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Background: Giant cell glioblastoma (GCGB) and pleomorphic xanthoastrocytoma (PXA) are rare astrocytic neoplasms. Although they share certain histopathological and histochemical findings, they are characterized by different clinical behaviour and prognosis. Nevertheless, few cases remain uncertain, as their histopathological features and immunophenotypes do not correspond to the typical pattern either of GCGB or PXA and require additional immunohistochemical diagnostic measures for appropriate diagnosis. Specific aims: We carried out this study to address the clinicopathological features of these neoplasms and to examine the expression profile of GFAP, synaptophysin, p53, CD34, and Ki67 proteins. Results: The mean age of the patients was high in GCGB (mean ± SD:49 ± 16.9 years) as compared to PXA (mean ± SD: 29 ± 10.6 years) and APXA (mean ± SD:31 ± 11.5 years). GCGB was more common in women, whereas both PXA and APXA were more common in men. The preferential localization of these tumours was the parietal (GCGB and APXA), and temporal (PXA) lobes. Statistically significant different expressions of P53 (P value = 0.024) and CD34 (P value = 0.001) between PXA and GCGB aid in discrimination between these entities. Interestingly, the similar expression patterns of p53 and CD34 proteins in both GCGB and APXA suggest the presence of possible common molecular mechanisms in both of them. Conclusions: Our work demonstrated that CD34 immunohistochemical expression is more pronounced in PXA, in contrast to p53 which is frequently expressed in GCGB, and APXA. The altered expression of p53, CD34 among GCGB, PXA, and APXA suggests possible roles of these proteins in the development of these neoplasms. [ABSTRACT FROM AUTHOR]

Glioblastomas (GBM) are most common types of primary brain tumors and miRNAs play an important role in pathogenesis of glioblastomas. Here, we reported a new miRNA, miR-3154, which regulates glioblastoma proliferation and metastasis. miR-3154 was elevated in glioblastoma tissue and cell lines, and its elevation was associated with grade of glioblastomas. Knockdown of miR-3154 in cell lines weakened ability of proliferation and colony formation, and caused cell cycle arrested and higher percentage of apoptosis. Knockdown of miR-3154 also impaired ability of migration and invasion in glioblastoma cells. In mechanism, miR-3154 bound directly to Tumor Protein P53 Inducible Nuclear Protein 1 (TP53INP1), down-regulating TP53INP1 expression at both mRNA and protein level. Silence of TP53INP1 reversed the effect of miR-3154 knockdown on proliferation and metastasis of glioblastoma cells. These findings show that miR-3154 promotes glioblastoma proliferation and metastasis via targeting TP53INP1. [ABSTRACT FROM AUTHOR]

Hypertrophic scar (HTS) formation is a pathological fibrotic skin disease, with no satisfactory treatments available currently. Inducing apoptosis of HTS-derived fibroblasts (HSFs) are becoming promising approaches. In this research, we aim to improve the technology with co-delivery COX-2 and TGF-β1 siRNAs and further investigate the underlying mechanism. Firstly, the HSFs were transfected with 1 µg/ml COX-2 and/or TGF-β1 siRNAs, and proved that the apoptosis of HSFs was greater induced by COX-2/TGF-β1 siRNAs than either COX-2 or TGF-β1 siRNA alone by flow cytometry. To investigate the impact of co-silencing TGF-β1 and COX-2 mRNA expression in vivo, we established HTSs model in rat tails. Our results confirmed that co-silencing of TGF-β1 and COX-2 mRNA expression could significantly alleviate the HTS formation in vivo. Furthermore, we explored the potential molecular mechanism and revealed that the protein levels of TP53, Bcl-2 and Caspase-3 were downregulated while Bax and Cleaved Caspase-3 were upregulated in the COX-2/TGF-β1 siRNA groups compared with HKP group. Taken together, our results demonstrated that simultaneous silencing of COX-2 and TGF-β1 expression by siRNAs induced HSF apoptosis through a TP53 mediated caspase pathway. Therefore, COX-2/TGF-β1 siRNAs might serve as a novel and effective therapeutic alternative for HTSs treatments. [ABSTRACT FROM AUTHOR]

Objective(s): Human papillomavirus-16 E6 (HPV-16 E6) forms a heterodimer complex to up-regulate the degradation of tumor suppressor protein p53 to promote cervical cancer. This study aims to identify a novel small molecule against E6 with anticancer efficacy against HPV-16, a prime high-risk serotype inducer for cervical cancer. Materials and Methods: Autodock-vina-based high-throughput virtual screening and atomistic molecular dynamic simulations were used for identification of targeted lead molecules. HPV-16 infected SiHa and CaSki cell lines were used to validate the lead compound in vitro. Proliferation of cancer cells was analyzed by MTT assay and flow cytometry was used to analyze target inhibition, apoptosis, and p53. Results: High throughput virtual screening and molecular dynamic simulation identified C-71980262 as a lead candidate that could bind HPV-E6. Atomistic molecular dynamic simulation of E6 bound C-71980262 for 200 ns showed that the predicted ligand binding was stable with minimal energy expenditure, proposing the viability and veracity of the assessed molecule. C-71980262 inhibited the proliferation of SiHa and CaSki cells with GI50 values of 355.70 nM and 505.90 nM, respectively. The compound reduced HPV-16 E6 while inducing early and late-phase apoptosis in these cells. Treatment with C-71980262 increased the p53-positive populations in SiHa and CaSki cells. Conclusion: C-71980262 was identified as a novel lead molecule that could inhibit the HPV-16 E6 and increase p53 in cervical cancer cells. Further in vitro and in vivo validation is warranted to consolidate and corroborate this lead compound against HPV-induced cancer progression. [ABSTRACT FROM AUTHOR]

Liver cancer is the second leading cause of tumor-related death worldwide, and a serious threat to lives and health. Circulating tumor cells (CTCs) facilitate the progression of various cancers, including liver cancer. The relationship between CTC/circulating tumor microemboli-related genes (CRGs) and the prognosis of liver cancer is unclear. The aim of the present study was to identify CTC/circulating tumour microemboli-related genes (CRGs) in hepatocellular carcinoma and to investigate their clinical significance. Transcriptomic data from The Cancer Genome Atlas (International Cancer Genome Consortium (ICGC) and GSE117623 databases were combined, and differentially expressed CRGs were identified. These were subsequently analyzed via least absolute shrinkage and selection operator and multivariate Cox analyses, and a five-gene risk signature was constructed. The signature was validated in the ICGC and GSE14520 dataset with survival analysis and receiver operating characteristic curve analysis. Immunocyte infiltration, tumor mutation burden (TMB), tumor immune dysfunction and exclusion (TIDE), and the somatic mutation rate were also compared between high- and low-risk groups, based on the median predictive index, to further evaluate the immunotherapeutic value of the model. Molecular subtypes of liver cancer were characterized by the non-negative matrix factorization method and potential therapeutic compounds were evaluated for different subtypes. Nomograms were utilized to predict the prognosis of patients, and the signature was compared with previous literature models. Additionally, the biological function of one of the CRGs, tumor protein p53 inducible protein 3 (TP53I3), in liver cancer was further explored through in vitro experiments. Analysis of the prognostic characteristics of the five CRGs led to the identification of two liver cancer subtypes. Patients in the low-risk group had a longer survival compared with those in the high-risk group, and patients in the latter group were associated with a higher TMB, immunocyte infiltration and somatic mutation rate, and lower TIDE scores. The prognostic profile was validated in the ICGC and GSE14520 datasets and exhibited a good predictive performance. In vitro analysis showed that the knockdown of TP53I3 suppressed liver cancer cell proliferation. In summary, CRGs were used to develop a new prognostic signature to predict the prognosis of patients with liver cancer. This signature may be used to assess the prognosis of patients and may provide new insights for clinical management strategies. In addition, TP53I3 is potentially a therapeutic target for liver cancer. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) is one of the greatest causes of cancer death worldwide. As a novel potential tumor biomarker, ubiquitin-conjugating enzyme E2C (UBE2C) is a critical factor during the onset and development of human cancers. However, the mechanisms of UBE2C in LUAD are not well understood. In this study, increased expression level of UBE2C was observed in LUAD tumor tissues. High LUAD level portended a worse prognosis of LUAD patients. Down-regulation of UBE2C attenuated the cell proliferation and cycle, migration, and invasion. Consistently, the tumorigenic capacity of LUAD cells in nude mice was significantly suppressed by the knockdown of UBE2C. Knockdown of UBE2C inhibited the degradation of p53 protein via an ubiquitin-proteasome pathway, thereby increasing p53 and p21 protein expression. Moreover, the inhibition of LUAD cell malignant phenotypes caused by UBE2C knockdown was attenuated on account of the inactivation of p53/p21 signaling pathway. In conclusion, UBE2C facilitates cell malignant behaviour in LUAD by ubiquitin-dependent degradation of p53 to suppress the p53/p21 signaling pathway. UBE2C is potentially developed as a therapeutic target for patients with LUAD. [ABSTRACT FROM AUTHOR]

The transcription factor p53 (encoded by TP53) plays diverse roles in human development and disease. While best known for its role in tumor suppression, p53 signaling also influences mammalian development by triggering cell fate decisions in response to a wide variety of stresses. After over 4 decades of study, a new pathway that triggers p53 activation in response to mitotic delays was recently identified. Termed the mitotic surveillance or mitotic stopwatch pathway, the USP28 and 53BP1 proteins activate p53 in response to delayed mitotic progression to control cell fate and promote genomic stability. In this Minireview, I discuss its identification, potential roles in neurodevelopmental disorders and cancer, as well as explore outstanding questions about its function, regulation and potential use as a biomarker for anti-mitotic therapies. [ABSTRACT FROM AUTHOR]

The p53 mutation is the most common genetic mutation associated with human neoplasia. TP53 missense mutations, which frequently arise early in breast cancer, are present in over thirty percent of breast tumors. In breast cancer, p53 mutations are linked to a more aggressive course of the disease and worse overall survival rates. TP53 mutations are mostly seen in triple-negative breast cancer, a very diverse kind of the disease. The majority of TP53 mutations originate in the replacement of individual amino acids within the p53 protein's core domain, giving rise to a variety of variations referred to as "mutant p53s." In addition to gaining carcinogenic qualities through gain-of-function pathways, these mutants lose the typical tumor-suppressive features of p53 to variable degrees. The gain-of-function impact of stabilized mutant p53 causes tumor-specific dependency and resistance to therapy. P53 is a prospective target for cancer therapy because of its tumor-suppressive qualities and the numerous alterations that it experiences in tumors. Phenotypic abnormalities in breast cancer, notably poorly differentiated basal-like tumors are frequently linked to high-grade tumors. By comparing data from cell and animal models with clinical outcomes in breast cancer, this study investigates the molecular mechanisms that convert gene alterations into the pathogenic consequences of mutant p53's tumorigenic activity. The study delves into current and novel treatment approaches aimed at targeting p53 mutations, taking into account the similarities and differences in p53 regulatory mechanisms between mutant and wild-type forms, as well. [ABSTRACT FROM AUTHOR]

The six most common missense mutations in the DNA binding domain of p53 are known as "hot spots" and include two of the most frequently occurring p53 mutations (p53-R175H and p53-R273H). p53 stability and function are regulated by various post-translational modifications such as phosphorylation, acetylation, sumoylation, methylation, and interactions with other proteins including plakoglobin. Previously, using various carcinoma cell lines we showed that plakoglobin interacted with wild-type and several endogenous p53 mutants (e.g., R280K, R273H, S241F, S215R, R175H) and restored their tumor suppressor activities in vitro. Since mutant p53 function is both mutant-specific and cell context-dependent, we sought herein, to determine if plakoglobin tumor suppressive effects on exogenously expressed p53-R273H and p53-R175H mutants are similarly maintained under the same genetic background using the p53-null and plakoglobin-deficient H1299 cell line. Functional assays were performed to assess colony formation, migration, and invasion while immunoblotting and qPCR were used to examine the subcellular distribution and expression of specific proteins and genes that are typically regulated by or regulate p53 function and are altered in mutant p53-expressing cell lines and tumors. We show that though, plakoglobin interacted with both p53-R273H and p53-R175H mutants, it had a differential effect on the transcription and subcellular distribution of their gene targets and their overall oncogenic properties in vitro. Notably, we found that plakoglobin's tumor suppressive effects were significantly stronger in p53-R175H expressing cells compared to p53-R273H cells. Together, our results indicate that exploring plakoglobin interactions with p53-R175H may be useful for the development of cancer therapeutics focused on the restoration of p53 function. [ABSTRACT FROM AUTHOR]

P53 is a transcription factor that controls a variety of genes, primarily involved in cell cycle and other processes related to cell survival and death. We have isolated peptides targeting P53 (protein and domains) using the "phage display" technique. Interestingly, adding ZnCl2 at 5–10 mM in panning solutions helped to recover more plaque-forming units at least at round one of the screening. Subtractive docking analyses were designed by using a pool of common redundant peptides known as parasites. This rationale helped us differentiate between possibly specific and non-specific bindings. We found notable differences in docking characteristics between different sets of peptides either related to different targets or related to zinc-conditions. The set of zinc-related peptides shows advantageous docking profiles: sharper binding for some positions and distinct exclusive bound residues, including the relevant R248 and R273. Zinc would have modulating/helping role in the targeting of protein P53 by phage displayed peptides in addition to an enhancement action on bacterial infection. [ABSTRACT FROM AUTHOR]

Investigating how transcription factors control complex cellular processes requires tools that enable responses to be visualised at the single-cell level and their cell fate to be followed over time. For example, the tumour suppressor p53 (also called TP53 in humans and TRP53 in mice) can initiate diverse cellular responses by transcriptional activation of its target genes: Puma to induce apoptotic cell death and p21 to induce cell cycle arrest/cell senescence. However, it is not known how these processes are regulated and initiated in different cell types. Also, the context-dependent interaction partners and binding loci of p53 remain largely elusive. To be able to examine these questions, we here developed knock-in mice expressing triple-FLAG-tagged p53 to facilitate p53 pull-down and two p53 response reporter mice, knocking tdTomato and GFP into the Puma/Bbc3 and p21 gene loci, respectively. By crossing these reporter mice into a p53-deficient background, we show that the new reporters reliably inform on p53-dependent and p53-independent initiation of both apoptotic or cell cycle arrest/senescence programs, respectively, in vitro and in vivo. Synopsis: The respective contribution of tumour suppressor p53-activated cellular response pathways to prevention of tumour development remains debated. This resource introduces three novel mouse strains for studying p53's interaction biochemistry and for assessing its contribution to cell cycle arrest and apoptosis in vitro and in vivo. Knock-in mice expressing N-terminally triple-FLAG tagged p53 facilitate identification of p53-interacting proteins and of genomic p53 binding sites. Knock-in mice expressing a p21-IRES-GFP reporter allow in situ imaging of p21-initiated cell cycle arrest and cell senescence in response to p53-dependent and p53-independent stimuli. Knock-in mice expressing a Puma-tdTomato allow in situ imaging of PUMA-initiated apoptotic programs activated in response to p53-dependent and p53-independent stimuli. Novel p53 knock-in and p53 target gene mouse strains enable interaction proteomics, DNA binding studies, as well as the imaging of p53 contributions to cell cycle arrest and apoptosis in situ. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is a frequently occurring malignancy in the head and neck region. The most commonly mutated gene in OSCC is the tumor suppressor gene p53 (TP53), linked to lower survival and treatment resistance in OSCC patients. Astilbin is a flavonoid amongst several herbal treatments with a variety of pharmacological actions mainly including antioxidant, anti-inflammatory, and anti-cancer characteristics. This study evaluated the effects of astilbin on proliferation of OSCC cell lines SCC90 and SCC4 (bearing a p53 mutation) in relevance to p53 and Mdm-2 pathways. Astilbin inhibited the proliferation of SCC4 and SCC90 cells in a dose- and time-dependent manner. The IC50 values for both the cell lines were about 75 μM for astilbin. A p53 activator (RITA) was used to determine the effects of astilbin on p53 activity, and the results demonstrated synergistic reduction in cell growth. However, when combined with pifithrin-α (a p53 inhibitor), astilbin demonstrated a strong inhibition of its response. Astilbin reduced the mitochondrial membrane potential in SCC4 cells, which is a sign of apoptotic activity. Astilbin decreased the amounts of Mdm-2 (negative regulator of p53) and increased the expression of the p53 gene and protein. In a p53-dependent manner, astilbin suppressed the ability of SCC4 cells to form colonies and heal wounds. This was followed by the induction of mitochondrial intrinsic apoptosis via the activation of caspases 9 and 3, cleavage of PARP, and the suppression of pro-apoptotic Bid. Astilbin-induced p53-mediated apoptosis in OSCC cells as herbal medicinal ingredients. [ABSTRACT FROM AUTHOR]

Introduction: TP53 is one of the most frequently mutated genes among all cancers, and TP53 mutants occur more than 40% in colorectal cancers (CRCs). Accumulation of mutant p53 may augment colorectal cancer stem cells (CCSCs) phenotype and enhance colorectal tumorigenesis. Thus, reducing the level of mutant p53 protein is an attractive anticancer strategy. Methods: CSC-enriched cancer cells were obtained by tumor sphere formation assay. The effects of USP7 on the proliferation of cancer cells were determined by MTS and colony formation assays. Wound healing assay was used to test cell migratory abilities. qPCR and western blotting assays were performed to verify the mRNA and protein levels of CSC markers, USP7 and p53. Co-immunoprecipitation assay was used to test the interaction effects between USP7 and p53. Results: In this study, we found that USP7 and mutant p53 were dramatically elevated in CSC-enriched colorectal cancer cells and USP7 expression was positively associated with self-renewal and maintenance of CCSCs. USP7 regulated cell growth, stemness and migration of colorectal cancer cells. USP7 depletion significantly reduced proliferation of cancer cells and suppressed the self-renewal of CSC-enriched colorectal cancer cells. Further studies indicated that USP7 knockdown could significantly decrease mutant p53 protein levels both in CRCs and CSC-enriched colorectal cancer cells. Moreover, mutant p53 was stabilized by USP7 and they interacted with each other. Furthermore, USP7 inhibitor P5091 also diminished CCSCs self-renewal and reduced mutant p53 levels. Conclusion: Taken together, our findings demonstrated that USP7 involved in the modulation of CCSCs stemness, as well as a critical target for clinical treatment of cancers with different p53 mutations. [ABSTRACT FROM AUTHOR]

The Trp53 gene encodes several isoforms of elusive biological significance. Here, we show that mice lacking the Trp53 alternatively spliced (AS) exon, thereby expressing the canonical p53 protein but not isoforms with the AS C-terminus, have unexpectedly lost a male-specific protection against Myc-induced B-cell lymphomas. Lymphomagenesis was delayed in Trp53+/+Eμ-Myc males compared to Trp53ΔAS/ΔAS Eμ-Myc males, but also compared to Trp53+/+Eμ-Myc and Trp53ΔAS/ΔAS Eμ-Myc females. Pre-tumoral splenic cells from Trp53+/+Eμ-Myc males exhibited a higher expression of Ackr4, encoding an atypical chemokine receptor with tumor suppressive effects. We identified Ackr4 as a p53 target gene whose p53-mediated transactivation is inhibited by estrogens, and as a male-specific factor of good prognosis relevant for murine Eμ-Myc-induced and human Burkitt lymphomas. Furthermore, the knockout of ACKR4 increased the chemokine-guided migration of Burkitt lymphoma cells. These data demonstrate the functional relevance of alternatively spliced p53 isoforms and reveal sex disparities in Myc-driven lymphomagenesis. [ABSTRACT FROM AUTHOR]

Understanding the environmental impact of nanoparticle (NP) mixtures is essential to accurately assess the risk they represent for aquatic ecosystems. However, although the toxicity of individual NPs has been extensively studied, information regarding the toxicity of combined NPs is still comparatively rather scarce. Hence, this research aimed to investigate the individual and combined toxicity mechanisms of two widely consumed nanoparticles, zinc oxide (ZnO NPs) and titanium dioxide (TiO2 NPs), using an in vitro model, the RTgill-W1 rainbow trout gill epithelial cell line. Sublethal concentrations of ZnO NPs (0.1 µg mL−1) and TiO2 (30 µg mL−1) and a lethal concentration of ZnO NPs causing 10% mortality (EC10, 3 µg mL−1) were selected based on cytotoxicity assays. Cells were then exposed to the NPs at the selected concentrations alone and to their combination. Cytotoxicity assays, oxidative stress markers, and targeted gene expression analyses were employed to assess the NP cellular toxicity mechanisms and their effects on the gill cells. The cytotoxicity of the mixture was identical to the one of ZnO NPs alone. Enzymatic and gene expression (nrf2, gpx, sod) analyses suggest that none of the tested conditions induced a strong redox imbalance. Metal detoxification mechanisms (mtb) and zinc transportation (znt1) were affected only in cells exposed to ZnO NPs, while tight junction proteins (zo1 and cldn1), and apoptosis protein p53 were overexpressed only in cells exposed to the mixture. Osmoregulation (Na + /K + ATPase gene expression) was not affected by the tested conditions. The overall results suggest that the toxic effects of ZnO and TiO2 NPs in the mixture were significantly enhanced and could result in the disruption of the gill epithelium integrity. This study provides new insights into the combined effects of commonly used nanoparticles, emphasizing the importance of further investigating how their toxicity may be influenced in mixtures. [ABSTRACT FROM AUTHOR]

The virus–host relationship is indispensable for executing successful viral infection. The pathogenesis of HIV is determined by an intricate interaction between the host and the virus for the regulation of HIV infection, thereby influencing various aspects, including the regulation of signaling pathways. High mutation rates and population heterogeneity characterize HIV with consequences for viral pathogenesis and the potential to escape the immune system and anti-viral inhibitors used in therapy. The origin of the high mutation rates exhibited by HIV may be attributed to a limited template-copied fidelity that likely operates in the cytoplasm. HIV-1 infection induces upregulation and activation of tumor suppressor p53 protein in the early stages of HIV-1 infection. p53 plays a multifaceted role in the context of HIV infection, thereby affecting viral replication. p53 is involved in maintaining genetic integrity, actively participating in various DNA repair processes through its various biochemical activities and via its ability to interact with components of the repair machinery. This report focuses on the impact of the p53 protein on the HIV-1 reverse transcription process while incorporating various incorrect and non-canonical nucleotides. The presence of functional host-coded p53 protein with proofreading–repair activities in the cytoplasm may lead to various biological outcomes. [ABSTRACT FROM AUTHOR]

The rapid variation of influenza challenges vaccines and treatments, which makes an urgent task to develop the high-efficiency and low-toxicity new anti-influenza virus drugs. Selenium is one of the essential trace elements for the human body that possesses a good antiviral activity. In this study, we assessed anti-influenza A virus (H1N1) activity of polyethylene glycol (PEG)-modified gray selenium nanoparticles (PEG-SeNPs) on Madin-Darby Canine Kidney (MDCK) cells in vitro. CCK-8 assay showed that PEG-SeNPs had a protective effect on H1N1-infected MDCK cells. Moreover, PEG-SeNPs significantly reduced the mRNA level of H1N1. TUNEL-DAPI test showed that DNA damage reached a high level but effectively prevented after PEG-SeNPs treatment. Meanwhile, JC-1, Annexin V-FITC and cell cycle assay demonstrated the apoptosis induced by H1N1 was reduced greatly when treated with PEG-SeNPs. Furthermore, the downregulation of p-ATM, p-ATR and P53 protein, along with the upregualation of AKT protein indicated that PEG-SeNPs could inhibit H1N1-induced cell apoptosis through reactive oxygen species (ROS)-mediated related signaling pathways. Finally, Cytokine detection demonstrated PEG-SeNPs inhibited the production of pro-inflammatory factors after infection, including IL-1β, IL-5, IL-6, and TNF-α. To sum up, PEG-SeNPs might become a new potential anti-H1N1 influenza virus drug due to its antiviral and anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion (I/R) injury, and the related mechanisms are unclear. Our previous study has shown that adipose stem cell-derived exosomes (ADSC-Exos) contain high levels of Mir221 and Mir222. The present study investigated the effects of PM exposure on I/R-induced cardiac injury through mitophagy and apoptosis, as well as the potential role of Mir221 and Mir222 in ADSC-Exos. Wild-type, mir221- and mir222-knockout (KO), and Mir221- and Mir222-overexpressing transgenic (TG) mice were intratracheally injected with PM (10 mg/kg). After 24 h, mice underwent left coronary artery ligation for 30 min, followed by 3 h of reperfusion (I/R). H9c2 cardiomyocytes were cultured under 1% O2 for 6 h, then reoxygenated for 12 h (hypoxia-reoxygenation [H/R]). PM aggravated I/R (or H/R) cardiac injury by increasing ROS levels and causing mitochondrial dysfunction, which increased the expression of mitochondrial fission-related proteins (DNM1L/Drp1 and MFF) and mitophagy-related proteins (BNIP3 and MAP1LC3B/LC3B) in vivo and in vitro. Treatment with ADSC-Exos or Mir221- and Mir222-mimics significantly reduced PM+I/R-induced cardiac injury. Importantly, ADSC-Exos contain Mir221 and Mir222, which directly targets BNIP3, MAP1LC3B/LC3B, and BBC3/PUMA, decreasing their expression and ultimately reducing cardiomyocyte mitophagy and apoptosis. The present data showed that ADSC-Exos treatment regulated mitophagy and apoptosis through the Mir221 and Mir222-BNIP3-MAP1LC3B-BBC3/PUMA pathway and significantly reduced the cardiac damage caused by PM+I/R. The present study revealed the novel therapeutic potential of ADSC-Exos in alleviating PM-induced exacerbation of myocardial I/R injury.Abbreviation: ADSC-Exos: adipose-derived stem cell exosomes; AL: autolysosome; ATP: adenosine triphosphate; BBC3/PUMA: BCL2 binding component 3; BNIP3: BCL2/adenovirus E1B interacting protein 3; CASP3: caspase 3; CASP9: caspase 9; CDKN1B/p27: cyclin dependent kinase inhibitor 1B; CVD: cardiovascular disease; DCFH-DA: 2‘,7’-dichlorodihydrofluorescein diacetate; DHE: dihydroethidium; DNM1L/Drp1: dynamin 1-like; EF: ejection fraction; FS: fractional shortening; H/R: hypoxia-reoxygenation; I/R: ischemia-reperfusion; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFF: mitochondrial fission factor; miRNA: microRNA; NAC: N-acetylcysteine; OCR: oxygen consumption rate; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PM: particulate matter; PRKAA1/AMPK: protein kinase AMP-activated catalytic subunit alpha 1; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TRP53/p53: transformation related protein 53; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling. [ABSTRACT FROM AUTHOR]

Sepsis associated Acute kidney injury (AKI) is a common clinical syndrome characterized by suddenly decreased in renal function and urinary volume. This study was designed to investigate the role of Aquaporin 1 (AQP1) and P53 in the development of sepsis-induced AKI and their potential regulatorymechanisms. Firstly, transcriptome sequencing analysis of mice kidney showed AQP1 expression was reduced and P53 expression was elevated in Cecal ligation and puncture (CLP)- induced AKI compared with controls. Bioinformatics confirmed that AQP1 expression was remarkably decreased and P53 expression was obviously elevated in renal tissues or peripheral blood of septic AKI patients. Moreover, we found in vivo experiments that AQP1mRNA levels were dramatically decreased and P53mRNA significantly increased following the increased expression of inflammation, apoptosis, fibrosis, NGAL and KIM-1 at various periods in septic AKI. Meanwhile, AQP1 and P53 protein levels increased significantly first and then decreased gradually in kidney tissue and serum of rats in different stages of septic AKI. Most importantly, in vivo and vitro experiments demonstrated that silencing of AQP1 greatly exacerbates renal or cellular injury by upregulating P53 expression promoting inflammatory response, apoptosis and fibrosis. Overexpression of AQP1 prevented the elevation of inflammation, apoptosis and fibrosis by down-regulating P53 expression in Lipopolysaccharide (LPS)-induced AKI or HK-2 cells. Therefore, our results suggested that AQP1 plays a protective role in modulating AKI and can attenuate inflammatory response, apoptosis and fibrosis via downregulating P53 in septic AKI or LPS-induced HK-2cells. The pharmacological targeting of AQP1mediated P53 expressionmight be identified as potential targets for the early treatment of septic AKI. [ABSTRACT FROM AUTHOR]

Salivary gland cancer (SGC) is a rare cancer that can present a diagnostic challenge to pathologists, with emerging, but still limited options for the treatment of recurrent/metastatic disease. We aimed to characterize the cohort of salivary gland cancers in our institute and generate a tissue microarray (TMA) with clinical data available for immunohistochemical analysis. We extracted the cases of salivary gland cancers in our institute and generated a TMA with 72 patients between 2002 and 2017 with sufficient paraffin block material. Follow-up data were present for all cases. The TMA was stained with three p53 antibodies as well as MSH2, MSH6, PMS2 and MLH1 antibodies. Additionally, we applied fragment analysis based on the Bethesda panel, and the IdyllaTM MSI test to cases with expression loss of any of the mismatch repair proteins (MMR-P) according to our immunohistochemistry (IHC). The investigated cohort shows that pT and pN stage are the only factors independently associated with survival, according to our multivariate analysis (p = 0.037 and p = 0.014). In univariate analysis, risk factors identified in our cohort were also age (p = 0.015), (lympho-) vascular invasion (p = 0.002 and p = 0.003) and risk stratification (p = 0.037). The p53 protein investigated by three antibodies showed no statistically significant association with survival or other tumor characteristics in the investigated cohort. According to MMR-P IHC, six cases of SGC showed an aberrant IHC phenotype. Additional IdyllaTM MSI test and fragment length analysis failed to confirm microsatellite instability. The pT and pN stage are the most important factors for survival in our cohort. In our cohort, antibodies directed against the protein p53 did not contribute to clinical decision-making and were not correlated with any known clinical characteristics. MSI appears to be insignificant in SGCs. Larger cohorts are needed for verification. [ABSTRACT FROM AUTHOR]

Modern research has shown that Cucurbitacin B (Cu B) possesses various biological activities such as liver protection, anti-inflammatory, and anti-tumor effects. However, the majority of research has primarily concentrated on its hepatoprotective effects, with limited attention devoted to exploring its potential impact on the prostate. Our research indicates that Cu B effectively inhibits the proliferation of human prostate stromal cells (WPMY-1) and fibroblasts (HPRF), while triggering apoptosis in prostate cells. When treated with 100 nM Cu B, the apoptosis rates of WPMY-1 and HPRF cells reached 51.73 ± 5.38% and 26.83 ± 0.40%, respectively. In addition, the cell cycle assay showed that Cu B had a G2/M phase cycle arrest effect on WPMY-1 cells. Based on RNA-sequencing analysis, Cu B might inhibit prostate cell proliferation via the p53 signaling pathway. Subsequently, the related gene and protein expression levels were measured using quantitative real-time PCR (RT-qPCR), immunocytochemistry (ICC), and enzyme-linked immunosorbent assays (ELISA). Our results mirrored the regulation of tumor protein p53 (TP53), mouse double minute-2 (MDM2), cyclin D1 (CCND1), and thrombospondin 1 (THBS1) in Cu B-induced prostate cell apoptosis. Altogether, Cu B may inhibit prostate cell proliferation and correlate to the modulation of the p53/MDM2 signaling cascade. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether 6 months of preoperative apalutamide for intermediate‐risk prostate cancer (IRPCa) reduces the aggregate postoperative radiotherapy risk and to evaluate associations of molecular perturbations with clinical outcomes in this study cohort. Patients and Methods: Between May 2018 and February 2020, eligible patients with IRPCa (Gleason 3 + 4 or 4 + 3 and clinical T2b‐c or prostate‐specific antigen level of 10–20 ng/mL) were treated with apalutamide 240 mg/day for 6 months followed by radical prostatectomy (RP) in this single‐arm, phase II trial. The primary endpoint was presence of any adverse pathological feature at risk of pelvic radiation (pathological T stage after neoadjuvant therapy [yp]T3 or ypN1 or positive surgical margins). Translational studies, including germline and somatic DNA alterations and RNA and protein expression, were performed on post‐apalutamide RP specimens, and assessed for associations with clinical outcomes. Results: A total of 40 patients underwent a RP, and only one patient discontinued apalutamide prior to 6 months. In all, 40% had adverse pathological features at time of RP, and the 3‐year biochemical recurrence (BCR) rate was 15%, with 27.5% being not evaluable. Genomic alterations frequently seen in metastatic PCas, such as androgen receptor (AR), tumour protein p53 (TP53), phosphatase and tensin homologue (PTEN), or BReast CAncer associated gene (BRCA1/2) were underrepresented in this localised cohort. Adverse pathological features and BCR at 3‐years were associated with increased expression of select cell cycle (e.g., E2F targets: adjusted P value [Padj] < 0.001, normalised enrichment score [NES] 2.47) and oxidative phosphorylation (Padj < 0.001, NES 1.62) pathways. Conclusions: Preoperative apalutamide did not reduce the aggregate postoperative radiation risk to the pre‐specified threshold in unselected men with IRPCa. However, transcriptomic analysis identified key dysregulated pathways in tumours associated with adverse pathological outcomes and BCR, which warrant future study. Further investigation of preoperative therapy is underway for men with high‐risk PCa. [ABSTRACT FROM AUTHOR]

Idebenone, an antioxidant used in treating oxidative damage-related diseases, has unclear neuroprotective mechanisms. Oxidative stress affects cell and mitochondrial membranes, altering Adp-ribosyl cyclase (CD38) and Silent message regulator 3 (SIRT3) protein expression and possibly impacting SIRT3's ability to deacetylate Tumor protein p53 (P53). This study explores the relationship between CD38, SIRT3, and P53 in H2O2-injured HT22 cells treated with Idebenone. Apoptosis was detected using flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after determining appropriate H2O2 and Idebenone concentrations. In this study, Idebenone was found to reduce apoptosis and decrease P53 and Caspase3 expression in H2O2-injured HT22 cells by detecting apoptosis-related protein expression. Through bioinformatics methods, CD38 was identified as the target of Idebenone, and it further demonstrated that Idebenone decreased the expression of CD38 and increased the level of SIRT3. An increased NAD+/NADH ratio was detected, suggesting Idebenone induces SIRT3 expression and protects HT22 cells by decreasing apoptosis-related proteins. Knocking down SIRT3 downregulated acetylated P53 (P53Ac), indicating SIRT3's importance in P53 deacetylation. These results supported that CD38 was used as a target of Idebenone to up-regulate SIRT3 to deacetylate activated P53, thereby protecting HT22 cells from oxidative stress injury. Thus, Idebenone is a drug that may show great potential in protecting against reactive oxygen species (ROS) induced diseases such as Parkinson's disease, and Alzheimer's disease. And it might be able to compensate for some of the defects associated with CD38-related diseases. [ABSTRACT FROM AUTHOR]

p53 is a star protein in cancer biology, and its oscillatory dynamics have received much attention. However, most studies do not consider spatial effects. For this reason, we introduce the diffusion term in a classical p53-Mdm2 autoregulatory loop model. First, the equation is linearized at the positive equilibrium so that we can discuss the local asymptotic stability of this equilibrium. By taking the delay as a bifurcation parameter, the positive equilibrium transitions from stable to unstable and occurs a Hopf bifurcation. Second, we determine the stability of the bifurcating period solution by using a multiple time scales approach. Finally, the theoretical analysis is verified by the numerical simulations. Our study contributes to providing new insight in the controlling of p53 dynamics. [ABSTRACT FROM AUTHOR]

Aim: Rhodojaponin VI (R‐VI) is the key compound of Rhododendron molle G. Don (Ericaceae) (RM) with effective clinical application in rheumatoid arthritis and chronic glomerulonephritis. In our study, we tried to explore the effect of R‐VI on the rat model of membranous nephropathy. Methods: The rat model of passive heymann nephritis (PHN) was established by injecting sheep anti‐rat Fx1A serum at a single dose through the tail. The rats were orally administered R‐VI (0.02 mg/kg) or FK506 (1 mg/kg) 1 day before PHN induction, which was kept for 4 weeks. Urine and blood samples as well as kidney tissue were collected for analysis. C5b‐9‐induced human podocyte cell (HPC) was employed for experiments in vitro. Results: R‐VI could alleviate glomerulonephritis progression and podocyte injury in PHN rats, as indicated by the decreased proteinuria and the elevated level of albumin, accompanied with reduced immune deposits, reversed podocyte injury in the kidneys. Furthermore, R‐VI suppressed murine double minute 2 (MDM2) expression without the alteration in the protein level of p53 and decreased Notch1 expression independent of Numb regulation. Pre‐treatment with R‐VI in C5b‐9‐induced HPC blocked MDM2/Notch1 signalling pathway. Conclusion: Thus, R‐VI ameliorates podocyte injury in rats with PHN, which was probably related with MDM2/Notch1 signalling pathway. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the pharmacological mechanism of Hedyotis diffusa Willd against CRC (colorectal cancer) using network pharmacological analysis combined with experimental validation. The active components and potential targets of Hedyotis diffusa Willd were screened from the tax compliance management program public database using network pharmacology. The core anti-CRC targets were screened using a protein-protein interaction (PPI) network. The mRNA and protein expression of core target genes in normal colon and CRC tissues and their relationship with overall CRC survival were evaluated using The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Functional and pathway enrichment analyses of the potential targets were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The first six core targets with stable binding were molecular-docked with the active components quercetin and β-sitosterol. Finally, the results of network pharmacology were verified using in vitro experiments. In total, 149 potential targets were identified by searching for seven types of active components and the intersection of all potential and CRC targets. PPI network analysis showed that ten target genes, including tumor protein p53 (TP53) and recombinant cyclin D1 (CCND1), were pivotal genes. GO enrichment analysis involved 2043 biological processes, 52 cellular components, and 191 molecular functions. KEGG enrichment analysis indicated that the anticancer effects of H. alba were mediated by tumor necrosis factor, interleukin-17, and nuclear factor-κB (NF-κB) signaling pathways. Validation of key targets showed that the validation results for most core genes were consistent with those in this study. Molecular docking revealed that the ten core target proteins could be well combined with quercetin and β-sitosterol and the structure remained stable after binding. The results of the in vitro experiment showed that β-sitosterol inhibited proliferation and induced apoptosis in SW620 cells. This study identified a potential target plant for CRC through network pharmacology and in vitro validation. [ABSTRACT FROM AUTHOR]

Macroautophagy/autophagy and apoptosis are pivotal interconnected host cell responses to viral infection, including picornaviruses. Here, the VP3 proteins of picornaviruses were determined to trigger autophagy, with the autophagic flux being triggered by the TP53-BAD-BAX axis. Using foot-and-mouth disease virus (FMDV) as a model system, we unraveled a novel mechanism of how picornavirus hijacks autophagy to bolster viral replication and enhance pathogenesis. FMDV infection induced both autophagy and apoptosis in vivo and in vitro. FMDV VP3 protein facilitated the phosphorylation and translocation of TP53 from the nucleus into the mitochondria, resulting in BAD-mediated apoptosis and BECN1-mediated autophagy. The amino acid Gly129 in VP3 is essential for its interaction with TP53, and crucial for induction of autophagy and apoptosis. VP3-induced autophagy and apoptosis are both essential for FMDV replication, while, autophagy plays a more important role in VP3-mediated pathogenesis. Mutation of Gly129 to Ala129 in VP3 abrogated the autophagic regulatory function of VP3, which significantly decreased the viral replication and pathogenesis of FMDV. This suggested that VP3-induced autophagy benefits viral replication and pathogenesis. Importantly, this Gly is conserved and showed a common function in various picornaviruses. This study provides insight for developing broad-spectrum antivirals and genetic engineering attenuated vaccines against picornaviruses. Abbreviations: 3-MA, 3-methyladenine; ATG, autophagy related; BAD, BCL2 associated agonist of cell death; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X, apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCL2, BCL2 apoptosis regulator; BID, BH3 interacting domain death agonist; BIP-V5, BAX inhibitor peptide V5; CFLAR/FLIP, CASP8 and FADD like apoptosis regulator; CPE, cytopathic effects; CQ, chloroquine; CV, coxsackievirus; DAPK, death associated protein kinase; DRAM, DNA damage regulated autophagy modulator; EV71, enterovirus 71; FMDV, foot-and-mouth disease virus; HAV, hepatitis A virus; KD, knockdown; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MOI, multiplicity of infection; MTOR, mechanistic target of rapamycin kinase; PML, promyelocytic leukemia; PV, poliovirus; SVA, Seneca Valley virus; TCID50, 50% tissue culture infectious doses; TOR, target of rapamycin. TP53/p53, tumor protein p53; WCL, whole-cell lysate. [ABSTRACT FROM AUTHOR]

Background: Gliomas are highly lethal malignancies that develop in the central nervous system. The primary treatment for gliomas involves surgical resection followed by chemoradiotherapy. However, due to the infiltrative growth nature of gliomas, surgical resection is often incomplete. Moreover, the efficacy of chemotherapeutic drugs is constrained by their ability to cross the blood–brain barrier, and the currently utilized agents can lose effectiveness, particularly with prolonged administration. Lentinan, an active compound in Lentinula edodes, exhibits various pharmacological activities. Purpose: This study aims to investigate the anti-tumor effects of lentinan on glioma U251 cells. Materials and Methods: Cell proliferation assays, cell fluorescence staining, scratch healing experiments, and transwell chamber experiments were conducted to assess the anti-tumor activity of lentinan on U251 cells. Additionally, quantitative real-time polymerase chain reaction (qPCR) and Western blot experiments were performed to validate the anti-tumor mechanism of lentinan. Results: The findings revealed that lentinan significantly suppressed the proliferation of U251 cells, induced robust apoptosis, and decreased the cells' migration and invasion capabilities. Furthermore, lentinan notably influenced the gene and protein expression of p53, Bcl-2, Cyto-c, Bax, Caspases, and MMP-9 in U251 cells. Conclusion: These findings suggest that lentinan may inhibit glioma cells by activating P53 and caspase-related apoptosis pathways. [ABSTRACT FROM AUTHOR]

• Emodin reduces HIBD in neonatal mice. • Emodin improves neurologic recovery of neonatal mice after HIBD. • Emodin can exert neuroprotective effects on HIBD by inhibiting neuronal apoptosis. Neonatal hypoxic-ischemic brain damage (HIBD) can lead to mortality and severe neurological dysfunction. Emodin is a natural anthraquinone derivative that is easy to obtain and has good neuroprotective effects. This study aimed to investigate the neuroprotective effect of emodin on neonatal mouse HIBD. The modified Rice–Vannucci method was used to induce HIBD in mouse pups. Eighty postnatal 7-day (P7) C57BL/6 neonatal mice were randomly divided into the sham group (sham), vehicle group (vehicle), and emodin group (emodin). TTC staining and whole-brain morphology were used to evaluate the infarct volume and morphology of the brain tissue. The condition of the neurons was observed through Nissl staining, HE staining, FJC staining, immunofluorescence and Western blot for NeuN, IBA-1, and GFAP. The physiological status of the mice was evaluated using weight measurements. The neural function of the mice was assessed using the negative geotaxis test, righting reflex test, and grip test. TUNEL staining was used to detect apoptosis in brain cells. Finally, Western blot and immunofluorescence were used to detect the expression levels of apoptosis-related proteins, such as P53, cleaved caspase-3, Bax and Bcl-2, in the brain. Experiments have shown that emodin can reduce the cerebral infarct volume, brain oedema, neuronal apoptosis, and degeneration and improve the reconstruction of brain tissue morphology, neuronal morphology, physiological conditions, and neural function. Additionally, emodin inhibited the expression of proapoptotic proteins such as P53, Bax and cleaved caspase-3 and promoted the expression of the antiapoptotic protein Bcl-2. Emodin attenuates HIBD by inhibiting neuronal apoptosis in neonatal mice. [ABSTRACT FROM AUTHOR]

Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance. Here the authors discovered that senescent cells increase protein synthesis through eIF5A regulation, involving polyamine metabolism and p53 pathways, crucial for immune surveillance and mitochondrial protein production in aging and cancer contexts. [ABSTRACT FROM AUTHOR]

Neuronal apoptosis is a mechanism used to clear the cells of oxidative stress or DNA damage and refine the final number of neurons for a functional neuronal circuit. The tumor suppressor protein p53 is a key regulator of the cell cycle and serves as a checkpoint for eliminating neurons with high DNA damage, hyperproliferative signals or cellular stress. During development, p53 is largely expressed in progenitor cells. In the adult brain, p53 expression is restricted to the neurogenic niches where it regulates cell proliferation and self-renewal. To investigate the functional consequences of p53 deletion in the cortex and hippocampus, we generated a conditional mutant mouse (p53-cKO) in which p53 is deleted from pallial progenitors and their derivatives. Surprisingly, we did not find any significant change in the number of neurons in the mutant cortex or CA region of the hippocampus compared with control mice. However, p53-cKO mice exhibit more proliferative cells in the subgranular zone of the dentate gyrus and more granule cells in the granular cell layer. Glutamatergic synapses in the CA3 region are more numerous in p53-cKO mice compared with control littermates, which correlates with overexcitability and higher epileptic susceptibility in the mutant mice. [ABSTRACT FROM AUTHOR]

The p53 protein, encoded by TP53, is a tumor suppressor that plays a critical role in regulating apoptosis, cell cycle regulation, and angiogenesis in tumor cells via controlling various downstream signals. Natural killer (NK) cell-mediated immune surveillance is a vital self-defense mechanism against cancer and other diseases, with NK cell activity regulated by various mechanisms. Among these, p53 plays a significant role in immune regulation by maintaining the homeostasis and functionality of NK cells. It enhances the transcriptional activity of NK cell-activating ligands and downregulates inhibitory ligands to boost NK cell activation and tumor-killing efficacy. Additionally, p53 influences NK cell cytotoxicity by promoting apoptosis, autophagy, and ferroptosis in different tumor cells. p53 is involved in the regulation of NK cell activity and effector functions through multiple pathways. p53 also plays a pivotal role in the tumor microenvironment (TME), regulating the activity of NK cells. NK cells are critical components of the TME and are capable of directly killing tumor cells. And p53 mutates in numerous cancers, with the most common alteration being a missense mutation. These mutations are commonly associated with poor survival rates in patients with cancer. This review details p53's role in NK cell tumor immunosurveillance, summarizing how p53 enhances NK cell recognition and tumor destruction. We also explore the potential applications of p53 in tumor immunotherapy, discussing strategies for modulating p53 to enhance NK cell function and improve the efficacy of tumor immunotherapy, along with the associated challenges. Understanding the interaction between p53 and NK cells within the TME is crucial for advancing NK cell-based immunotherapy and developing p53-related novel therapeutics. [ABSTRACT FROM AUTHOR]

TP53 mutation (TP53-mut) correlates with inferior survival in many cancers, whereas its prognostic role in diffuse large B-cell lymphoma (DLBCL) is still in controversy. Therefore, more precise risk stratification needs to be further explored for TP53-mut DLBCL patients. A set of 2637 DLBCL cases from multiple cohorts, was enrolled in our analysis. Among the 2637 DLBCL patients, 14.0% patients (370/2637) had TP53-mut. Since missense mutations account for the vast majority of TP53-mut DLBCL patients, and most non-missense mutations affect the function of the P53 protein, leading to worse survival rates, we distinguished patients with missense mutations. A TP53 missense mutation risk model was constructed based on a 150-combination machine learning computational framework, demonstrating excellent performance in predicting prognosis. Further analysis revealed that patients with high-risk missense mutations are significantly associated with early progression and exhibit dysregulation of multiple immune and metabolic pathways at the transcriptional level. Additionally, the high-risk group showed an absolutely suppressed immune microenvironment. To stratify the entire cohort of TP53-mut DLBCL, we combined clinical characteristics and ultimately constructed the TP53 Prognostic Index (TP53PI) model. In summary, we identified the truly high-risk TP53-mut DLBCL patients and explained this difference at the mutation and transcriptional levels. [ABSTRACT FROM AUTHOR]

Artichokes (Cynara scolymus L.) are valuable foods, thanks to their health benefits, but they generate significant waste during their production, harvesting, and processing, which poses sustainability issues. This study applied an agroprospecting approach to convert Tema artichoke biowaste (TB) into valuable resources, starting from a global perspective of the production chain to the targeted applications based on chemical and biological analysis. The major TB was identified in the outer bracts of the immature flower heads, which were collected throughout the harvesting season, extracted, and analyzed. The most abundant compounds were phenolic acids including chlorogenic acid and caffeoylquinic derivatives. Among flavonoids, cynaroside was the most abundant compound. Multivariate analysis distinguished batches by collection period, explaining 77.7% of the variance, with most compounds increasing in concentration later in the harvest season. Subsequently, TB extracts were analyzed for their potential in wound healing and anti-aging properties. Fibroblasts were used to assess the effect of selected extracts on cell migration through a scratch wound assay and on cellular senescence induced by etoposide. The results show a significant decrease in senescence-associated β-galactosidase activity, γH2AX nuclear accumulation, and both p53 and p21 protein levels. Overall, this study ascribes relevant anti-skin aging effects to TB, thus increasing its industrial value in cosmeceutical and nutraceutical applications. [ABSTRACT FROM AUTHOR]

CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3), a member of the CMTM family that is closely related to tumor occurrence and progression, plays crucial roles in the immune system, cardiovascular system, and male reproductive system. Recently, CMTM3 has emerged as a potential target for treating diseases related to bone formation. However, additional studies are needed to understand the mechanisms by which CMTM3 regulates the process of osteogenic differentiation. In this study, we observed a significant downregulation of Cmtm3 expression during the transdifferentiation of C2C12 myoblasts into osteoblasts induced by BMP4. Cmtm3 overexpression suppressed proliferation and osteogenic differentiation in BMP4-induced C2C12 cells, whereas its knockdown conversely facilitated the process. Mechanistically, Cmtm3 overexpression upregulated both the protein and mRNA levels of p53 and p21. Conversely, Cmtm3 knockdown exerted the opposite effects. Additionally, we found that Cmtm3 interacts with p53 and increases protein stability by inhibiting proteasome-mediated ubiquitination and degradation. Notably, Trp53 downregulation abrogated the inhibitory effect of Cmtm3 on BMP4-induced proliferation and osteogenic differentiation of C2C12 myoblasts. Collectively, our findings provide key insights into the role of CMTM3 in regulating myoblast proliferation and transdifferentiation into osteoblasts, highlighting its significance in osteogenesis research. [ABSTRACT FROM AUTHOR]

AbstractPurposeMethodsResultsConclusionsProliferative vitreoretinopathy (PVR) can cause blindness and the pathogenesis is unclear. Transforming growth factor (TGF)-β-induced epithelial-mesenchymal transition (EMT) of RPE cells is vital. P53 protein 2 (ASPP2) was previously reported to inhibit EMT in PVR rats, but the specific mechanism is unveiled.TGF-β was used to induce EMT in ARPE-19 cells, and evaluated by immunofluorescence and western blot. ARPE-19 cells were transfected with scrambled/ASPP2-lentivirus, followed by TGF-β treatment. After that, alterations of EMT and autophagy were measured by western blot and transmission electron microscopy. Moreover, TGF-β and ARPE-19 cells treated with scrambled/ASPP2-lentivirus were employed to establish the PVR model via intravitreal injection to SD rats, and retinal changes as well as EMT and autophagy activity were evaluated accordingly.ASPP2 expression was decreased during TGF-β-induced EMT in ARPE-19 cells. In vitro, EMT and autophagy was activated by TGF-β, which could be partly reversed by ASPP2 upregulation. In vivo, ASPP2 upregulation protected against structural and functional changes in PVR retinas. Additionally, expressions of EMT and autophagy markers in retinas were inhibited by ASPP2 upregulation.ASPP2 upregulation inhibited the EMT and autophagy process caused by TGF-β in ARPE-19 cells. Correspondingly, upregulation of ASPP2 alleviated intraocular fibrosis and protected visual function in PVR rats. [ABSTRACT FROM AUTHOR]

The factors driving glioma progression remain poorly understood. Here, the epigenetic regulator TRIM24 is identified as a driver of glioma progression, where TRIM24 overexpression promotes HRasV12 anaplastic astrocytoma (AA) progression into epithelioid GBM (Ep‐GBM)‐like tumors. Co‐transfection of TRIM24 with HRasV12 also induces Ep‐GBM‐like transformation of human neural stem cells (hNSCs) with tumor protein p53 gene (TP53) knockdown. Furthermore, TRIM24 is highly expressed in clinical Ep‐GBM specimens. Using single‐cell RNA‐sequencing (scRNA‐Seq), the authors show that TRIM24 overexpression impacts both intratumoral heterogeneity and the tumor microenvironment. Mechanically, HRasV12 activates phosphorylated adaptor for RNA export (PHAX) and upregulates U3 small nucleolar RNAs (U3 snoRNAs) to recruit Ku‐dependent DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs). Overexpressed TRIM24 is also recruited by PHAX to U3 snoRNAs, thereby facilitating DNA‐PKcs phosphorylation of TRIM24 at S767/768 residues. Phosphorylated TRIM24 induces epigenome and transcription factor network reprogramming and promotes Ep‐GBM‐like transformation. Targeting DNA‐PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep‐GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep‐GBM‐like transformation and suggest a potential therapeutic strategy for patients with Ep‐GBM. [ABSTRACT FROM AUTHOR]

Background: In advanced cirrhotic conditions, hepatorenal syndrome detrimentally affects renal function. Interest has grown in propolis for its cytoprotective properties against various exogenous agents. This study evaluates the efficacy of Saudi propolis extracts in mitigating hepatorenal toxicity induced by carbon tetrachloride in mice. Methods: Thirty-two male Swiss Albino mice were divided into four groups: a Control (-) group receiving distilled water; a Control (+) group subjected to intraperitoneal CCl4 at 0.5 mL/kg (20% v/v in corn oil) on day 6; a Standard group treated daily with silymarin at 200 mg/kg and a group given an oral dose of aqueous propolis extract (APE) at 8.4 mg/kg. Result: Histological and biochemical analyses confirm propolis extract's role in preventing hepatocyte apoptosis and reducing inflammatory infiltrates in kidney tissues, improving the histological appearance of hepatic and renal tissues with fewer fibrotic changes. The application of immunohistochemistry, along with reductions in anti-apoptotic proteins such as BCL-2 and p53, supports these findings, highlighting the antioxidant potential of Saudi propolis extracts in addressing hepatorenal toxicity. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to determine the correlation between microscopic degeneration in the long head of the biceps tendon (LHBT) and the apoptotic process. Methods: This study included 26 consecutive patients who had undergone arthroscopic biceps tenodesis or tenotomy for symptomatic LHBT with or without concomitant rotator cuff tears (RCTs). Histological examination of the specimens under a light microscope was conducted after staining with hematoxylin, eosin, and the Alcian blue. Histopathological changes were assessed using the original Bonar score and the modified Bonar score and then correlated with the expression of the subsequent apoptosis markers: activated caspase-3 (casp3), tumor protein p53 (p53), and B-cell lymphoma 2 (BCL-2). Results: The mean original Bonar score was 8.65 (range 5–11), while the modified Bonar score was 7.61. There was no correlation between the original Bonar score and the age of the patients, but a positive correlation was found between the modified Bonar score and the age of the patients (p = 0.0022). There was no correlation between the age of patients and the expression indexes of BCL-2 and casp3. However, the expression of the p53 index showed a positive correlation with patient aging (p = 0.0441). Furthermore, there was no correlation observed between the expression of apoptotic indexes and both the original and modified Bonar scale. Conclusions: In LHB tendinopathy, the expression of apoptosis does not seem to directly correlate with the extent of degeneration, particularly in the late stages of tendinopathy. However, the transformations observed in collagen and ground substance were significantly associated with age, as well as tendinous tissue degeneration quantified according to modified Bonar score. The age of patients was also linked with the expression of the p53 index, as an increased apoptosis in the studied population. [ABSTRACT FROM AUTHOR]

10-hydroxy-2-decenoic acid (10-HDA), which is a unique bioactive fatty acid of royal jelly synthesized by nurse bees for larvae and adult queen bees, is recognized for its dual utility in medicinal and nutritional applications. Previous research has indicated that 10-HDA exerts antitumor effects on numerous tumor cell lines, including colon cancer cells, A549 human lung cancer cells, and human hepatoma cells. The present study extends this inquiry to lymphoma, specifically evaluating the impact of 10-HDA on the SU-DHL-2 cell line. Our findings revealed dose-dependent suppression of SU-DHL-2 cell survival, with an IC50 of 496.8 μg/mL at a density of 3 × 106 cells/well after 24 h. For normal liver LO2 cells and human fibroblasts (HSFs), the IC50 values were approximately 1000 μg/mL and over 1000 μg/mL, respectively. The results of label-free proteomics revealed 147 upregulated and 347 downregulated differentially expressed proteins that were significantly enriched in the complement and coagulation cascades pathway (adjusted p-value = 0.012), including the differentially expressed proteins prothrombin, plasminogen, plasminogen, carboxypeptidase B2, fibrinogen beta chain, fibrinogen gamma chain, and coagulation factor V. The top three hub proteins, ribosomal protein L5, tumor protein p53, and ribosomal protein L24, were identified via protein–protein interaction (PPI) analysis. This result showed that the complement and coagulation cascade pathways might play a key role in the antitumor process of 10-HDA, suggesting a potential therapeutic avenue for lymphoma treatment. However, the specificity of the effect of 10-HDA on SU-DHL-2 cells warrants further investigation. [ABSTRACT FROM AUTHOR]

Our previous studies indicated that calcitonin gene-related peptide (CGRP) alleviates hyperoxia-induced lung injury and suggested the possible involvement of autophagy in this process. Herein, we aimed to further explore the potential involvement of tumor protein p53 (TP53) and autophagy in the mode of action of CGRP against hyperoxia-induced lung injury in vitro and in vivo. The study conducted tests on type II alveolar epithelial cells (AECII) and rats that were subjected to hyperoxia treatment or combined treatment of hyperoxia with CGRP, CGRP inhibitor, rapamycin (an autophagy agonist), 3-methyladenine (3-MA, an autophagy inhibitor), TP53 silencing/inhibitor (pifithrin-α), or expression vector/activator (PRIMA-1 (2,2-bis(hydroxymethyl)-3-quinuclidinone)) and their corresponding controls. We found that oxidative stress, apoptosis, and autophagy were all increased by hyperoxia treatment in vitro. However, treating AECII cells with CGRP reversed hyperoxia-induced oxidative stress and apoptosis but further promoted autophagy. In addition, the combined treatment with rapamycin or TP53 silencing with CGRP promoted the effect of CGRP, while contrary results were obtained with combined therapy with 3-MA or TP53 overexpression. In vivo, the number of hyperoxia-induced autophagosomes was promoted in the lung tissue of neonatal rats. Furthermore, hyperoxia increased the expression levels of AMP-activated protein kinase (AMPK) alpha 1 (also known as protein kinase AMP-activated catalytic subunit alpha 1 (PRKAA1)) but inhibited TP53 and mechanistic target of rapamycin (MTOR); these expression trends were regulated by CGRP treatment. In conclusion, we showed that CGRP can attenuate hyperoxia-induced lung injury in neonatal rats by enhancing autophagy and regulating the TP53/AMPK/MTOR crosstalk axis. [ABSTRACT FROM AUTHOR]

The wide biological activity of the Moringa oleifera represents a potential opportunity for developing selective cancer treatment drugs. The bioactive phytochemicals in Moringa seed extract (MSE) indicated large numbers of phytochemicals (21 compounds) with dominant abundance for cycloisolongifolene, 8,9‐dehydro‐9‐vinyl, and chamazulene accounting for 12.7% and 12.19% of the total detected compounds. The MSE showed a potent anticancer effect toward Caco‐2, MDA, and HepG‐2 cells with half‐maximal inhibitory concentration (IC50) values of 9.15 ± 1.18, 4.85 ± 0.11, and 7.36 ± 0.22 µg/mL, respectively, with higher safety (≥31‐folds) toward normal human cells (IC50 of 150.7 ± 11.11 µg/mL). It appears that MSE stimulates selective‐dose‐dependent cell shrinkage, and nuclear condensation in the tumor cells, which finally induces the apoptosis pathway to increase its anticancer action. Additionally, MSE showed a potent capability to stimulate cell cycle arrest in both main checkpoint phases (G0/G1 and G2/M) of cell population growth. The apoptotic death stimulation was confirmed through upregulation of tumor protein p53 (p53) and cyclin‐dependent kinase inhibitor p21 (p21) expression by more than three‐ to sixfold and downregulation of B‐cell lymphoma 2 expression (threefold) in MSE‐treated cells compared to 5‐fluorouracil (5‐FU)‐treated tumor cells. Furthermore, the MSE revealed strong anti‐inflammatory activity with significant antioxidant activity by lowering nitric oxide levels and enhancing the superoxide dismutase activity. On the other hand, the MSE revealed broad‐spectrum antibacterial activity in a dose‐dependent manner against Staphylococcus aureus minimum inhibitory concentration (MIC of 1.25 mg/mL), followed by Salmonella typhimurium (MIC of 1.23 mg/mL), whereas Escherichia coli was the least sensitive to MSE activity (MIC of 22.5 mg/mL) with significant antibiofilm activity against sensitive pathogens. [ABSTRACT FROM AUTHOR]

Background: Alexithymia is a trait involving difficulties in processing emotions. Genetic association studies have investigated candidate genes involved in alexithymia's pathogenesis. Therefore, the aim of the present study was to perform a systematic review of the genetic background associated with alexithymia. Methods: A systematic review of genetic studies of people with alexithymia was conducted. Electronic databases including PubMed, Scopus, and Web of Science were searched for the study purpose. We used the words "Alexithymia", "gene", "genetics", "variants", and "biomarkers". The present systematic review was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. We found only candidate gene studies. A total of seventeen studies met the eligibility criteria, which comprised 22,361 individuals. The candidate genes associated with alexithymia were the serotoninergic pathway genes solute carrier family 6 member 4 (SLC6A4), serotonin 1A receptor (HTR1A), and serotonin 1A receptor (HTR2A); the neurotransmitter metabolism genes dopamine receptor D2 (DRD2), ankyrin repeat and kinase domain containing 1 (ANKK1), catechol-o-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and oxytocin receptor (OXTR); and other pathway genes, vitamin D-binding protein (VDBP), tumor protein P53 regulated apoptosis inducing protein 1 (TP53AIP1), Rho GTPase Activating Protein 32 (ARHGAP32), and transmembrane protein 88B (TMEM88B). Conclusion: The results of this study showed that only case–control gene studies have been performed in alexithymia. On the basis of our findings, the majority of alexithymia genes and polymorphisms in this study belong to the serotoninergic pathway and neurotransmitter metabolism genes. These data suggest a role of serotoninergic neurotransmission in alexithymia. Nevertheless, more and future research is required to learn about the role of these genes in alexithymia. [ABSTRACT FROM AUTHOR]

Mutations resulting in decreased activity of p53 tumor suppressor protein promote tumorigenesis. P53 protein levels are tightly regulated through the Ubiquitin Proteasome System (UPS). Several E3 ligases were shown to regulate p53 stability, including MDM2. Here we report that the ubiquitin E3 ligase XIAP (X-linked Inhibitors of Apoptosis) is a direct ligase for p53 and describe a novel approach for modulating the levels of p53 by targeting the XIAP pathway. Using in vivo (live-cell) and in vitro (cell-free reconstituted system) ubiquitylation assays, we show that the XIAP-antagonist ARTS regulates the levels of p53 by promoting the degradation of XIAP. XIAP directly binds and ubiquitylates p53. In apoptotic cells, ARTS inhibits the ubiquitylation of p53 by antagonizing XIAP. XIAP knockout MEFs express higher p53 protein levels compared to wild-type MEFs. Computational screen for small molecules with high affinity to the ARTS-binding site within XIAP identified a small-molecule ARTS-mimetic, B3. This compound stimulates apoptosis in a wide range of cancer cells but not normal PBMC (Peripheral Blood Mononuclear Cells). Like ARTS, the B3 compound binds to XIAP and promotes its degradation via the UPS. B3 binding to XIAP stabilizes p53 by disrupting its interaction with XIAP. These results reveal a novel mechanism by which ARTS and p53 regulate each other through an amplification loop to promote apoptosis. Finally, these data suggest that targeting the ARTS binding pocket in XIAP can be used to increase p53 levels as a new strategy for developing anti-cancer therapeutics. [ABSTRACT FROM AUTHOR]

Overexpression of CDKN1A--a downstream p53 gene--can trigger apoptosis in old cells but can also lead to chemoresistance and serve as a poor prognosis marker in cancer. This study explores apoptosis mechanisms via the p53 signaling pathway, focusing on the expression of CDKN1A (p21). Differential expression gene (DEG) analysis was performed on downstream p53 signaling genes using GSE23773 data from the Gene Expression Omnibus database, which includes whole human genome microarray data of colorectal cancer cells (HT-29) over time. Molecular docking simulations of compounds in ginger (Zingiber officinale Roscoe) ginger (Zingiber officinale Roscoe) against against TP53- related kinase (TP53RK), a protein that activates p53, were conducted to assess the potential of these compounds to influence downstream genes in the p53 signaling pathway. The DEGs were validated using machine learning and principal component analysis methods. Molecular docking and dynamic simulations of ginger compounds against TP53RK were performed on the crystal structure of the D-chain protein with PDB code 6WQX [D]. The docking scores of these compounds were then compared with pomalidomide, a known inhibitor of TP53RK. DEG analysis of GSE23773 data revealed that BAX, STEAP3 (TSAP6), AIFM2, SIVA1, GTSE1 (B99), and CDKN1A (p21) are downstream p53 genes whose expression undergoes regulatory changes in old HT-29 cells (day 7 cultures). Molecular docking and molecular dynamic simulation analysis indicated that gingerenone A, 6-shogaol, gingerol, and 6-paradol in Z. officinale Roscoe have the potential to down-regulate CDKN1A (p21) by inhibiting p53 activation through TP53RK and stable during 10ns. [ABSTRACT FROM AUTHOR]

Background and Aims: Breast cancer (BC) is considered one of the most common malignant tumors leading to death in women, and genetic factors have a crucial role in BC pathogenesis. Zyxin (ZYX) is one of these factors that may be important in p53 level and function. Thus, the present work aimed to investigate the ZYX gene and protein expression in tumor tissue and matched margin tissue and its correlation with the p53 expression. Methods: In a present case‐control study, 30 tumors and 30 matched margin tissues were obtained from Iran Tumor Bank/Tehran University of Medical Sciences. Real‐time polymerase chain reaction and western blot analysis techniques were applied to evaluate the genes and protein expression, respectively. Results: The data showed that expression of the ZYX gene in tumor tissues significantly decreased (p = 0.0274) compared to matched margin tissues. In contrast, the p53 gene expression in tumor tissues had no significant difference with matched margin tissues. Additionally, we observed that ZYX and p53 genes expression in tumor tissues of estrogen receptor‐positive patients had significant elevation than estrogen receptor‐negative patients (p < 0.001, p < 0.001, respectively). The data of the western blot analysis technique showed that protein expression of ZYX (p = 0.0024) and P53 protein (p = 0.0218) in tumor tissues was significantly reduced compared to matched margin tissues. Additionally, our analysis showed a direct and significant correlation between the expression of ZYX and p53 proteins (r = 0.7797, p = 0.0126) and expression of ZYX and p53 genes (r = 0.3079, p = 0.0187). Conclusion: Based on our observation, ZYX might have a tumor suppressor role and is associated with p53. [ABSTRACT FROM AUTHOR]

Background: Cancer of unknown primary (CUP) is an orphan disease generally presented by undifferentiated and aggressive morphological phenotype. The treatment of CUP is solely dependent upon the origin of cancer. Despite extensive diagnostic testing, in most of the cases the primary site remains unidentifiable. Case presentation: This case demonstrates a 75-year-old male patient, who initially presented with the complaints of swelling over right side of the neck since 2 months. A cervical lymph node biopsy was taken for immunohistochemistry, which revealed cytokeratin (CK) and CK7 markers to be positive. Computerized tomography (CT) of Thorax showed subcentimetric subpleural nodules in bilateral lungs fields, predominantly in lower lobes (metastatic in nature). A subsequent pulmoCORE 12 gene panel test was recommended, and patient was discharged with tablet gefitinib 250mg and capsule containing vitamins plus minerals. After one month, patient revisited with the pulmoCORE 12 gene test report which revealed polymorphism in TP53. A pathogenic variant of tumor protein p53 (TP53), i.e., p.Glu198Ter (amino acid alteration) and c.592G > T (coding) variant, was detected, which has 17.2% variant allele frequency. There are no treatment guidelines for TP53 mutation; therefore, the patient was treated with injection paclitaxel 70mg and carboplatin 100mg for 12 cycles along with palliative radiotherapy of 20 Gy for 5 fractions. The overall prognosis of patient was found to be favorable. Conclusions: There is a need for development of comprehensive guidelines and new molecularly targeted therapies for treatment of CUP which can be tailored for each patient and achieve precise therapeutic outcome. [ABSTRACT FROM AUTHOR]

We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers. [ABSTRACT FROM AUTHOR]

[Display omitted] Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer types. Despite extensive efforts, the absence of a druggable active site for small molecules has rendered these mutants therapeutically non-actionable. Here we develop a selective and effective proteolysis-targeting chimera (PROTAC) for p53-R175H, a common hotspot mutant with dominant-negative and oncogenic activity. Using a novel iterative molecular docking-guided post-SELEX (systematic evolution of ligands by exponential enrichment) approach, we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for p53-R175H. Leveraging this resulting aptamer as a binder for PROTACs, we successfully developed a selective p53-R175H degrader, named dp53m. dp53m induces the ubiquitin–proteasome-dependent degradation of p53-R175H while sparing wildtype p53. Importantly, dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo , without toxicity. Moreover, dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin, a commonly used chemotherapy drug. These findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers. [ABSTRACT FROM AUTHOR]

The infusion of Santolina impressa, an endemic Portuguese plant, is traditionally used to treat various infections and disorders. This study aimed to assess its chemical profile by HPLC-DAD-ESI-MSn and validate its anti-inflammatory potential. In addition, the antioxidant capacity and effects on wound healing, lipogenesis, melanogenesis, and cellular senescence, all processes in which a dysregulated inflammatory response plays a pivotal role, were unveiled. The anti-inflammatory potential was assessed in lipopolysaccharide (LPS)-stimulated macrophages, cell migration was determined using a scratch wound assay, lipogenesis was assessed on T0901317-stimulated keratinocytes and melanogenesis on 3-isobutyl-1-methylxanthine (IBMX)-activated melanocytes. Etoposide was used to induce senescence in fibroblasts. Our results point out a chemical composition predominantly characterized by dicaffeoylquinic acids and low amounts of flavonols. Regarding the infusion's bioactive potential, an anti-inflammatory effect was evident through a decrease in nitric oxide production and inducible nitric oxide synthase and pro-interleukin-1β protein levels. Moreover, a decrease in fibroblast migration was observed, as well as an inhibition in both intracellular lipid accumulation and melanogenesis. Furthermore, the infusion decreased senescence-associated β-galactosidase activity, γH2AX nuclear accumulation and both p53 and p21 protein levels. Overall, this study confirms the traditional uses of S. impressa and ascribes additional properties of interest in the pharmaceutical and dermocosmetics industries. [ABSTRACT FROM AUTHOR]