Single-cell transcriptomics reveals antigen-presenting capacity and therapeutic resistance potential of immunomodulatory endothelial cells in colorectal cancer.

BACKGROUND: The heterogeneity of tumor endothelial cells (TECs) hinders the efficacy of antiangiogenic therapies (AATs). Only a small percentage of angiogenic TECs are considered effective targets for AATs. Immunomodulatory ECs (IMECs), as a newly focused functional subgroup of endothelial cells (ECs), are being evaluated for their ability to regulate tumor immune balance and influence existing AATs. METHODS: Based on single-cell transcriptome data from colorectal cancer in a publicly available database, we conducted a wide array of bioinformatic approaches to study EC subsets that meet the IMECs definition. Our investigation encompassed the gene expression signatures of these subsets, cellular composition differences, cell-cell interactions. RESULTS: Two subsets that meet the IMECs definition were found in tumors and para-cancerous tissues. Combined with the results of gene ontological analysis and interaction with CD4+ T cells, we found that IMECs can present MHC-II antigens to mature CD4+ T cells. There were differences in the level of interaction between IMECs and different types of mature CD4+ T cell subsets. In addition, IMEC subsets had different expression levels of angiogenesis related genes. The angiogenesis score of IMECs decreased after patients received immunotherapy. IMEC subsets do not depend on a single proangiogenic receptor and are involved in regulating angiogenesis, which may reduce the efficacy of AATs. The adverse effects of specific IMEC subsets on AATs were validated in the RNA-seq dataset of the bevacizumab treatment group. CONCLUSION: Our study suggests the potential MHC-II antigen presentation capacity of IMECs and the enhanced angiogenesis characteristics within tumors. The function of IMECs in the vascular network may have a potentially adverse effect on AATs. Controlling the functional properties of IMECs may be a new angle for tumor therapy.

Lipopolysaccharides protect mesenchymal stem cell against cardiac ischemia-reperfusion injury by HMGB1/STAT3 signaling.

BACKGROUND: Myocardial ischemia-reperfusion (I/R) is a serious and irreversible injury. Bone marrow-derived mesenchymal stem cells (MSCs) is considered to be a potential therapy for I/R injury due to the paracrine effects. High-mobility group box 1 (HMGB1) is a novel mediator in MSC and regulates the response of inflammation injury. Signal Transduction and Transcription Activator 3 (STAT3) is a critical transcription factor and important for release of paracrine factors. However, the relationship between HMGB1 and STAT3 in paracrine effect of MSC remains unknown. METHODS: In vitro, hypoxia/reoxygenation injury model was established by AnaeroPack System and examined by Annexin V flow cytometry, CCK8 assay and morphology observation. Detection of apoptotic proteins and protein expression of HMGB1 and STAT3 by Western blot. RESULTS: The conditioned medium of MSCs with or without LPS pretreatment was cocultured with H9C2 cells for 24 h before hypoxia treatment and MSC showed obvious cardiomyocytes protect role, as evidence by decreased apoptosis rate and improved cells viability, and LPS pretreated MSC exhibited better protect role than untreated MSC. However, such effect was abolished in HMGB1 deficiency group, silencing HMGB1 decreased the secretion of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin growth factor (IGF), cell viability, and the expression of STAT3. Furthermore, STAT3 silence attenuated the protective effect of LPS in MSC. CONCLUSIONS: These findings suggested that LPS improved MSC-mediated cardiomyocytes protection by HMGB1/STAT3 signaling.

Time-dependent photo-activated aminoborane room-temperature phosphorescence materials with unprecedented properties: simple, versatile, multicolor-tuneable, water resistance, optical information writing/erasing, and multilevel data encryption.

Triarylboranes-based pure organic room-temperature phosphorescence (RTP) materials are rarely investigated because of their large steric hindrance and the electron defect of the boron atom. As a result, creating functional triarylborane RTP materials is difficult. Herein, we report the first photo-activated RTP materials with lifetimes/quantum yields ≤0.18 s/6.83% based on donor (D)-π-acceptor (A) from methylene carbazole-functionalized aminoborane (BN)-doped polymethyl methacrylate (BN-o-Met-Cz@PMMA) under 365 nm UV irradiation (30 s). Incredibly, BN-o-Met-Cz@PMMA films exhibited unprecedented photo-activated RTP dual-response properties (e.g., air + 365 nm: τ P = 0.18 s, Φ P = 6.83%; N2 + 365 nm: τ P = 0.42 s, Φ P = 17.34%). Intriguingly, the BN (D-π-A) system demonstrated good versatility for photo-activated RTP whether the electron-donating group or electron-withdrawing group was placed in the ortho (meta)-position of the B atom. As a result, a series of photo-activated single-molecule organic RTP materials with multi-color emission, high quantum yields, and ultra-long lifetimes can be prepared rapidly. BN-X@PMMA films showed broad application prospects for information encryption, data erasure, anti-counterfeiting, and water resistance. Our method provides new strategies for the design, synthesis, and application of RTP materials, thereby enriching the types of organic RTP materials and facilitating further developments in this area.

Multicolor Adjustable B-N Molecular Switches: Simple, Efficient, Portable, and Visual Identification of Butanol Isomers.

As intelligent probes, dynamic and controllable molecular switches are useful tools for probing and intervening in life processes. However, the types and properties of molecular switches are still relatively single and often can only make two actions: "off" and "on". Therefore, the development of novel molecular switches with multiple colors and multiple instructions is very challenging. Herein, we propose a novel strategy based on the instability of the Lewis acid-base pair (boron (B) and nitrogen (N)), such as introducing the Schiff base (C═N) group into the aminoborane skeleton and preparing the novel molecular switches BN-HDZ and BN-HDZ-N. These two molecules were found to have good multicolor fluorescence switching capability for methanol. Surprisingly, the compound BN-HDZ-N shows unprecedented visual identification for the butanol isomers and could be made into a portable strip for simple and rapid visual identification of the four isomers of butanol, promising an alternative to conventional Lucas reagents. This provides a novel strategy for the design and fabrication of novel multicolor-tunable molecular switches with visual identification of isomers.

Osteoimmunomodulatory Nanoparticles for Bone Regeneration.

Treatment of large bone fractures remains a challenge for orthopedists. Bone regeneration is a complex process that includes skeletal cells such as osteoblasts, osteoclasts, and immune cells to regulate bone formation and resorption. Osteoimmunology, studying this complicated process, has recently been used to develop biomaterials for advanced bone regeneration. Ideally, a biomaterial shall enable a timely switch from early stage inflammatory (to recruit osteogenic progenitor cells) to later-stage anti-inflammatory (to promote differentiation and terminal osteogenic mineralization and model the microstructure of bone tissue) in immune cells, especially the M1-to-M2 phenotype switch in macrophage populations, for bone regeneration. Nanoparticle (NP)-based advanced drug delivery systems can enable the controlled release of therapeutic reagents and the delivery of therapeutics into specific cell types, thereby benefiting bone regeneration through osteoimmunomodulation. In this review, we briefly describe the significance of osteoimmunology in bone regeneration, the advancement of NP-based approaches for bone regeneration, and the application of NPs in macrophage-targeting drug delivery for advanced osteoimmunomodulation.

Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics.

Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and overall health of the cancer survivors seriously. However, there is still a lack of effective protection strategies against such injury. Cellular senescence can be induced by chemotherapeutic agents in multiple organs and may corrode the structure and function of normal tissues. We hypothesized that the widely used first-line chemotherapy drug, doxorubicin, could increase senescent cell burden in normal ovarian tissue during the therapeutic process and that elimination of senescent cells with senolytics would ameliorate doxorubicin-induced ovarian injury. Here, we demonstrated an accumulation of cellular senescence in doxorubicin-treated ovaries through detecting p16 and p21 expression levels and senescence-associated ß-galactosidase (SA-ß-gal) activity as well as senescence-associated secretory phenotype (SASP) factors. Short-term intervention with the classic senolytic combination dasatinib and quercetin (DQ) or fisetin significantly reduced the load of senescent cells in ovaries after doxorubicin treatment. However, neither DQ nor fisetin alleviated doxorubicin-related ovarian dysfunction. Further experiments showed that ovarian apoptosis and fibrosis following doxorubicin exposure could not be improved by senolytics. Collectively, our study shows that senolytic treatment can eliminate accumulated senescent cells, but cannot reverse the massive follicle loss and ovarian stromal fibrosis caused by doxorubicin, suggesting that cellular senescence may not be one of the key mechanisms in doxorubicin-induced ovarian injury.

Simple Stimulus-Responsive Organic Long Persistent Luminescence Systems Based on Methoxy-Functionalized Triphenylphosphine.

Triarylphosphine-based pure organic long persistent luminescence materials are rarely investigated because of their poor stability and low photoluminescence quantum yield. Herein, we demonstrate that the introduction of a methoxy group (TPP-o-3OMe) at the ortho position of triphenylphosphine (TPP) can essentially promote the n → π* transition and promote intersystem crossing to generate more triplet excitons. Simultaneously, generating abundant intramolecular and intermolecular hydrogen bonds to stable excited triplet excitons is beneficial, thereby causing high-efficiency phosphorescence emission (τp = 394.1 ms; Φp = 9.28%). Interestingly, it shows a good acid response to protonic acids and can often be cycled many times under the heating or ammonia fumigation conditions. This research provides a new idea for enriching the types of pure organic room-temperature phosphorescent materials, widening their applications in the fields of anticounterfeiting and smart response, and promotes the further development of this field.

Senotherapy Protects against Cisplatin-Induced Ovarian Injury by Removing Senescent Cells and Alleviating DNA Damage.

Ovarian damage induced by platinum-based chemotherapy seriously affects young women with cancer, manifesting as infertility, early menopause, and premature ovarian insufficiency. However, effective prevention strategies for such damage are lacking. Senescent cells may be induced by chemotherapeutic agents. We hypothesized that cisplatin can lead to senescence in ovarian cells during the therapeutic process, and senolytic drugs can protect animals against cisplatin-induced ovarian injury. Here, we demonstrated the existence of senescent cells in cisplatin-treated ovaries, identified the senescence-associated secretory phenotype, and observed significant improvement of ovarian function by treatment with metformin or dasatinib and quercetin (DQ) independently or in combination. These senotherapies improved both oocyte quality and fertility, increased the ovarian reserve, and enhanced hormone secretion in cisplatin-exposed mice. Additionally, attenuated fibrosis, reorganized subcellular structure, and mitigated DNA damage were observed in the ovaries of senotherapeutic mice. Moreover, RNA sequencing analysis revealed upregulation of the proliferation-related genes Ki, Prrx2, Sfrp4, and Megfl0; and the antioxidative gene H2-Q10 after metformin plus DQ treatment. Gene ontology analysis further revealed that combining senotherapies enhanced ovarian cell differentiation, development, and communication. In this study, we demonstrated that metformin plus DQ recovered ovarian function to a greater extent compared to metformin or DQ independently, with more follicular reserve, increased pups per litter, and reduced DNA damage. Collectively, our work indicates that senotherapies might prevent cisplatin-induced ovarian injury by removing senescent cells and reducing DNA damage, which represent a promising therapeutic avenue to prevent chemotherapy-induced ovarian damage.

Lipopolysaccharide-pretreated mesenchymal stem cell-conditioned medium optimized with 10 kDa filter attenuates the injury of H9c2 cardiomyocytes in a model of hypoxia/reoxygenation.

Mesenchymal stem cell-derived conditioned medium (MSC-CM) improves cardiac function, which is partly attributed to the released paracrine factors. Since such cardioprotection is moderate and transient, it is essential that MSC-CM's effective components are optimized to alleviate myocardial injury. To optimize MSC-CM, MSCs were treated with or without lipopolysaccharides (LPSs) for 48 h (serum-free), and the supernatant was collected. Then, LPS-CM (MSC stimulated by LPS) was further treated with LPS remover (LPS Re-CM) or was concentrated with a 10 kDa cutoff filter (10 kDa-CM). Enzyme-linked immunosorbent assay showed that all the pretreatments increased the levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and insulin growth factor (IGF) except LPS Re-CM; 10 kDa-CM was superior to the other CMs. Cell Counting Kit-8 displayed that the viability of injured H9c2 cells was enhanced with the increase in the MSC-CM concentration. We also found that the 10 kDa-CM significantly alleviated H9c2 hypoxia/reoxygenation (H/R) injury, as evidenced by the increased Bcl-2/Bax ratio, and decreased the levels of lactate dehydrogenase and cardiac troponin. Transmission electron microscopy (TEM), TdT-mediated dUTP nick-end labelling (TUNEL), and hematoxylin and eosin staining (H&E) confirmed that 10 kDa-CM inhibited H/R-induced H9c2 morphological changes. Proteomic analysis identified 41 differentially expressed proteins in 10 kDa-CM, among which anti-inflammation, proangiogenesis, and antiapoptosis were related to cardiac protection. This study indicates that 10 kDa-CM protects H9c2 cardiomyocytes from H/R injury by preserving most of the protective factors, such as VEGF, HGF, and IGF, in MSC-CM.

Vaginal Microbiota Changes in Patients With Premature Ovarian Insufficiency and Its Correlation With Ovarian Function.

Objectives: To reveal the characteristics of vaginal microbiota in premature ovarian insufficiency (POI) patients and their relationship with ovarian function. Materials and Methods: In this case-control study, the vaginal bacterial composition of 30 POI patients and 26 healthy women of comparable age was assessed by 16S rRNA gene sequencing targeting the V3-V4 hypervariable regions. The metabolic functions of vaginal microflora were preliminarily predicted through the PICRUSt2 analysis. Redundancy analysis and Spearman's correlation analyzed the relationships between vaginal microbiota and ovarian function indicators. Results: Actinobacteria, Atopobium, and Gardnerella were significantly increased in POI patients. Their increments were significantly negatively correlated with anti-müllerian hormone (AMH) and inhibin B, and positively correlated with follicle-stimulating hormone (FSH) and luteinizing hormone (LH). While Bifidobacterium was significantly decreased in POI patients. Its relative abundance was significantly positively correlated with AMH and negatively correlated with FSH and LH. Then, POI patients included in this study were divided into POI (25 < FSH ≤ 40) (n = 9) and premature ovarian failure (POF) (FSH > 40) (n = 21) subgroups according to serum FSH levels. Compared with the controls, Firmicutes and Lactobacillus were significantly decreased only in POF (FSH > 40) patients, while no difference was observed in POI (25 < FSH ≤ 40) patients. Lactobacillus was negatively correlated with FSH. Firmicutes was significantly reduced and Actinobacteria was significantly increased in POF (FSH > 40) patients compared with POI (25 < FSH ≤ 40) patients. The key bacterial taxa Gardnerella and Atopobium showed potency in predicting POI. Conclusions: Here we demonstrated significant changes in the vaginal microbiota of POI patients, and these changes were significantly correlated with reduced ovarian reserve, endocrine disruption, and symptoms of perimenopausal syndrome. Differences in vaginal microbiota between POI (25 < FSH ≤ 40) and POF (FSH > 40) patients were also identified. These findings may provide new evidence for the relationship between vaginal microbiota and ovarian function.

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.

Can Inhibin B Reflect Ovarian Reserve of Healthy Reproductive Age Women Effectively?

Objective: The reference range and potential value of inhibin B are still unclear and controversial. This study aimed to define the variation trend of inhibin B in healthy women with age and explore its value in the reflection of ovarian reserve. Methods: A total of 2524 healthy reproductive age women from eight medical institutes nationwide were recruited. The variation tendency of inhibin B with age was primarily established in the first group of 948 women and validated in another 605. We evaluated the relationship between inhibin B and classic ovarian reserve and function markers. The potency of inhibin B in predicting AFC <5-7 was also estimated and compared with FSH. Results: The nomogram showed that serum levels of inhibin B rapidly decreased after the age of 40. Inhibin B was positively correlated with AMH (R = 0.57, P < 0.001), AFC (R = 0.34, P < 0.001) and testosterone (R = 0.10, P = 0.002), and negatively correlated with FSH (R = -0.41, P < 0.001) and LH (R = -0.20, P < 0.001) and FSH/LH (R=-0.18, P < 0.001), while no correlation was found with PRL. Unexpectedly, Inhibin B (AUC = 0.74, P < 0.001 for the establishment population; AUC = 0.78, P < 0.001 for the validation population) had a slightly higher value than FSH (AUC = 0.71, P < 0.001 for the establishment population; AUC = 0.72, P < 0.001 for the validation population) in diagnosing AFC <5-7. Conclusions: For healthy reproductive age women, the decline of inhibin B can reflect decreased ovarian reserve effectively, having a good consistency with AMH and AFC. More importantly, inhibin B had an advantage in predicting AFC <5-7 compared with FSH, which suggested the potential of inhibin B in predicting ovarian response. These results will be helpful to the clinical application of inhibin B in the evaluation of female ovarian reserve and the assessment of their reproductive capacity. Trial registration: http://clinicaltrials.gov; NCT02294500.

Acupuncture Medical Therapy and its Underlying Mechanisms: A Systematic Review.

As a traditional Chinese alternative health care approach, acupuncture is gaining increasing attention and reputation in China and overseas. While becoming increasingly popular globally, some consumers and professionals still know little about the therapy and underlying mechanisms of acupuncture. Due to local superiority, there are large numbers of both clinical applications and mechanistic studies performed in China compared to countries overseas. Herein, this review attempts to give a comprehensive profile of the development, application, and mechanisms of acupuncture in treating major diseases. The number of clinical publications concerning acupuncture-treated neurological diseases, endocrine and metabolic diseases, circulatory diseases, respiratory diseases, etc. is first counted, and then, the application and therapeutic mechanisms of acupuncture on the predominant diseases in each category, including obesity, facial paralysis, sciatica, depression, hypertension, asthma, etc., are specifically discussed in this paper. The evolution of acupuncture tools and the rationality of acupoints are also discussed. This review not only summarizes the mechanisms of acupuncture but also provides useful information, such as specific acupoints and acupuncture procedures, for treating common diseases. Therefore, the current study provides useful information for both investigators and acupuncturists.

The optimization conditions of establishing an H9c2 cardiomyocyte hypoxia/reoxygenation injury model based on an AnaeroPack System.

Ischemia-reperfusion (I/R) injury is a major cause of cardiomyocyte apoptosis after vascular recanalization, which was mimicked by a hypoxia/reoxygenation (H/R) injury model of cardiomyocytes in vitro. In this study, we explored an optimal H/R duration procedure using the AnaeroPack System. To study the H/R procedure, cardiomyocytes were exposed to the AnaeroPack System with sugar and serum-free medium, followed by reoxygenation under normal conditions. Cell injury was detected through lactate dehydrogenase (LDH) and cardiac troponin (c-Tn) release, morphological changes, cell apoptosis, and expression of apoptosis-related proteins. The results showed that the damage to H9c2 cells increased with prolonged hypoxia time, as demonstrated by increased apoptosis rate, LDH and c-Tn release, HIF-1α expression, as well as decreased expression of Bcl-2. Furthermore, hypoxia for 10 h and reoxygenation for 6 h exhibited the highest apoptosis rate and damage and cytokine release; in addition, cells were deformed, small, and visibly round. After 12 h of hypoxia, the majority of the cells were dead. Taken together, this study showed that subjecting H9c2 cells to the AnaeroPack System for 10 h and reoxygenation for 6 h can achieve a practicable and repeatable H/R injury model.

Reproductive risk factors for angiographic obstructive coronary artery disease among postmenopausal women.

OBJECTIVE: Reproductive factors are female-specific coronary artery disease (CAD) risk factors. However, the importance of reproductive factors in angiographic obstructive CAD in postmenopausal women remains uncertain. This study aimed to compare reproductive factors between postmenopausal women with no apparent CAD, nonobstructive CAD, and obstructive CAD and identify reproductive risk factors for obstructive CAD. METHODS: In this hospital-based cross-sectional study, 1,474 postmenopausal women, admitted with chest pain and referred for invasive coronary angiography were enrolled between April 2013 and October 2018. RESULTS: Adjusted odds ratio (95% CI) for obstructive CAD were 1.81 (1.03-3.17) for multigravidity (three or more pregnancies), 1.77 (1.14-2.76) for early menopause (≤40 y old), and 1.72 (1.26-2.35) for short reproductive life span (≤30 y). Each additional year in age at menopause or reproductive life span was associated with a 4% reduction in obstructive CAD risk in postmenopausal women (odds ratio, 0.96; 95% CI, 0.94-0.99; P = 0.011). The other reproductive factors, including parity, age at first birth, spontaneous abortion, induced abortion, stillbirth, hypertensive disorders of pregnancy, gestational diabetes mellitus, and age at menarche, were not correlated with obstructive CAD risk in postmenopausal women. CONCLUSIONS: Multigravidity (three or more pregnancies), early menopause, and a shorter reproductive life span were independent risk factors of angiographic obstructive CAD among postmenopausal women, which suggested that pregnancy and ovarian function may be important for the early identification and prevention of increased risk of female angiographic obstructive CAD.

High-Choline Diet Exacerbates Cardiac Dysfunction, Fibrosis, and Inflammation in a Mouse Model of Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Trimethylamine N-oxide, a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, has been associated with a poor prognosis for patients with cardiovascular disease. However, the role and underlying mechanisms of trimethylamine N-oxide in the cardiac function of patients with heart failure with preserved ejection fraction (HFpEF) have not been elucidated. METHODS AND RESULTS: C57BL/6 mice were fed a normal diet, high-choline (1.2%) diet, and/or 3-dimethyl-1-butanol diet 3 weeks before the operation (uninephrectomy followed by a continuous saline or aldosterone infusion). Mice were assessed for 4 weeks after the operation. Echocardiographic and hemodynamic measurements were performed. Blood samples were evaluated for choline, trimethylamine N-oxide, and inflammatory factor levels. Left ventricular tissues were collected to assess myocardial fibrosis and inflammation. Left ventricular hypertrophy, pulmonary congestion, and diastolic dysfunction were markedly exacerbated in HFpEF mice fed high-choline diets compared with mice fed the control diet. Myocardial fibrosis and inflammation were markedly increased in HFpEF mice fed high-choline diets compared with animals fed the control diet. Additionally, 3,3-dimethyl-1-butanol DMB markedly ameliorated cardiac diastolic dysfunction, myocardial fibrosis and inflammation in the choline-fed HFpEF mice. CONCLUSIONS: A high-choline diet exacerbates cardiac dysfunction, myocardial fibrosis, and inflammation in HFpEF mice, and 3,3-dimethyl-1-butanol ameliorates the high-choline diet-induced cardiac remodeling.

Metformin prevents murine ovarian aging.

A number of studies have shown that metformin can delay aging process and extend healthy lifespan in animals. However, its role in female reproductive lifespan is unclear. This study was aimed to explore the potential anti-aging effect of metformin on the ovary and its possible mechanisms. Female C57BL/6 mice of 27-week old were divided into two groups, the control group (CON) and metformin-treated group (MET). CON mice were fed ad libitum, while MET mice were fed on chows supplied with 100mg/kg metformin for half a year. Ovarian reserve and function were assessed by ovarian follicle counts, estrous cycle and sex hormones levels. The expressions of oxidized metabolites, such as 8-hydroxy-2´-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), and ovarian aging associated proteins P16, SIRT1, p-rpS6 and Bcl2 were examined. The MET mice exhibited increased level of serum E2 hormone and higher percentage of regular estrous cycles after 6 months' feeding, compared to the CON mice. The amount of primordial and primary follicles and the expression of SIRT1 were significantly increased, but the levels of P16, 8-OHdG, 4-HNE and p-rpS6 were decreased in the MET mice. These results indicate that metformin can delay ovarian aging process, probably by inducing the expression of SIRT1 and reducing the oxidative damage.

Can ovarian aging be delayed by pharmacological strategies?

Aging has been regarded as a treatable condition, and delaying aging could prevent some diseases. Ovarian aging, a special type of organ senescence, is the earliest-aging organ, as ovaries exhibit an accelerated rate of aging with characteristics of gradual declines in ovarian follicle quantity and quality since birth, compared to other organs. Ovarian aging is considered as the pacemaker of female body aging, which drives the aging of multiple organs of the body. Hence, anti-ovarian aging has become a research topic broadly interesting to both biomedical scientists and pharmaceutical industry. A marked progress has been made in exploration of possible anti-ovarian agents or approaches, such as calorie restriction mimetics, antioxidants, autophagy inducers etc., over the past years. This review is attempted to discuss recent advances in the area of anti-ovarian aging pharmacology and to offer new insights into our better understanding of molecular mechanisms underlying ovarian aging, which might be informative for future prevention and treatment of ovarian aging and its related diseases.

Age-associated up-regulation of EGR1 promotes granulosa cell apoptosis during follicle atresia in mice through the NF-κB pathway.

Follicular atresia is the main process responsible for the loss of follicles and oocytes from the ovary, and it is the root cause of ovarian aging. Apoptosis of granulosa cells (GCs) is the cellular mechanism responsible for follicular atresia in mammals. Recent advances have highlighted fundamental roles for EGR1 in age-related diseases via the induction of apoptosis. In the present study, we found that the expression of EGR1 was significantly increased in aged mouse ovaries compared with young ovaries. Immunohistochemical analysis revealed strongly positive EGR1 staining in atretic follicles, especially in apoptotic granulosa cells. We further showed that EGR1 up-regulation in mouse primary granulosa cells inhibited cell proliferation and promoted apoptosis. In addition, the promotion of apoptosis in GCs by EGR1 increases over time and with reactive oxygen species (ROS) stimulation. Our mechanistic study suggested that EGR1 regulates GC apoptosis in a mitochondria-dependent manner and that this mainly occurs through the NF-κB signaling pathway. In conclusion, our results suggested that age-related up-regulation of EGR1 promotes GC apoptosis in follicle atresia during ovarian aging.