong oxidative stress and the high expression of the proinflammatory cytokine mediated ovarian fibrosis.

Adipose tissue and ovarian aging: Potential mechanism and protective strategies.

Ovarian aging occurs approximately 10 years prior to the natural age-associated functional decline of other organ systems. With the increase of life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Therefore, understanding the causes and molecular mechanisms of ovarian aging is very essential for the inhibition of age-related diseases and the promotion of health and longevity in women. Recently, studies have revealed an association between adipose tissue (AT) and ovarian aging. Alterations in the function and quantity of AT have profound consequences on ovarian function because AT is central for follicular development, lipid metabolism, and hormonal regulation. Moreover, the interplay between AT and the ovary is bidirectional, with ovary-derived signals directly affecting AT biology. In this review, we summarize the current knowledge of the complex molecular mechanisms controlling the crosstalk between the AT and ovarian aging, and further discuss how therapeutic targeting of the AT can delay ovarian aging.

DDX04+ Stem Cells in the Ovaries of Postmenopausal Women: Existence and Differentiation Potential.

Ovarian aging is a pacemaker with multiple organ dysfunction. Recently, stem cells with the ability to generate new oocytes have been identified, which provides the possibility of stem cell therapy for ovarian aging. Several studies have revealed the existence of stem cells in the human postmenopausal ovary. In this study, we describe a new method using magnetic-activated cell sorting combined with differential adhesion to isolate DDX4+ stem cells from ovaries of postmenopausal women and show that the cells exhibit similar gene expression profiles and growth characteristics with primitive germ cells. Furthermore, the DDX4+ stem cells could enter the meiosis stage and differentiation into oocytes. The RNA-seq data of the differentiated oocytes shows that mitochondrial metabolism may play an important role in the oogenesis process of the DDX4+ stem cells. Through using the human ovarian cortical fragments transplantation model, we indicated that the GFP-DDX4+ stem cells differentiated into some GFP positive oocyte-like structure in vivo. Our study provided a new method for the isolation of DDX4+ stem cells from the ovaries of postmenopausal women and confirmed the ability of these stem cells to differentiate into oocytes.

Machine Learning-Assisted Ensemble Analysis for the Prediction of Response to Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer.

The clinical benefit of neoadjuvant chemotherapy (NACT) before concurrent chemoradiotherapy (CCRT) vs. adjuvant chemotherapy after CCRT is debated. Non-response to platinum-based NACT is a major contributor to poor prognosis, but there is currently no reliable method for predicting the response to NACT (rNACT) in patients with locally advanced cervical cancer (LACC). In this study we developed a machine learning (ML)-assisted model to accurately predict rNACT. We retrospectively analyzed data on 636 patients diagnosed with stage IB2 to IIA2 cervical cancer at our hospital between January 1, 2010 and December 1, 2020. Five ML-assisted models were developed from candidate clinical features using 2-step estimation methods. Receiver operating characteristic curve (ROC), clinical impact curve, and decision curve analyses were performed to evaluate the robustness and clinical applicability of each model. A total of 30 candidate variables were ultimately included in the rNACT prediction model. The areas under the ROC curve of models constructed using the random forest classifier (RFC), support vector machine, eXtreme gradient boosting, artificial neural network, and decision tree ranged from 0.682 to 0.847. The RFC model had the highest predictive accuracy, which was achieved by incorporating inflammatory factors such as platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, neutrophil-to-albumin ratio, and lymphocyte-to-monocyte ratio. These results demonstrate that the ML-based prediction model developed using the RFC can be used to identify LACC patients who are likely to respond to rNACT, which can guide treatment selection and improve clinical outcomes.

Chronic exposure to propylparaben at the humanly relevant dose triggers ovarian aging in adult mice.

Parabens, a type of endocrine-disrupting chemicals, are widely used as antibacterial preservatives in food and cosmetics in daily life. Paraben exposure has gained particular attention in the past decades, owing to its harmful effects on reproductive function. Whether low-dose paraben exposure may cause ovarian damage has been ignored recently. Here, we investigated the effects of chronic low-dose propylparaben (PrPB) exposure on ovarian function. Female C57BL/6J mice were exposed to PrPB at a humanly relevant dose for 8 months. Our results showed that chronic exposure to PrPB at a humanly relevant dose significantly altered the estrus cycle, hormone levels, and ovarian reserve, accelerating ovarian aging in adult mice. These effects are accompanied by oxidative stress enrichment, leading to steroidogenesis dysfunction and acceleration of primordial follicle recruitment. Notably, melatonin supplementation has been shown to protect against PrPB-induced steroidogenesis dysfunction in granulosa cells. Here, we report that daily chronic PrPB exposure may contribute to ovarian aging by altering oxidative stress-mediated JNK and PI3K-AKT signaling regulation, and that melatonin may serve as a pharmaceutical candidate for PrPB-associated ovarian dysfunction.

Recent Advances in Second Near-Infrared Region (NIR-II) Fluorophores and Biomedical Applications.

Fluorescence imaging technique, characterized by high sensitivity, non-invasiveness and no radiation hazard, has been widely applicated in the biomedical field. However, the depth of tissue penetration is limited in the traditional (400-700 nm) and NIR-I (the first near-infrared region, 700-900 nm) imaging, which urges researchers to explore novel bioimaging modalities with high imaging performance. Prominent progress in the second near-infrared region (NIR-II, 1000-1700 nm) has greatly promoted the development of biomedical imaging. The NIR-II fluorescence imaging significantly overcomes the strong tissue absorption, auto-fluorescence as well as photon scattering, and has deep tissue penetration, micron-level spatial resolution, and high signal-to-background ratio. NIR-II bioimaging has been regarded as the most promising in vivo fluorescence imaging technology. High brightness and biocompatible fluorescent probes are crucial important for NIR-II in vivo imaging. Herein, we focus on the recently developed NIR-II fluorescent cores and their applications in the field of biomedicine, especially in tumor delineation and image-guided surgery, vascular imaging, NIR-II-based photothermal therapy and photodynamic therapy, drug delivery. Besides, the challenges and potential future developments of NIR-II fluorescence imaging are further discussed. It is expected that our review will lay a foundation for clinical translation of NIR-II biological imaging, and inspire new ideas and more researches in this field.

Red blood cell membrane-camouflaged nanoparticles loaded with AIEgen and Poly(I : C) for enhanced tumoral photodynamic-immunotherapy.

Red blood cell (RBC)-mimicking nanoparticles (NPs) offer a promising platform for drug delivery because of their prolonged circulation time, reduced immunogenicity and specific targeting ability. Herein, we report the design and preparation of RBC membrane-bound NPs (M@AP), for tumoral photodynamic-immunotherapy. The M@AP is formed by self-assembly of the positively charged aggregation-induced emission luminogen (AIEgen) (named P2-PPh3) and the negatively charged polyinosinic : polycytidylic acid (Poly(I : C)), followed by RBC membrane encapsulation. P2-PPh3 is an AIE-active conjugated polyelectrolyte with additional photosensitizing ability for photodynamic therapy (PDT), while Poly(I : C) serves as an immune-stimulant to stimulate both tumor and immune cells to activate immunity, and thus reduces tumor cell viability. When applied in tumor-bearing mice, the M@AP NPs are enriched in both the tumor region as a result of an enhanced permeability and retention (EPR) effect, and the spleen because of the homing effect of the RBC-mimicking shell. Upon light irradiation, P2-PPh3 promotes strong ROS generation in tumor cells, inducing the release of tumor antigens (TA). The anti-tumor immunity is further enhanced by the presence of Poly(I : C) in M@AP. Thus, this strategy combines the PDT properties of the AIE-active polyelectrolyte and immunotherapy properties of Poly(I : C) to achieve synergistic activation of the immune system for anti-tumor activity, providing a novel strategy for tumor treatment.

Co-expression of the SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in human ovaries: Identification of cell types and trends with age.

The high rate of SARS-CoV-2 infection poses a serious threat to public health. Previous studies have suggested that SARS-CoV-2 can infect human ovary, the core organ of the female reproductive system. However, it remains unclear which type of ovarian cells are easily infected by SARS-CoV-2 and whether ovarian infectivity differs from puberty to menopause. In this study, public datasets containing bulk and single-cell RNA-Seq data derived from ovarian tissues were analyzed to demonstrate the mRNA expression and protein distribution of the two key entry receptors for SARS-CoV-2-angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2). Furthermore, an immunohistochemical study of ACE2 and TMPRSS2 in human ovaries of different ages was conducted. Differentially expressed gene (DEG) analysis of ovaries of different ages and with varying ovarian reserves was conducted to explore the potential functions of ACE2 and TMPRSS2 in the ovary. The analysis of the public datasets indicated that the co-expression of ACE2 and TMPRSS2 was observed mostly in oocytes and partially in granulosa cells. However, no marked difference was observed in ACE2 or TMPRSS2 expression between young and old ovaries and ovaries with low and high reserves. Correspondingly, ACE2 and TMPRSS2 were detected in the human ovarian cortex and medulla, especially in oocytes of different stages, with no observed variations in their expression level in ovaries of different ages, which was consistent with the results of bioinformatic analyses. Remarkably, DEG analysis showed that a series of viral infection-related pathways were more enriched in ACE2-positive ovarian cells than in ACE2-negative ovarian cells, suggesting that SARS-CoV-2 may potentially target specific ovarian cells and affect ovarian function. However, further fundamental and clinical research is still needed to monitor the process of SARS-CoV-2 entry into ovarian cells and the long-term effects of SARS-CoV-2 infection on the ovarian function in recovered females.

Human Umbilical Cord Mesenchymal Stem Cells Improve Ovarian Function in Chemotherapy-Induced Premature Ovarian Failure Mice Through Inhibiting Apoptosis and Inflammation via a Paracrine Mechanism.

Human umbilical cord mesenchymal stem cell (UC-MSC) application is a promising arising therapy for the treatment of premature ovarian failure (POF). However, little is known about the inflammation regulatory effects of human umbilical cord MSCs (UC-MSCs) on chemotherapy-induced ovarian damage, regardless of in vivo or in vitro. This study was designed to investigate the therapeutic effects of UC-MSC transplantation and underlying mechanisms regarding both apoptosis and inflammation in POF mice. The chemotherapy-induced POF models were induced by intraperitoneal injection of cyclophosphamide. Ovarian function parameters, granulosa cell (GC) apoptosis, and inflammation were examined. Morphological staining showed that UC-MSC treatment increased the ovary size, and the numbers of primary and secondary follicles, but decreased the number of atretic follicles. Estradiol levels in the UC-MSC-treated group were increased while follicle-stimulating hormone levels were reduced compared to those in the POF group. UC-MSCs inhibited cyclophosphamide-induced GC apoptosis and inflammation. Meanwhile, phosphorylation of AKT and P38 was elevated after UC-MSC treatment. Tracking of UC-MSCs in vivo indicated that transplanted UC-MSCs were only located in the interstitium of ovaries rather than in follicles. Importantly, UC-MSC-derived extracellular vesicles protected GCs from alkylating agent-induced apoptosis and inflammation in vitro. Our results suggest that UC-MSC transplantation can reduce ovary injury and improve ovarian function in chemotherapy-induced POF mice through anti-apoptotic and anti-inflammatory effects via a paracrine mechanism.