Search Results (24)

Pubertal initiation critically determines reproductive performance in female pigs. Histone H3 lysine 27 trimethylation (H3K27me3) has been implicated in ovarian development. However, its genome-wide regulatory landscape during the pubertal transition remains unexplored. Here, we obtained transcriptomes of GCs treated with the pharmacological H3K27me3 agonist GSK-J4 or H3K27me3 inhibitor EPZ005687. We found that H3K27me3 substantially remodels the transcriptomic landscape of porcine GCs, with differentially expressed genes significantly enriched in pathways governing cell proliferation and apoptosis. Mechanistically, H3K27me3 suppressed GC proliferation by downregulating the expression of PCNA and promoting apoptosis through upregulation of CASP3, thereby delaying pubertal initiation. Furthermore, genome-wide ChIP-seq analysis on porcine ovaries from pre-pubertal and in-pubertal gilts revealed higher H3K27me3 enrichment around transcription start sites in the In-puberty stage than in the Pre-puberty stage. Genes with promoters exhibiting reduced H3K27me3 occupancy during the pubertal transition were enriched in pathways related to sex differentiation and serine-type endopeptidase inhibitor activity. Notably, secretory leukocyte peptidase inhibitor (SLPI) was identified by ChIP-qPCR as a direct target repressed by H3K27me3. Functional validation demonstrated that SLPI promoted GC proliferation and inhibited GC apoptosis in vitro. Intraperitoneal injection of LV-Slpi or sh-Slpi into C57BL/6J mice showed that Slpi accelerated pubertal initiation of mice in vivo. Collectively, our findings confirmed that developmental stage-specific loss of H3K27me3 at the SLPI promoter derepressed SLPI transcription, which in turn promoted porcine GC proliferation, suppressed apoptosis, and facilitated pubertal initiation in mice. These results provided valuable insights into the epigenetic regulation of pubertal initiation in mammals. Full article

The brain maintains homeostasis partially by scavenging waste products. Failure of this function is closely associated with the onset and pathogenesis of various brain diseases, such as Alzheimer’s disease, sleep disorder, and the delay of the reparative process after brain injuries. We recently demonstrated that brain pericytes (BPCs) are sources of lipocalin-type prostaglandin D synthase (L-PGDS), a waste scavenger, in the brain. Based on the above, chemical compounds which promote L-PGDS production could have potential against brain diseases, such as dementia, sleep disorders, and brain injuries. However, the specific chemical compounds that may enhance L-PGDS production in BPCs have not yet been identified. In this study, we explored 158 chemical compounds from FDA-approved drug libraries with these activities. qPCR analysis showed that mirtazapine (MTZ), a noradrenergic and specific serotonergic antidepressant, can increase L-PGDS expression in BPCs as well as in mouse- (m-BPCs) and human-derived BPCs (h-BPCs) in a dose-dependent manner. Since L-PGDS is a secretory protein, m-BPCs and h-BPCs were treated with various MTZ doses and L-PGDS levels in the culture supernatant were investigated. Western blot analysis showed that L-PGDS levels were significantly increased in a dose-dependent manner in both cell types, indicating that MTZ promoted L-PGDS secretion from m-BPCs and h-BPCs. Thus, MTZ may have the potential to be applied as drug repositioning for various brain diseases other than depression by activating L-PGDS production in BPCs, highlighting the importance of BPCs as the source to maintain brain homeostasis. Full article

Background/Objectives: Low milk production is more prevalent after preterm birth and may be associated with infrequent milk expression, delayed secretory activation and elevated milk biomarkers including sodium (Na) and sodium–potassium ratio (Na:K). This study aimed to describe milk production, expression frequency, and milk biomarkers (Na and Na:K) in the first 4 weeks and explore associations in the first 2 weeks after preterm birth. Methods: Women who birthed at 28–34 weeks of gestation provided milk expression data and milk samples every second day from birth to Day 10, then every third day until infant transfer/discharge from the neonatal unit. Lactation characteristics and milk Na and Na:K across the first 4 weeks were described, and associations between milk production, expression frequency and milk biomarkers were examined. Results: In a sample of N = 44 women that maintained a median expression frequency of 6–7 × 24 h, temporal patterns in milk Na and Na:K were similar to those observed after birth at term, and a milk production ≥ 600 mL/24 h was achieved by 61.5% on Day 13. One third of women experienced delayed secretory activation. Expression volumes on Day 4 were associated with milk production on Day 13 and Day 16 (both p < 0.001). Conclusions: Our findings suggest that low expression volumes in the days after preterm birth may indicate women at risk of low milk production. Further research is needed to determine the predictive value of early expression frequency and milk composition on subsequent milk production. Full article

Background/Objectives: Cardiac aging is characterized by increased oxidative stress and mitochondrial dysfunction in cardiomyocytes, leading to structural remodeling and functional decline. Polygonatum cyrtonema polysaccharides (PCPs), the principal active components derived from Polygonatum cyrtonema, exhibit well-documented antioxidant and anti-inflammatory effects. Despite this, their protective role against cardiac aging and the underlying molecular mechanisms remain largely unexplored. This study aimed to investigate the protective action of PCPs against D-galactose(D-gal)-induced cardiomyocyte senescence. Methods: In vitro, a cellular senescence model was established in H9c2 cardiomyocytes by D-gal induction to elucidate the effects of PCPs on senescence and mitochondrial dysfunction. In vivo, a mouse aging model was generated in C57BL/6J mice via continuous intraperitoneal injection of D-gal for three months to evaluate the ameliorative effects of PCPs on aging phenotypes and cardiac function. Results: PCPs enhanced the antioxidant capacity of cardiomyocytes, improved energy metabolism homeostasis, maintained mitochondrial integrity, thereby synergistically regulating key aging-related signaling pathways such as suppressing overactivation of the p53/p21 axis and downregulating the expression of the senescence-associated secretory phenotype, thereby effectively mitigating myocardial injury and delaying cellular senescence. Conclusions: This study demonstrates the anti-cardiac aging effects of PCPs at both cellular and animal levels, confirming that they protect cardiomyocytes by antagonizing oxidative stress, suppressing the p53/p21 pathway, and improving mitochondrial function. These findings provide an experimental basis for developing PCPs as a naturally sourced intervention against cardiac aging. Full article

Background: Cellular senescence is a state of irreversible cell cycle arrest that serves as a critical regulator of tissue homeostasis, aging, and disease. While transient senescence contributes to development, wound healing, and tumor suppression, chronic senescence drives inflammation, tissue dysfunction, and age-related pathologies, including cataracts. Lens epithelial cells (LECs), essential for maintaining lens transparency, are particularly vulnerable to oxidative stress-induced senescence, which accelerates lens aging and cataract formation. This review examines the dual role of senescence in LEC function and its implications for age-related cataractogenesis, alongside emerging senotherapeutic interventions. Methods: This review synthesizes findings on the molecular mechanisms of senescence, focusing on oxidative stress, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). It explores evidence linking LEC senescence to cataract formation, highlighting key studies on stress responses, DNA damage, and antioxidant defense. Recent advances in senotherapeutics, including senolytics and senomorphics, are analyzed for their potential to mitigate LEC senescence and delay cataract progression. Conclusions: LEC senescence is driven by oxidative damage, mitochondrial dysfunction, and impaired redox homeostasis. These factors activate senescence path-ways, including p53/p21 and p16/Rb, resulting in cell cycle arrest and SASP-mediated inflammation. The accumulation of senescent LECs reduces regenerative capacity, disrupts lens homeostasis, and contributes to cataractogenesis. Emerging senotherapeutics, such as dasatinib, quercetin, and metformin, show promise in reducing the senescent cell burden and modulating the SASP to preserve lens transparency. Full article

Objective: A pentacyclic triterpene, oleanolic acid (OA), has anti-inflammatory activity. The role of oleanolic acid in aging is poorly understood, and the regulatory mechanism of IGF-1 signaling in aging is still not fully understood. Thus, we hypothesized that OA could delay aging by regulating the PI3K/AKT/mTOR pathway via insulin-like growth factor-1 (IGF-1). Method: This study initially established a replicative aging model and a bleomycin-induced aging model in human dermal fibroblast (HDF) and mouse embryonic fibroblast (MEF) cell lines. On this basis, IGF-1 inhibitors or IGF-1 recombinant proteins were then combined with OA (at a concentration of 20 μM) and treated for 72 h. The project plans to detect the expression of aging-related proteins such as CDKN2A (p16) using Western blot technology, detect the expression of aging-related factors such as Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), and Interleukin-8 (IL-8) using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), Enzyme-Linked Immunosorbent Assay (ELISA), and other technologies, and combine Senescence-Associated β-Galactosidase (SA-β-gal) staining to detect changes in aging. Results: The expression of IGF-1, PI3K/AKT/mTOR, aging-related proteins P16, and aging-related secretory factors (SASP) IL-1β, IL-6, and IL-8 was increased in senescent cells. After treatment with jujuboside, the expression of IGF-1, PI3K/AKT/mTOR, aging-related protein P16, and aging-related secretory factors IL-1β, IL-6, and IL-8 were decreased. Conclusion: The findings suggested that OA slowed down aging by inhibiting the PI3K/AKT/mTOR expression through IGF-1. These findings suggest OA as a potential new drug and its mechanisms for anti-aging. Full article

Gestational diabetes mellitus (GDM) has been associated with suboptimal breastfeeding outcomes, including low milk supply, and the aetiology of this is not well understood. As postpartum frequency of milk removal is critical to the establishment of milk production, we compared the early feeding patterns of breastfeeding women with and without GDM. Women with GDM (n = 54) and without GDM (n = 54) provided detailed birth and feeding data within 48 hours of birth and at one and three weeks postpartum and measured their 24 h milk production. Sociodemographic characteristics were similar between groups (p > 0.05), and GDM was associated with an earlier birth gestation (38.5 ± 0.7 vs. 39.5 ± 0.2 weeks, p < 0.001). The median timing of breastfeeding initiation was < 1 h for both groups, yet breastfeeding frequency in the first 24 h was lower in the GDM group (5.9 ± 3.5 vs. 7.8 ± 4.4, p = 0.016). Both in-hospital commercial milk formula supplementation (57% vs. 26%, p < 0.001) and delayed secretory activation beyond day 4 postpartum (32% vs. 7%, p = 0.003) were more prevalent in the GDM group. Combined breastfeeding and breast expression frequencies were similar between groups in the first 24 h (p = 0.48) and at one week (p = 0.46) and three weeks postpartum (p = 0.05). Low milk production (<600 mL/24 h) was more prevalent in the GDM group, i.e., 19/50 (38%) compared to those without GDM, i.e., 8/50 (16%), (p = 0.006). Furthermore, four participants with GDM had weaned/withdrawn due to low milk supply, i.e., 23/54 (43%). The prevalence of low milk supply, despite frequent breastfeeding and breast expression across the first three weeks postpartum, suggests that endocrine factors may impair the autocrine control of milk production in some women with GDM. Full article

Anti-aging functional foods benefit the elderly. Telomeres are chromosomal ends that maintain genome stability extended by telomerase catalytic subunit TERT. Due to the end-replication problem, telomeres shorten after each cell cycle without telomerase in most human cells, and eventually the cell enters the senescence stage. Natural products can attenuate the aging process by increasing telomerase activity, such as TA-65. However, TA-65 is expensive. Other Chinese natural products may achieve comparable effects. Here, we found that Rosa roxburghii fruit extracts effectively increase TERT expression and telomerase activity in cultured human mesenchymal stem cells. Both R. roxburghii fruit extracts obtained by freeze-drying and spray-drying increased the activity of telomerase. R. roxburghii fruit extracts were able to reduce reactive oxygen species levels, enhance superoxide dismutase activity, and reduce DNA damage caused by oxidative stress or radiation. R. roxburghii fruit extracts promoted cell proliferation, improved senescent cell morphology, delayed replicative cellular senescence, attenuated cell cycle suppressors, and alleviated the senescence-associated secretory phenotype. Transcriptome and metabolic profiling revealed that R. roxburghii fruit extracts promote DNA replication and telomere maintenance pathways and decrease triglyceride levels. Overall, we provide a theoretical basis for the application of R. roxburghii fruit as an anti-aging product. Full article

Oral vaccines, unlike injected, induce intestinal secretory immunoglobulin A (sIgA) mimicking our natural defense against gut pathogens. We previously observed sIgA responses after administering the Clostridioides difficile colonisation factor CD0873 orally in enteric capsules to hamsters. Enteric-coated capsules are designed to resist dissolution in the stomach and disintegrate only at the higher pH of the small intestine. However, the variable responses between animals led us to speculate suboptimal transit of antigens to the small intestine. The rate of gastric emptying is a controlling factor in the passage of oral drugs for subsequent availability in the small intestine for absorption. Whilst in humans, food delays gastric emptying, in rats, capsules can empty quicker from fed stomachs than from fasted. To test in hamsters if fasting improves the delivery of antigens to the small intestine, as inferred from the immune responses generated, 24 animals were dosed intragastrically with enteric capsules containing recombinant CD0873. Twelve hamsters were fasted for 12 h prior to each dose and the other 12 fed. Significantly higher sIgA titres, with significantly greater bacterial-adherence-blocking activity, were detected in small intestinal lavages in the fasted group. We conclude that fasting in hamsters improves intestinal delivery leading to more robust responses. Full article

The myostatin (MSTN) gene also regulates the developmental balance of skeletal muscle after birth, and has long been linked to age-related muscle wasting. Many rodent studies have shown a correlation between MSTN and age-related diseases. It is unclear how MSTN and age-associated muscle loss in other animals are related. In this study, we utilized MSTN gene-edited bovine skeletal muscle cells to investigate the mechanisms relating to MSTN and muscle cell senescence. The expression of MSTN was higher in older individuals than in younger individuals. We obtained consecutively passaged senescent cells and performed senescence index assays and transcriptome sequencing. We found that senescence hallmarks and the senescence-associated secretory phenotype (SASP) were decreased in long-term-cultured myostatin inactivated (MT-KO) bovine skeletal muscle cells (bSMCs). Using cell signaling profiling, MSTN was shown to regulate the SASP, predominantly through the cycle GMP-AMP synthase-stimulator of antiviral genes (cGAS-STING) pathway. An in-depth investigation by chromatin immunoprecipitation (ChIP) analysis revealed that MSTN influenced three prime repair exonuclease 1 (TREX1) expression through the SMAD2/3 complex. The downregulation of MSTN contributed to the activation of the MSTN-SMAD2/3-TREX1 signaling axis, influencing the secretion of SASP, and consequently delaying the senescence of bSMCs. This study provided valuable new insight into the role of MSTN in cell senescence in large animals. Full article

The liver is the primary organ accountable for complex physiological functions, including lipid metabolism, toxic chemical degradation, bile acid synthesis, and glucose metabolism. Liver function homeostasis is essential for the stability of bodily functions and is involved in the complex regulation of the balance between cell proliferation and cell death. Cell proliferation-halting mechanisms, including autophagy and senescence, are implicated in the development of several liver diseases, such as cholestasis, viral hepatitis, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Among various cell death mechanisms, autophagy is a highly conserved and self-degradative cellular process that recycles damaged organelles, cellular debris, and proteins. This process also provides the substrate for further metabolism. A defect in the autophagy machinery can lead to premature diseases, accelerated aging, inflammatory state, tumorigenesis, and cellular senescence. Senescence, another cell death type, is an active player in eliminating premalignant cells. At the same time, senescent cells can affect the function of neighboring cells by secreting the senescence-associated secretory phenotype and induce paracrine senescence. Autophagy can promote and delay cellular senescence under different contexts. This review decodes the roles of autophagy and senescence in multiple liver diseases to achieve a better understanding of the regulatory mechanisms and implications of autophagy and senescence in various liver diseases. Full article

Auricularia auricula is a traditional medicinal and edible mushroom with anti-aging effects. Many studies focused on polysaccharides and melanin. However, the anti-aging effects and mechanism of the nutritional supplementation of Auricularia auricula peptides (AAPs) were not elucidated. In this study, AAPs were prepared by enzymolysis of flavor protease and the protective effects on H₂O₂-induced senescence of HepG2 cells were explored for the first time. The potential mechanism was also investigated. AAPs were mostly composed of low molecular weights with less than 1000 Da accounting for about 79.17%, and contained comprehensive amino acids nutritionally, including seven essential amino acids, aromatic, acidic, and basic amino acids. AAPs nutritional supplementation could significantly decrease the levels of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), and increase the activities of antioxidant enzymes (SOD, CAT, and GSH-Px). In addition, the senescence-associated-β-galactosidase (SA-β-gal) activity was restrained, and the expression levels of senescence-associated secretory phenotype (SASP) (IL-6, IL-8, IL-1β, and CXCL2) were also decreased. Ribonucleic acid sequencing (RNA-Seq) was carried out to screen the differentially expressed genes (DEGs) between different groups. GO and KEGG enrichment analysis showed that the mechanism was related to the MAPK/NF-κB signaling pathways. Quantitative real-time PCR (qRT-PCR) analysis and Western blot were carried out to verify the key genes and proteins in the pathways, respectively. AAPs nutritional supplementation resulted a significant down-regulation in key the genes c-fos and c-jun and up-regulation in DUSP1 of the MAPK signaling pathway, and down-regulation in the key genes CXCL2 and IL-8 of the NF-κB signaling pathway. The results of Western blot demonstrate that AAPs nutritional supplementation could inhibit MAPK/NF-κB pathways by reducing the expression levels of IKK, IκB, P65, and phosphorylation of ERK, thus decreasing the inflammatory reaction and delaying cell senescence. It is the first time that AAPs nutritional supplementation was proved to have protective effects on H₂O₂-induced oxidative damage in HepG2 cells. These results implicate that dietary AAPs could be used as nutrients to reduce the development or severity of aging. Full article

Accumulating evidence indicates that the increased burden of senescent cells (SCs) in aged organisms plays an important role in many age-associated diseases. The pharmacological elimination of SCs with “senolytics” has been emerging as a new therapy for age-related diseases and extending the healthy lifespan. In the present study, we identified that cycloastragenol (CAG), a secondary metabolite isolated from Astragalus membrananceus, delays age-related symptoms in mice through its senolytic activity against SCs. By screening a series of compounds, we found that CAG selectively kills SCs by inducing SCs apoptosis and that this process is associated with the inhibition of Bcl-2 antiapoptotic family proteins and the PI3K/AKT/mTOR pathway. In addition, CAG treatment also suppressed the development of the senescence-associated secretory phenotype (SASP) in SCs, thereby inhibiting cell migration mediated by the SASP. Furthermore, the administration of CAG for 2 weeks to mice with irradiation-induced aging alleviated the burden of SCs and improved the animals’ age-related physical dysfunction. Overall, our studies demonstrate that CAG is a novel senolytic agent with in vivo activity that has the potential to be used in the treatment of age-related diseases. Full article

Vascular aging is an important factor contributing to cardiovascular diseases, such as hypertension and atherosclerosis. Hyperlipidemia or fatty accumulation may play an important role in vascular aging and cardiovascular diseases. Canagliflozin (CAN), a sodium-glucose cotransporter inhibitor, can exert a cardiovascular protection effect that is likely independent of its hypoglycemic activities; however, the exact mechanisms remain undetermined. We hypothesized that CAN might have protective effects on blood vessels by regulating vascular aging induced by hyperlipidemia or fatty accumulation in blood vessel walls. In this study, which was undertaken on the basis of aging and inflammation, we investigated the protective effects and mechanisms of CAN in human umbilical vein endothelial cells induced by palmitic acid. We found that CAN could delay vascular aging, reduce the secretion of the senescence-associated secretory phenotype (SASP) and protect DNA from damage, as well as exerting an effect on the cell cycle of senescent cells. These actions likely occur through the attenuation of the excess reactive oxygen species (ROS) produced in vascular endothelial cells and/or down-regulation of the p38/JNK signaling pathway. In summary, our study revealed a new role for CAN as one of the sodium-dependent glucose transporter 2 inhibitors in delaying lipotoxicity-induced vascular aging by targeting the ROS/p38/JNK pathway, giving new medicinal value to CAN and providing novel therapeutic ideas for delaying vascular aging in patients with dyslipidemia. Full article

Continued breastfeeding attenuates maternal and infant risks associated with gestational diabetes mellitus (GDM), which may be more difficult after a GDM pregnancy, with reports of delayed secretory activation and reduced milk production. The total 24 h milk production cycle is not routinely measured; therefore, it is unclear whether reported low milk production is actual or perceived. We aimed to describe early lactation outcomes and 24 h milk production in women with GDM. Women with GDM-complicated pregnancies recorded early feeding practices. The 24 h cycle of milk production was measured at 3 weeks by weighing infants pre- and post-breastfeeds, as well as breast expression volumes. Electronic scales sensitive to 2 g were used. Low 24 h milk production was classified as <600 mL. For women with GDM (n = 40), the median time to the initiation of breastfeeding was 55 min, and delayed secretory activation (n = 24, 60%) was common. Most women achieved frequent milk removal (≥8 × 24 h) in the first 24 h after birth (n = 27, 68%) was at one week (n = 38, 95%) and three weeks postpartum (n = 36, 90%). However, median 24 h milk production was 639 mL (range 100–1220 mL), with low milk production measured in n = 16 (40%, range 100–592 mL). Conclusions: Delayed secretory activation and low milk production are more common in women with GDM despite regular milk removal from the breast, suggesting that altered endocrine pathways inherent to GDM may be implicated. Full article