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Aims: TP53 alterations have a significant prognostic effect in myeloid neoplasms. Our objective was to investigate the TP53 gene mutation status, p53 protein expression and their relationship in dysplasia‐related myeloid neoplasms with varying levels of myeloblast counts. Methods and results: A total of 76 bone marrow biopsy samples with different blast counts were analysed. Total and strong (3+) p53 expression was determined. Dual immunohistochemical staining was performed to determine the cell population associated with p53 expression. NGS analysis was performed using the Accel‐Amplicon Comprehensive TP53 panel. Both p53 expression and TP53 VAF showed a significant correlation with the myeloblast ratio (P < 0.0001); however, p53 expression was also present in other cell lineages. The VAF value exhibited a significant correlation with p53 expression. A high specificity (0.9800) was observed for TP53 mutation using the ≥ 10% strong (3+) p53 cut‐off value, although the sensitivity (0.4231) was low. Conclusions: Strong (3+) p53 expression using a ≥ 10% cut‐off value accurately predicts TP53 mutation but does not reveal the allelic state. The p53 expression is significantly influenced by myeloblast count, and histological interpretation should consider the presence of intermixed non‐neoplastic marrow cells with varying physiological p53 expression. [ABSTRACT FROM AUTHOR]

This article describes a rare case of lobular endocervical glandular hyperplasia (LEGH) observed in a liquid-based cytology (LBC) Pap sample. LEGH is a precursor to gastric-type adenocarcinoma (GAE) of the endocervix, and reports of it in cervical cytology are limited. The article includes a case history and discusses the cytomorphological features, clinical presentation, imaging findings, histopathology, and immunohistochemistry of LEGH. It also provides a table comparing LEGH to other diagnostic entities in Pap samples. This is the first reported case of LEGH in an LBC Pap sample. [Extracted from the article]

Hepatitis B virus (HBV) infects approximately 300 million people worldwide, causing chronic infections. The HBV X protein (HBx) is crucial for viral replication and induces reactive oxygen species (ROS), leading to cellular damage. This study explores the relationship between HBx-induced ROS, p53 activation, and HBV replication. Using HepG2 and Hep3B cell lines that express the HBV receptor NTCP, we compared ROS generation and HBV replication relative to p53 status. Results indicated that HBV infection significantly increased ROS levels in p53-positive HepG2-NTCP cells compared to p53-deficient Hep3B-NTCP cells. Knockdown of p53 reduced ROS levels and enhanced HBV replication in HepG2-NTCP cells, whereas p53 overexpression increased ROS and inhibited HBV replication in Hep3B-NTCP cells. The ROS scavenger N-acetyl-L-cysteine (NAC) reversed these effects. The study also found that ROS-induced degradation of the HBx is mediated by the E3 ligase Siah-1, which is activated by p53. Mutations in p53 or inhibition of its transcriptional activity prevented ROS-mediated HBx degradation and HBV inhibition. These findings reveal a p53-dependent negative feedback loop where HBx-induced ROS increases p53 levels, leading to Siah-1-mediated HBx degradation and HBV replication inhibition. This study offers insights into the molecular mechanisms of HBV replication and identifies potential therapeutic targets involving ROS and p53 pathways. [ABSTRACT FROM AUTHOR]

3D printing technology is a powerful tool in scaffold engineering for biomedical applications, especially in anticancer activities and drug delivery. The present study developed a 3D-printed gelatin–alginate scaffold incorporating letrozole-loaded niosomes (Let/Nio@Gel-AL-SC) as a more effective drug delivery system. The findings showed that the fabricated niosomes appeared spherical. 3D-printed scaffolds exhibited biodegradability and sustained drug-release properties. The drug release from the scaffold was less prominent under acidic conditions than physiological ones. Cytotoxicity analysis showed that the engineered Let/Nio@Gel-AL-SC scaffold exhibited significant cytotoxicity against MCF-7 cancer cells. Gene expression analysis demonstrated a significant decrease in the expression of BCL2, CCND1, MMP2, and CDK4 genes and a notable increase in the expression of BAX and P53 genes, as well as the activity of Caspase 3/7 enzyme following treatment with Let/Nio@Gel-AL-SC. In addition, flow cytometry analysis revealed that Let/Nio@Gel-AL-SC significantly reduced necrosis and dramatically increased apoptosis. Also, the Let/Nio@Gel-AL-SC formulation exhibited a significantly greater increase in ROS values. The incorporation of letrozole-loaded niosomes into 3D printing gelatin/alginate scaffold has enhanced the efficacy of anticancer therapy. This is demonstrated by the sustained release of drugs, which indicates a promising potential for effective anticancer activity. Consequently, this combination holds promise as a potential future cancer therapy strategy. [ABSTRACT FROM AUTHOR]

O-GlcNAcase (OGA) is the only human enzyme that catalyzes the hydrolysis (deglycosylation) of O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) from numerous protein substrates. OGA has broad implications in many challenging diseases including cancer. However, its role in cell malignancy remains mostly unclear. Here, we report that a cancer-derived point mutation on the OGA's noncatalytic stalk domain aberrantly modulates OGA interactome and substrate deglycosylation toward a specific set of proteins. Interestingly, our quantitative proteomic studies uncovered that the OGA stalk domain mutant preferentially deglycosylated protein substrates with +2 proline in the sequence relative to the O-GlcNAcylation site. One of the most dysregulated substrates is PDZ and LIM domain protein 7 (PDLIM7), which is associated with the tumor suppressor p53. We found that the aberrantly deglycosylated PDLIM7 suppressed p53 gene expression and accelerated p53 protein degradation by promoting the complex formation with E3 ubiquitin ligase MDM2. Moreover, deglycosylated PDLIM7 significantly up-regulated the actin-rich membrane protrusions on the cell surface, augmenting the cancer cell motility and aggressiveness. These findings revealed an important but previously unappreciated role of OGA's stalk domain in protein substrate recognition and functional modulation during malignant cell progression. [ABSTRACT FROM AUTHOR]

p53 was discovered 45 years ago as an SV40 large T antigen binding protein, coded by the most frequently mutated TP53 gene in human cancers. As a transcription factor, p53 is tightly regulated by a rich network of post-translational modifications to execute its diverse functions in tumor suppression. Although early studies established p53-mediated cell-cycle arrest, apoptosis, and senescence as the classic barriers in cancer development, a growing number of new functions of p53 have been discovered and the scope of p53-mediated anti-tumor activity is largely expanded. Here, we review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that contribute to tumor suppression. We also discuss the challenge regarding how to activate p53 function specifically effective in inhibiting tumor growth without harming normal homeostasis for cancer therapy. p53 plays a central role in suppressing tumorigenesis. In this issue, Liu et al. review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that largely expand the scope of its anti-tumor activity. [ABSTRACT FROM AUTHOR]

Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer. Synopsis: Genome-wide p53 protein stability screens provide a comprehensive network view of the processes regulating wild type and mutant p53 and uncover potential targets for reinforcing wild-type p53 or targeting mutant p53 in cancer. Most proteins regulating wild-type p53 also affect mutant p53, except for p53 R337H, which harbors a distinct set of regulators. FBXO42 is a novel positive regulator for a subset of p53 mutants and collaborates with CCDC6 in regulating USP28-mediated stabilization of mutant p53. Loss of FBXO42 or CCDC6 reduces metastasis of p53 mutant pancreatic cancer cells, similar to depletion of mutant p53 itself. C16orf72/HAPSTR1 is a negative regulator affecting the stability of both wild-type and mutant p53, depending on its nuclear localization and the activity of the E3 ubiquitin ligase HUWE1. C16orf72/HAPSTR1 is a proto-oncogene and its overexpression reduces p53 levels and accelerates tumor growth in a p53 wild-type breast cancer mouse model. Genome-wide p53 protein stability screens provide a comprehensive network view of the processes regulating wildtype and mutant p53 and uncover potential targets for reinforcing wild-type p53 or targeting mutant p53 in cancer. [ABSTRACT FROM AUTHOR]

Non-antibiotic adjuncts may improve Helicobacter pylori infection control. Our aim was to emphasize curcumin benefits in controlling H. pylori infection. We discussed publications in English mostly published since 2020 using keyword search. Curcumin is the main bioactive substance in turmeric. Curcumin inhibited H. pylori growth, urease activity, three cag genes, and biofilms through dose- and strain-dependent activities. Curcumin also displayed numerous anticancer activities such as apoptosis induction, anti-inflammatory and anti-angiogenic effects, caspase‐3 upregulation, Bax protein enhancement, p53 gene activation, and chemosensitization. Supplementing triple regimens, the agent increased H. pylori eradication success in three Iranian studies. Bioavailability was improved by liposomal preparations, lipid conjugates, electrospray-encapsulation, and nano-complexation with proteins. The agent was safe at doses of 0.5–>4 g daily, the most common (in 16% of the users) adverse effect being gastrointestinal upset. Notably, curcumin favorably influences the intestinal microbiota and inhibits Clostridioides difficile. Previous reports showed the inhibitory effect of curcumin on H pylori growth. Curcumin may become an additive in the therapy of H. pylori infection, an adjunct for gastric cancer control, and an agent beneficial to the intestinal microbiota. Further examination is necessary to determine its optimal dosage, synergy with antibiotics, supplementation to various eradication regimens, and prophylactic potential. [ABSTRACT FROM AUTHOR]

The search for relevant molecular targets is one of the main tasks of modern tumor chemotherapy. To successfully achieve this, it is necessary to have the most complete understanding of the functioning of a transcriptional apparatus of the cell, particularly related to proliferation. The p53 protein plays an important role in regulating processes such as apoptosis, repair, and cell division, and the loss of its functionality often accompanies various types of tumors and contributes to the development of chemoresistance. Additionally, the proliferative activity of tumor cells is closely related to the metabolism of transition metals. For example, the metallochaperone Atox1 - a copper transporter protein - acts as a transcription activator for cyclin D1, promoting progression through the G1/S phase of the cell cycle. On the other hand, p53 suppresses cyclin D1 at the transcriptional level, thereby these proteins have divergent effects on cell cycle progression. However, the contribution of the interaction between these proteins to cell survival is poorly understood. This work demonstrates that not only exists a positive feedback loop between Atox1 and cyclin D1 but also that the activity of this loop depends on the status of the TP53 gene. Upon inactivation of TP53 in A549 and HepG2 cell lines, the expression of ATOX1 and CCND1 genes is enhanced, and their suppression in these cells leads to pronounced apoptosis. This fundamental observation may be useful in selecting more precise interventions for combined therapy of p53-negative tumors. [ABSTRACT FROM AUTHOR]

Purpose: Tumor hypoxia contributes to aggressive phenotypes and diminished therapeutic responses to radiation therapy (RT) with hypoxic tissue being 3-fold less radiosensitive than normoxic tissue. A major challenge in implementing hypoxic radiosensitizers is the lack of a high-resolution imaging modality that directly quantifies tissue-oxygen. The electron paramagnetic resonance oxygen-imager (EPROI) was used to quantify tumor oxygenation in two murine tumor models: E0771 syngeneic transplant breast cancers and primary p53/MCA soft tissue sarcomas, with the latter autochthonous model better recapitulating the tumor microenvironment in human malignancies. We hypothesized that tumor hypoxia differs between these models. We also aimed to quantify the absolute change in tumor hypoxia induced by the mitochondrial inhibitor papaverine (PPV) and its effect on RT response. Procedures: Tumor oxygenation was characterized in E0771 and primary p53/MCA sarcomas via EPROI, with the former model also being quantified indirectly via diffuse reflectance spectroscopy (DRS). After confirming PPV's effect on hypoxic fraction (via EPROI), we compared the effect of 0 versus 2 mg/kg PPV prior to 20 Gy on tumor growth delay and survival. Results: Hypoxic sarcomas were more radioresistant than normoxic sarcomas (p=0.0057, 2-way ANOVA), and high baseline hypoxic fraction was a significant (p=0.0063, Cox Regression Model) hazard in survivability regardless of treatment. Pre-treatment with PPV before RT did not radiosensitize tumors in the sarcoma or E0771 model. In the sarcoma model, EPROI successfully identified baseline hypoxic tumors. DRS quantification of total hemoglobin, saturated hemoglobin, changes in mitochondrial potential and glucose uptake showed no significant difference in E0771 tumors pre- and post-PPV. Conclusion: EPROI provides 3D high-resolution pO2 quantification; EPR is better suited than DRS to characterize tumor hypoxia. PPV did not radiosensitize E0771 tumors nor p53/MCA sarcomas, which may be related to the complex pattern of vasculature in each tumor. Additionally, understanding model-dependent tumor hypoxia will provide a much-needed foundation for future therapeutic studies with hypoxic radiosensitizers. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel HDACi with nanomolar activity against leukemic cells were synthesized. • HDACi of the KH-series are superior to a clinical grade HDACi. • HDACi of the KH-series modulate acetylation and phosphorylation of proteins. • The new HDACi KH16 regulates cell cycle arrest, apoptosis, and autophagy. • Apoptosis acts upstream of autophagy in KH16-treated cells. Posttranslational modification of proteins by reversible acetylation regulates key biological processes. Histone deacetylases (HDACs) catalyze protein deacetylation and are frequently dysregulated in tumors. This has spurred the development of HDAC inhibitors (HDACi). Such epigenetic drugs modulate protein acetylation, eliminate tumor cells, and are approved for the treatment of blood cancers. We aimed to identify novel, nanomolar HDACi with increased potency over existing agents and selectivity for the cancer-relevant class I HDACs (HDAC1,-2,-3,-8). Moreover, we wanted to define how such drugs control the apoptosis-autophagy interplay. As test systems, we used human leukemic cells and embryonic kidney-derived cells. We synthesized novel pyrimidine-hydroxamic acid HDACi (KH9/KH16/KH29) and performed in vitro activity assays and molecular modeling of their direct binding to HDACs. We analyzed how these HDACi affect leukemic cell fate, acetylation, and protein expression with flow cytometry and immunoblot. The publicly available DepMap database of CRISPR-Cas9 screenings was used to determine sensitivity factors across human leukemic cells. Novel HDACi show nanomolar activity against class I HDACs. These agents are superior to the clinically used hydroxamic acid HDACi SAHA (vorinostat). Within the KH-series of compounds, KH16 (yanostat) is the most effective inhibitor of HDAC3 (IC 50 = 6 nM) and the most potent inducer of apoptosis (IC 50 = 110 nM; p < 0.0001) in leukemic cells. KH16 though spares embryonic kidney-derived cells. Global data analyses of knockout screenings verify that HDAC3 is a dependency factor in 115 human blood cancer cells of different lineages, independent of mutations in the tumor suppressor p53. KH16 alters pro- and anti-apoptotic protein expression, stalls cell cycle progression, and induces caspase-dependent processing of the autophagy proteins ULK1 and p62. These data reveal that HDACs are required to stabilize autophagy proteins through suppression of apoptosis in leukemic cells. HDAC3 appears as a valid anti-cancer target for pharmacological intervention. [ABSTRACT FROM AUTHOR]

Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a high mortality rate. Direct reprogramming of glial cells to different cell lineages, such as induced neural stem cells (iNSCs) and induced neurons (iNeurons), provides genetic tools to manipulate a cell's fate as a potential therapy for neurological diseases. NeuroD1 (ND1) is a master transcriptional factor for neurogenesis and it promotes neuronal differentiation. In the present study, we tested the hypothesis that the expression of ND1 in GBM cells can force them to differentiate toward post-mitotic neurons and halt GBM tumor progression. In cultured human GBM cell lines, including LN229, U87, and U373 as temozolomide (TMZ)-sensitive and T98G as TMZ-resistant cells, the neuronal lineage conversion was induced by an adeno-associated virus (AAV) package carrying ND1. Twenty-one days after AAV-ND1 transduction, ND1-expressing cells displayed neuronal markers MAP2, TUJ1, and NeuN. The ND1-induced transdifferentiation was regulated by Wnt signaling and markedly enhanced under a hypoxic condition (2% O2 vs. 21% O2). ND1-expressing GBM cultures had fewer BrdU-positive proliferating cells compared to vector control cultures. Increased cell death was visualized by TUNEL staining, and reduced migrative activity was demonstrated in the wound-healing test after ND1 reprogramming in both TMZ-sensitive and -resistant GBM cells. In a striking contrast to cancer cells, converted cells expressed the anti-tumor gene p53. In an orthotopical GBM mouse model, AAV-ND1-reprogrammed U373 cells were transplanted into the fornix of the cyclosporine-immunocompromised C57BL/6 mouse brain. Compared to control GBM cell-formed tumors, cells from ND1-reprogrammed cultures formed smaller tumors and expressed neuronal markers such as TUJ1 in the brain. Thus, reprogramming using a single-factor ND1 overcame drug resistance, converting malignant cells of heterogeneous GBM cells to normal neuron-like cells in vitro and in vivo. These novel observations warrant further research using patient-derived GBM cells and patient-derived xenograft (PDX) models as a potentially effective treatment for a deadly brain cancer and likely other astrocytoma tumors. [ABSTRACT FROM AUTHOR]

Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds. miR-34 genes are highly conserved and syntenic between zebrafish and humans. Zebrafish miR-34a and miR-34b/c have similar expression timing in development, but miR-34a is more abundant. DNA damage by camptothecin led to p53-dependent induction of miR-34 genes, while miR-34a mutants were adult-viable and had normal DNA damage-induced apoptosis. Nevertheless, miR-34a-/- compound mutants with a gain-of-function tp53R217H/ R217H or tp53-/- mutants were more cancer-prone than tp53 mutants alone, confirming the tumor-suppressive function of miR-34a. Through transcriptomic comparisons at 28 hours post-fertilization (hpf), we characterized DNA damage-induced transcription, and at 8, 28 and 72 hpf we determined potential miR-34a-regulated genes. At 72 hpf, loss of miR-34a enhanced erythrocyte levels and up-regulated myb-positive hematopoietic stem cells. Overexpression of miR-34a suppressed its reporter mRNA, but not p53 target induction, and sensitized injected embryos to camptothecin but not to γ-irradiation. Author summary: Li-Fraumeni syndrome, rooted in inherited mutations of the TP53 tumor suppressor gene, presents a complex interplay with microRNA34a (miR-34a), a known p53 target and modifier gene. Notably, miR-34 triple-null mice, despite exhibiting typical p53 responses and no evident cancer development, unveil a crucial role for miR-34 genes in suppressing tumorigenesis, particularly in predisposed conditions. The evolutionary conservation of miR-34 genes across zebrafish and humans underscores their significance. Studying zebrafish embryos reveals intriguing insights into miR-34a dynamics during development and its response to DNA damage, illuminating its involvement in cancer susceptibility. Additionally, experiments involving miR-34a mutants further confirm its tumor-suppressive function, especially when coupled with tp53 mutations. Transcriptomic analysis at different developmental stages uncover potential genes regulated by miR-34a, shedding light on its broader regulatory role. These findings enhance our understanding of the intricate mechanisms underlying cancer susceptibility and highlight miR-34a as a potential therapeutic target for Li-Fraumeni syndrome and related malignancies. [ABSTRACT FROM AUTHOR]

Mammalian somatic cells undergo terminal proliferation arrest after a limited number of cell divisions, a phenomenon termed cellular senescence. However, cells acquire the ability to proliferate infinitely (cellular immortalization) through multiple genetic alterations. Inactivation of tumor suppressor genes such as p53, RB and p16 is important for cellular immortalization, although additional molecular alterations are required for cellular immortalization to occur. Here, we aimed to gain insights into these molecular alterations. Given that cellular immortalization is the escape of cells from cellular senescence, genes that regulate cellular senescence are likely to be involved in cellular immortalization. Because senescent cells show altered heterochromatin organization, we investigated the implications of lamin A/C, lamin B1 and lamin B receptor (LBR), which regulate heterochromatin organization, in cellular immortalization. We employed human immortalized cell lines, KMST‐6 and SUSM‐1, and found that expression of LBR was upregulated upon cellular immortalization and downregulated upon cellular senescence. In addition, knockdown of LBR induced cellular senescence with altered chromatin configuration. Additionally, enforced expression of LBR increased cell proliferation likely through suppression of genome instability in human primary fibroblasts that expressed the simian virus 40 large T antigen (TAg), which inactivates p53 and RB. Furthermore, expression of TAg or knockdown of p53 led to upregulated LBR expression. These observations suggested that expression of LBR might be upregulated to suppress genome instability in TAg‐expressing cells, and, consequently, its upregulated expression assisted the proliferation of TAg‐expressing cells (i.e. p53/RB‐defective cells). Our findings suggest a crucial role for LBR in the process of cellular immortalization. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common malignant tumors, and chemotherapy is the main treatment for advanced gastric cancer. However, chemotherapy resistance leads to treatment failure and poor prognosis in patients with gastric cancer. Multidrug resistance (MDR) is a major challenge that needs to be overcome in chemotherapy. According to recent research, ferroptosis activation is crucial for tumor therapeutic strategies. In this work, we explored the solution to chemoresistance in gastric cancer by investigating the effects of the Chinese medicine monomer baicalin on ferroptosis. Baicalin with different concentrations was used to treat the parent HGC27 and drug-resistant HGC27/L cells of gastric cancer. Cell viability was measured by CCK8, and synergistic effects of baicalin combined with oxaliplatin were evaluated using Synergy Finder software. The effects of baicalin on organelles and cell morphology were investigated using projective electron microscopy. Iron concentration, MDA production and GSH inhibition rate were measured by colorimetry. ROS accumulation was detected by flow cytometry. The ferroptosis-related genes (IREB2, TfR, GPX4, FTH1), P53, and SLC7A11 were analysed by Western blot, and the expression differences of the above proteins between pretreatment and pretreatment of different concentrations of baicalin, were assayed in both parental HGC27 cells and Oxaliplatin-resistant HGC27/L cells. Mechanically, Baicalin disrupted iron homeostasis and inhibits antioxidant defense, resulting in iron accumulation, lipid peroxide aggregation, and specifically targeted and activated ferroptosis by upregulating the expression of tumor suppressor gene p53, thereby activating the SLC7A11/GPX4/ROS pathway mediated by it. Baicalin activates ferroptosis through multiple pathways and targets, thereby inhibiting the viability of oxaliplatin-resistant gastric cancer HGC27/L cells and enhancing the sensitivity to oxaliplatin chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the potential of small extracellular vesicles (sEVs) as vehicles for delivering therapeutic agents, with a focus on the p53 tumor suppressor gene. Fusion with CD63 or ARRDC1 was found to facilitate the overexpression and proper localization of p53 and significantly increase the yield and loading efficiency of sEVs with p53 mRNA and proteins. Moreover, the functional assessment of these engineered sEVs on H1299 cells demonstrated an enhanced anti-tumor effect, particularly with ARP-sEVs, suggesting a superior inhibition of cell proliferation and promotion of apoptosis. These results are expected to be informative in the application of EV therapy. Small extracellular vesicles (sEVs) have emerged as promising therapeutic agents and drug delivery vehicles. Targeted modification of sEVs and their contents using genetic modification strategies is one of the most popular methods. This study investigated the effects of p53 fusion with arrestin domain-containing protein 1 (ARRDC1) and CD63 on the generation of sEVs, p53 loading efficiency, and therapeutic efficacy. Overexpression of either ARRDC1–p53 (ARP) or CD63–p53 (CDP) significantly elevated p53 mRNA and protein levels. The incorporation of ARRDC1 and CD63 significantly enhanced HEK293T-sEV biogenesis, evidenced by significant increases in sEV-associated proteins TSG101 and LAMP1, resulting in a boost in sEV production. Importantly, fusion with ARRDC1 or CD63 substantially increased the efficiency of loading both p53 fusion proteins and its mRNA into sEVs. sEVs equipped with ARP or CDP significantly enhanced the enrichment of p53 fusion proteins and mRNA in p53-null H1299 cells, resulting in a marked increase in apoptosis and a reduction in cell proliferation, with ARP-sEVs demonstrating greater effectiveness than CDP-sEVs. These findings underscore the enhanced functionality of ARRDC1- and CD63-modified sEVs, emphasizing the potential of genetic modifications in sEV-based therapies for targeted cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The mink is a small and valuable fur animal resource. RNA-seq was utilized to identify key genes associated with the growth and development of mink. Consequently, genes related to embryonic development (PEG10, IGF2, NRK), cell cycle regulation (CDK6, CDC6, CDC27, CCNA2), and the FGF family (FGF2, FGF6, FGFR2) exhibited upregulation at 45 days of age in mink. This suggests their potential involvement in early growth and developmental processes. Conversely, genes associated with skeletal muscle development (PRVA, TNNI1, TNNI2, MYL3, MUSTN1), a negative regulator of the cell cycle gene (CDKN2C), and IGFBP6 were found to be upregulated at 90 days of age in mink, indicating their potential involvement in rapid growth. In summary, our experimental data establish a foundation for the individual selection of larger-sized mink and elucidate the regulatory mechanisms underlying their growth and development. Mink is a kind of small and precious fur animal resource. In this study, we employed transcriptomics technology to analyze the gene expression profile of mink pectoral muscle tissue, thereby elucidating the regulatory mechanisms underlying mink growth and development. Consequently, a total of 25,954 gene expression profiles were acquired throughout the growth and development stages of mink at 45, 90, and 120 days. Among these profiles, 2607 genes exhibited significant differential expression (|log2(fold change)| ≥ 2 and p_adj < 0.05). GO and KEGG enrichment analyses revealed that the differentially expressed genes were primarily associated with the mitotic cell cycle process, response to growth factors, muscle organ development, and insulin resistance. Furthermore, GSEA enrichment analysis demonstrated a significant enrichment of differentially expressed genes in the p53 signaling pathway at 45 days of age. Subsequent analysis revealed that genes associated with embryonic development (e.g., PEG10, IGF2, NRK), cell cycle regulation (e.g., CDK6, CDC6, CDC27, CCNA2), and the FGF family (e.g., FGF2, FGF6, FGFR2) were all found to be upregulated at 45 days of age in mink, which suggested a potential role for these genes in governing early growth and developmental processes. Conversely, genes associated with skeletal muscle development (PRVA, TNNI1, TNNI2, MYL3, MUSTN1), a negative regulator of the cell cycle gene (CDKN2C), and IGFBP6 were found to be up-regulated at 90 days of age, suggesting their potential involvement in the rapid growth of mink. In summary, our experimental data provide robust support for elucidating the regulatory mechanisms underlying the growth and development of mink. [ABSTRACT FROM AUTHOR]

Surpassing the diffraction barrier revolutionized modern fluorescence microscopy. However, intrinsic limitations in statistical sampling, the number of simultaneously analyzable channels, hardware requirements, and sample preparation procedures still represent an obstacle to its widespread diffusion in applicative biomedical research. Here, we present a novel pipeline based on automated multimodal microscopy and super-resolution techniques employing easily available materials and instruments and completed with open-source image-analysis software developed in our laboratory. The results show the potential impact of single-molecule localization microscopy (SMLM) on the study of biomolecules' interactions and the localization of macromolecular complexes. As a demonstrative application, we explored the basis of p53-53BP1 interactions, showing the formation of a putative macromolecular complex between the two proteins and the basal transcription machinery in situ, thus providing visual proof of the direct role of 53BP1 in sustaining p53 transactivation function. Moreover, high-content SMLM provided evidence of the presence of a 53BP1 complex on the cell cytoskeleton and in the mitochondrial space, thus suggesting the existence of novel alternative 53BP1 functions to support p53 activity. [ABSTRACT FROM AUTHOR]

Breast cancer is often treated with chemotherapy. However, the development of chemoresistance results in treatment failure. Long non‐coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been shown to contribute to chemoresistance in breast cancer cells. In studying the transcriptional regulation of NEAT1 using multi‐omics approaches, we showed that NEAT1 is up‐regulated by 5‐fluorouracil in breast cancer cells with wild‐type cellular tumor antigen p53 but not in mutant‐p53‐expressing breast cancer cells. The regulation of NEAT1 involves mediator complex subunit 12 (MED12)‐mediated repression of histone acetylation marks at the promoter region of NEAT1. Knockdown of MED12 but not coactivator‐associated arginine methyltransferase 1 (CARM1) induced histone acetylation at the NEAT1 promoter, leading to elevated NEAT1 mRNAs, resulting in a chemoresistant phenotype. The MED12‐dependent regulation of NEAT1 differs between wild‐type and mutant p53‐expressing cells. MED12 depletion led to increased expression of NEAT1 in a wild‐type p53 cell line, but decreased expression in a mutant p53 cell line. Chemoresistance caused by MED12 depletion can be partially rescued by NEAT1 knockdown in p53 wild‐type cells. Collectively, our study reveals a novel mechanism of chemoresistance dependent on MED12 transcriptional regulation of NEAT1 in p53 wild‐type breast cancer cells. [ABSTRACT FROM AUTHOR]

Tissue-specific gene manipulations are widely used in genetically engineered mouse models. A single recombinase system, such as the one using Alb-Cre, has been commonly used for liver-specific genetic manipulations. However, most diseases are complex, involving multiple genetic changes and various cell types. A dual recombinase system is required for conditionally modifying different genes sequentially in the same cell or inducing genetic changes in different cell types within the same organism. A FlpO cDNA was inserted between the last exon and 3′-UTR of the mouse albumin gene in a bacterial artificial chromosome (BAC-Alb-FlpO). The founders were crossed with various reporter mice to examine the efficiency of recombination. Liver cancer tumorigenesis was investigated by crossing the FlpO mice with FSF-KrasG12D mice and p53frt mice (KPF mice). BAC-Alb-FlpO mice exhibited highly efficient recombination capability in both hepatocytes and intrahepatic cholangiocytes. No recombination was observed in the duodenum and pancreatic cells. BAC-Alb-FlpO-mediated liver-specific expression of mutant KrasG12D and conditional deletion of p53 gene caused the development of liver cancer. Remarkably, liver cancer in these KPF mice manifested a distinctive mixed hepatocellular carcinoma and cholangiocarcinoma phenotype. A highly efficient and liver-specific BAC-Alb-FlpO mouse model was developed. In combination with other Cre lines, different genes can be manipulated sequentially in the same cell, or distinct genetic changes can be induced in different cell types of the same organism. NEW & NOTEWORTHY: A liver-specific Alb-FlpO mouse line was generated. By coupling it with other existing CreERT or Cre lines, the dual recombinase approach can enable sequential gene modifications within the same cell or across various cell types in an organism for liver research through temporal and spatial gene manipulations. [ABSTRACT FROM AUTHOR]

In consideration of the chromones' therapeutic potential and anticancer activity, a new series of chromanone derivatives have been synthesized through a straightforward reaction between 6-formyl-7-hydroxy-5-methoxy-2-methylchromone (2) and various organic active compounds. The cytotoxic activity of the newly synthesized congeners was investigated against MCF-7 (human breast cancer), HCT-116 (colon cancer), HepG2 (liver cancer), and normal skin fibroblast cells (BJ1). The obtained data indicated that compounds 14b, 17, and 19 induce cytotoxic activity in the breast MCF7, while compounds 6a, 6b, 11 and 14c showed highly potent activity in the colon cancer cell lines. Overall, the results demonstrate that the potential cytotoxic effects of the studied compounds may be based on their ability to induce DNA fragmentation in cancer cell lines, down-regulate the expression level of CDK4 as well as the anti-apoptotic gene Bcl-2 and up-regulate the expression of the pro-apoptotic genes P53 and Bax. Furthermore, compounds 14b and 14c showed a dual mechanism of action by inducing apoptosis and cell cycle arrest. The docking studies showed that the binding affinity of the most active cytotoxic compounds within the active pocket of the CDK4 enzyme is stronger due to hydrophobic and H-bonding interactions. These results were found to be consistent with the experimental results. [ABSTRACT FROM AUTHOR]

Cervical cancer is a major cause of death in women despite the advancement of current treatment modalities. The conventional therapeutic agent, cisplatin (CCDP), is the standard treatment for CC; however, resistance often develops due to the cancer's heterogeneity. Therefore, a detailed elucidation of the specific molecular mechanisms driving CC is crucial for the development of targeted therapeutic strategies. Retinoblastoma binding protein 6 (RBBP6) is a potential biomarker associated with cell proliferation and is upregulated in cervical cancer sites, exhibiting apoptosis and dysregulated p53 expression. Furthermore, RBBP6 has been demonstrated to sensitize cancer cells to radiation and certain chemotherapeutic agents by regulating the Bcl-2 gene, thus suggesting a crosstalk among RBBP6/p53/BCL-2 oncogenic signatures. The present study, therefore, investigated the relationship between cisplatin and RBBP6 expression in CC cells. Herein, we first explored bioinformatics simulations and identified that the RBBP6/p53/BCL-2 signaling pathway is overexpressed and correlated with CC. For further analysis, we explored the Genomics of Drug Sensitivity in Cancer (GDSC) and found that most of the CC cell lines are sensitive to CCDP. To validate these findings, RBBP6 was silenced in HeLa and Vero cells using RNAi technology, followed by measurement of wild-type p53 and Bcl-2 at the mRNA level using qPCR. Cells co-treated with cisplatin and siRBBP6 were subsequently analyzed for apoptosis induction and real-time growth monitoring using flow cytometry and the xCELLigence system, respectively. Cancer cells in the co-treatment group showed a reduction in apoptosis compared to the cisplatin-treated group. Moreover, the real-time growth monitoring revealed a reduced growth rate in RBBP6 knockdown cells treated with cisplatin. Although wild-type p53 remained unchanged in the co-treatment group of cancer cells, Bcl-2 was completely repressed, suggesting that RBBP6 is necessary for sensitizing cervical cancer cells to cisplatin treatment by downregulating Bcl-2. The Vero cell population, which served as a non-cancerous control cell line in this study, remained viable following treatment with both siRBBP6 and cisplatin. Findings from this study suggest that RBBP6 expression promotes cisplatin sensitivity in HeLa cells through Bcl-2 downregulation. Knockdown of RBBP6 limits apoptosis induction and delays cell growth inhibition in response to cisplatin. The knowledge obtained here has the potential to help improve cisplatin efficacy through personalized administration based on the expression profile of RBBP6 among individual patients. [ABSTRACT FROM AUTHOR]

Background: DNA damage and oxidative stress induced by chemotherapy are important factors in the onset of premature ovarian insufficiency (POI). Studies have shown that mitochondria derived from mesenchymal stem cells (MSC-Mito) are beneficial for age-related diseases, but their efficacy alone is limited. Pyrroloquinoline quinone (PQQ) is a potent antioxidant with significant antiaging and fertility enhancement effects. This study aimed to investigate the therapeutic effect of MSC-Mito in combination with PQQ on POI and the underlying mechanisms involved. Methods: A POI animal model was established in C57BL/6J mice by cyclophosphamide and busulfan. The effects of MSC-Mito and PQQ administration on the estrous cycle, ovarian pathological damage, sex hormone secretion, and oxidative stress in mice were evaluated using methods such as vaginal smears and ELISAs. Western blotting and immunohistochemistry were used to assess the expression of SIRT1, PGC-1α, and ATM/p53 pathway proteins in ovarian tissues. A cell model was constructed using KGN cells treated with phosphoramide mustard to investigate DNA damage and apoptosis through comet assays and flow cytometry. SIRT1 siRNA was transfected into KGN cells to further explore the role of the SIRT1/ATM/p53 pathway in combination therapy with MSC-Mito and PQQ for POI. Results: The combined treatment of MSC-Mito and PQQ significantly restored ovarian function and antioxidant capacity in mice with POI. This treatment also reduced the loss of follicles at various stages, improving the disrupted estrous cycle. In vitro experiments demonstrated that PQQ facilitated the proliferation of MitoTracker-labelled MSC-Mito, synergistically restoring mitochondrial function and inhibiting oxidative stress in combination with MSC-Mito. Both in vivo and in vitro, the combination of MSC-Mito and PQQ increased mitochondrial biogenesis mediated by SIRT1 and PGC-1α while inhibiting the activation of ATM and p53, consequently reducing DNA damage-mediated cell apoptosis. Furthermore, pretreatment of KGN cells with SIRT1 siRNA reversed nearly all the aforementioned changes induced by the combined treatment. Conclusions: Our research findings indicate that PQQ facilitates MSC-Mito proliferation and, in combination with MSC-Mito, ameliorates chemotherapy-induced POI through the SIRT1/ATM/p53 signaling pathway. [ABSTRACT FROM AUTHOR]

Lung cancer is a major public health issue and heavy burden in China and worldwide due to its high incidence and mortality without effective treatment. It's imperative to develop new treatments to overcome drug resistance. Natural products from food source, given their wide-ranging and long-term benefits, have been increasingly used in tumor prevention and treatment. This study revealed that Hibiscus manihot L. flower extract (HML) suppressed the proliferation and migration of A549 cells in a dose and time dependent manner and disrupting cell cycle progression. HML markedly enhanced the accumulation of ROS, stimulated the dissipation of mitochondrial membrane potential (MMP) and that facilitated mitophagy through the loss of mitochondrial function. In addition, HML induced apoptosis by activation of the PTEN-P53 pathway and inhibition of ATG5/7-dependent autophagy induced by PINK1-mediated mitophagy in A549 cells. Moreover, HML exert anticancer effects together with 5-FU through synergistic effect. Taken together, HML may serve as a potential tumor prevention and adjuvant treatment for its functional attributes. [ABSTRACT FROM AUTHOR]

Background: Porcine acute diarrhea syndrome coronavirus (SADS-CoV) is one of the novel pathogens responsible for piglet diarrhea, contributing to substantial economic losses in the farming sector. The broad host range of SADS-CoV raises concerns regarding its potential for cross-species transmission. Currently, there are no effective means of preventing or treating SADS-CoV infection, underscoring the urgent need for identifying efficient antiviral drugs. This study focuses on evaluating quercetin as an antiviral agent against SADS-CoV. Results: In vitro experiments showed that quercetin inhibited SADS-CoV proliferation in a concentration-dependent manner, targeting the adsorption and replication stages of the viral life cycle. Furthermore, quercetin disrupts the regulation of the P53 gene by the virus and inhibits host cell cycle progression induced by SADS-CoV infection. In vivo experiments revealed that quercetin effectively alleviated the clinical symptoms and intestinal pathological damage caused by SADS-CoV-infected piglets, leading to reduced expression levels of inflammatory factors such as TLR3, IL-6, IL-8, and TNF-α. Conclusions: Therefore, this study provides compelling evidence that quercetin has great potential and promising applications for anti- SADS-CoV action. [ABSTRACT FROM AUTHOR]

The forkhead box family transcription factor FOXQ1 is highly induced in several types of carcinomas, where it promotes epithelial-to-mesenchymal transition and tumor metastasis. The molecular mechanisms that lead to FOXQ1 deregulation in cancer are incompletely understood. Here, we used CRISPR--Cas9-based genomic locus proteomics and promoter reporter constructs to discover transcriptional regulators of FOXQ1 and identified the tumor suppressor p53 as a negative regulator of FOXQ1 expression. Chromatin immunoprecipitation followed by quantitative PCR as well as complementary gain and loss-of-function assays in model cell lines indicated that p53 binds close to the transcription start site of the FOXQ1 promoter, and that it suppresses FOXQ1 expression in various cell types. Consistently, pharmacological activation of p53 using nutlin-3 or doxorubicin reduced FOXQ1 mRNA and protein levels in cancer cell lines harboring wildtype p53. Finally, we observed that p53 mutations are associated with increased FOXQ1 expression in human cancers. Altogether, these results suggest that loss of p53 function--a hallmark feature of many types of cancer--derepresses FOXQ1, which in turn promotes tumor progression. [ABSTRACT FROM AUTHOR]

FOXO1 is a transcription factor and potential tumor suppressor that is negatively regulated downstream of PI3K-PKB/ AKT signaling. Paradoxically, FOXO also promotes tumor growth, but the detailed mechanisms behind this role of FOXO are not fully understood. In this study, we revealed a molecular cascade by which the Thr24 residue of FOXO1 is phosphorylated by AKT and is dephosphorylated by calcineurin, which is a Ca2+-dependent protein phosphatase. Curiously, single nucleotide somatic mutations of FOXO1 in cancer occur frequently at and near Thr24. Using a calcineurin inhibitor and shRNA directed against calcineurin, we revealed that calcineurin-mediated dephosphorylation of Thr24 regulates FOXO1 protein stability. We also found that FOXO1 binds to the promoter region of MDM2 and activates transcription, which in turn promotes MDM2-mediated ubiquitination and degradation of p53. FOXO3a and FOXO4 are shown to control p53 activity; however, the significance of FOXO1 in p53 regulation remains largely unknown. Supporting this notion, FOXO1 depletion increased p53 and p21 protein levels in association with the inhibition of cell proliferation. Taken together, these results indicate that FOXO1 is stabilized by calcineurin-mediated dephosphorylation and that FOXO1 supports cancer cell proliferation by promoting MDM2 transcription and subsequent p53 degradation. [ABSTRACT FROM AUTHOR]

p53 kinetics plays a key role in regulating cell fate. Based on the p53 gene regulatory network composed by the core regulatory factors ATM, Mdm2, Wip1, and PIDD, the effect of the delays in the process of transcription and translation of Mdm2 and Wip1 on the dynamics of p53 is studied theoretically and numerically. The results show that these two time delays can affect the stability of the positive equilibrium. With the increase of delays, the dynamics of p53 presents an oscillating state. Further, we also study the effects of PIDD and chemotherapeutic drug etoposide on the kinetics of p53. The model indicates that (i) PIDD low-level expression does not significantly affect p53 oscillatory behavior, but high-level expression could induce two-phase kinetics of p53; (ii) Too high and too low concentration of etoposide is not conducive to p53 oscillation. These results are in good agreement with experimental findings. Finally, we consider the influence of internal noise on the system through Binomial τ -leap algorithm. Stochastic simulations reveal that high-intensity noise completely destroys p53 dynamics in the deterministic model, whereas low-intensity noise does not alter p53 dynamics. Interestingly, for the stable focus, the internal noise with appropriate intensity can induce quasi-limit cycle oscillations of the system. Our work may provide the useful insights for the development of anticancer therapy. [ABSTRACT FROM AUTHOR]

Tumour protein 63 (p63) is a transcription factor of the p53 gene family, encoded by the TP63 gene located at chromosome 3q28, which regulates the activity of genes involved in growth and development of the ectoderm and derived tissues. p63 protein is normally expressed in the nuclei of the basal cell layer of glandular organs, including breast, in squamous epithelium and in urothelium. p63 immunohistochemical (IHC) staining has several applications in diagnostic breast pathology. It is commonly used to demonstrate myoepithelial cells at the epithelial stromal interface to differentiate benign and in situ lesions from invasive carcinoma and to characterize and classify papillary lesions including the distinction of breast intraduct papilloma from skin hidradenoma. p63 IHC is also used to identify and profile lesions showing myoepithelial cell and/or squamous differentiation, e.g. adenomyoepithelioma, salivary gland‐like tumours including adenoid cystic carcinoma, and metaplastic breast carcinoma including low‐grade adenosquamous carcinoma. This article reviews the applications of p63 IHC in diagnostic breast pathology and outlines a practical approach to the diagnosis and characterization of breast lesions through the identification of normal and abnormal p63 protein expression. The biology of p63, the range of available antibodies with emphasis on staining specificity and sensitivity, and pitfalls in interpretation are also discussed. The TP63 gene in humans, which shows a specific genomic structure, resulting in either TAp63 (p63) isoform or ΔNp63 (p40) isoform. As illustrated in the figure, both isoforms contain a DNA‐binding domain (Orange box) and an oligomerization domain (Grey box). TAp63 contains an N‐terminal transactivation (TA) domain (Green box), while ΔNp63 has an alternative terminus (Yellow box). Antibodies against conventional pan‐p63 (TP63) bind to the DNA binding domain common to both isoforms (TAp63 and p40) and does not distinguish between them. Antibodies against TAp63 bind to the N‐terminal TA domain, while antibodies specific to ΔNp63 (p40) bind to the alternative terminus. Each isoform has variant isotypes (α, β, γ, δ, and ε). [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common and highly metastatic cancer affecting people worldwide. Drug resistance and unwanted side effects are some of the limitations of current treatments for CRC. Naringenin (NAR) is a naturally occurring compound found in abundance in various citrus fruits such as oranges, grapefruits, and tomatoes. It possesses a diverse range of pharmacological and biological properties that are beneficial for human health. Numerous studies have highlighted its antioxidant, anticancer, and anti‐inflammatory activities, making it a subject of interest in scientific research. This review provides a comprehensive overview of the effects of NAR on CRC. The study's findings indicated that NAR: (1) interacts with estrogen receptors, (2) regulates the expression of genes related to the p53 signaling pathway, (3) promotes apoptosis by increasing the expression of proapoptotic genes (Bax, caspase9, and p53) and downregulation of the antiapoptotic gene Bcl2, (4) inhibits the activity of enzymes involved in cell survival and proliferation, (5) decreases cyclin D1 levels, (6) reduces the expression of cyclin‐dependent kinases (Cdk4, Cdk6, and Cdk7) and antiapoptotic genes (Bcl2, x‐IAP, and c‐IAP‐2) in CRC cells. In vitro CDK2 binding assay was also performed, showing that the NAR derivatives had better inhibitory activities on CDK2 than NAR. Based on the findings of this study, NAR is a potential therapeutic agent for CRC. Additional pharmacology and pharmacokinetics studies are required to fully elucidate the mechanisms of action of NAR and establish the most suitable dose for subsequent clinical investigations. Significance statement: The review discusses the molecular and biochemical processes related to naringenin (NAR's) effects on colorectal cancer (CRC), emphasizing its diverse pharmacological and biological properties. NAR interacts with estrogen receptors, regulates gene expression related to the p53 signaling pathway, promotes apoptosis, inhibits enzymes involved in cell survival and proliferation, decreases cyclin D1 levels, and reduces the expression of cyclin‐dependent kinases and antiapoptotic genes in CRC cells. In vitro studies demonstrate that NAR derivatives have better inhibitory activities on CDK2 than NAR, suggesting their potential as therapeutic agents for CRC. [ABSTRACT FROM AUTHOR]

Background: The present study attempts to assess the role of BCL-2 and p53 family of genes in chronic myeloid leukemia (CML) and correlation of their immunoreactivity with the status of remission on followup. Objectives: Primary objective of the study is to assess and score the expression of BCL2 and p53 in bone marrow trephine biopsies of cases of CML and to correlate the expression of these markers with the prognosis of the patients. Assessment of demographic distribution of CML were also included as secondary objective. Methods: Present study is a cross-sectional study conducted in the Department of Pathology, Govt. Medical College, Kozhikode from January 2017 to December 2020. The study population included confirmed cases of CML received in Pathology Department during the study period. 55 cases were selected. The paraffin embedded blocks of bone marrow trephine biopsy were retrieved and immunohistochemical testing were done in the department. Clinical details of patients were obtained from patient records. All variables needed for study were collected. Consecutive sampling technique was adopted for the study. Statistical analysis was done by chi square test. A p value less than 0.05 was considered as statistically significant. Results: Among the study population, majority (69%) of patients were in chronic phase at initial presentation. Most of the patients in chronic phase were in remission(62%). 25% of the study population presented in the blast crisis phase. Majority of the patients in blast crisis were not in remission and were in an elderly age group. Most of the patients presented with massive splenomegaly at diagnosis and only 5 patients didn't have significant organomegaly. It was found that there is an association between BCL2, haemoglobin, platelet and age with the status of remission (p<0.05) and there is no association between P53 and total count with the status of remission (p>0.05). Conclusion: These findings are in line with numerous studies that discovered a unique approach to eliminate quiescent stem cells in CML that cause relapse by targeting BCL-2 coupled with BCR-ABL and inhibiting the MDM2 protein that breaks down p53. [ABSTRACT FROM AUTHOR]

BACKGROUND: There are many treatment methods for knee osteoarthritis, among which electroacupuncture, as an important non-drug treatment, is effective in the treatment of knee osteoarthritis, but its exact mechanism is not clear. OBJECTIVE: Effect of electroacupuncture on the expression of p53 and P21 in articular cartilage and subchondral bone of aged rats with knee osteoarthritis. METHODS: Eight 6-month-old male Sprague-Dawley rats were included in the young group and sixteen 24-month-old male Sprague-Dawley rats were randomly divided into old group (n=8) and electroacupuncture group (n=8). The rats in the electroacupuncture group received electroacupuncture stimulation once a day, 5 days a week, for 8 continuous weeks, and the other two groups did not do any treatment. Eight weeks later, the level of type II collagen C-terminal peptide in peripheral blood was detected by ELISA, the morphology of left knee cartilage and subchondral bone was observed by safranin O-fast green staining, the degree of knee cartilage degeneration was evaluated by modified Mankin’s score, the microstructure of left knee cartilage and subchondral bone was detected by micro-CT, and the expression levels of matrix metalloproteinase 13, P53, P21 mRNA and protein were detected by RT-PCR and western blot respectively. RESULTS AND CONCLUSION: Compared with the young group, the level of C-terminal peptide of type II collagen in the peripheral blood was increased in the old group (P < 0.05). The micro-CT results showed that the bone volume fraction, bone mineral density and the number of bone trabeculae were decreased in the old group compared with the young group (P < 0.05), while the trabecular separation increased (P < 0.05). Safranin O-fast green staining showed that in the old group, the surface layer of cartilage was uneven with fissures, the morphology of chondrocytes was irregular and stained unevenly, the boundary between the cartilage and subchondral bone was blurred, and the matrix loss was serious. The Mankin’s score was higher in the old group than the young group (P < 0.05). The expression of matrix metalloproteinase 13, P53, P21 at mRNA and protein levels increased in the old group compared with the young group (P < 0.05). Compared with the old group, electroacupuncture decreased the level of C-terminal peptide of type II collagen (P < 0.05), increased the bone volume fraction, bone mineral density and the number of bone trabeculae (P < 0.05), and decreased the trabecular separation (P < 0.05). Safranin O-fast green staining showed that in the electroacupuncture group, the surface of cartilage was smooth and red staining was uniform, and the cell morphology and structure were between the young group and the old group. Following electroacupuncture treatment, the Mankin’s score (P < 0.05), matrix metalloproteinase 13 and P21 mRNA expression (P < 0.05), and matrix metalloproteinase 13 and P53 protein expression decreased (P < 0.05), while there was a decreasing trend of P53 mRNA and P21 protein expression, but with no statistical significance (P > 0.05). To conclude, electroacupuncture may delay articular cartilage degeneration and subchondral osteoporosis in aged rats by inhibiting the expression of P53 and P21, so as to protect joints and delay joint aging. [ABSTRACT FROM AUTHOR]

As a space project, in "Stem Cells" by the Japan Aerospace Exploration Agency (JAXA), frozen mouse ES cells were stored on the International Space Station (ISS) in the Minus Eighty Degree Laboratory Freezer for ISS (MELFI) for 1584 days. After taking these cells back to the ground, the cells were thawed and cultured, and their gene expressions were comprehensively analyzed using RNA sequencing in order to elucidate the early response of the cells to long-time exposure to space radiation consisting of various ionized particles. The comparisons of gene expression involved in double-stranded break (DSB) repair were examined. The expressions of most of the genes that were involved in homologous recombination (HR) and non-homologous end joining (NHEJ) were not significantly changed between the ISS-stocked cells and ground-stocked control cells. However, the transcription of Trp53inp1 (tumor protein 53 induced nuclear protein-1), Cdkn1a (p21), and Mdm2 genes increased in ISS-stocked cells as well as Fe ion-irradiated cells compared to control cells. This suggests that accumulated DNA damage caused by space radiation exposure would activate these genes, which are involved in cell cycle arrest for repair and apoptosis in a p53-dependent or -independent manner, in order to prevent cells with damaged genomes from proliferating and forming tumors. [ABSTRACT FROM AUTHOR]

Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2-deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut. [ABSTRACT FROM AUTHOR]

Liver cancer is notoriously refractory to conventional therapeutics. Tumor progression is governed by the interplay between tumor-promoting genes and tumor-suppressor genes. BRD4, an acetyl lysine-binding protein, is overexpressed in many cancer types, which promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains incompletely understood. In addition, understanding the regulatory mechanism of BRD4 protein level will shed insight into BRD4-targeting therapeutics. In this study, we investigated the potential relation between BRD4 protein level and P53, the most frequently dysregulated tumor suppressor. By analyzing the TCGA datasets, we first identify a strong negative correlation between protein levels of P53 and BRD4 in liver cancer. Further investigation shows that P53 promotes BRD4 protein degradation. Mechanistically, P53 indirectly represses the transcription of USP1, a deubiquitinase, through the P21-RB1 axis. USP1 itself is also overexpressed in liver cancer and we show USP1 deubiquitinates BRD4 in vivo and in vitro, which increases BRD4 stability. With cell proliferation assays and xenograft model, we show the protumor role of USP1 is partially mediated by BRD4. With functional transcriptomic analysis, we find the USP1-BRD4 axis upholds expression of a group of cancer-related genes. In summary, we identify a functional P53-P21-RB1-USP1-BRD4 axis in liver cancer. [ABSTRACT FROM AUTHOR]

Hydroxychloroquine (HCQ), a derivative of chloroquine (CQ), is an antimalarial and antirheumatic drug. Since there is limited data available on the genotoxicity of HCQ, in the current study, we used a battery of in vitro assays to systematically examine the genotoxicity of HCQ in human lymphoblastoid TK6 cells. We first showed that HCQ is not mutagenic in TK6 cells up to 80 μM with or without exogenous metabolic activation. Subsequently, we found that short-term (3–4 h) HCQ treatment did not cause DNA strand breakage as measured by the comet assay and the phosphorylation of histone H2A.X (γH2A.X), and did not induce chromosomal damage as determined by the micronucleus (MN) assay. However, after 24-h treatment, both CQ and HCQ induced comparable and weak DNA damage and MN formation in TK6 cells; upregulated p53 and p53-mediated DNA damage responsive genes; and triggered apoptosis and mitochondrial damage that may partially contribute to the observed MN formation. Using a benchmark dose (BMD) modeling analysis, the lower 95% confidence limit of BMD 50 values (BMDL 50) for MN induction in TK6 cells were about 19.7 μM for CQ and 16.3 μM for HCQ. These results provide additional information for quantitative genotoxic risk assessment of these drugs. ● Hydroxychloroquine induces weak genotoxicity in human TK6 cells after 24-h treatments. ● Hydroxychloroquine is not mutagenic in TK6 cells up to 80 µM after 4-h treatments. ● Hydroxychloroquine upregulates p53 and p53-mediated DNA damage responsive genes. ● The BMDL 50 value for the micronucleus data is about 16.3 μM for hydroxychloroquine. [ABSTRACT FROM AUTHOR]

Cerebral ischemic stroke is a cerebrovascular disease, which is related to DNA damage. Many researches have shown that Ku70 is a key regulator for DNA damage. Here, we aimed to explore Ku70 roles in cerebral ischemic stroke and its potential molecular mechanism. In our study, neural stem cells (NSCs) were induced by oxygen-glucose deprivation/reoxygenation (OGD/R) for constructing cerebral ischemic stroke cell model. CCK8 assay, Brdu/GFP staining, flow cytometry and TUNEL staining were performed to examine cell proliferation, cell cycle and apoptosis, respectively. Relative mRNA and protein levels were detected by quantitative real-time PCR and western blot analysis, respectively. Ku70 positive cells were examined by immunofluorescence staining. Comet assay was employed to determine DNA damage. Animal experiments were performed to assess the effect of transplanting NSCs and Ku70-overexpressed NSCs on neurological deficits, infarct volume, brain edema and blood‒brain barrier (BBB) integrity in middle cerebral artery occlusion (MCAO) model. Our data found that Ku70 expression was decreased in NSCs after OGD/R. Overexpression of Ku70 reduced DNA damage and apoptosis of OGD/R-induced NSCs. Knockdown of Ku70 promoted the activity of ATM/p53. Moreover, KU60019 (ATM-specific inhibitor) reversed the promoting effects of Ku70 silencing on DNA damage and apoptosis in OGD/R-induced NSCs. In animal experiments, transplantation of NSCs-overexpressed Ku70 enhanced cell survival, improved motor function, reduced infarct volume, relieved brain edema and alleviated BBB dysfunction in MCAO mice models. In conclusion, Ku70 overexpression repressed the DNA damage and apoptosis in OGD/R-induced NSCs by regulating ATM/p53 pathway, and transplantation of NSCs-overexpressed Ku70 played neuroprotective effects in MCAO mice models. [ABSTRACT FROM AUTHOR]

I propose a new strategy to suppress human cancer completely with two entirely new drug compounds exploiting cancer's Warburg effect characterized by a defective mitochondrial aerobic respiration, substituted by cytosolic aerobic fermentation/glycolysis of D-(+)-glucose into L-(+)-lactic acid. The two essentially new drugs, compound 1 [P(op)T(est)162] and compound 3 (PT167), represent new highly symmetric, four-bladed propeller-shaped polyammonium cations. The in vitro antineoplastic highly efficacious drug compound 3 represents a covalent combination of compound 1 and compound 2 (PT166). The intermediate drug compound 2 is an entirely new colchic(in)oid derivative synthesized from colchicine. Compound 2's structure was determined using X-ray crystallography. Compound 1 and compound 3 were active in vitro versus 60 human cancer cell lines of the National Cancer Institute (NCI) Developmental Therapeutics Program (DTP) 60-cancer cell testing. Compound 1 and compound 3 not only stop the growth of cancer cells to ±0% (cancerostatic effect) but completely kill nearly all 60 cancer cells to a level of almost −100% (tumoricidal effect). Compound 1 and compound 3 induce mitochondrial apoptosis (under cytochrome c release) in all cancer cells tested by (re)activating (in most cancers impaired) p53 function, which results in a decrease in cancer's dysregulated cyclin D1 and an induction of the cell cycle-halting cyclin-dependent kinase inhibitor p21Waf1/p21Cip1. [ABSTRACT FROM AUTHOR]

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells from ferroptosis inducers, and ferroptosis inhibitors reverse the effects of mutant p53 loss in vivo. Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6, which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death. [ABSTRACT FROM AUTHOR]

TP53 encodes a transcription factor that is centrally-involved in several pathways, including the control of metabolism, the stress response, DNA repair, cell cycle arrest, senescence, programmed cell death, and others. Since the discovery of TP53 as the most frequently-mutated tumor suppressor gene in cancer over four decades ago, the field has focused on uncovering target genes of this transcription factor that are essential for tumor suppression. This search has been fraught with red herrings, however. Dozens of p53 target genes were discovered that had logical roles in tumor suppression, but subsequent data showed that most were not tumor suppressive, and were dispensable for p53-mediated tumor suppression. In this review, we focus on p53 transcriptional targets in two categories: (1) canonical targets like CDKN1A (p21) and BBC3 (PUMA), which clearly play critical roles in p53-mediated cell cycle arrest/senescence and cell death, but which are not mutated in cancer, and for which knockout mice fail to develop spontaneous tumors; and (2) a smaller category of recently-described p53 target genes that are mutated in human cancer, and which appear to be critical for tumor suppression by p53. Interestingly, many of these genes encode proteins that control broad cellular pathways, like splicing and protein degradation, and several of them encode proteins that feed back to regulate p53. These include ZMAT3, GLS2, PADI4, ZBXW7, RFX7, and BTG2. The findings from these studies provide a more complex, but exciting, potential framework for understanding the role of p53 in tumor suppression. [ABSTRACT FROM AUTHOR]

The suppression of tumor proliferation via cellular senescence has emerged as a promising approach for anti-tumor therapy. Tumor necrosis factor receptor-associated factor 2 (TRAF2), an adaptor protein involved in the NF-κB signaling pathway and reactive oxygen species (ROS) production, has been implicated in hepatocellular carcinoma (HCC) proliferation. However, little is currently known about whether TRAF2 promotes HCC development by inhibiting cellular senescence. Replicative senescence model and IR-induced mouse model demonstrated that TRAF2 expression was decrease in senescence cells or liver tissues. Depletion of TRAF2 could inhibit proliferation and arrest the cell cycle via activating p53/p21WAF1 and p16INK4a/pRb signaling pathways in HCC cells and eventually lead to cellular senescence. Mechanistically, TRAF2 deficiency increased the expression of mitochondrial protein reactive oxygen species modulator 1 (ROMO1) and subsequently activated the NAD+/SIRT3/SOD2 pathway to promote the production of ROS and cause mitochondrial dysfunction, which eventually contributed to DNA damage response (DDR). Our findings demonstrate that TRAF2 deficiency inhibits the proliferation of HCC by promoting senescence. Therefore, targeting TRAF2 through various approaches holds therapeutic potential for treating HCC. [Display omitted] • Early detection and treatment of liver cancer encounters difficulties. • Excessive Reactive oxygen species damages mitochondria homeostasis. • Disrupting mitochondrial functions induces senescence of cancer cells. • Pro-senescence therapies, a potential strategy for treatment of liver cancer. [ABSTRACT FROM AUTHOR]

Purpose: Platinum-based chemotherapy remains a standard-of-care for most patients with advanced non-small cell lung cancer (NSCLC). DNA damage response (DDR) induced by platinum or Etoposide activated a panel of cell cycle-regulatory proteins including p21 through p53 pathway. Previous studies have reported that RanBPM has been involved in various cellular processes such as DDR by interacting with multiple proteins. However, the underlying mechanism remains unclear. Methods: NSCLC tissue microarrays were used for assessing the expression of RanBPM by immunohistochemical staining. The roles of RanBPM in the DDR of NSCLC progression was examined in in vitro cell lines and in vivo animal models. The regulation of RanBPM on protein stability and ubiquitination levels were investigated by immunoblots and in vivo ubiquitylation assay. Results: The level of p21 or RanBPM is lower in NSCLC than non-malignant tissues and has a highly positive correlation. Mechanistically, RanBPM protein physically interacts with p21, and RanBPM deubiquitinates p21 by recruiting a deubiquitinase USP11 to maintain protein stability of p21. RanBPM silencing significantly decreased p21 protein level. Conversely, RanBPM overexpression led to the accumulation of endogenous p21 protein regardless of p53 status. Functionally, RanBPM regulates DDR in a p21-dependent manner. Furthermore, DNA damage significantly promoted the nuclear translocation of RanBPM protein through ATM signaling pathways. Conclusion: RanBPM is a novel regulator of P21 protein stability, and plays a critical role in the regulation of DDR. [ABSTRACT FROM AUTHOR]

Purpose: Retinoblastoma, a childhood cancer, is most frequently caused by bi-allelic inactivation of RB1 gene. However, other oncogenic mutations such as MYCN amplification can induce retinoblastoma with proficient RB1. Previously, we established RB1-proficient MYCN-overexpressing retinoblastoma models both in human organoids and chicken. Here, we investigate the regulatory events in MYCN-induced retinoblastoma carcinogenesis based on the model in chicken. Methods: MYCN transformed retinal cells in culture were obtained from in vivo MYCN electroporated chicken embryo retina. The expression profiles were analysed by RNA sequencing. Chemical treatments, qRT-PCR, flow cytometry, immunohisto- and immunocytochemistry and western blot were applied to study the properties and function of these cells. Results: The expression profile of MYCN-transformed retinal cells in culture showed cone photoreceptor progenitor signature and robustly increased levels of E2Fs. This expression profile was consistently observed in long-term culture. Chemical treatments confirmed RB1 proficiency in these cells. The cells were insensitive to p53 activation but inhibition of E2f efficiently induced cell cycle arrest followed by apoptosis. Conclusion: In conclusion, with proficient RB1, MYCN-induced high level of E2F expression dysregulates the cell cycle and contributes to retinoblastoma carcinogenesis. The increased level of E2f renders the cells to adopt a similar mechanistic phenotype to a RB1-deficient tumour. [ABSTRACT FROM AUTHOR]

Endometriosis (E) and adenomyosis (A) are associated with a wide spectrum of symptoms and may present various histopathological transformations, such as the presence of hyperplasia, atypia, and malignant transformation occurring under the influence of local inflammatory, vascular and hormonal factors and by the alteration of tumor suppressor proteins and the inhibition of cell apoptosis, with an increased degree of lesion proliferation. Material and methods: This retrospective study included 243 patients from whom tissue with E/A or normal control uterine tissue was harvested and stained by histochemical and classical immunohistochemical staining. We assessed the symptomatology of the patients, the structure of the ectopic epithelium and the presence of neovascularization, hormone receptors, inflammatory cells and oncoproteins involved in lesion development. Atypical areas were analyzed using multiple immunolabeling techniques. Results: The cytokeratin (CK) CK7+/CK20− expression profile was present in E foci and differentiated them from digestive metastases. The neovascularization marker cluster of differentiation (CD) 34+ was increased, especially in areas with malignant transformation of E or A foci. T:CD3+ lymphocytes, B:CD20+ lymphocytes, CD68+ macrophages and tryptase+ mast cells were abundant, especially in cases associated with malignant transformation, being markers of the proinflammatory microenvironment. In addition, we found a significantly increased cell division index (Ki67+), with transformation and inactivation of tumor suppressor genes p53, B-cell lymphoma 2 (BCL-2) and Phosphatase and tensin homolog (PTEN) in areas with E/A-transformed malignancy. Conclusions: Proinflammatory/vascular/hormonal changes trigger E/A progression and the onset of cellular atypia and malignant transformation, exacerbating symptoms, especially local pain and vaginal bleeding. These triggers may represent future therapeutic targets. [ABSTRACT FROM AUTHOR]

Purpose: To determine the mechanism of action of Tripterygium wilfordii Hook F (TwHF) in the treatment of rheumatoid arthritis (RA) based on network pharmacology and molecular docking. Methods: The active constituents and targets of TwHF were screened by searching the TCMSP, TCMIP, PharmMapper database, and BATMAN-TCM platform combined with oral bioavailability and drug-like analysis. The drug-component-target maps were drawn using the UniProt database and Cytoscape 3.9.0 software. The drug-target maps were searched in GeneCards, OMIM, TTD, PharmGKB, and DrugBank databases to obtain the predicted targets of RA, Venn diagrams were drawn to derive the common targets of TwHF components and RA and protein-protein interaction (PPI) network, GO enrichment as well as KEGG pathway analyses were performed. The potential binding activities between the active constituents of TwHF and the targets were predicted using molecular docking. Results: Seven active components and 131 potential targets were found for TwHF while RA had 4,917 related targets. However, TwHF and RA had 87 common targets. The target genes obtained from the PPI network include tumor necrosis factor (TNF), p53 tumor protein (TP53) and vascular endothelial growth factor A (VEGFA). The GO enrichment and KEGG pathway analysis yielded 336 results and 121 signal pathways, respectively. Conclusion: Tripterygium wilfordii Hook F therapy for RA may be a multi-component, multi-target and multi-signal pathway biological process, which may regulate VEGFA, TNF, TP53 and other targets and also exhibit anti-inflammatory and immunomodulatory functions amongst others. Future studies should determine the relationship of the identified targets in vivo to produce alternative treatments for RA. [ABSTRACT FROM AUTHOR]

Inhaling xenobiotics, such as tobacco smoke is a major risk factor for pulmonary diseases, e.g., COPD/emphysema, interstitial lung disease, and pre‐invasive diseases. Shelterin complex or telosome provides telomeric end protection during replication. Telomere protection protein 1 (TPP1) is one of the main six subunits of the shelterin complex supporting the telomere stability and genomic integrity. Dysfunctional telomeres and shelterin complex are associated as a disease mechanism of tobacco smoke‐induced pulmonary damage and disease processes. The airway epithelium is critical to maintaining respiratory homeostasis and is implicated in lung diseases. Club cells (also known as clara cells) play an essential role in the immune response, surfactant production, and metabolism. Disrupted shelterin complex may lead to dysregulated cellular function, DNA damage, and disease progression. However, it is unknown if the conditional removal of TPP1 from Club cells can induce lung disease pathogenesis caused by tobacco smoke exposure. In this study, conditional knockout of Club‐cell specific TPP1 demonstrated the instability of other shelterin protein subunits, such as TRF1, dysregulation of cell cycle checkpoint proteins, p53 and downstream targets, and dysregulation of telomeric genes. This was associated with age‐dependent senescence‐associated genes, increased DNA damage, and upregulated RANTES/IL13/IL33 mediated lung inflammation and injury network by cigarette smoke (CS). These phenomena are also associated with alterations in cytochrome P450 and glutathione transferases, upregulated molecular pathways promoting lung lesions, bronchial neoplasms, and adenocarcinomas. These findings suggest a pivotal role of TPP1 in maintaining lung homeostasis and injurious responses in response to CS. Thus, these data TPP1 may have therapeutic value in alleviating telomere‐related chronic lung diseases. [ABSTRACT FROM AUTHOR]

Mucinous ovarian carcinoma (MOC) is a rare type of ovarian cancer with a better prognosis compared to other types. However, some patients with stage I disease experience tumor recurrence and poor outcomes. Recent studies have shown that the growth pattern of MOC, either expansile or infiltrative invasion, is a better predictor of clinical behavior than tumor grading. A study published in Histopathology found that MOCs with infiltrative invasion were associated with a higher risk of death, independent of other factors. The study also confirmed that MOCs with expansile invasion have better outcomes. The study recommends including the pattern of invasion in histopathologic reporting and risk stratification for MOC patients. Additionally, the study found that stromal markers FAP and THBS2 were more commonly expressed in MOCs with infiltrative invasion, which was associated with worse disease-specific survival. The study suggests that evaluating growth pattern and stromal markers can aid in the classification and understanding of biological differences in MOC. The authors emphasize the need for standardized criteria and increased awareness among pathologists for evaluating growth pattern in MOC. Pathologic staging and p53 mutation-type staining were also found to be important prognostic factors in MOC. The authors envision a future where patient management is based on important tumor parameters like growth pattern and p53 status, which can be easily incorporated into routine practice and may lead to improved patient stratification and tailored approaches. [Extracted from the article]

Cellular immortalization is a complex process that requires multiple genetic alterations to overcome restricting barriers, including senescence. Not surprisingly, many of these alterations are associated with cancer; two tumor suppressor pathways, the cellular tumor antigen p53 and p16‐Retinoblastoma (RB) pathways, are the best‐characterized examples, but their mutations alone are known to be insufficient to drive full immortalization. En et al. identified a role for the lamin B receptor (LBR) in promoting cellular proliferation and immortalization in p53‐ and RB‐deficient cells by maintaining their genome integrity and suppressing senescence. Thus, modulation of LBR could be exploited to treat cancer and potentially also to promote cell rejuvenation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Blueberries and apples exhibit favorable bioactivity and health benefits as a result of their rich phytochemicals. Natural phytochemicals exist in complex forms, but there are few reports on whether have additive, synergistic or antagonistic effects between different phytochemicals. The present study aimed to elucidate the synergistic effects of blueberry extract (BE) and apple peel extract (APE) together with respect to inhibiting the proliferation of HepG2 liver cancer cells. Meanwhile, phytochemical characterization of BE and APE was conducted by HPLC, and total antioxidant activity was determined via a cellular antioxidant activity assay, oxygen radical absorption capacity assay and peroxy radical scavenging capacity assay. RESULTS: The results showed that BE and APE were rich in phytochemicals and had potent antioxidant activities, which synergistically inhibited cell proliferation. In the bilateral combination, the dose reduction index value increased by two‐fold, and the combination index value at 95% inhibition was less than 1. Additionally, BE + APE supplementation could promote the expression levels of p53 and c‐myc genes. In conclusion, the BE and APE had strong antioxidant activity and exhibited synergistic inhibition against proliferation of HepG2 cells. CONCLUSION: The present study can provide a theoretical basis for the synergistic effect of different phytochemicals in health care. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]