Testis-specific H2B.W1 disrupts nucleosome integrity by reducing DNA-histone interactions.

Multiple testis-specific histone variants are involved in the dynamic chromatin transitions during spermatogenesis. H2B.W1 (previously called H2BFWT) is an H2B variant specific to primate testis with hitherto unclear functions, although its single-nucleotide polymorphisms (SNPs) are closely associated with male non-obstructive infertility. Here, we found that H2B.W1 is only expressed in the mid-late spermatogonia stages, and H2B.W1 nucleosomes are defined by a more flexible structure originating from weakened interactions between histones and DNA. Furthermore, one of its SNPs, H2B.W1-H100R, which is associated with infertility, further destabilizes the nucleosomes and increases the nucleosome unwrapping rate by interfering with the R100 and H4 K91/R92 interaction. Our results suggest that destabilizing H2B.W1 containing nucleosomes might change the chromatin structure of spermatogonia, and that H2B.W1-H100R enhances the nucleosome-destabilizing effects, leading to infertility.

Ailanthone ameliorates pulmonary fibrosis by suppressing JUN-dependent MEOX1 activation.

Pulmonary fibrosis poses a significant health threat with very limited therapeutic options available. In this study, we reported the enhanced expression of mesenchymal homobox 1 (MEOX1) in pulmonary fibrosis patients, especially in their fibroblasts and endothelial cells, and confirmed MEOX1 as a central orchestrator in the activation of profibrotic genes. By high-throughput screening, we identified Ailanthone (AIL) from a natural compound library as the first small molecule capable of directly targeting and suppressing MEOX1. AIL demonstrated the ability to inhibit both the activation of fibroblasts and endothelial-to-mesenchymal transition of endothelial cells when challenged by transforming growth factor-ß1 (TGF-ß1). In an animal model of bleomycin-induced pulmonary fibrosis, AIL effectively mitigated the fibrotic process and restored respiratory functions. Mechanistically, AIL acted as a suppressor of MEOX1 by disrupting the interaction between the transcription factor JUN and the promoter of MEOX1, thereby inhibiting MEOX1 expression and activity. In summary, our findings pinpointed MEOX1 as a cell-specific and clinically translatable target in fibrosis. Moreover, we demonstrated the potent anti-fibrotic effect of AIL in pulmonary fibrosis, specifically through the suppression of JUN-dependent MEOX1 activation.

Structure of tetrameric forms of the serotonin-gated 5-HT3A receptor ion channel.

Multimeric membrane proteins are produced in the endoplasmic reticulum and transported to their target membranes which, for ion channels, is typically the plasma membrane. Despite the availability of many fully assembled channel structures, our understanding of assembly intermediates, multimer assembly mechanisms, and potential functions of non-standard assemblies is limited. We demonstrate that the pentameric ligand-gated serotonin 5-HT3A receptor (5-HT3AR) can assemble to tetrameric forms and report the structures of the tetramers in plasma membranes of cell-derived microvesicles and in membrane memetics using cryo-electron microscopy and tomography. The tetrameric structures have near-symmetric transmembrane domains, and asymmetric extracellular domains, and can bind serotonin molecules. Computer simulations, based on our cryo-EM structures, were used to decipher the assembly pathway of pentameric 5-HT3R and suggest a potential functional role for the tetrameric receptors.

Personalized mRNA vaccine combined with PD-1 inhibitor therapy in a patient with advanced esophageal squamous cell carcinoma.

Therapeutic cancer vaccines are valuable tools for educating the immune system to fight tumors precisely. Cancer cells are characterized with genetic instability and abundant somatic mutations, leading to the production of tumor specific antigens (TSA) called neoantigens. The main goal of neoantigen-based cancer vaccines is to activate the immune system and elicit effective tumor-specific T-cell responses. There have been no reports of advanced esophageal squamous cell carcinoma (ESCC) cases achieving partial remission after personalized mRNA (messenger RNA) vaccine treatment. As personalized neoantigen-based immunotherapies are emerging, here we report a 67-year-old male patient diagnosed with ESCC and multiple enlarged mediastinal lymph nodes, where mRNA vaccines were used for the first time. Tissue samples from the recurrence focus in the esophagus were subjected to whole transcriptome sequencing. The neoantigens were identified by bioinformatics analyses. The top 20 neoantigens were selected to compose the polyneoantigen vaccine, which were administered at 1 mg every 3 weeks for 4 cycles in combination with a PD-1 (programmed death-1) inhibitor. The patient was boosted with a single dose of the PD-1 inhibitor 8 weeks after the 4th cycle. In addition, immune responses were evaluated before and after the 4 cycles of vaccine therapy, and the lesions were evaluated by imaging examination. Our results revealed that neoantigen-based vaccines significantly activated the tumour-specific immune response. TCR (T cell receptor) V-J pairing analysis showed an increase in the abundance of oligoclonal TCRs, indicating improved homogeneity. No grade 3 or higher drug-related adverse events were observed, except for grade 4 thrombocytopenia caused by PD-1 inhibitor treatment. The patient achieved a partial response (PR), with a progression-free survival (PFS) time of 457 days, the OS (overall survival) time of 457 days, and DOR (duration of response) of 377 days. Our report suggests that combining the personalized mRNA vaccine therapy with PD-1 blockade therapy may be an effective treatment strategy for patient with advanced esophageal cancer. However, further clinical trials are necessary to confirm the efficacy and safety of personalized neoantigen-based immunotherapies in the treatment of advanced ESCC. This trial is registered with ClinicalTrials.gov, NCT03468244 on March 16, 2018, and is now complete.

Testosterone-Induced H3K27 Deacetylation Participates in Granulosa Cell Proliferation Suppression and Pathogenesis of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the leading cause of infertility in reproductive-age women. Hyperandrogenism, polycystic ovaries, and chronic anovulation are its typical clinical features. However, the correlation between hyperandrogenism and ovarian follicle growth aberrations remains undisclosed. To advance our understanding of the molecular alterations in ovarian granulosa cells (GCs) with excessive androgen, epigenetic changes and affected gene expression in human granulosa-lutein cells and immortalized human GCs were evaluated. A PCOS mouse model induced by dihydrotestosterone was also established. This study found excessive testosterone significantly decreased the acetylation of lysine 27 on histone H3 (H3K27ac). H3K27ac chromatin immunoprecipitation- sequencing data showed down-regulated expression of cell cycle-related genes (CCND1/CCND3/PCNA), which was confirmed by real-time quantitative PCR and Western blot analysis. Testosterone application impeding cell proliferation was also proved by Ki-67 immunofluorescence and flow-cytometric analysis. Moreover, testosterone influenced CK2α nuclear translocation, which increased the phosphorylation level of histone deacetylase 2 (HDAC2). Inhibition of CK2α nuclear translocation or silenced HDAC2 expression efficiently retarded H3K27 acetylation. Meanwhile, PCOS mouse model experiments also demonstrated decreased H3K27ac and enhanced HDAC2 phosphorylation in GCs. Cell proliferation-related genes were also down-regulated in PCOS mouse GCs. In conclusion, hyperandrogenism in human and mouse GCs caused H3K27Ac aberrations, which are associated with CK2α nuclear translocation and HDAC2 phosphorylation, participating in abnormal follicle development in patients with PCOS.

Transiently formed nucleus-to-cilium microtubule arrays mediate senescence initiation in a KIFC3-dependent manner.

Despite the importance of cellular senescence in human health, how damaged cells undergo senescence remains elusive. We have previously shown that promyelocytic leukemia nuclear body (PML-NBs) translocation of the ciliary FBF1 is essential for senescence induction in stressed cells. Here we discover that an early cellular event occurring in stressed cells is the transient assembly of stress-induced nucleus-to-cilium microtubule arrays (sinc-MTs). The sinc-MTs are distinguished by unusual polyglutamylation and unique polarity, with minus-ends nucleating near the nuclear envelope and plus-ends near the ciliary base. KIFC3, a minus-end-directed kinesin, is recruited to plus-ends of sinc-MTs and interacts with the centrosomal protein CENEXIN1. In damaged cells, CENEXIN1 co-translocates with FBF1 to PML-NBs. Deficiency of KIFC3 abolishes PML-NB translocation of FBF1 and CENEXIN1, as well as senescence initiation in damaged cells. Our study reveals that KIFC3-mediated nuclear transport of FBF1 along polyglutamylated sinc-MTs is a prerequisite for senescence induction in mammalian cells.

Comparative global profiling of Perilla leaf and stem via transcriptomics and metabolomics.

Perilla (Perilla frutescens L.) is a time-honored herbal plant with widespread applications in both medicine and culinary practices around the world. Profiling the essential organs and tissues with medicinal significance on a global scale offers valuable insights for enhancing the yield of desirable compounds in Perilla and other medicinal plants. In the present study, genome-wide RNA-sequencing (RNA-seq) and assessing the global spectrum of metabolites were carried out in the two major organs/tissues of stem (PfST) and leaf (PfLE) in Perilla. The results showed a total of 18,490 transcripts as the DEGs (differentially expressed genes) and 144 metabolites as the DAMs (differentially accumulated metabolites) through the comparative profiling of PfST vs PfLE, and all the DEGs and DAMs exhibited tissue-specific trends. An association analysis between the transcriptomics and metabolomics revealed 14 significantly enriched pathways for both DEGs and DAMs, among which the pathways of Glycine, serine and threonine metabolism (ko00260), Glyoxylate and dicarboxylate metabolism (ko00630), and Glucagon signaling pathway (ko04922) involved relatively more DEGs and DAMs. The results of qRT-PCR assays of 18 selected DEGs confirmed the distinct tissue-specific characteristics of all identified DEGs between PfST and PfLE. Notably, all eight genes associated with the flavonoid biosynthesis/metabolism pathways exhibited significantly elevated expression levels in PfLE compared to PfST. This observation suggests a heightened accumulation of metabolites related to flavonoids in Perilla leaves. The findings of this study offer a comprehensive overview of the organs and tissues in Perilla that have medicinal significance.

Regulation of cancer cell ferroptosis by PTRF/Cavin-1.

Ovarian cancer, marked by high rate of recurrence, novel therapeutic strategies are needed to improve patient outcome. One of the potential strategies is inducing ferroptosis in ovarian cancer cells. Ferroptosis is an iron-dependent, lipid peroxidation-driven mode of cell death primarily occurring on the cell membrane. PTRF, an integral component of the caveolae structures located on the cell membrane, is involved in a multitude of physiological processes, including but not limited to, endocytosis, signal transduction, and lipid metabolism. This study elucidates the relationship between PTRF and ferroptosis in ovarian cancer, offering a fresh perspective for the development of new therapeutic strategies. We knocked down PTRF employing siRNA in the ovarian cancer cell lines HEY and SKOV3, following which we stimulated ferroptosis with Erastin (Era). Our research indicates that the lack of PTRF sensitizes cancer cells to ferroptosis, likely by altering membrane stability and tension, thereby affecting signal pathways related to ferroptosis, such as lipid and atherosclerosis, fluid shear stress, and atherosclerosis. Our findings provide new insights for developing new treatments for ovarian cancer.

EIF2S2 transcriptionally upregulates HIF1α to promote gastric cancer progression via activating PI3K/AKT/mTOR pathway.

Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) is a protein that controls protein synthesis under various stress conditions and is abnormally expressed in several cancers. However, there is limited insight regarding the expression and molecular role of EIF2S2 in gastric cancer. In this study, we identified the overexpression of EIF2S2 in gastric cancer by immunohistochemical (IHC) staining and found a positive correlation between EIF2S2 expression and shorter overall survival and disease-free survival. Functionally, we revealed that EIF2S2 knockdown suppressed gastric cancer cell proliferation and migration, induced cell apoptosis, and caused G2 phase cell arrest. Additionally, EIF2S2 is essential for in vivo tumor formation. Mechanistically, we demonstrated that EIF2S2 transcriptionally regulated hypoxia induicible factor-1 alpha (HIF1α) expression by NRF1. The promoting role of EIF2S2 in malignant behaviors of gastric cancer cells depended on HIF1α expression. Furthermore, the PI3K/AKT/mTOR signaling was activated upon EIF2S2 overexpression in gastric cancer. Collectively, EIF2S2 exacerbates gastric cancer progression via targeting HIF1α, providing a fundamental basis for considering EIF2S2 as a potential therapeutic target for gastric cancer patients.

Genetic Engineering Bacillus thuringiensis Enable Melanin Biosynthesis for Anti-Tumor and Anti-Inflammation.

Collaboration between cancer treatment and inflammation management has emerged as an integral facet of comprehensive cancer care. Nevertheless, the development of interventions concurrently targeting both inflammation and cancer has encountered significant challenges stemming from various external factors. Herein, a bioactive agent synthesized by genetically engineering melanin-producing Bacillus thuringiensis (B. thuringiensis) bacteria, simultaneously achieves eco-friendly photothermal agent and efficient reactive oxygen/nitrogen species (RONS) scavenger benefits, perfectly tackling present toughies from inflammation to cancer therapies. The biologically derived melanin exhibits exceptional photothermal-conversion performance, facilitating potent photonic hyperthermia that effectively eradicates tumor cells and tissues, thereby impeding tumor growth. Additionally, the RONS-scavenging properties of melanin produced by B. thuringiensis bacteria contribute to inflammation reduction, augmenting the efficacy of photothermal tumor repression. This study presents a representative paradigm of genetic engineering in B. thuringiensis bacteria to produce functional agents tailored for diverse biomedical applications, encompassing inflammation and cancer therapy.

Liquid-Metal-Based Spin-Coating Exfoliation for Atomically Thin Metal Oxide Synthesis.

Two-dimensional (2D) semiconductors possess exceptional electronic, optical, and magnetic properties, making them highly desirable for widespread applications. However, conventional mechanical exfoliation and epitaxial growth methods are insufficient in meeting the demand for atomically thin films covering large areas while maintaining high quality. Herein, leveraging liquid metal oxidation reaction, we propose a motorized spin-coating exfoliation strategy to efficiently produce large-area 2D metal oxide (2DMO) semiconductors with high crystallinity, atomically thin thickness, and flat surfaces on diverse substrates. Moreover, we realized a 2D gallium oxide-based deep ultraviolet solar-blind photodetector featuring a metal-semiconductor-metal structure, showcasing high responsivity (8.24 A W-1) at 254 nm and excellent sensitivity (4.3 × 1012 cm Hz1/2 W-1). This novel liquid-metal-based spin-coating exfoliation strategy offers great potential for synthesizing atomically thin 2D semiconductors, opening new avenues for future functional electronic and optical applications.

CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to prevent DNA hypermethylation and ensure normal transcription in growing oocytes.

The DNA methylation is gradually acquired during oogenesis, a process sustained by successful follicle development. However, the functional roles of methyl-CpG-binding protein 2 (MeCP2), an epigenetic regulator displaying specifical binding with methylated DNA, remains unknown in oogenesis. In this study, we found MeCP2 protein was highly expressed in primordial and primary follicle, but was almost undetectable in secondary follicles. However, in aged ovary, MeCP2 protein is significantly increased in both oocyte and granulosa cells. Overexpression of MeCP2 in growing oocyte caused transcription dysregulation, DNA hypermethylation, and genome instability, ultimately leading to follicle growth arrest and apoptosis. MeCP2 is targeted by DCAF13, a substrate recognition adaptor of the Cullin 4-RING (CRL4) E3 ligase, and polyubiquitinated for degradation in both cells and oocytes. Dcaf13-null oocyte exhibited an accumulation of MeCP2 protein, and the partial rescue of follicle growth arrest induced by Dcaf13 deletion was observed following MeCP2 knockdown. The RNA-seq results revealed that large amounts of genes were regulated by the DCAF13-MeCP2 axis in growing oocytes. Our study demonstrated that CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to ensure normal DNA methylome and transcription in growing oocytes. Moreover, in aged ovarian follicles, deceased DCAF13 and DDB1 protein were observed, indicating a potential novel mechanism that regulates ovary aging.

Evaluation of laboratory and environmental exposure systems for protein modification upon gas pollutants and environmental factors.

Chemical modifications of proteins induced by ambient ozone (O3) and nitrogen oxides (NOx) are of public health concerns due to their potential to trigger respiratory diseases. The laboratory and environmental exposure systems have been widely used to investigate their relevant mechanism in the atmosphere. Using bovine serum albumin (BSA) as a model protein, we evaluated the two systems and aimed to reduce the uncertainties of both the reactants and products in the corresponding kinetic study. In the laboratory simulation system, the generated gaseous pollutants showed negligible losses. Ten layers of BSA were coated on the flow tube with protein extraction recovery of 87.4%. For environmental exposure experiment, quartz fiber filter was selected as the upper filter with low gaseous O3 (8.0%) and NO2 (1.7%) losses, and cellulose acetate filter was appropriate for the lower filter with protein extraction efficiency of 95.2%. The protein degradation process was observed without the exposure to atmospheric oxidants and contributed to the loss of protein monomer mass fractions, while environmental factors (e.g., molecular oxygen and ultraviolet) may cause greater protein monomer losses. Based on the evaluation, the study exemplarily applied the two systems to protein modification and both showed that O3 promotes the protein oligomerization and nitration, while increased temperature can accelerate the oligomerization and increased relative humidity can inhibit the nitration in the environmental exposure samples. The developed laboratory and environmental systems are suitable for studying protein modifications formed under different atmospheric conditions. A combination of the two will further reveal the actual mechanism of protein modifications.

Multiphase reactions of proteins in the air: Oligomerization, nitration and degradation of bovine serum albumin upon ambient exposure.

Proteins in atmospheric aerosol can react with atmospheric pollutants such as ozone (O3) and nitrogen dioxide (NO2) in the atmosphere via the reactions of oxidation, nitration, and cross-linking etc. Currently, the reactions have been more thoroughly studied in the laboratory but rarely investigated in the ambient environment. In this study, we used bovine serum albumin (BSA) as the model protein to conduct the exposure experiment in the ambient environment in southern China, an area with increasing oxidative capacity, to investigate the reactions of proteins in the atmosphere. We observed the occurrence of oligomerization, nitration and degradation of BSA upon exposure. The mass fraction of BSA monomer decreased by 5.86 ± 1.61% after exposure and those of dimers, trimers and higher oligomers increased by 1.04 ± 0.49%, 1.37 ± 0.74% and 3.40 ± 1.06%, respectively. Simultaneously, the nitration degrees of monomers, dimers, trimers and higher oligomers increased by 0.42 ± 0.15%, 0.53 ± 0.15%, 0.55 ± 0.28% and 2.15 ± 1.01%, respectively. The results show that oligomerization was significantly affected by O3 and temperature and nitration was jointly affected by O3, temperature and relative humidity, indicating the important role of atmospheric oxidants in the atmospheric reactions of protein. Atmospheric degradation of BSA was observed with the release of free amino acids (FAAs) such as glycine, alanine, serine and methionine. Glycine was the dominant FAA with a molar yield ranging from ∼8% to 33% for BSA. The estimated stoichiometric coefficient (α) of glycine is 10-7-10-6 for the degradation of BSA upon O3. Our observation suggests the occurrence of protein reactions in the oxidative ambient environment, leading to the production of nitrated products, oligomers and low molecular weight products such as peptides and FAAs. This study may deepen the current understanding of the atmospheric reaction mechanisms and reveal the influence of environmental factors in the atmosphere.

Laparoscopic treatment of a patient with multiple organ dysfunction syndrome induced by necrotising fasciitis.

Necrotising fasciitis (NF) is an uncommon surgical emergency that threatens the life and health of patients. We report the treatment of a 76-year-old female patient with NF. The patient developed NF due to chronic poor glycaemic control, which further progressed to multiple organ dysfunction syndrome due to the severity of the hyperglycaemia. After resuscitation at the intensive care unit, surgical treatment was recommended and the patient underwent laparoscopic surgery. She had an uneventful post-operative recovery with aggressive anti-inflammatory therapy, glycaemic control and systemic nutritional support. There were no recurrences during the next 6 months of follow-up. NF should be diagnosed and treated as early as possible to gain valuable treatment time for the patient. Laparoscopic surgery is a treatment option.

Parental histone transfer caught at the replication fork.

In eukaryotes, DNA compacts into chromatin through nucleosomes1,2. Replication of the eukaryotic genome must be coupled to the transmission of the epigenome encoded in the chromatin3,4. Here we report cryo-electron microscopy structures of yeast (Saccharomyces cerevisiae) replisomes associated with the FACT (facilitates chromatin transactions) complex (comprising Spt16 and Pob3) and an evicted histone hexamer. In these structures, FACT is positioned at the front end of the replisome by engaging with the parental DNA duplex to capture the histones through the middle domain and the acidic carboxyl-terminal domain of Spt16. The H2A-H2B dimer chaperoned by the carboxyl-terminal domain of Spt16 is stably tethered to the H3-H4 tetramer, while the vacant H2A-H2B site is occupied by the histone-binding domain of Mcm2. The Mcm2 histone-binding domain wraps around the DNA-binding surface of one H3-H4 dimer and extends across the tetramerization interface of the H3-H4 tetramer to the binding site of Spt16 middle domain before becoming disordered. This arrangement leaves the remaining DNA-binding surface of the other H3-H4 dimer exposed to additional interactions for further processing. The Mcm2 histone-binding domain and its downstream linker region are nested on top of Tof1, relocating the parental histones to the replisome front for transfer to the newly synthesized lagging-strand DNA. Our findings offer crucial structural insights into the mechanism of replication-coupled histone recycling for maintaining epigenetic inheritance.

Metallo-supramolecular branched polymer protects particles from air-water interface in single-particle cryo-electron microscopy.

Recent technological breakthroughs in single-particle cryo-electron microscopy (cryo-EM) enable rapid atomic structure determination of biological macromolecules. A major bottleneck in the current single particle cryo-EM pipeline is the preparation of good quality frozen cryo-EM grids, which is mostly a trial-and-error process. Among many issues, preferred particle orientation and sample damage by air-water interface (AWI) are common practical problems. Here we report a method of applying metallo-supramolecular branched polymer (MSBP) in the cryo-sample preparation for high-resolution single-particle cryo-EM. Our data shows that MSBP keeps a majority of particles away from air-water interface and mitigates preferred orientation as verified by the analyses of apoferritin, hemagglutinin) trimer and various sample proteins. The use of MSBP is a simple method to improve particle distribution for high-resolution structure determination in single-particle cryo-EM.

Diagnostic value of serum dia in acute myocardial infarction and aortic dissection in athletic patients and those with optimal physical health

Objective: To explore the relationship between serum lipoprotein (a) levels and acute myocardial infarction (AMI) and aortic dissection in athletic patients and those with optimal physical health. Methods: This study involved 216 athletic patients admitted to a Chinese hospital for AMI who underwent Percutaneous Coronary Intervention (PCI) between 2018 and 2019. These patients, characterized by their athletic background and optimal physical health, were divided based on their serum lipoprotein (a) levels: 133 in the low-lipoprotein (a) group (<300 mg/L) and 83 in the high-lipoprotein (a) group (≥300 mg/L). Data including baseline demographics, laboratory tests, and details of interventional treatment were collected from medical records. All patients were followed up for two years post-discharge to record Major Adverse Cardiac Events (MACE). Factors influencing MACE were analyzed using univariate and multivariate logistic regression. Results: The low lipoprotein (a) group exhibited lower age, reduced Killip grades III-IV, lower LDL-C levels, and fewer diseased vessels than the high lipoprotein (a) group (P><0.05). The incidence of MACE was significantly lower in the low lipoprotein (a) group (5.3%, 7/133) compared to the high lipoprotein (a) group (27.87%, 51/183) (P><0.05). Univariate analysis identified significant differences in age, post-surgery β-blocker use, LDL-C levels, serum lipoprotein (a) levels, revascularization strategies, and the> <3 00 mg/L) and 83 in the high-lipoprotein (a) group (≥300 mg/L). Data including baseline demographics, laboratory tests, and details of interventional treatment were collected from medical records. All patients were followed up for two years post-discharge to record Major Adverse Cardiac Events (MACE). Factors influencing MACE were analyzed using univariate and multivariate logistic regression (AU)

Targeting cellular senescence in senile osteoporosis: therapeutic potential of traditional Chinese medicine.

Senile osteoporosis (SOP) is a prevalent manifestation of age-related bone disorders, resulting from the dysregulation between osteoblast (OB)-mediated bone formation and osteoclast (OC)-mediated bone resorption, coupled with the escalating burden of cellular senescence. Traditional Chinese medicine (TCM) herbs, renowned for their remarkable attributes encompassing excellent tolerability, low toxicity, heightened efficacy, and minimal adverse reactions, have gained considerable traction in OP treatment. Emerging evidence substantiates the therapeutic benefits of various TCM formulations and their active constituents, including Zuogui wan, Fructus Ligustri Lucidi, and Resveratrol, in targeting cellular senescence to address SOP. However, a comprehensive review focusing on the therapeutic efficacy of TCM against SOP, with a particular emphasis on senescence, is currently lacking. In this review, we illuminate the pivotal involvement of cellular senescence in SOP and present a comprehensive exploration of TCM formulations and their active ingredients derived from TCM, delineating their potential in SOP treatment through their anti-senescence properties. Notably, we highlight their profound effects on distinct aging models that simulate SOP and various senescence characteristics. Finally, we provide a forward-looking discussion on utilizing TCM as a strategy for targeting cellular senescence and advancing SOP treatment. Our objective is to contribute to the unveiling of safer and more efficacious therapeutic agents for managing SOP.

The EZH2-H3K27me3 axis modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury.

Chemotherapy-induced ovarian damage and infertility are significant concerns for women of childbearing age with cancer; however, the underlying mechanisms are still not fully understood. Our study has revealed a close association between epigenetic regulation and cyclophosphamide (CTX)-induced ovarian damage. Specifically, CTX and its active metabolite 4-hydroperoxy cyclophosphamide (4-HC) were found to increase the apoptosis of granulosa cells (GCs) by reducing EZH2 and H3K27me3 levels, both in vivo and in vitro. Furthermore, RNA-seq and CUT&Tag analyses revealed that the loss of H3K27me3 peaks on promoters led to the overactivation of genes associated with transcriptional regulation and apoptosis, indicating that stable H3K27me3 status could help to provide a safeguard against CTX-induced ovarian damage. Administration of the H3K27me3-demethylase inhibitor, GSK-J4, prior to CTX treatment could partially mitigate GC apoptosis by reversing the reduction of H3K27me3 and the aberrant upregulation of specific genes involved in transcriptional regulation and apoptosis. GSK-J4 could thus potentially be a protective agent for female fertility when undergoing chemotherapy. The results provide new insights into the mechanisms for chemotherapy injury and future clinical interventions for fertility preservation.