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Stem cell senescence is an important cause of aging. Delaying senescence may present a novel way to combat aging and age‐associated diseases. This study provided a mechanistic insight into the protective effect of ganoderic acid D (GA‐D) against human amniotic mesenchymal stem cell (hAMSCs) senescence. GA‐D, a Ganoderma lucidum‐derived triterpenoid, markedly prevented hAMSCs senescence via activating the Ca2+ calmodulin (CaM)/CaM‐dependent protein kinase II (CaMKII)/nuclear erythroid 2‐related factor 2 (Nrf2) axis, and 14‐3‐3ε was identified as a target of GA‐D. 14‐3‐3ε‐encoding gene (YWHAE) knockdown in hAMSCs reversed the activation of the CaM/CaMKII/Nrf2 signals to attenuate the GA‐D anti‐aging effect and increase senescence‐associated β‐galactosidase (SA‐β‐gal), p16 and p21 expression levels, including reactive oxygen species (ROS) production, thereby promoting cell cycle arrest and decreasing differentiation potential. YWHAE overexpression maintained or slightly enhanced the GA‐D anti‐aging effect. GA‐D prevented d‐galactose‐caused aging in mice by significantly increasing the total antioxidant capacity, as well as superoxide dismutase and glutathione peroxidase activity, and reducing the formation of malondialdehyde, advanced glycation end products, and receptor of advanced glycation end products. Consistent with the protective mechanism of GA‐D against hAMSCs senescence, GA‐D delayed the senescence of bone‐marrow mesenchymal stem cells in this aging model in vivo, reduced SA‐β‐gal and ROS production, alleviated cell cycle arrest, and enhanced cell viability and differentiation via regulating 14‐3‐3ε and CaM/CaMKII/Nrf2 axis. Therefore, GA‐D retards hAMSCs senescence by targeting 14‐3‐3ε to activate the CaM/CaMKII/Nrf2 signaling pathway. Furthermore, the in vivo GA‐D anti‐aging effect may involve the regulation of stem cell senescence via the same signal axis. GA‐D prevents MSC senescence via regulating 14‐3‐3e to activate the CaM/CaMKII/Nrf2 pathway; GA‐D prevents d‐gal‐caused aging in mice by enhancing antioxidative defense and retards the BMSCs senescence in d‐gal‐caused aging mice; GA‐D may be a potential anti‐aging agent.

Diabetic retinopathy (DR) is the leading cause of blindness among working‐age adults, yet its pathogenesis remains incompletely understood. The retinal pigment epithelium (RPE) plays a vital role in maintaining retinal homeostasis. In this study, the expression of senescence marker protein p16 is observed to be upregulated in the RPE of early DR mouse models. Transcriptomic profiling reveals that PDZ domain protein 1 (PDZK1) expression is downregulated in RPE cells after 48 hours of high‐glucose stimulation. Overexpression of PDZK1 reduces senescence markers in RPE cells, promoting cell proliferation and transport functions. Mechanistically, PDZK1 alleviates RPE cell senescence by interacting with 14‐3‐3ε to regulate the mTOR pathway, which is closely related to reducing oxidative stress and enhancing autophagy flux. In streptozotocin‐induced DR mouse models, both PDZK1 overexpression‐mediated senescence inhibition and Nutlin‐3a‐induced clearance of senescent RPE cells successfully downregulate retinal senescence markers and improve early‐stage DR lesions. In summary, this study identifies a novel PDZK1‐14‐3‐3ε‐mTOR axis governing high‐glucose‐induced RPE cell senescence, and provides the first direct evidence linking RPE cell senescence to DR pathogenesis. These findings reveal a promising therapeutic strategy for DR intervention. PDZK1 down‐regulation couples high‐glucose stress to RPE senescence via a PDZK1–14‐3‐3ε–mTOR axis. Restoring PDZK1 or clearing senescent cells rescues retinal homeostasis and mitigates early diabetic retinopathy (DR). This study provides direct evidence linking RPE cell senescence to DR pathogenesis and reveals a promising therapeutic strategy for DR intervention.

Breast cancer is the most common female‐specific malignancy in Taiwan and developed countries worldwide, and its incidence continues to grow. 14‐3‐3ε (YWHAE), which belong to 14‐3‐3 family, it has been reported up‐regulated in breast cancer tissues. However, the clinical implication and function of YWHAE in breast cancer remains unclear. In this study, we investigated the prognostic value of the YWHAE in human breast cancer. Immunohistochemistry was used to analyze YWHAE expression in breast cancer tissues. Cell model was applied to examine the functions of YWHAE. The chemotherapeutic agents were used to evaluate the effect of YWHAE in breast cancer cell lines. YWHAE expression was associated with tumor size, lymph node metastasis, and poor patient survival in patients with breast cancer. YWHAE overexpression significantly increased the proliferation, migration, and invasion abilities of breast cancer cells. Knockdown of YWHAE expression reduced the expression of Snail and Twist in breast cancer cells. We also found that YWHAE was responsible for the resistance of breast cancer cells to chemotherapeutic agents, and knockdown of YWHAE enhanced sensitivity to multiple chemotherapeutic agents in breast cancer cells. Taken together, our findings indicated that YWHAE promoted cancer progression and chemoresistance in breast cancer cells and can be a potential therapeutic target for breast cancer.

4‐amino‐2‐trifluoromethyl‐phenyl retinate (ATPR) was able to induce the G0/G1 phase arrest in gastric cancer SGC‐7901 cells by downregulating 14‐3‐3ε. However, the mechanisms underlying this effect have not been fully elucidated. Because 14‐3‐3ε functions as a molecular chaperone on cell cycle regulation, the interaction between 14‐3‐3ε and the target proteins is worth an in‐depth study. In this study, the use of targeting proteomics identified 352 14‐3‐3ε‐binding proteins in SGC‐7901 cells. Analysis of gene ontology (GO) was performed using PANTHER to annotate the biological processes, protein classes, and pathways of these proteins. In 25 cell cycle‐related proteins, filamin A was reduced following ATPR treatment, and this change was validated by immunoprecipitation. The cell cycle was arrested at the G0/G1 phase following ATPR treatment or filamin A silencing in SGC‐7901 cells. Furthermore, subcellular expression analysis showed that 14‐3‐3ε and filamin A were transferred from the cytoplasm to the nucleus after ATPR treatment. On the other hand, overexpression of 14‐3‐3ε, in SGC‐7901 cells, resulted in an increase in the total cellular level of filamin A and an increase in the subcellular localization of filamin A in the cytoplasm. ATPR treatment of the 14‐3‐3ε overexpression cells decreased the total level of filamin A and redistributed filamin A protein from the cytoplasm to the nucleus. Immunohistochemical analysis showed that the expression levels of 14‐3‐3ε and filamin A in gastric cancer tissues were significantly higher, with a predominant localization in the cytoplasm, compared to the levels in matched tissues. Taken together, our results suggest that ATPR can induce nuclear localization of filamin A by reducing the binding of 14‐3‐3ε and filamin A, which may be the mechanism of ATPR‐induced G0/G1 phase arrest. Our results suggest that ATPR can induce nuclear localization of filamin A by reducing the binding of 14‐3‐3ε and filamin A, which may be the mechanism of ATPR‐induced G0/G1 phase arrest. The overexpression of 14‐3‐3ε and filamin A proteins highly correlated with the occurrence of gastric cancer.

Poly(A) polymerase (PAP) is a key enzyme responsible for the addition of the poly(A) at the 3′ end of pre‐mRNA. The C‐terminal region of mammalian PAP carries target sites for protein–protein interaction with the 25 kDa subunit of cleavage factor I and with splicing factors U1A and U2AF65. We used a yeast two‐hybrid screen to identify 14‐3‐3ϵ as an additional protein binding to the C‐terminal region of PAP. Interaction between PAP and 14‐3‐3ϵ was confirmed by both in vitro and in vivo binding assays. This interaction is dependent on PAP phosphorylation. Deletion analysis of PAP suggests that PAP contains multiple binding sites for 14‐3‐3ϵ. The binding of 14‐3‐3ϵ to PAP inhibits the polyadenylation activity of PAP in vitro , and overexpression of 14‐3‐3ϵ leads to a shorter poly(A) mRNA tail in vivo . In addition, the interaction between PAP and 14‐3‐3ϵ redistributes PAP within the cell by increasing its cytoplasmic localization. These data suggest that 14‐3‐3ϵ is involved in regulating both the activity and the nuclear/ cytoplasmic partitioning of PAP through the phosphorylation‐dependent interaction.