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Background: Eccrine porocarcinoma (EPC) is a rare malignant skin tumor arising from the eccrine gland. Investigations into the genomic landscape of EPC have uncovered potential drivers of its development and progression. However, there is limited information on the discrepancies between EPC and its benign counterpart, eccrine poroma (EP). Methods: Formalin-fixed paraffin-embedded (FFPE) samples from 15 EPCs and 5 EPs were retrieved from Helsinki Biobank and Finnish Clinical Biobank Tampere. One EPC was found to be digital papillary adenocarcinoma in review of diagnoses. Whole-exome sequencing was used to conduct a comprehensive analysis to elucidate the genomic features of EPCs and EPs. Results: There was general heterogeneity within EPCs and EPs, with discrepancies such as exclusive TP53, NCOR1, and CDKN2A mutations in EPCs and a higher mutational load in EPCs than in EPs. Furthermore, we identified alterations in pathways associated with cell adhesion and the extracellular matrix in EPCs, while pathways associated with ketone body and amino acid metabolism were altered in EPs. The MAPK and Ras signaling pathways were enriched in genes mutated only in EPCs. Conclusions: EPCs and EPs are generally heterogeneous tumor entities with a few distinct discrepancies from each other. The findings from this study emphasize the need to further verify the roles of disrupted genes and pathways in the initiation and progression of EPCs and EPs. [ABSTRACT FROM AUTHOR]

Background: Human polyomaviruses (HPyVs), JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV), have been found in upper tract urothelial carcinoma UTUC; however, the association of the viral oncogenic factors and clinical characteristics of UTUC remains unclear. This study aimed to investigate the prevalence of JCPyV and BKPyV in UTUC and their correlation with cancer progression among the southwest Taiwanese population from 2020 to 2022. Methods: A total of 72 paraffin-embedded UTUC tissue samples and 41 adjacent tissue samples were collected from 72 patients. Nested polymerase chain reaction and DNA sequencing were used to detect viral DNA and genotypes. Immunohistochemistry was performed using anti- large T (LT) and anti-p53 monoclonal antibodies to detect the expression of viral early LT protein and cellular p53 protein, respectively. Results: The overall prevalence of JCPyV and BKPyV were higher in UTUC than in adjacent tissue samples (65.3% [47/72] vs. 17.1% [7/41]). JCPyV and BKPyV were detected in 95.7% (45/47) and 4.3% (2/47) of the HPyVs-positive UTUC samples, respectively. JCPyV-TW-3 was the predominant strain of JCPyV infection. In UTUC samples, the LT protein of JCPyV and BKPyV positivity rate was 65.3%, while that of mutant p53 protein was 52.7%. JCPyV infection and LT protein expression increased the odds ratio (OR) of UTUC by 9.13-fold. The OR of UTUC was higher by 10.34-fold in patients with mutant p53 and by 10.37-fold in those with simultaneous LT and mutant p53 expression. The presence of LT protein in UTUC patients may increase the OR of mutant p53 protein expression by 2.93-fold compared to its absence. Women had a 5.19-fold higher superiority of JCPyV infection and LT expression than men. Patients with chronic kidney disease (CKD) had a 3.15-fold higher OR for mutant p53 protein expression than those without it. In the UTUC advanced stages, the OR of virus and LT expression was 3.18-fold higher compared to those who do not require chemotherapy. Conclusions: JCPyV infection is highly prevalent in UTUC, and the presence of CKD concurrent with high expressions of LT and mutant p53 proteins in patients may be a useful indicator for chemotherapy and poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Disorder in bile acid (BA) metabolism is known to be an important factor contributing to diarrhea. However, the pathogenesis of BA disorder-induced diarrhea remains unclear. Methods: The colonic BA pool and microbiota between health piglets and BA disorder-induced diarrheal piglets were compared. Fecal microbiota transplantation and various cell experiments further indicated that chenodeoxycholic acid (CDCA) metabolic disorder produced CDCA-3β-glucuronide, which is the main cause of BA disorder diarrhea. Non-targeted metabolomics uncovered the inhibition of the BA glucuronidation by Lactobacillus reuteri (L. reuteri) is through deriving indole-3-carbinol (I3C). In vitro, important gene involved in the reduction of BA disorder induced-diarrhea were screened by RNA transcriptomics sequencing, and activation pathway of FXR-SIRT1-LKB1 to alleviate BA disorder diarrhea and P53-mediated apoptosis were proposed in vitro by multifarious siRNA interference, CO-IP, immunofluorescence, and so on, which mechanism was also verified in a variety of mouse models. Results: Here, we reveal for the first time that core microbiota derived I3C represses gut epithelium glucuronidation, particularly 3β-glucuronic CDCA production, which reaction is mediated by host UDP glucuronosyltransferase family 1 member A4 (UGT1A4) and necessary of BA disorder induced diarrhea. Mechanistically, L. reuteri derived I3C activates aryl hydrocarbon receptor to decrease UGT1A4 transcription and CDCA-3β-glucuronide content, thereby upregulating FXR-SIRT1-LKB1 signal. LKB1 binds with P53 based on protein interaction, ultimately resists to apoptosis and diarrhea. Moreover, I3C assists CDCA to attain the ameliorative effects of FXR activation in BA disorder diarrhea, through reversion of abnormal metabolism pathway, improving the outcomes of CDCA supplement. Conclusion: These findings uncover the crucial interplay between gut epithelial cells and microbes, highlighting UGT1A4-mediated conversion of CDCA-3β-glucuronide as a key target for ameliorating BA disorder-induced diarrhea. FSirWKmfeZU8YSVhEvyAL2 Video Abstract [ABSTRACT FROM AUTHOR]

Flaviviruses transmit through a wide range of vertebrate and arthropod hosts, while the other genera in Flaviviridae replicate in a limited set of vertebrate hosts. Flaviviruses possess a 5′ cap in their genome RNA for translation, while the other genera utilize their internal ribosome entry site (IRES) sequences instead of a 5′ cap. In this study, the translational modification to add an IRES sequence was examined. An IRES sequence derived from encephalomyocarditis (EMCV) was inserted into dengue virus serotype 2 (DENV2); a non-structural (NS) polyprotein was translated by IRES separately from 5′ cap-induced structural polyprotein translation. It was revealed that the IRES-integrated DENV2 is prevented from replicating in C6/36 mosquito cells, suggesting that the 5′ cap is an advantageous mechanism for flavivirus translation in invertebrate species. I further created dual IRES-integrated DENV2, in which a non-viral gene can be expressed by the flanking IRESs. The insertion of eGFP fluorescently visualized the virus spread. The renilla luciferase (Rluc) integration enabled the viral replication quantification. It was also revealed that a cellular gene, Mdm2, which antagonizes tumor suppressor protein p53 (TP53), could terminate the viral replication in BHK21 cells. Thus, the modifications of the DENV genome with IRES and the subsequent foreign gene could be utilized for controlling viral replications. [ABSTRACT FROM AUTHOR]

Background and Aims: Previous studies have demonstrated that peptidylarginine deiminase 4 (PAD4) functions as a suppressor, promoter, or both in cancer pathogenesis and therapeutic outcomes. Although PAD4 expression has been proposed to be one of the molecular features of gastric cancer (GC), the biological basis of PAD4 in GC progression and chemotherapy has not been formally established. Methods: Cell type-preferential expression of PAD4 was analyzed in both preclinical and clinical models. The colocalization of PAD4 expression and tumor-infiltrating neutrophils in GC patients was evaluated by immunofluorescence assay. The effects of forced expression of PAD4 on GC cell proliferation were evaluated both in vitro and in vivo. The effects of forced expression of PAD4 on the cytotoxicity of 5-fluorouracil and oxaliplatin were performed by EdU, Annexin V/PI, and comet assays. Co-immunoprecipitation assay was used to investigate the endogenous and exogenous interaction between PAD4 and p53. To investigate whether p53 participated in the chemopotentiating effects of PAD4, small interfering RNA (siRNA)-mediated knockdown of p53 was conducted in PAD4-overexpressing GC cells. Results: Contrary to the previous report, we initially observed that PAD4 was underexpressed in GC patients and presented as a favorable prognostic factor across the TCGA cohort. Interestingly, the normal gastric epithelial cell line GES-1 exhibited low-level expression of PAD4. In comparison, PAD4 was not detected in GC cell lines, including AGS, HGC-27, and MKN-45. Using an orthotopic mouse model of GC, we found that PAD4 was surprisingly abundant in HGC-27 cell line-derived xenografts. Immunofluorescence staining for PAD4 and neutrophil elastase indicated that PAD4 was mainly expressed in neutrophils but not in GC cells. PAD4 expression was upregulated in all-trans retinoic acid-induced neutrophil-like dHL-60 cells, which were used as a positive control for PAD4 expression. Surprisingly, the enforced expression of PAD4 suppressed the proliferation of GC cells in vitro and in vivo. In addition, cells harboring high PAD4 expression were more susceptible to G1/S boundary arrest, apoptotic death, and DNA damage by regulating p53 target proteins. Mechanistically, PAD4 might affect p53 function through physical interaction with p53, and the chemopotentiating effects of PAD4 could be compromised by p53 knockdown. Conclusions: PAD4 appeared to be constitutively expressed in tumor-infiltrating neutrophils but not in GC cells. Our findings highlight unique roles of PAD4, in which origin-dependent PAD4 might work complementarily on the progression and treatment vulnerability of GC. [ABSTRACT FROM AUTHOR]

Telomeres protect chromosome ends from damage, but they shorten with each cell division due to the limitations of DNA replication and are further affected by oxidative stress. This shortening is a key feature of aging, and telomerase, an enzyme that extends telomeres, helps mitigate this process. Aging is also associated with mitochondrial dysfunction, leading to increased reactive oxygen species (ROS) that exacerbate cellular damage and promote apoptosis. Elevated ROS levels can damage telomeres by oxidizing guanine and disrupting their regulation. Conversely, telomere damage impacts mitochondrial function, and activation of telomerase has been shown to reverse this decline. A critical link between telomere shortening and mitochondrial dysfunction is the DNA damage response, which activates the tumor suppressor protein p53, resulting in reduced mitochondrial biogenesis and metabolic disruptions. This highlights the bidirectional relationship between telomere maintenance and mitochondrial function. This review explores the complex interactions between telomeres and mitochondria across various cell types, from fibroblasts to sperm cells, shedding light on the interconnected mechanisms underlying aging and cellular function. [ABSTRACT FROM AUTHOR]

Objective: We investigate gastric-type endocervical adenocarcinoma (ECA), a prominent HPV-independent adenocarcinoma, and its coexistence with high-grade squamous intraepithelial lesion (HSIL) through the examination of three such tumors. Methods: In this study, we conducted an in-depth review of three patients with gastric-type ECA, each associated with high-risk HPV infection as detected on Pap smears. We detailed the clinical and pathological features of each patient and utilized RNAscope for high-risk HPV testing to ascertain HPV status in both gastric-type ECA and HSIL components. Immunohistochemistry with p16, p53, and other biomarkers was also applied. Results: The gastric-type ECA component, characterized by well-differentiated glands with abundant, clear to eosinophilic cytoplasm, distinct cellular borders, and pale nuclei with conspicuous nucleoli, tested negative for both p16 and high-risk HPV, unlike the concurrent HSIL components which were positive. Additionally, two tumors showed aberrant p53 protein expression in the gastric-type ECA areas, and elevated carbohydrate antigen19-9 levels were noted in two patients. Treatment consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy, supplemented by chemotherapy and/or radiation, with disease-free intervals of 24, 12, and 40 months post-treatment, respectively. Conclusion: This study highlights the critical need for meticulous diagnostic protocols that combine morphological examination, immunohistochemistry, and HPV RNA in situ hybridization. The rarity of gastric-type ECA coexisting with HPV infection underscores the necessity for continuous research and vigilant monitoring in the field of gynecological oncology. [ABSTRACT FROM AUTHOR]

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Background: The Apoptosis-Stimulating Protein of P53 (ASPP) family contributes to apoptosis regulation and tumor suppression, with ASPP1 influencing processes like cancer cell proliferation, invasion, and migration. Its expression varies across cancer types, suggesting a potential role in oncogenesis. Methods: This study investigates ASPP1's role across various cancers using a comprehensive bioinformatics approach. Data were extracted from public resources, including The Cancer Genome Atlas (TCGA), GTEx, and the Human Protein Atlas, and analyzed via tools such as cBioPortal, GEPIA, and TIMER2. Statistical and network analyses were performed with R, Cytoscape, and Hiplot. ASPP1's function in colorectal cancer was further explored through in vitro assays, including qRT-PCR, Western blotting, colony formation, Transwell, and wound healing. Results: ASPP1 expression exhibited significant variability across different cancer types, with marked associations with patient outcomes, particularly overall survival (OS) and disease-specific survival (DSS) across several cancer types. In-depth protein-protein interaction (PPI) analysis revealed ASPP1's involvement in apoptosis and cancer progression networks. Functional enrichment analysis further linked ASPP1 to key apoptotic signaling pathways and transcriptional regulatory processes, underscoring its potential impact on tumor biology. Additionally, the expression of ASPP1 correlates with immune cell infiltration patterns, including cancer-associated fibroblasts and various immune markers, suggesting roles in immune response modulation. In vitro assays with colorectal cancer cell lines revealed significantly lower ASPP1 expression levels compared to normal colon cells (HCM460), and ASPP1 overexpression experiments showed a marked reduction in colorectal cancer cell proliferation, colony formation, invasion, and migration abilities. These cellular findings align with the bioinformatics predictions, highlighting ASPP1's role as a suppressor of metastatic traits in colorectal cancer. Conclusion: This study highlights ASPP1 as a forecasting biomarker in the colorectal cancers and potentially across other cancers. The findings support ASPP1's involvement in tumor biology, particularly regarding cell proliferation and metastatic potential, establishing a foundation for further investigation into its therapeutic relevance. [ABSTRACT FROM AUTHOR]

Influenza A viruses (IAVs) are highly contagious pathogens that cause zoonotic disease with limited availability of antiviral therapies, presenting ongoing challenges to both public health and the livestock industry. Unveiling host proteins that are crucial to the IAV life cycle can help clarify mechanisms of viral replication and identify potential targets for developing alternative host-directed therapies. Using a four-dimensional (4D), label-free methodology coupled with bioinformatics analysis, we analyzed the expression patterns of cellular proteins that changed following H9N2 virus infection. Compared to the control group, the H9N2 infected group displayed 732 differentially expressed proteins (DEPs), with 298 proteins showing upregulation and 434 proteins showing downregulation. Gene Ontology (GO) functional analysis showed that DEPs were catalog in 11 biological processes, three cellular components, and eight molecular functions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that DEPs were involved in processes including cytokine signaling pathways induced by virus infection and protein digestion and absorption. Proteins including TP53, DDX58, and STAT3 were among the top hub proteins in the protein–protein interaction (PPI) analysis, suggesting that these signaling cascades could be essential for the propagation of IAVs. Furthermore, the host protein SNAPIN was chosen to ascertain the accuracy of expression changes identified through a proteomic analysis. The results indicated that SNAPIN was downregulated following infection with IAVs both in vitro and in vivo, which is consistent with the proteomics results, suggesting that SNAPIN may serve as a key regulatory factor in the viral life cycle of IAVs. Our research delineates an extensive interaction map of IAV infection within the A549 cells, facilitating the discovery of pivotal proteins that contribute to the virus's propagation, potentially offering target candidates to screen for antiviral therapeutics. [ABSTRACT FROM AUTHOR]

Background: The global incidence of early onset colorectal cancer (CRC) is rapidly rising. However the reason for this and genomic characteristics of early onset CRC is largely unknown. p53 mutation is common in CRC and has been linked to an increased risk of early onset CRC. Materials & Methods: All CRC patients operated at Department of Surgical Oncology, NICRH, between October 1, 2021 and September 30, 2022 were included in this study. Demographic and clinical data and surgical findings were recorded. Histopathology and p53 immunohistochemistry (IHC) analysis was done. Patients were categorized in two groups – ‘Early onset’ (diagnosed before 50 years of age) and ‘Late onset’ (diagnosed at or after 50 years of age). p53 protein IHC status (Mutant or Wild type) and other clinicopathological features were compared between the two groups. Result: Out of 129 patients operated, 75 (58.14%) patients were in the early onset group. Compared to the late onset group, early onset patients had longer duration of symptoms (112.4 days vs. 88.7 days; p = .032), more peritoneal seedlings during surgery (14.7% vs. 1.9%, p = .011), and more poor differentiation (p = .062) and higher grades (p = .017) on histopathological analysis. Early onset patients had significantly more p53 mutation on IHC analysis than elderly ones (34.7% vs. 16.7%, p = .018). Age of onset showed no significance on either disease free survival (DFS) or overall survival (OS) in this study. On comparison of patients with either mutant (MT) or wild type (WT) p53 protein, those with MTp53 had more positive family history (20.0% vs. 3.2%, p=.004), higher levels of CEA (6.4 vs. 4.3, p = .028), higher pathological stage (p = .029), more chance of disease progression or recurrence during follow up (p=.035). Short term survival analysis showed patients with p53 mutation had significantly less DFS (p < .001) and OS (p = .001). Conclusion: Early onset CRC was more prevalent in this study, and was associated with significantly more p53 mutation than the elderly patients. The clinical application of p53 mutation analysis by IHC in all CRC cases, particularly in the early onset patients, should be evaluated. [ABSTRACT FROM AUTHOR]

AIM: This study aims to investigate the protective effect of α-lipoic acid (α-LA) against alcohol-induced damage in H9c2 rat cardiomyocytes and to explore the underlying mechanisms. METHODS: An alcohol-induced injury model of H9c2 cells was established, and the cells were divided into 4 groups: control group, alcohol group, α-LA group, and alcohol+α-LA group. Additionally, H9c2 cells overexpressing aldehyde dehydrogenase 2 (ALDH2) were created and further divided into 6 groups: normal control group, normal cells treated with alcohol group, normal cells treated with alcohol+ α -LA group, ALDH2 overexpression group, ALDH2-overexpressing cardiomyocytes treated with alcohol group, and ALDH2-overexpressing cardiomyocytes treated with alcohol+α-LA group. Cell proliferation was assessed using 5-ethynyl-2'-deoxyuridine (EdU) staining. Reactive oxygen species (ROS) levels in each group were measured using dihydroethidium (DHE) staining, while the expression levels of ALDH2, silent information regulator 1 (SIRT1), heme oxygenase 1 (HO1) and P53 proteins were detected by Western blot analysis. RESULTS: (1) Alcohol exposure resulted in a decrease in the proliferation of H9c2 cells and an increase in intracellular oxidative stress, evidenced by elevated ROS levels and decreased expression of related proteins (ALDH2, SIRT1 and HO1) . However, α-LA treatment significantly mitigated the decline in cell proliferation and the oxidative stress induced by alcohol. (2) Alcohol may induce cellular senescence, as demonstrated by the up-regulation of P53 expression, which were reversed by α-LA. (3) The H9c2 cells with high ALDH2 expression markedly improved the cell proliferation in the presence of alcohol, suppressed the ROS production, prevented the down-regulation of oxidative stress-related proteins (ALDH2, SIRT1 and HO1), and reversed the enhanced expression of the senescence marker P53. CONCLUSION: Treatment with α -LA may counteract oxidative stress and attenuate cellular senescence by activating ALDH2, thereby protecting cardiomyocytes from alcohol-induced damage. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate associations between TP53 status and outcomes after transarterial embolization (TAE) for the treatment of patients with hepatocellular carcinoma (HCC). This single-institution study included patients from 1/2014 to 6/2022 who underwent TAE of HCC and genomic analysis of tumoral tissue. The primary outcome was overall survival (OS) with relation to TP53 status, and the secondary outcome was the time to progression. Survival analysis was performed using the Kaplan–Meier method. The time to progression with death or the last patient contact without progression as competing risks were used to obtain a cumulative incidence function, and the association with TP53 status was evaluated using the Gray test. In total, 75 patients (63 men) with a median age of 70.0 (IQR 62.0–76.3) years were included. Of these, 26/75 (34.7%) patients had TP53-mutant HCC. Patients with TP53-mutant HCC had a significantly worse median OS of 15.2 (95% CI, 9.5–29.3) months, versus 31.2 (95% CI, 21.2–52.4) months as the median OS (p = 0.023) for TP53 wild-type HCC. Competing risk analysis showed a shorter time to local hepatic progression (at the site of the previously treated tumor) after TAE in patients with TP53-mutant HCC. The cumulative incidences of local progression at 6 and 12 months for TP53-mutant HCC were 65.4% and 84.6%, versus 40.8% and 55.1% for TP53 wild-type HCC (p = 0.0072). A TP53 mutation may predict a worse overall survival and a shorter time to local progression in HCC patients treated with TAE. [ABSTRACT FROM AUTHOR]

MDM2 and MDM4 are major negative regulators of tumor suppressor p53. Beyond regulating p53, MDM2 possesses p53-independent activity in promoting cell cycle progression and tumorigenesis via its RING domain ubiquitin E3 ligase activity. MDM2 and MDM4 form heterodimer polyubiquitin E3 ligases via their RING domain interaction. Inhibitors disrupting p53 interaction with MDM2/MDM4 are in clinical trials in patients bearing wild-type p53 cancers. However, these inhibitors are not designed to work for p53-null/mutant cancer cells. Owing to the importance of the E3 ligase of MDM2 in its p53-independent oncogenic activity, inhibitors targeting the E3 ligase activity of MDM2-MDM4 are desirable for p53-mutant cancer cells. Here, we report the development of such inhibitors with pro-apoptotic activity in p53-null leukemic cells. Among analogues of MDM2-MDM4 E3 ligase inhibitors, we initially identified MMRi36 as a potent pro-apoptotic compound in p53-null leukemic cells with acquired drug resistance. MMRi36 acts as an activator of MDM2-MDM4 E3 ligase by stabilizing MDM2-MDM4 heterodimers and promotes MDM2/MDM4 degradation in cells. Interestingly, replacement of the sulfur in 1,3,4-thiadiazole MMRi36 with a carbon led to identification of pyrazole MMRi36C that dissociates the MDM2-MDM4 RING heterodimers, inhibits the E3 ligase activity of the complex, and induces p53 protein accumulation, but retains the p53-independent pro-apoptotic activity. A brief SAR study identified a fluorine derivative of MMRi36C with improved pro-apoptotic activity. This study discovered a novel class of compound that targets MDM2-MDM4 ubiquitin E3 ligase activity for apoptosis induction in p53-mutant cancer cells. [ABSTRACT FROM AUTHOR]

Cells meticulously regulate free calcium ion (Ca2+) concentrations, with the endoplasmic reticulum (ER) being crucial for Ca2+ homeostasis. Disruptions in ER Ca2+ balance can contribute to various diseases, including cancer. Although considerable research has focused on the direct mechanisms of ER Ca2+ regulation, the role of microRNAs (miRNAs) in this process remains underexplored. Mainly using data from a CRISPR-based genomic screening previously conducted in our laboratory, we identified 33 candidate miRNAs that may regulate ER Ca2+ levels. From these, 10 miRNAs were found to significantly lower basal ER Ca2+ levels. RNA sequencing analysis indicated that these miRNAs downregulate the tumor suppressor tumor protein p53 (TP53)-inducible protein 11 gene (TP53I11), which is a key regulator of ER Ca2+ levels. Functional assays confirmed that TP53I11 influences ER Ca2+ levels and affects cancer cell proliferation. Additionally, the chemotherapeutic agent doxorubicin (DOX) was shown to upregulate TP53I11 and enhance ER Ca2+ accumulation. These findings elucidate the central role of TP53I11 in miRNA-mediated regulation of ER Ca2+ homeostasis and suggest potential therapeutic strategies targeting ER Ca2+ upregulation for cancer intervention. [ABSTRACT FROM AUTHOR]

Purpose: Proliferative 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. Methods: 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. Results: 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. Conclusions: 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 skin consists of collagen fibers, which play a role in maintaining the stability of the skin and regeneration of damaged cells. Several studies have shown that exposure to UVB typically causes a decrease in the production of collagen fibers. Noni (Morinda citrifolia) has been reported to be an effective medicinal plant with strong antioxidant activity. Therefore, this study aimed to determine the effect of noni gel on collagen density and p53 protein expression in rats exposed to UVB. Twenty-Five male Wistar rats were divided into five groups of five rats each, and treated as follows; Group I consisted of healthy rats not exposed to UVB, Group II consisted of rats exposed to UVB, while Groups III, IV, and V were consisted of rats exposed to UVB and treated with gel base, noni extract gel (10%), and tretinoin (vitacid 0.025%) gel, respectively. UVB exposure was carried out for 5 days/week over a period of 14 days. On the 14th day, skin tissues were collected and assessed for collagen using Masson's Trichrome staining, and p53 expression was assayed by polymerase chain reaction (PCR) technique. The results showed that noni extract gel significantly increased collagen density, and significantly decreased p53 gene expression in the skin of UVB-exposed rats. The effects were comparable to that of the positive control (tretinoin). These observations suggest that noni extract could be a natural source of compound(s) with potential anti-aging properties that could be used in the prevention and treatment of photo-induced aging. [ABSTRACT FROM AUTHOR]

Abstract The tumor-suppressing p-53 binding protein is a crucial protein that is involved in the prevention of cancer via its regulatory effect on a number of cellular processes. Recent evidence indicates that it interacts with a number of other proteins involved in cancer in ways that are not fully understood. An understanding of such interactions could provide insights into novel ways p53 further exerts its tumour prevention role via its interactions with diverse proteins. Thus, this study aimed to examine the interactions of the p53 protein with other proteins (peptides and histones) using molecular simulation dynamics. We opted for a total of seven proteins, namely 2LVM, 2MWO, 2MWP, 4CRI, 4X34, 5Z78, and 6MYO (control), and had their PBD files retrieved from the protein database. These proteins were then docked against the p-53 protein and the resulting interactions were examined using molecular docking simulations run at 500 ns. The result of the interactions revealed the utilisation of various amino acids in the process. The peptide that interacted with the highest number of amino acids was 5Z78 and these were Lys10, Gly21, Trp24, Pro105, His106, and Arg107, indicating a stronger interaction. The RMSD and RMSF values indicate that the complexes formed were stable, with 4CRI, 6MYO, and 2G3R giving the most stable values (less than 2.5 Å). Other parameters, including the SASA, Rg, and number of hydrogen bonds, all indicated the formation of fairly stable complexes. Our study indicates that overall, the interactions of 53BP1 with p53K370me2, p53K382me2, methylated K810 Rb, p53K381acK382me2, and tudor-interacting repair regulator protein indicated interactions that were not as strong as those with the histone protein. Thus, it could be that P53 may mediate its tumour suppressing effect via interactions with amino acids and histone.

ABSTRACT Concurrent mutations in tumor protein p53 (TP53) or Kelch‐like ECH‐associated protein 1‐nuclear factor erythroid 2‐related factor 2‐pathway components are linked to poor outcomes in epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC), but the impact of triple mutations remains unclear. We report a case of EGFR‐, TP53‐, and Cullin 3 (CUL3)‐mutant NSCLC in a 43‐year‐old woman with widespread metastases at diagnosis, including those in the contralateral lung, distant lymph nodes, pericardium, liver, bones, left adrenal gland, and brain. She received osimertinib as first‐line therapy, but pericardial effusion and liver metastases progressed rapidly over 3 months, and she was switched to carboplatin and pemetrexed. By the eighth cycle of pemetrexed, the bone metastases had progressed, resulting in disseminated intravascular coagulation (DIC) due to bone marrow carcinomatosis. The patient received third‐line therapy with albumin‐bound paclitaxel and fourth‐line therapy with docetaxel, but further treatment was suspended owing to DIC progression. She passed away 23 months after the initiation of osimertinib. Public database analysis revealed that the EGFR/TP53/CUL3 triple mutation accounts for 0.4% of EGFR‐mutant NSCLC cases, yielding significantly shorter survival than EGFR mutations alone and likely shorter than EGFR/TP53 double mutations. Gaining a deeper understanding of the clinical significance of coexisting genetic mutations in patients with EGFR‐mutant NSCLC will be crucial to develop future therapies. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extra-cranial solid tumour in children. Over half of all high-risk cases are expected to succumb to the disease even after chemotherapy, surgery, and immunotherapy. Although the importance of MYCN amplification in this disease is indisputable, the mechanistic details remain enigmatic. Here, we present a multicellular model of neuroblastoma comprising a continuous automaton, discrete cell agents, and a centre-based mechanical model, as well as the simulation results we obtained with it. The continuous automaton represents the tumour microenvironment as a grid-like structure, where each voxel is associated with continuous variables such as the oxygen level therein. Each discrete cell agent is defined by several attributes, including its cell cycle position, mutations, gene expression pattern, and more with behaviours such as cell cycling and cell death being stochastically dependent on these attributes. The centre-based mechanical model represents the properties of these agents as physical objects, describing how they repel each other as soft spheres. By implementing a stochastic simulation algorithm on modern GPUs, we simulated the dynamics of over one million neuroblastoma cells over a period of months. Specifically, we set up 1200 heterogeneous tumours and tracked the MYCN-amplified clone's dynamics in each, revealed the conditions that favour its growth, and tested its responses to 5000 drug combinations. Our results are in agreement with those reported in the literature and add new insights into how the MYCN-amplified clone's reproductive advantage in a tumour, its gene expression profile, the tumour's other clones (with different mutations), and the tumour's microenvironment are inter-related. Based on the results, we formulated a hypothesis, which argues that there are two distinct populations of neuroblastoma cells in the tumour; the p53 protein is pro-survival in one and pro-apoptosis in the other. It follows that alternating between inhibiting MDM2 to restore p53 activity and inhibiting ARF to attenuate p53 activity is a promising, if unorthodox, therapeutic strategy. The multicellular model has the advantages of modularity, high resolution, and scalability, making it a potential foundation for creating digital twins of neuroblastoma patients. Author summary: Neuroblastoma is the most common extra-cranial solid tumour in children. Although very low–risk, low-risk, and intermediate-risk cases have good survival rates, most high-risk patients succumb to the disease or relapse despite modern therapies. Neuroblastoma biology is still full of unanswered questions and successful treatment is likely to require a personalised approach. Mathematical and computational modelling could contribute to a better understanding of its origin and nature, as well as the ongoing effort to advance patient-specific therapies, partly because of the potential for integration with other emerging technologies such as multi-omics, medical imaging, data mining, machine learning, and high-performance computing. During the PRIMAGE project, we built, calibrated, and validated, to the best of our knowledge, the first multicellular computational model of neuroblastoma. As we reported in an earlier paper, this was integrated into a multi-scale orchestrated computational framework. Here, we describe how we used the multicellular computational model as a standalone component, to gain new insights into neuroblastoma. Armed with it, we carried out large-scale computer simulations involving over a million independent cell agents in the most expensive case and 5000 hypothetical drug combinations. Our results confirm and add new insights into the non-linear dynamics spanning the intracellular, intercellular, and microenvironmental scales of neuroblastoma. They also indicate that an unconventional therapy targeting a frequently overlooked role of p53 (DNA repair) is promising. On the basis of these results, we believe that our model will be useful for the in silico medicine community. We hope that it will one day become the foundation of a virtual neuroblastoma. [ABSTRACT FROM AUTHOR]

ABSTRACT The de‐ubiquitinase USP33 has been shown to possess either tumour‐promoting or inhibitory effect on human cancer cells. However, all these findings are mainly based on in vitro cell culture models, and the in vivo evidence, which is more plausible to digest the functional role of USP33 in carcinogenic process, is still lacking. Here, we demonstrate that USP33 modulates DNA damage responses including cell cycle arrest and apoptosis induction through associating with p53. It directly interacts with p53 to mediate its de‐ubiquitination and further  stabilisation under DNA damage condition. Depletion of USP33 induces an enhanced level of p53 ubiquitination, which de‐stabilises p53 protein leading to impaired DNA damage responses. Furthermore, USP33 silencing shows either promoted or inhibited effect on cell proliferation in human cancer cells with p53 WT and mutant background, respectively. Consistently, mice with hepatocyte‐specific USP33 knockout are more sensitive to nitrosodiethylamine (DEN)‐induced hepatocarcinogenesis compared to wild type mice. Thus, our in vitro and in vivo evidences illustrate that USP33 possesses anti‐tumour activity via regulating p53 stability and activity. [ABSTRACT FROM AUTHOR]

Liquid-liquid phase separation of various transcription factors into biomolecular condensates plays an essential role in gene regulation. Here, using cellular models and in vitro studies, we show the spatiotemporal formation and material properties of p53 condensates that might dictate its function. In particular, p53 forms liquid-like condensates in the nucleus of cells, which can bind to DNA and perform transcriptional activity. However, cancer-associated mutations promote misfolding and partially rigidify the p53 condensates with impaired DNA binding ability. Irrespective of wild-type and mutant forms, the partitioning of p53 into cytoplasm leads to the condensate formation, which subsequently undergoes rapid solidification. In vitro studies show that abundant nuclear components such as RNA and nonspecific DNA promote multicomponent phase separation of the p53 core domain and maintain their liquid-like property, whereas specific DNA promotes its dissolution into tetrameric functional p53. This work provides mechanistic insights into how the life cycle and DNA binding properties of p53 might be regulated by phase separation. [ABSTRACT FROM AUTHOR]

Background: 1-Bromoacetyl-3,3-dinitroazetidine (RRx-001) has potent antitumor effects, indicating its promising therapeutic potential against various cancers. This research investigates RRx-001 activity against hepatocellular carcinoma (HCC) and elucidates its underlying mechanisms. Methods: Huh7, Hepa1-6, and MHCC97H cells were cultured and treated with varying RRx-001 concentrations for 24, 48, and 72 h. Cell viability was assessed using cell counting kit-8. The cells were divided into control and RRx-001 treatment groups at 0.5 × IC50, 1.0 × IC50, and 2.0 × IC50 concentrations for each cell line. Migration and invasion were evaluated using scratch and Transwell assays, and apoptosis was examined by apoptosis assays. RNA sequencing was performed on the Huh7 cells treated with RRx-001 for 24 h to identify differential gene expression. CD47 and TP53 protein levels were measured by Western blot. A xenograft mouse model was utilized to evaluate the effect of RRx-001 on HCC. Results: RRx-001 inhibits HCC cell viability, migration, and invasion while inducing apoptosis, These effects are potentially mediated by the downregulation of CD47 and the upregulation of TP53, both of which modulate key signaling pathways. In vivo experiments demonstrated that RRx-001 effectively inhibits tumor growth. Conclusion: RRx-001 reduces the viability of HCC cells and induces apoptosis. This effect may be due to the downregulation of CD47 expression and the alteration of the TP53 protein regulatory pathway. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T‐IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome‐dependent manner. Patient‐derived tumor organoids (PDOs), patient‐derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs‐resistant HCC with adeno‐associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy. [ABSTRACT FROM AUTHOR]

The p53 protein has attracted huge research interest over several decades due to its role as one of the most important tumor suppressors in mammals, which orchestrates a synchronous response from normal cells in the body to various forms of stress. The diverse cellular activities of the p53 protein are regulated mainly via its post-translational modifications (PTMs). PTMs affect p53 on several levels: at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes, at the level of the assembly of tetrameric complexes on DNA to transactivate its target genes; at the level of proteolysis in the absence of stress; and on the contrary, at the level of augmented protein stability in response to stress signals. Disruptions in these regulatory mechanisms can lead to deviations from normal cellular function, boosting tumor initiation and progression. Conversely, targeted interventions in these pathways could prove beneficial for the development of antitumor therapies. Advancing our understanding of p53 modifiers and the proteins involved in its regulation equips researchers with an expanded toolkit for studying cellular processes and for developing biologically active molecules that influence p53-mediated responses. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most common endocrine malignancy in the United States, with an overall favorable prognosis. However, some patients experience poor outcomes due to the development of resistance to conventional therapies. Genetic alterations, including mutations in BRAF, Met, and p53, play critical roles in thyroid cancer progression, with the BRAF V600E mutation detected in over 60% of cases. This study investigates the tumor-suppressive role of Annexin A7 (ANXA7) in thyroid cancer, focusing on its potential impact on tumor behavior and therapeutic response. Our analysis, which included RNA sequencing and protein profiling, revealed reduced ANXA7 expression in thyroid cancer cells, particularly in those harboring the BRAF V600E mutation. Upon treatment with inhibitors targeting BRAF and MEK, ANXA7 expression increased, leading to reduced phosphorylation of ERK and activation of apoptotic pathways. Additionally, we identified the cyclin-dependent kinase inhibitor p21 as a key player in modulating resistance to BRAF inhibitors. Combination therapies aimed at concurrently increasing p21 and ANXA7 levels resulted in a marked enhancement of apoptosis. These findings suggest a previously uncharacterized regulatory network involving the ANXA7/p21/BRAF/MAPK/p53 axis, which may contribute to drug resistance in thyroid cancer. This study provides new insights into overcoming resistance to BRAF and MAPK inhibitors, with implications for treating thyroid cancer and potentially other BRAF-mutant tumors. Future efforts will focus on high-throughput screening approaches to explore ANXA7-targeted therapeutic strategies for thyroid cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • Colorectal cancer, which is mainly caused by epigenetic and lifestyle factors, is very often associated with plasticity during its development. • Tumor cell plasticity leads to metabolic reprogramming of cells, drug resistance metastasis, which is of great therapeutic importance. • p53 acts as one of suppressors of carcinogenesis by regulating its genes involved in plasticity, autophagy, cell cycle, apoptosis and DNA repair. • The specific modulation of such proteins by natural compounds as prophylaxis or intervention therefore represents a therapeutic approach. • There is a link between anti-plasticity and pro-apoptosis by modulating p53 as a key resveratrol anti-CRC mechanism with therapeutic impact. Colorectal cancer (CRC), which is mainly caused by epigenetic and lifestyle factors, is very often associated with functional plasticity during its development. In addition, the malignant plasticity of CRC cells underscores one of their survival abilities to functionally adapt to specific stresses, including inflammation, that occur during carcinogenesis. This leads to the generation of various subsets of cancer cells with phenotypic diversity and promotes epithelial-mesenchymal transition (EMT), formation of cancer cell stem cells (CSCs) and metabolic reprogramming. This can enhance cancer cell differentiation and facilitate tumorigenic potential, drug resistance and metastasis. The tumor protein p53 acts as one of the central suppressors of carcinogenesis by regulating its target genes, whose proteins are involved in the plasticity of cancer cells, autophagy, cell cycle, apoptosis, DNA repair. The aim of this review is to summarize the latest published research on resveratrol's effect in the prevention of CRC, its regulatory actions, specifically on the p53 pathway, and its treatment options. Resveratrol, a naturally occurring polyphenol, is a potent inducer of a variety of tumor-controlling. However, the underlying mechanisms linking the p53 signaling pathway to the functional anti-plasticity effect of resveratrol in CRC are still poorly understood. Therefore, this review discusses novel relationships between anti-cellular plasticity/heterogeneity, pro-apoptosis and modulation of tumor protein p53 signaling in CRC oncogenesis, as one of the crucial mechanisms by which resveratrol prevents malignant phenotypic changes leading to cell migration and drug resistance, thus improving the ongoing treatment of CRC. [ABSTRACT FROM AUTHOR]

Human tissue pathology examination is mainly used for the diagnosis and treatment of various tumors. Immunohistochemical technique has important clinical significance in the early screening of colorectal cancer. In order to accurately determine the expression level of the tumor suppressor gene p53 in colorectal cancer, this study proposes a grading diagnostic method based on transfer learning with block-wise fine-tuning strategy. The parameters of the cell nucleus segmentation model are transferred to the diagnostic framework through image preprocessing, supervised model pre-training, and block-wise fine-tuning. The generated cell nucleus segmentation mask is subjected to PCA(Principal Component Analysis) dimensionality reduction and SVM(Support Vector Machine) multivariate classification to obtain the final image diagnosis result. The proposed method is verified on colorectal cancer p53 protein IHC(Immunohistochemistry) image dataset. Dice value of the model reaches 0.887 6 and classification accuracy reaches 90.28%. The results show that the proposed method can effectively grade the immunohistochemical images of colorectal cancer, and provide reliable auxiliary information for doctors to read the film. [ABSTRACT FROM AUTHOR]

Mutations in the TP53 tumor suppressor gene are the most abundant genetic occurrences in cancer. Some of these mutations lead to loss of function of p53 protein, some are gain of function, and some variants are hypomorphic (partially functional). Currently, there is no clinical distinction between different p53 mutations and cancer therapy or prognosis. Mutations in the oligomerization domain of p53 appear to be quite distinct in function, compared to mutations in the DNA binding domain. Here we show that, like other p53 oligomerization domain mutants, the Ashkenazi-specific G334R mutant accumulates to very high levels in cells and is significantly impaired for the transactivation of canonical p53 target genes. Surprisingly, we find that this mutant retains the ability to bind to consensus p53 target sites. A mouse model reveals that mice containing the G334R variant show increased predisposition to cancer, but only a fraction of these mice develop late-onset cancer. We show that the G334R variant retains the ability to interact with the SP1 transcription factor and contributes to the transactivation of joint SP1-p53 target genes. The combined evidence indicates that G334R is a unique oligomerization domain mutant that retains some tumor suppressor function. [ABSTRACT FROM AUTHOR]

Polo-like kinase 2 (Plk2) belongs to a family of serine/threonine kinases, and it is involved in tumorigenesis of diverse kind of tissues. We previously reported that Plk2 gene was a transcriptional target of the mutant p53/NF-Y oncogenic complex. Plk2 protein can bind to and phosphorylate mutant p53 triggering an oncogenic autoregulatory feedback loop involved in cancer cell proliferation and chemoresistance. In this study, we aimed to assess whether the specific inhibition of Plk2 kinase activity by the selective TC-S 7005 inhibitor could decrease cell proliferation and migration inhibiting mutant p53 phosphorylation, thus disarming its oncogenic potential. We found that the Plk2 inhibitor treatment sensitized the cells to the irradiation and chemotherapy drugs, thereby overcoming the mutant p53-dependent chemoresistance. Taken together, we provided results that Plk2 could be considered a tractable pharmacological target for cancers expressing mutant p53 proteins. The combined treatment with conventional chemotherapeutic drugs and Plk2 inhibitors may represent a new candidate intervention approach, which may be considered for improving tumor cell sensitivity to DNA damaging drugs. Key messages: Missense mutations are present in the TP53 gene in about half of all human cancers and correlate with poor patient outcome. Mutant p53 proteins exert gain of function (GOF) activities in tumor cells such as increased proliferation, genomic instability and resistance to therapies. Polo-like kinase 2 (PLK2) binds and phosphorylates mutant p53 protein strengthening its GOF activities. Pharmacologically targeting PLK2 weakens mutant p53 proteins and sensitizes tumor cells to therapeutic treatments. [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]

Objective: To investigate the effect of the in vitro activation product of cyclophosphamide, 4 - hydroperoxy cyclophosphamide (4-HC), on the functional impairment of the human ovarian granulosa cell line SVOG, and the potential underlying mechanisms. Methods: SVOG cells were treated with 0.2, 2.0, and 10.0 μmol/L of 4-HC for 24, 48, and 72 h. The cell viability in each group was measured using the CCK-8 assay to determine the optimal time and concentration for constructing an injury model. Western blot and RT -qPCR were used to detect changes in mitochondrial autophagy flux. Transmission electron microscopy was employed to observe mitochondrial changes in both normal and 4-HC -injured cells. RT -qPCR was used to assess the expression of P53- related genes, and immunofluorescence was applied to detect the expression levels of P53, Parkin, and the translocase of the outer mitochondrial membrane 20 (TOMM20) proteins. Results: A model of SVOG cell injury induced by 2.0 μmol/L 4-HC for 48 h was established in vitro. Mitochondrial autophagy flux was inhibited, and mitochondrial morphology was abnormal in 4-HC-injured SVOG cells, with a significant increase in damaged mitochondria. The expression level of P53 was significantly increased in 4-HC -injured SVOG cells. An increase in the cytoplasmic interaction between P53 and Parkin protein was observed, while the binding of TOMM20 and Parkin protein was inhibited in 4 - HC -injured SVOG cells. Conclusion: In vitro, 4 - HC may induce damage to human ovarian granulosa cells by inhibiting mitochondrial autophagy through the P53-Parkin pathway. [ABSTRACT FROM AUTHOR]

Cancer is one of most lethal diseases worldwide. Chemotherapeutics and surgeries are among the treatment facilities available for curing cancer. However due to their negative impact on normal cells and drug resistance development, new treatment strategies have yet to be developed. Some microbial products exhibit therapeutic potential for treating cancer. Pseudomonas aeruginosa Azurins have shown anticancer effects against breast cancer without affecting normal cells. To enhance its cytotoxic effect and targeted delivery, we fused Azurin with a cell-penetrating peptide (BR2) through a rigid linker and evaluated its anticancer potential via in silico analysis. The prediction of the secondary and the tertiary structures and analysis of physiochemical properties of chimeric proteins were computationally performed. The Azurin-BR2 chimeric protein has a basic nature with a molecular weight of 16.8 kDa. The quality indices and validation of chimeric proteins were performed with ERRAT2 and Ramachandran plot values, respectively. The quality index of the chimeric protein was predicted to be 81% to 84.6%, and residues residing in the most favoured region were identified. The HDOCK bioinformatics tool was used for docking a chimeric protein with a cancer suppressor protein p53. The results of the current study support that an Azurin-BR2 fusion protein has a high binding affinity for p53 can induce apoptosis in cancerous cells, and can be used in tumor-targeting therapy. [ABSTRACT FROM AUTHOR]

The tumor-suppressing p-53 binding protein is a crucial protein that is involved in the prevention of cancer via its regulatory effect on a number of cellular processes. Recent evidence indicates that it interacts with a number of other proteins involved in cancer in ways that are not fully understood. An understanding of such interactions could provide insights into novel ways p53 further exerts its tumour prevention role via its interactions with diverse proteins. Thus, this study aimed to examine the interactions of the p53 protein with other proteins (peptides and histones) using molecular simulation dynamics. We opted for a total of seven proteins, namely 2LVM, 2MWO, 2MWP, 4CRI, 4 × 34, 5Z78, and 6MYO (control), and had their PBD files retrieved from the protein database. These proteins were then docked against the p-53 protein and the resulting interactions were examined using molecular docking simulations run at 500 ns. The result of the interactions revealed the utilisation of various amino acids in the process. The peptide that interacted with the highest number of amino acids was 5Z78 and these were Lys10, Gly21, Trp24, Pro105, His106, and Arg107, indicating a stronger interaction. The RMSD and RMSF values indicate that the complexes formed were stable, with 4CRI, 6MYO, and 2G3R giving the most stable values (less than 2.5 Å). Other parameters, including the SASA, Rg, and number of hydrogen bonds, all indicated the formation of fairly stable complexes. Our study indicates that overall, the interactions of 53BP1 with p53K370me2, p53K382me2, methylated K810 Rb, p53K381acK382me2, and tudor-interacting repair regulator protein indicated interactions that were not as strong as those with the histone protein. Thus, it could be that P53 may mediate its tumour suppressing effect via interactions with amino acids and histone. [ABSTRACT FROM AUTHOR]

The COVID-19 infection caused by SARS-CoV-2 in late 2019 posed unprecedented global health challenges of massive proportions. The persistent effects of COVID-19 have become a subject of significant concern amongst the medical and scientific community. This article aims to explore the probability of a link between the COVID-19 infection and the risk of lung cancer development. First, this article reports that SARS-CoV-2 induces severe inflammatory response and cellular stress, potentially leading to tumorigenesis through common pathways between SARS-CoV-2 infection and cancer. These pathways include the JAK/STAT3 pathway which is activated after the initiation of cytokine storm following SARS-CoV-2 infection. This pathway is involved in cellular proliferation, differentiation, and immune homeostasis. The JAK/STAT3 pathway is also hyperactivated in lung cancer which serves as a link thereof. It predisposes patients to lung cancer through myriad molecular mechanisms such as DNA damage, genomic instability, and cell cycle dysregulation. Another probable pathway to tumorigenesis is based on the possibility of an oncogenic nature of SARS-CoV-2 through hijacking the p53 protein, leading to cell oxidative stress and interfering with the DNA repair mechanisms. Finally, this article highlights the overexpression of the SLC22A18 gene in lung cancer. This gene can be overexpressed by the ZEB1 transcription factor, which was found to be highly expressed during COVID-19 infection. [ABSTRACT FROM AUTHOR]

The development of drug resistance reduces the efficacy of cancer therapy. Tumor cells can acquire resistance to MDM2 inhibitors, which are currently under clinical evaluation. We generated RG7388-resistant neuroblastoma cells, which became more proliferative and metabolically active and were less sensitive to DNA-damaging agents in vitro and in vivo, compared with wild-type cells. The resistance was associated with a mutation of the p53 protein (His193Arg). This mutation abated its transcriptional activity via destabilization of the tetrameric p53-DNA complex and was observed in many cancer types. Finally, we found that Cisplatin and various BH3-mimetics could enhance RG7388-mediated apoptosis in RG7388-resistant neuroblastoma cells, thereby partially overcoming resistance to MDM2 inhibition. [ABSTRACT FROM AUTHOR]

Background: Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear. Methods: To elucidate the metabolic regulations and molecular underpinnings associated with the specific p53R270H and p53R172H mutant variants (the mouse equivalents of human p53R273H and p53R175H, respectively), we employed a comprehensive approach. This included integrating global metabolomic analysis with epigenomic and transcriptomic profiling in mouse pancreatic cancer cells. Additionally, we assessed metabolic parameters such as oxygen consumption rate and conducted analyses of proliferation and cell–cell competition to validate the biological impact of metabolic changes on pancreatic ductal adenocarcinoma (PDAC) phenotype. Our findings were further corroborated through analysis of clinical datasets from human cancer cohorts. Results: Our investigation revealed that the p53R270H variant, but not p53R172H, sustains mitochondrial function and energy production while also influencing cellular antioxidant capacity. Conversely, p53R172H, while not affecting mitochondrial metabolism, attenuates the activation of pro-tumorigenic metabolic pathways such as the urea cycle. Thus, the two variants selectively control different metabolic pathways in pancreatic cancer cells. Mechanistically, p53R270H induces alterations in the expression of genes associated with oxidative stress and reduction in mitochondrial respiration. In contrast, p53R172H specifically impacts the expression levels of enzymes involved in the urea metabolism. However, our analysis of cell proliferation and cell competition suggested that the expression of either p53R270H or p53R172H does not influence confer any selective advantage to this cellular model in vitro. Furthermore, assessment of mitochondrial priming indicated that the p53R270H-driven mitochondrial effect does not alter cytochrome c release or the apoptotic propensity of pancreatic cancer cells. Conclusions: Our study elucidates the mutant-specific impact of p53R270H and p53R172H on metabolism of PDAC cancer cells, highlighting the need to shift from viewing p53 mutant variants as a homogeneous group of entities to a systematic assessment of each specific p53 mutant protein. Moreover, our finding underscores the importance of further exploring the significance of p53 mutant proteins using models that more accurately reflect tumor ecology. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a degenerative joint disorder characterized by progressive cartilage degradation. Excessive oxidative stress (OS), inflammatory responses, extracellular matrix breakdown, and cellular senescence of chondrocytes play crucial roles in the pathological development of OA. Currently, curing OA remains a significant challenge. In this study, we aimed to elucidate the protective effects of Annexin A1 protein Mimetic Peptide (Ac2‐26) against tumor necrosis factor‐α (TNF‐α)‐induced damage in CHON‐001 chondrocytes by assessing cellular senescence, OS, and the expression levels of matrix metalloproteinase‐13 (MMP‐13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)‐4. Our results show that Ac2‐26 mitigated the reduction of telomerase activity and the exacerbation of cellular senescence induced by TNF‐α in CHON‐001 chondrocytes. Treatment with TNF‐α led to decreased expression of the human telomerase reverse transcriptase gene and increased expression of the telomeric repeat‐binding factor 2 gene, which were reversed by Ac2‐26 treatment. The TNF‐α‐induced increases in the gene and protein expressions of p53 and p16 were restored by Ac2‐26 in a dose‐dependent manner. Additionally, we found that TNF‐α caused elevations in the mRNA and protein levels of MMP‐13 and ADAMTS‐4, which were reduced by Ac2‐26 in a dose‐dependent fashion. Furthermore, TNF‐α triggered the activation of nuclear factor κ‐B (NF‐κB) by increasing the levels of phosphorylated NF‐κB p65 and the luciferase activity of NF‐κB. Notably, Ac2‐26 alleviated OS by reducing mitochondrial reactive oxygen species levels and promoting the activation of NF‐E2‐related factor 2 (Nrf2) in TNF‐α‐challenged CHON‐001 chondrocytes. Silencing Nrf2 abolished the Ac2‐26‐induced activation of NF‐κB and cellular senescence in CHON‐001 chondrocytes. Collectively, these findings offer new insights into the potential therapeutic use of Ac2‐26 for treating OA. [ABSTRACT FROM AUTHOR]

Introduction: Luteolin, a naturally occurring flavonoid compound, demonstrates promising anti-cancer properties. However, its mechanism against non-small-cell lung cancer (NSCLC) remains unknown. This study employed network pharmacology, molecular docking, molecular dynamics simulation (MDS), and in vitro experiments to investigate the potential mechanisms by which luteolin against NSCLC. Methods: Initially, the potential targets of luteolin and NSCLC-related targets were identified from public databases such as TCMSP, GeneCards, OMIM, DrugBank, and TTD. Subsequently, the protein-protein interaction (PPI) network screening and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. The binding affinity and stability of luteolin with the core targets were assessed using molecular docking and MDS. Finally, the results were validated by in vitro experiments. Results: A total of 56 luteolin targets and 2145 NSCLC-related targets were identified. Six core targets, TP53, EGFR, AKT1, TNF, JUN, and CASP3, were screened via the PPI network. The GO and KEGG analyses indicated that luteolin's activity against NSCLC potentially involves PI3K-Akt, NF-kappa B, and other signaling pathways. Molecular docking revealed that luteolin had high binding affinity with the core targets. MDS confirmed the stable interaction between luteolin and key proteins TP53 and AKT1. in vitro , luteolin significantly inhibited the proliferation and migration of A549 cells, while also inducing apoptosis. In addition, luteolin downregulated the expression of p-Akt (Ser473), MDM2, and Bcl-2 but upregulated the expression of p53 and Bax, which was consistent with the effect of LY294002. Conclusion: Luteolin had a good anti-NSCLC effect, and the apoptosis-inducing effect might be related to the Akt/MDM2/p53 signaling pathway. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma is one of the most aggressive types of cancer. Among different mechanisms generally believed to be important for the development of cancer, aberrant regulation of the p53 protein is a well-known and common feature for many cancer entities. Our work aims to analyze the impact of p53 deregulation and proteins encoded by p53 target genes on the survival of patients suffering from pancreatic adenocarcinoma. We, therefore, focused on the analysis of the selected collective for the TP53 mutation status, the p53 protein level, their correlation, and possible impacts on the prognosis/survival. We compared and analyzed a set of 123 patients. We have extracted information regarding the TP53 mutation status, p53 protein levels, the level of proteins encoded by prominent p53 target genes, and information on the overall survival. Survival analyses were displayed by Kaplan–Meier plots, using the log-rank test, in order to check for statistical significance. Protein levels were compared using the Mann–Whitney Test. We did not find any statistically significant correlation between the TP53 mutation status and the survival of the patients. Moreover, we have not found any significant correlation between the protein amount of prominent p53 target genes and the patients' survival. However, we see a significant correlation between the p53 protein level in cancer samples and the overall survival of pancreatic adenocarcinoma patients: patients having tumors with a p53 protein level within the upper quartile of all measured cases show a significantly reduced survival compared to the rest of the patients. Thus, in pancreatic adenocarcinoma, the p53 protein level is a relevant marker for prognosis, and cancers having a high p53 protein amount show a shortened patients' survival. In contrast, for this cancer entity, the TP53 mutation status or the protein amount of prominent p53 target genes on their own seems not to have a significant impact on survival. [ABSTRACT FROM AUTHOR]

Lamina cribrosa (LC) cells play an integral role in extracellular matrix remodeling and fibrosis in human glaucoma. LC cells bear similarities to myofibroblasts that adopt an apoptotic-resistant, proliferative phenotype, a process linked to dysregulation of tumor suppressor-gene p53 pathways, including ubiquitin-proteasomal degradation via murine-double-minute-2 (MDM2). Here, we investigate p53 and MDM2 in glaucomatous LC cells. Primary human LC cells were isolated from glaucomatous donor eyes (GLC) and age-matched normal controls (NLC) (n = 3 donors/group). LC cells were cultured under standard conditions ± 48-h treatment with p53-MDM2-interaction inhibitor RG-7112. Markers of p53-MDM2, fibrosis, and apoptosis were analyzed by real-time polymerase chain reaction (qRT-PCR), western blotting, and immunofluorescence. Cellular proliferation and viability were assessed using colorimetric methyl-thiazolyl-tetrazolium salt assays (MTS/MTT). In GLC versus NLC cells, protein expression of p53 was significantly decreased (p < 0.05), MDM2 was significantly increased, and immunofluorescence showed reduced p53 and increased MDM2 expression in GLC nuclei. RG-7112 treatment significantly increased p53 and significantly decreased MDM2 gene and protein expression. GLC cells had significantly increased protein expression of αSMA, significantly decreased caspase-3 protein expression, and significantly increased proliferation after 96 h. RG-7112 treatment significantly decreased COL1A1 and αSMA, significantly increased BAX and caspase-3 gene expression, and significantly decreased proliferation in GLC cells. MTT-assay showed equivocal cellular viability in NLC/GLC cells with/without RG-7112 treatment. Our data suggests that proliferation and the ubiquitin-proteasomal pathway are dysregulated in GLC cells, with MDM2-led p53 protein degradation negatively impacting its protective role. [ABSTRACT FROM AUTHOR]

The p53 protein, encoded by the TP53 gene, serves as a critical tumor suppressor, playing a vital role in maintaining genomic stability and regulating cellular responses to stress. Dysregulation of p53 is frequently observed in hematological malignancies, significantly impacting disease progression and patient outcomes. This review aims to examine the regulatory mechanisms of p53, the implications of TP53 mutations in various hematological cancers, and emerging therapeutic strategies targeting p53. We conducted a comprehensive literature review to synthesize recent findings related to p53's multifaceted role in hematologic cancers, focusing on its regulatory pathways and therapeutic potential. TP53 mutations in hematological malignancies often lead to treatment resistance and poor prognosis. Current therapeutic strategies, including p53 reactivation and gene therapy, show promise in improving treatment outcomes. Understanding the intricacies of p53 regulation and the consequences of its mutations is essential for developing effective diagnostic and therapeutic strategies in hematological malignancies, ultimately enhancing patient care and survival. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a serious condition that occurs when the body's response to infection becomes uncontrolled, resulting in a high risk of death. Despite improvements in healthcare, identifying sepsis early is difficult because of its diverse nature and the absence of distinct biomarkers. Recent studies suggest that 5-methylcytosine (m5C)-related genes play a significant role in immune responses, yet their diagnostic potential in sepsis remains unexplored. Methods: This research combined and examined four sepsis-related datasets (GSE95233, GSE57065, GSE100159, and GSE65682) sourced from the Gene Expression Omnibus (GEO)database to discover m5C-related genes with differential expression. Various machine learning methods, such as decision tree, random forest, and XGBoost, were utilized in identifying crucial hub genes. Receiver Operating Characteristic (ROC) curve analysis was used to assess the diagnostic accuracy of these genetic markers. Additionally, single-gene enrichment and immune infiltration analyses were conducted to investigate the underlying mechanisms involving these hub genes in sepsis. Results: Three hub genes, DNA Methyltransferase 1 (DNMT1), tumor protein P53 (TP53), and toll-like receptor 8 (TLR8), were identified and validated for their diagnostic efficacy, showing area under the curve (AUC) values above 0.7 in both test and validation sets. Enrichment analyses revealed that these genes are involved in key pathways such as p53 signaling and Toll-like receptor signaling. Immune infiltration analysis indicated significant correlations between hub genes and various immune cell types, suggesting their roles in modulating immune responses during sepsis. Conclusion: The study highlights the diagnostic potential of m5C-related genes in sepsis and their involvement in immune regulation. These findings offer new insights into sepsis pathogenesis and suggest that DNMT1 , TP53 , and TLR8 could serve as valuable biomarkers for early diagnosis. Further studies should prioritize validating these biomarkers in clinical settings and investigating their potential for therapy. [ABSTRACT FROM AUTHOR]

A novel series of six [1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)prop-2-en-1-ones (3a–3f) was designed and synthesized. They were characterized based on spectral and elemental analyses. In silico studies were also committed to provide insights and a better understanding of their structural features. The six compounds were screened for their antiproliferative activity using the MTT assay against five human cancer cell lines, namely, A549, HCT116, PC3, HT29, and MCF-7 in parallel with the non-cancerous human lung cell line WI-38. The results showed that 3e and 3f have potential cytotoxic activities, especially on A549 cells with IC50 = 2.3 µM and 1.15 µM, respectively. Meanwhile, they recorded a minimal cytotoxic effect on WI-38 cells. Concerning the molecular mechanism of action, the present study showed the inhibitory effect of the six compounds against total EGFR. The most potent EGFR inhibitors were 3e and 3f with IC50 = 0.031 µM and 0.023 µM, respectively. The selectivity index of 3f for EGFRT790M was 1.81 times more selective than that of lapatinib. In addition, 3e and 3f initiated cell cycle arrest at the G2/M and pre-G1 phases along with the downregulation of anti-apoptotic protein Bcl2 and the upregulation of pro-apoptotic proteins: p53, Bax, and caspases 3, 8, and 9. Further studies are recommended to evaluate animal models' promising anticancer activity and molecular mechanism of triazolo[3,4-a]isoquinoline derivatives 3e and 3f. [ABSTRACT FROM AUTHOR]

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]

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]

Gastric cancer remains a significant therapeutic challenge, highlighting the need for new strategies to improve treatment efficacy. This study investigates the potential of combined therapy with the novel Thiopyrano[2,3-d]Thiazole derivative LES-6400 and the anti-HER2 antibody trastuzumab in AGS gastric cancer cells. The antitumor effects of the combined therapy were evaluated using various techniques, including the MTT assay for cell viability, [3H]-thymidine incorporation for DNA synthesis, and flow cytometry to assess apoptosis (Annexin V-FITC/PI staining), mitochondrial membrane potential (MMP), and inflammatory cytokine levels. ELISA was employed to measure the levels of IL-6, p53, and cytochrome C. The combination of LES-6400 (1 µM) and trastuzumab (10 µg/mL) demonstrated superior antitumor activity compared to monotherapy with either agent in AGS gastric cancer cells. The combination therapy enhanced apoptosis, presumably by inducing oxidative stress in the cells and disrupting mitochondrial membrane potential. Additionally, a significant increase in p53 protein levels and modulation of interleukin levels, including a marked reduction in IL-6 levels, were observed, suggesting an impact on apoptotic and inflammatory responses. These findings indicate that the combined use of LES-6400 and trastuzumab is a promising therapeutic strategy for gastric cancer, warranting further investigation into the mechanisms of action and potential clinical applications of this combined approach. [ABSTRACT FROM AUTHOR]

Background/aim: The p53 protein, a crucial tumor suppressor, governs cell cycle regulation and apoptosis. Similarly, p63, a member of the p53 family, exhibits traits of both tumor suppression and oncogenic behavior through its isoforms. However, the functional impact of ΔNp63β, an isoform of the p63 protein, on human glioma cancer cells like T98G cells remains poorly understood, representing the novelty of this study in the current literature. Materials and methods: Employing the pRetroX-Tet-On vector system, the apoptotic effects of ΔNp63β on T98G cell lines was investigated and its influence on the cell cycle was assessed. Initially, an rtTA-expressing vector, a component of the pRetroX-Tet-On system, was established in the T98G cell lines. Subsequently, the ΔNp63β cDNA was cloned into the Retropur Tight retroviral vector and transfected into T98G cells containing the pRetroX-Tet-On system for functional analysis. The gene expression and cell cycle regulation were evaluated through reverse-transcription polymerase chain reaction and flow cytometry, determining protein translation via western blotting. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ß-galactosidase cell staining were employed to assess the cytotoxicity and senescence of ΔNp63β, respectively Results: The overexpression of ΔNp63β in the T98G cells correlated with increased cell viability and altered cell cycle regulation, notably upregulating the p21 expression independent of p53. Caspase-3/7 activity analyses showed no changes in the apoptotic genes but revealed an increase in antiapoptotic gene expression. Surprisingly, cell death in the ΔNp63β-overexpressing T98G cells did not occur through apoptosis as anticipated. Instead, it resulted from the cytotoxic effects of the ΔNp63β protein. Conclusion: Δp63ß increased the p21 levels, induced cell death, and caused cell cycle arrest at the G1 phase, while exhibiting antiapoptotic properties and promoting senescence. Unexpectedly, overexpression of Δp63ß in T98G cells led to significant cell death, potentially through necrosis rather than apoptosis, suggesting a complex role for Δp63ß in cell cycle regulation and tumor suppression. [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]