The choroid plexus (CP) serves as the primary source of cerebrospinal fluid (CSF). The blood-CSF barrier, composed of tight junctions among the epithelial cells in the CP, safeguards CSF from unrestricted exposure to bloodborne factors. This barrier is thus indispensable to brain homeostasis and is associated with age-related neural disorders. Nevertheless, its aging is poorly understood. Here, we report that cathepsin S (CTSS), a protease secreted from the CP macrophages, is upregulated in aged CP due to increased cell senescence. CTSS cleaves the essential tight junction component, claudin 1 (CLDN1), and, in turn, impairs the blood-CSF barrier. Notably, inhibiting CTSS or upregulating CLDN1 in aged CP rejuvenates the blood-CSF barrier and brain functions. Our findings uncover a vital interplay between immune and barrier cells that accelerates CP and brain aging, identify CTSS as a potential target to improve brain homeostasis in aged animals, and underscore the critical role of circulating proteinases in aging.

TP53 mutations are linked to aggressive progression and chemoresistance in gastric cancer (GC). Frameshift mutation is the second most common mutation type of TP53. However, the consequences of this mutation type in GC were not well understood, and targeted therapies for cancer patients harboring frameshift mutations were also not established. Histone methylation significantly influences tumorigenesis in TP53-mutated cancers, and related inhibitors are emerging as specific therapeutic strategies.

By treating GC cell lines harboring various TP53 mutation types with a library of histone demethylase inhibitors, we identified that GSK690, a reversible inhibitor of lysine-specific demethylase 1 (LSD1), selectively inhibits GC cells harboring TP53 frameshift mutations without nuclear localization sequence (NLS) (termed TP53 Frameshift NLS), which accounts for 89% TP53 frameshift mutations in GC patients. GSK690 showed significant specific inhibition in vitro and in vivo against this subtype by inducing G1/S cell cycle arrest via the LSD1-CCNA2 axis. Importantly, dual-luciferase assays and ChIP-qPCR confirmed that the loss of transcriptional repression activities of p53 in drives LSD1 upregulation in TP53 Frameshift NLS cancer cells.

In summary, our results indicate that the nuclear localization deficiency of p53 accounts for increased expression of LSD1 in TP53 Frameshift NLS GCs. GSK690 inhibits cell cycle progression and tumor growth by suppressing aberrantly activated LSD1-CCNA2 signaling in this GC subtype, counteracting malignant proliferation and thereby providing a precise therapeutic strategy for GC patients with TP53 Frameshift NLS.

Increasing lifespans and external environmental factors have contributed to the increase of age-related diseases, particularly cancer. A decrease in immune surveillance and clearance of cancer cells is the result of immunosenescence, which involves the remodeling of immune organs, the changes and functional decline of immune cell subsets, in association with systemic low-grade chronic inflammation. Stem cells aging in bone marrow and thymic involution are the most important causes of immunosenescence. Senescent cancer cells promote the differentiation, recruitment, and functional upregulation of immune-suppressive cell subsets e.g. regulatory T cells (Tregs), myeloid-derived suppressor cell (MDSC), tumor-associated macrophages (TAMS) through senescence-associated secretory phenotype (SASP) further exacerbating the immunosuppressive microenvironment. For digestive system cancers, age-related damage to the intestinal mucosal barrier, the aging of gut-associated lymphoid tissue (GALT), exposure to xenobiotic stimuli throughout life, and dysbiosis make the local immune microenvironment more vulnerable. This article systematically reviews the research progress of immunosenescence and immune microenvironment in digestive system cancers, as well as the exploration of related therapy strategies, hoping to point out new directions for research in the digestive system cancers.

Gastric cancer (GC) remains a significant public health concern because of its lethality, underscoring the need for deeper insights into its molecular mechanisms. Recent studies have increasingly highlighted the role of epigenetic modifications as critical players in cancer progression. Despite their importance, research specifically addressing epigenetic factors in GC is relatively scarce. This paper seeks to bridge that gap by examining recent literature that elucidates the epigenetic landscape associated with GC. The investigation of long noncoding RNAs (lncRNAs) has revealed their substantial involvement in gene dysregulation and epigenetic alterations within GC tumors. Notably, lncRNAs such as LINC00853 and LINC01266 have been identified as significant contributors to the epigenetic modulation of gene expression. Furthermore, the overexpression of KAT5 and GPX4 has been shown to mitigate the antiproliferative effects resulting from the depletion of circRHOT1, suggesting a complex interplay between these molecules in GC pathophysiology. Another pivotal aspect of epigenetic regulation in GC involves modifications in N6-methyladenosine (m6A), which play crucial roles in mRNA maturation processes such as splicing, export, degradation, and translation. m6A modifications are known for their influence on various cancer-related pathways, thus presenting a potential avenue for targeted interventions. Our findings indicate that the most pronounced instances of epigenetic dysregulation in GC can be traced back to the effects of long lncRNAs and alterations in m6A modification patterns. This underscores the urgent need for comprehensive investigations into these epigenetic factors, as a deeper understanding could lead to enhanced diagnostic markers and innovative therapeutic strategies. The integration of genetic and epigenetic considerations is essential for advancing the field of GC research. This synthesis of recent findings concerning epigenetic regulation offers valuable insights that could inform future studies and therapeutic developments. There is a critical need for ongoing research to elucidate the complexities of epigenetic modifications in GC, ultimately improving patient outcomes through tailored interventions.

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance. Human epidermal growth factor receptor 2 (HER2) is one of the most important targets in targeted therapy for gastric cancer. Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer. The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified. However, monoclonal antibodies, due to their large molecular weight, inability to penetrate the blood-brain barrier, and drug resistance, lead to decreased therapeutic efficacy, so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer. Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Bortezomib (BTZ), a proteasome inhibitor, is a promising therapeutic option for multiple myeloma (MM) patients. However, drug resistance often occurs, leading to disease relapse and poor prognosis. In this study, we aimed to identify novel genes associated with drug resistance and investigate their roles in BTZ resistance. Through the screening of 26 genes frequently associated with chemosensitivity or drug resistance, we discovered that KDM4C, a histone demethylase, exhibited increased expression in BTZ-resistant MM cells compared to their sensitive counterparts. Overexpression of KDM4C enhanced the tolerance of a MM cell line to the drug, whereas the knockdown of KDM4C, using shRNA, increased the sensitivity of resistant cells to BTZ treatment. This suggests that KDM4C plays a pivotal role in conferring BTZ resistance. Our study offers fresh insights into BTZ resistance in MM and highlights KDM4C as a potential target for overcoming drug resistance.

The involvement of cellular senescence in the initiation and propagation of diseases is clearly characterized, making the elimination of senescent cells essential to treat age-related diseases. The development of senolytic drugs demonstrated that targeting these cells limits the deterioration of patients' condition, by inducing apoptosis. Nevertheless, the first generations of senolytics which has been developed displayed their activities through specific mechanisms and demonstrated several limitations during clinical development. However, the rational to eliminate senescent cells remains evident, with the necessity to develop specific therapies in a context of diseases and tissues. The evolutions in the field of drug discovery open the way to a new generation of senolytic therapies, such as immunological approaches (CAR-T cells, Antibody-Drug Conjugated or vaccines), which require preliminary steps of research to identify markers specifically expressed on senescent cells, demonstrating promising specific effects. Currently, the preclinical development of these strategies appears more challenging to avoid strong side effects, but the expected results are commensurate with patients' hopes for treatments. In this review, we highlight the fact that the classical senolytic approach based on drug repurposing display limited efficacy and probably reached its limits in term of clinical development. The recent development of more complex therapies and the extension of interest in the domain of senescence in different fields of research allow to extend the possibility to discover powerful therapies. The future of age-related diseases treatment is linked to the development of new approaches based on cell therapy or immunotherapy to offer the best treatment for patients.

Gastric cancer has become the leading type of cancer on an international scale, with metastatic cancer being the leading cause of mortality associated with this illness. Consequently, methods for early detection have been established, mainly through the use of non-invasive biomarkers present in different bodily fluids. Exosomes are distinct extracellular vehicles that transport cellular signals over long distances via diverse contents. They may be readily seen in bodily fluids due to their secretion by gastric cancer cells or cells in the gastric cancer-tumor microenvironment. Given this context, multiple biological and functional features of human tumors, especially gastric cancer, are intricately connected to exosomal non-coding RNAs (ncRNAs). Exosomal microRNAs play a crucial role in several stages of gastric cancer progression, facilitating the transfer of genetic information between cancer cells and other cells. This process regulates tumor angiogenesis, growth, metastasis, immunological responses, and medication resistance. They engage with several regulatory complexes that have different enzymatic activities. These complexes then alter the chromatin landscapes, including changes to nucleosomes, DNA methylation, and alterations to histones. This research delves into the essential regulatory mechanisms of exosomes in gastric cancer. Furthermore, the existing understanding of the functions of exosomal miRNAs in this context was evaluated, aiming to confirm their potential significance in identifying biomarkers, elucidating their roles in immune evasion and drug resistance, and ultimately evaluating therapeutic strategies.