P53 Pathway Research Articles

AMPK/PGC-1α and p53 modulate VDAC1 expression mediated by reduced ATP level and metabolic oxidative stress in neuronal cells.

Voltage-dependent anion channel 1 (VDAC1) is a pore protein located in the outer mitochondrial membrane. Its channel gating mediates mitochondrial respiration and cell metabolism, and it has been identified as a critical modulator of mitochondria-mediated apoptosis. In many diseases characterized by mitochondrial dysfunction, such as cancer and neurodegenerative diseases, VDAC1 is considered a promising potential therapeutic target. However, there is limited research on the regulatory factors involved in VDAC1 protein expression in both normal and pathological states. In this study, we find that VDAC1 protein expression is up-regulated in various neuronal cell lines in response to intracellular metabolic and oxidative stress. We further demonstrate that VDAC1 expression is modulated by intracellular ATP level. Through the use of pharmacological agonists and inhibitors and small interfering RNA (siRNA), we reveal that the AMPK/PGC-1α signaling pathway is involved in regulating VDAC1 expression. Additionally, based on bioinformatics predictions and biochemical verification, we identify p53 as a potential transcription factor that regulates VDAC1 promoter activity during metabolic oxidative stress. Our findings suggest that VDAC1 expression is regulated by the AMPK/PGC-1α and p53 pathways, which contributes to the maintenance of stress adaptation and apoptotic homeostasis in neuronal cells.

Identification of Molecular Mechanisms in Radiation Cystitis: Insights from RNA Sequencing.

Pelvic cancer survivors who were treated with radiation therapy are at risk for developing (hemorrhagic) radiation cystitis (RC) many years after completion of radiation therapy. Patients with RC suffer from lower urinary tract symptoms, including frequency, nocturia, pelvic pain, and incontinence. In advanced stages, hematuria can occur, potentially escalating to life-threatening levels. Current therapeutic options for RC are limited, partly due to ethical concerns regarding bladder biopsy in patients with fragile bladder tissue. This study aimed to leverage our established preclinical model to elucidate the molecular pathways implicated in radiation-induced tissue changes in the bladder. Female C57Bl/6 mice received a single dose of 40 Gy using CT-guided imaging and a two-beam irradiation approach using the SARRP irradiator. Bladders from irradiated and age-matched littermate controls were harvested at 1 week [n = 5/group] or 6 months [n = 5/group] after irradiation, RNA was harvested, and mRNA sequencing was performed at paired-end 150bp on the Illumina NovaSeq6000 with a target of 30 million reads per sample. Following RNA sequencing, thorough bioinformatics analysis was performed using iPathwayGuide v2012 (ADVAITA Bioinformatics). Findings of the RNA sequencing were validated using qPCR analysis. At 1 week post-irradiation, altered gene expression was detected in genes involved in DNA damage response, apoptosis, and transcriptional regulation. By 6 months post-irradiation, significant changes in gene expression were observed in inflammation, collagen catabolism, and vascular health. Affected pathways included the p53, JAK-STAT, and PI3K-Akt pathways. These findings were validated in vivo in bladder tissues from our preclinical model. This is the first study to determine the molecular changes in the bladder in response to radiation treatment. We have successfully pinpointed several pathways and specific genes that undergo modification, thereby contributing to the progression of radiation cystitis. These insights enhance our understanding of the pathophysiology of radiation cystitis and may ultimately pave the way to the identification of potential new therapeutic targets.

Corticosterone Impairs Hippocampal Neurogenesis and Behaviors through p21-Mediated ROS Accumulation.

Stress is known to induce a reduction in adult hippocampal neurogenesis (AHN) and anxiety-like behaviors. Glucocorticoids (GCs) are secreted in response to stress, and the hippocampus possesses the greatest levels of GC receptors, highlighting the potential of GCs in mediating stress-induced hippocampal alterations and behavior deficits. Herein, RNA-sequencing (RNA-seq) analysis of the hippocampus following corticosterone (CORT) exposure revealed the central regulatory role of the p21 (Cdkna1a) gene, which exhibited interactions with oxidative stress-related differentially expressed genes (DEGs), suggesting a potential link between p21 and oxidative stress-related pathways. Remarkably, p21-overexpression in the hippocampal dentate gyrus partially recapitulated CORT-induced phenotypes, including reactive oxygen species (ROS) accumulation, diminished AHN, dendritic atrophy, and the onset of anxiety-like behaviors. Significantly, inhibiting ROS exhibited a partial rescue of anxiety-like behaviors and hippocampal alterations induced by p21-overexpression, as well as those induced by CORT, underscoring the therapeutic potential of targeting ROS or p21 in the hippocampus as a promising avenue for mitigating anxiety disorders provoked by chronic stress.

Prognosis and biological function of SGOL1 in clear cell renal cell carcinoma: a multiomics analysis.

Shugoshin-1 (SGOL1) is a mammalian ortholog of Shugoshin in yeast and is essential for precise chromosome segregation during mitosis and meiosis. Aberrant SGOL1 expression was reported to be closely correlated with the malignant progression of various tumors. However, the expression pattern and biological function of SGOL1 in clear cell renal cell carcinoma (ccRCC) are unclear. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases provide mRNA expression data and outcome information for ccRCC patients. Immunohistochemistry (IHC) of ccRCC tissue chips verified SGOL1 protein expression in ccRCC patients. Data processing and visualization were performed with the UALCAN, TISIDB, TIMER, GSCA, LinkedOmics, and starBase databases. Gene Ontology (GO) annotation and gene set enrichment analysis (GSEA) were used to identify SGOL1-related biological functions and signaling pathways. Immune infiltration analysis was performed using the TISIDB database, ssGSEA algorithm, and TCGA-KIRC cohort. The biological role of SGOL1 in ccRCC was investigated using a series of in vitro cytological assays, including the MTT assay, EdU staining assay, flow cytometry analysis, Transwell assay, and wound healing assay. SGOL1 was highly expressed in ccRCC and linked to adverse clinicopathological parameters and unfavorable prognosis. Multivariate logistic regression and nomogram calibration suggested that SGOL1 might serve as an independent and reliable prognostic predictor of ccRCC. Functional enrichment analysis indicated that SGOL1 may be involved in the cell cycle, the p53 pathway, DNA replication, and T-cell activation. Furthermore, tumor microenvironment (TME) analysis suggested that SGOL1 was positively associated with Treg infiltration and immune checkpoint upregulation. In addition, we identified a potential SNHG17/PVT1/ZMIZ1-AS1-miR-23b-3p-SGOL1 axis correlated with ccRCC carcinogenesis and progression. Finally, we demonstrated that SGOL1 promoted ccRCC cell proliferation, migratory capacity, and invasion in vitro. SGOL1 potentially functions as an oncogene in ccRCC progression and might contribute to the immunosuppressive TME by increasing Treg infiltration and checkpoint expression, suggesting that targeting SGOL1 could be a novel therapeutic strategy for the treatment of ccRCC patients.

TGF-β2-induced alterations of m6A methylation in hTERT RPE-1 cells

N6-methyladenosine (m6A) is a major type of RNA modification implicated in various pathophysiological processes. Transforming growth factor β2 (TGF-β2) induces epithelial-mesenchymal transition (EMT) in retinal pigmental epithelial (RPE) cells and promotes the progression of proliferative vitreoretinopathy (PVR). However, the role of m6A methylation in the EMT of human telomerase reverse transcriptase (hTERT) retinal pigmental epithelium (RPE)-1 cells has not been clarified. Here, we extracted RNA from RPE cells subjected to 0 or 20 ng/mL TGF-β2 for 72 h and identified differentially methylated genes (DMGs) by m6A-Seq and differentially expressed genes (DEGs) by RNA-Seq. We selected the genes related to EMT by conjoint m6A-Seq/RNA-Seq analysis and verified them by qRT-PCR. We then confirmed the function of m6A methylation in the EMT of RPE cells by knocking down the methyltransferase METTL3 and the m6A reading protein YTHDF1. Sequencing yielded 5814 DMGs and 1607 DEGs. Conjoint analysis selected 467 genes altered at the m6A and RNA levels that are closely associated with the EMT-related TGF-β, AGE-RAGE, PI3K-Akt, P53, and Wnt signaling pathways. We also identified ten core EMT genes ACTG2, BMP6, CDH2, LOXL2, SNAIL1, SPARC, BMP4, EMP3, FOXM1, and MYC. Their RNA levels were evaluated by qRT-PCR and were consistent with the sequencing results. We observed that METTL3 knockdown enhanced RPE cell migration and significantly upregulated the EMT markers N-cadherin (encoded by CDH2), fibronectin (FN), Snail family transcription repressor (SLUG), and vimentin. However, YTHDF1 knockdown had the opposite effects and decreased both cell migration and the N-cadherin, FN, and SLUG expression levels. The present study clarified TGF-β2-induced m6A- and RNA-level differences in RPE cells, indicated that m6A methylation might regulate EMT marker expression, and showed that m6A could regulate TGF-β2-induced EMT.

The application of silver nanoparticles green-formulated by Origanum majorana leaf extract as a hydrazine sensor and treatment of human breast cancer by following the P53 and STAT3 signaling pathways

Silver nanoparticles, because of their large absorption surface and small size, are considered to be intelligent magnetic particles. The advancements in nanotechnology have revolutionized cancer treatment, with silver nanoparticles playing a crucial role in this field. In a recent experiment, the effects of Ag nanoparticles formulated from Origanum majorana on breast cancer cells were investigated. It was found that these nanoparticles induce apoptosis through the signal transducer and activator of transcription 3 and P53 signaling pathways. The nanoparticle characterization was conducted using FE-SEM, XRD, and UV–Vis techniques. Furthermore, the Ag nanoparticles exhibited significant antioxidant activity by preventing 50% of DPPH at 183 μg/mL. The MTT assay revealed the anti-breast carcinoma properties of silver NPs on MCF-7, T-47D, and SkBr3 cells. The outcomes demonstrated that as the nanoparticle concentration increased, the cancer cells survival percentage reduced for 3 days. The most effective anticancer effect was observed at 1000 μg/ml. MTT findings indicate that a concentration of nanoparticles at IC50 = 97, 186, and 180 μg/ml effectively targets 50% of MCF-7, T-47D, and SkBr3 breast carcinoma cells. The presence of silver NPs induces cell apoptosis, which is with the Bax markers regulation and the pro-apoptotic cleaved caspase-8 upregulation, while the anti-apoptotic Bcl-2 marker is downregulated. Besides, silver NPs inhibit the formation of colonies. Molecular pathway analysis of breast cells treated with silver NPs reveals an increase in p53 expression, while the total and phosphorylated STAT3 expression is inhibited, suggesting that p53 and STAT3 have a notable role in the remedial efficacies of silver NPs on breast carcinoma cells. Additionally, the Ag nanoparticles exhibit high sensitivity in the hydrazine electrochemical detection, a potentially carcinogenic substance, with a detection limit of 0.25 μM. The developed sensor, utilizing Ag nanoparticles, shows great promise for the environmental monitoring of hydrazine due to its excellent catalytic performance and simple preparation process. Based on clinical research, recent silver nanoparticles have emerged as a viable option for breast cancer treatment.

Design, synthesis, biological evaluation and in silico studies of novel quinoline derivatives as potential radioprotective molecules targeting the TLR2 and p53 pathways

Ionizing radiation in space, radiation devices or nuclear disasters are major threats to human health and public security. In this paper, in order to find the potential novel compounds decreasing the radiation-induced damage by targeting p53 apoptosis pathway and TLR2 passway, a series of novel quinoline derivatives were designed, synthesized, and evaluated their biological activities. Most of the synthesized compounds showed significant radioprotective effects in vitro, and the compound 5 has the best performance. Therefore, we verified its radioprotective activity in vivo and investigated the mechanism of its excellent activity. The results in vivo indicated that compound 5 not only markedly enhanced the survival rate (80 %) of mice 30 days after lethal exposure to irradiation, but also significantly reduced the radiation-induced damage to haematopoietic system and intestinal tissue of mice. The mechanistic studies indicated that compound 5 acted on the p53 pathway to reduce radiation-induced cell apoptosis and at the same time stimulated TLR2 to up-regulate the expressions of radiation protection factors. Molecular dynamics study shows that compound 5 would effectively bind to the TLR2 protein and further revealed the binding mechanism. Taken together, all the findings of our study demonstrate the quinoline derivative 5 is a potent radioprotective compound, which holds a great therapeutic potential for further development.

Machine learning developed an intratumor heterogeneity signature for predicting prognosis and immunotherapy benefits in skin cutaneous melanoma.

Intratumor heterogeneity (ITH) is defined as differences in molecular and phenotypic profiles between different tumor cells and immune cells within a tumor. ITH was involved in the cancer progression, aggressiveness, therapy resistance and cancer recurrence. Integrative machine learning procedure including 10 methods was conducted to develop an ITH-related signature (IRS) in The Cancer Genome Atlas (TCGA), GSE54467, GSE59455 and GSE65904 cohort. Several scores, including tumor immune dysfunction and exclusion (TIDE) score, tumor mutation burden (TMB) score and immunophenoscore (IPS), were used to evaluate the role of IRS in predicting immunotherapy benefits. Two immunotherapy datasets (GSE91061 and GSE78220) were utilized to the role of IRS in predicting immunotherapy benefits of skin cutaneous melanoma (SKCM) patients. The optimal prognostic IRS constructed by Lasso method acted as an independent risk factor and had a stable and powerful performance in predicting the overall survival rate in SKCM, with the area under the curve of 2-, 3- and 4-year receiver operating characteristic curve being 0.722, 0.722 and 0.737 in TCGA cohort. We also constructed a nomogram and the actual 1-, 3- and 5-year survival times were highly consistent with the predicted survival times. SKCM patients with low IRS scores had a lower TIDE score, lower immune escape score and higher TMB score, higher PD1&CTLA4 IPS. Moreover, SKCM patients with low IRS scores had a lower gene sets score involved in DNA repair, angiogenesis, glycolysis, hypoxia, IL2-STAT5 signaling, MTORC1 signaling, NOTCH signaling and P53 pathway. The current study constructed a novel IRS in SKCM using 10 machine learning methods. This IRS acted as an indicator for predicting the prognosis and immunotherapy benefits of SKCM patients.

Recognizing the role of Epstein-Barr virus in gastric cancer: transcriptomic insights into malignancy modulation

BackgroundStudies show that Epstein-Barr virus (EBV) infection can play a role in malignancy and increase the risk of gastric cancer (GC). The objective of this research was to pinpoint genes whose expression may be influenced by EBV and play a role in the development of GC.MethodsCandidate genes potentially susceptible to expression modulation in the presence of EBV were identified through the analysis of GSE185627 and GSE51575 datasets. The association of candidate genes with GC and the survival rate of patients was investigated based on the cancer genome atlas (TCGA) data. Also, pathways related to candidate genes were examined through the MsigDB database. The PPI network was used to identify Hub genes. To corroborate the obtained results, we utilized the RT-qPCR method, employing GC samples from both EBV + and EBV-cases, as well as adjacent normal samples.ResultsOur results showed that genes upregulated by the EBV in the GC cell line, as well as in EBV + samples, are significantly linked to pathways involving the immune response, inflammation, and the P53 pathway. Conversely, genes downregulated by EBV are closely linked to pathways involving cell proliferation and mTORC1. Examining the candidate genes revealed that a considerable portion of genes susceptible to downregulation under the influence of EBV exhibit oncogenic roles based on TCGA data. Moreover, some of these genes are associated with an unfavorable prognosis. Protein-protein interaction network analysis of candidate genes highlighted IFI44L and OAS2 as potential hub genes in the EBV-GC axis. Our RT-qPCR results further validated these findings, demonstrating that the expression levels of IFI44L and OAS2 were higher in EBV + samples compared to both healthy and EBV-samples.ConclusionOur study underscores the capacity of EBV to exert regulatory control over genes associated with GC malignancy. In addition to its inflammatory effects, EBV elicits transcriptomic changes that appear to attenuate the progression of GC.

YY1: a key regulator inhibits gastric cancer ferroptosis and mediating apatinib-resistance

ObjectiveGastric cancer (GC) stands as a prevalent and deadly global malignancy. Despite its role as a preoperative neoadjuvant therapy, Apatinib’s effectiveness is curtailed among GC patients exhibiting elevated YY1 expression. YY1’s connection to adverse prognosis, drug resistance, and GC metastasis is established, yet the precise underlying mechanisms remain elusive. This study aims to unravel potential pathogenic pathways attributed to YY1.DesignUtilizing bioinformatics analysis, we conducted differentially expressed genes, functional annotation, and pathway enrichment analyses, and further validation through cellular and animal experiments.ResultsHigher YY1 expression correlated with diminished postoperative progression-free survival (PFS) and disease-specific survival (DSS) rates in TCGA analysis, identifying YY1 as an independent DSS indicator in gastric cancer (GC) patients. Notably, YY1 exhibited significantly elevated expression in tumor tissues compared to adjacent normal tissues. Bioinformatics analysis revealed noteworthy differentially expressed genes (DEGs), transcriptional targets, factors, and co-expressed genes associated with YY1. LASSO Cox analysis unveiled Transferrin as a prospective pivotal protein regulated by YY1, with heightened expression linked to adverse DSS and PFS outcomes. YY1’s role in governing the p53 signaling pathway and ferroptosis in GC cells was further elucidated. Moreover, YY1 overexpression dampened immune cell infiltration within GC tumors. Additionally, YY1 overexpression hindered GC cell ferroptosis and mediated Apatinib resistance via the p53 pathway. Remarkably, IFN-a demonstrated efficacy in reversing Apatinib resistance and immune suppression in GC tissues.ConclusionsOur findings underscore the pivotal role of YY1 in driving GC progression and influencing prognosis, thus pinpointing it as a promising therapeutic target to enhance patient outcomes.

Isolation and Identification of a Tibetan Pig Porcine Epidemic Diarrhoea Virus Strain and Its Biological Effects on IPEC-J2 Cells.

Porcine epidemic diarrhoea virus (PEDV) is a coronavirus that can cause severe watery diarrhoea in piglets, with high morbidity and mortality rates, seriously hindering the healthy development of the global swine industry. In this study, we isolated a strain of PEDV from Tibetan pigs and named it CH/GS/2022. Subsequently, we screened the apoptosis signals of PEDV-infected IPEC-J2 cells and studied the correlation between apoptosis signals and cell apoptosis. The results showed that different infections of PEDV induced different degrees of apoptosis in cells, and PEDV-induced cell apoptosis was dose-dependent. We then detected the expression of the p53, p38, JNK, Bax, and Bcl-2 genes in the apoptosis signal pathway. The results showed that 24 h after PEDV infection, the expression of the p53, p38, JNK, and Bax genes in IPEC-J2 cells increased significantly, while the expression of the Bcl-2 gene decreased significantly (p < 0.05). Subsequently, we used Western blot to detect the protein levels of these five genes, and the results showed that PEDV infection upregulated the expression of p53, p38, JNK, and Bax proteins (p < 0.05) while downregulating the expression of Bcl-2 protein (p < 0.05). Thus, it was initially inferred that PEDV infection could regulate cell apoptosis by activating the p53, p38, and JNK signalling pathways. Finally, we further investigated the apoptosis of the cells through the use of inhibitors. The results indicated that the p53 inhibitor Pifithrin-α has a significant inhibitory effect on the expression of the p53 protein after PEDV infection and can reverse the expression levels of Bax and Bcl-2 proteins. This suggested that p53 is involved in PEDV-induced cell apoptosis. Similarly, the p38 MAPK inhibitor SB203580 has an inhibitory effect on the expression of the p38 protein and can reverse the expression levels of Bax and Bcl-2 proteins. This suggested that p38 is also involved in PEDV-induced cell apoptosis. On the other hand, the JNK inhibitor SP600125 has no inhibitory effect on the expression of the JNK protein after PEDV infection, but the expression levels of Bax and Bcl-2 proteins have changed. Furthermore, it is noteworthy that SP600125 can inhibit the activity of apoptotic proteins but not their levels, resulting in reduced cell apoptosis. These preliminary results indicated that JNK may be involved in PEDV-induced IPEC-J2 cell apoptosis.

β-catenin mediates growth defects induced by centrosome loss in a subset of APC mutant colorectal cancer independently of p53.

Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths worldwide. The centrosome is the main microtubule-organizing center in animal cells and centrosome amplification is a hallmark of cancer cells. To investigate the importance of centrosomes in colorectal cancer, we induced centrosome loss in normal and cancer human-derived colorectal organoids using centrinone B, a Polo-like kinase 4 (Plk4) inhibitor. We show that centrosome loss represses human normal colorectal organoid growth in a p53-dependent manner in accordance with previous studies in cell models. However, cancer colorectal organoid lines exhibited different sensitivities to centrosome loss independently of p53. Centrinone-induced cancer organoid growth defect/death positively correlated with a loss of function mutation in the APC gene, suggesting a causal role of the hyperactive WNT pathway. Consistent with this notion, β-catenin inhibition using XAV939 or ICG-001 partially prevented centrinone-induced death and rescued the growth two APC-mutant organoid lines tested. Our study reveals a novel role for canonical WNT signaling in regulating centrosome loss-induced growth defect/death in a subset of APC-mutant colorectal cancer independently of the classical p53 pathway.

Cadmium disrupts spermatogenic cell cycle via piRNA-DQ717867/p53 pathway

Cadmium (Cd) is a harmful environmental pollutant that disrupts public health, including respiratory, digestive, and reproductive systems. In this study, male rats were exposed to CdCl2 at a dose of 3 mg/kg by oral for 28 days to investigate the impact on spermatogenesis. Testis tissue samples were collected after sacrifice, and piRNA expression levels were measured using piRNA microarray and qPCR. PiRNAs, specialized molecules involved in spermatogenesis, were examined. CdCl2 exposure led to disrupted piRNA expression, particularly in piRNA-DQ759395 in rats. This piRNA was found to have a binding site with p53, and a similar piRNA-DQ717867 was discovered in mice. In GC-2spd cells, CdCl2 exposure increased piRNA-DQ717867 expression, which resulted in cell cycle arrest and abnormal expression of cell cycle-related proteins. The activation of p53-related pathways and disruptions in cell cycle regulation were also observed. Antagomir-717867 transfections and PFT-a pretreatment in GC-2spd cells supported the involvement of piRNA-DQ717867 in regulating cell cycle-related proteins. This study suggests that Cd exposure induces abnormal expression of piRNA-DQ759395 in rat testis and that piRNA-DQ717867 may regulate p53, causing cell cycle abnormalities in GC-2spd cells. These findings help understand the mechanisms of male reproductive toxicity caused by Cd exposure and emphasize the role of piRNAs in cell cycle regulation and male reproductive health.

Multipathway regulation induced by4-(phenylsulfonyl)morpholine derivatives against triple-negative breast cancer.

Phenotypic drug discovery (PDD) is an effective drug discovery approach by observation of therapeutic effects on disease phenotypes, especially in complex disease systems. Triple-negative breast cancer (TNBC) is composed of several complex disease features, including high tumor heterogeneity, high invasive and metastatic potential, and a lack of effective therapeutic targets. Therefore, identifying effective and novel agents through PDD is a current trend in TNBC drug development. In this study, 23 novel small molecules were synthesized using 4-(phenylsulfonyl)morpholine as a pharmacophore. Among these derivatives, GL24 (4m) exhibited the lowest half-maximal inhibitory concentration value (0.90 µM) in MDA-MB-231 cells. To investigate the tumor-suppressive mechanisms of GL24, transcriptomic analyses were used to detect the perturbation for gene expression upon GL24 treatment. Followed by gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, multiple ER stress-dependent tumor suppressive signals were identified, such as unfolded protein response (UPR), p53 pathway, G2/M checkpoint, and E2F targets. Most of the identified pathways triggered by GL24 eventually led to cell-cycle arrest and then to apoptosis. In summary, we developed a novel 4-(phenylsulfonyl)morpholine derivative GL24 with a strong potential for inhibiting TNBC cell growth through ER stress-dependent tumor suppressive signals.

Green formulation of iron nanoparticles by plant extract induces apoptosis via P53 and STAT3 signaling pathways in prostate cancer cells

There has been a high interest in utilizing natural anticancer composites, such as medicinal plants extracts. Punica granatum, a popular medicinal plant, has various pharmacological applications. In this particular research, iron NPs were formulated by the Punica granatum aqueous extract, following the principles of green chemistry. The research objective was to determine the efficacy of FeNPs on prostate cancer cells. The usual analytical examinations were applied for FeNPs. The FE-SEM results confirmed that the nanoparticles exhibited a spherical morphology, with sizes ranging from 10 to 40 nm. The nanoparticles UV–Vis spectrum is showcasing the confirmation of their formation through the band presence at 293 nm. The signals at 2θ values of 62.3, 57.4, 53, 40.5, and 35.6 correspond to the (440), (511), (422), (222), and (311) planes, respectively. The FeNPs crystal size was determined to be 24.95 nm by X-ray diffraction and Scherer's equation. To investigate the antioxidant efficacy, the DPPH assay was conducted. FeNPs prevented 50 % of DPPH in the dilation of 127 µg/mL. To measure the anti-prostate cancer efficacy of FeNPs, a MTT assay was applied on NCI-H660 and DU 145 cells. FeNPs had high anti-prostate cancer efficacy on the above tumor cells without any significant toxicity on HUVEC. The highest finding of anti-prostate cancer efficacies of FeNPs was seen in NCI-H660. IC50 of iron NPs was 117 and 110 on DU 145 and NCI-H660 prostate cancer cells. Cell apoptosis was observed as a result of NPs, with an increase in pro-apoptotic markers (cleaved caspase-8 and Bax) and a decrease in the anti-apoptotic marker, Bcl-2. Additionally, the presence of Fe NPs hindered colony formation when compared to the control group. Fe NPs-treated cells molecular pathway analysis revealed an elevation in p53 expression, while preventing the total and phosphorylated STAT3 expression in cancer cells. This suggests that STAT3 and p53 have a notable role in the medicinal effects induced by the Fe NPs in prostate cancer cells.

A role of BPTF in viral oncogenicity delineated through studies of heritable Kaposi sarcoma.

Kaposi sarcoma (KS), caused by Herpesvirus-8 (HHV-8; KSHV), shows sporadic, endemic, and epidemic forms. While familial clustering of KS was previously recorded, the molecular basis of hereditary predilection to KS remains largely unknown. We demonstrate through genetic studies that a dominantly inherited missense mutation in BPTF segregates with a phenotype of classical KS in multiple immunocompetent individuals in two families. Using an rKSHV.219-infected CRISPR/cas9-model, we show that BPTFI2012T mutant cells exhibit higher latent-to-lytic ratio, decreased virion production, increased LANA staining, and latent phenotype in viral transcriptomics. RNA-sequencing demonstrated that KSHV infection dysregulated oncogenic-like response and P53 pathways, MAPK cascade, and blood vessel development pathways, consistent with KS. BPTFI2012T also enriched pathways of viral genome regulation and replication, immune response, and chemotaxis, including downregulation of IFI16, SHFL HLAs, TGFB1, and HSPA5, all previously associated with KSHV infection and tumorigenesis. Many of the differentially expressed genes are regulated by Rel-NF-κB, which regulates immune processes, cell survival, and proliferation and is pivotal to oncogenesis. We thus demonstrate BPTF mutation-mediated monogenic hereditary predilection of KSHV virus-induced oncogenesis, and suggest BPTF as a drug target.

Identification of the shared genes in type 2 diabetes mellitus and osteoarthritis and the role of quercetin.

This study investigated the underlying comorbidity mechanism between type 2 diabetes mellitus (T2DM) and osteoarthritis (OA), while also assessing the therapeutic potential of quercetin for early intervention and treatment of these two diseases. The shared genes were obtained through GEO2R, limma and weighted gene co-expression network analysis (WGCNA), and validated using clinical databases and the area under the curves (ROC). Functional enrichment analysis was conducted to elucidate the underlying mechanisms of comorbidity between T2DM and OA. The infiltration of immune cells was analysed using the CIBERSORT algorithm in conjunction with ESTIMATE algorithm. Subsequently, transcriptional regulation analysis, potential chemical prediction, gene-disease association, relationships between the shared genes and ferroptosis as well as immunity-related genes were investigated along with molecular docking. We identified the 12 shared genes (EPHA3, RASIP1, PENK, LRRC17, CEBPB, EFEMP2, UBAP1, PPP1R15A, SPEN, MAFF, GADD45B and KLF4) across the four datasets. Our predictions suggested that targeting these shared genes could potentially serve as therapeutic interventions for both T2DM and OA. Specifically, they are involved in key signalling pathways such as p53, IL-17, NF-kB and MAPK signalling pathways. Furthermore, the regulation of ferroptosis and immunity appears to be interconnected in both diseases. Notably, in this context quercetin emerges as a promising drug candidate for treating T2DM and OA by specifically targeting the shared genes. We conducted a bioinformatics analysis to identify potential therapeutic targets, mechanisms and drugs for T2DM and OA, thereby offering novel insights into molecular therapy for these two diseases.

DHCR24 in Tumor Diagnosis and Treatment: A Comprehensive Review.

As an important nutrient in the human body, cholesterol can not only provide structural components for the body's cells, but also can be transformed into a variety of active substances to regulate cell signaling pathways. As an important cholesterol synthase, DHCR24 participates in important regulatory processes in the body. The application of DHCR24 in tumor clinical diagnosis and treatment also attracts much attention. This article reviews the structure and regulatory characteristics of DHCR24, and the research of DHCR24 on tumor progression. We summarize the possible mechanisms of DHCR24 promoting tumor progression through reactive oxygen species (ROS), p53, Ras and PI3K-AKT pathways. Through our review, we hope to provide more research ideas and reference value for the application of DHCR24 in tumor prevention and treatment.

Activated CD4 T cells/Tregs derived immune-metabolism signature provide precise prognosis assessment for gastric cancer and beneficial for treatment option

BackgroundThe prognostic significance of the ratio of activated CD4 T cells to Tregs infiltrating tumor tissues in gastric cancer (GC) remains unknown. Materials and methodsFor the quantification of infiltration of immune cells, the ssGSEA algorithm, which is a single sample gene set enrichment analysis, was utilized. Group A was defined as having activated CD4 T cells/Tregs >1, while group B was defined as having activated CD4 T cells/Tregs <1. To compare the overall survival (OS) of the two groups, the Kaplan-Meier survival analysis was employed. The R package 'limma' was used to identify the immune and metabolism related genes that were expressed differentially between the two groups, with a false discovery rate (FDR) less than 0.05. The risk score (RS) was constructed by combining univariate Cox regression analysis, LASSO penalized Cox regression analysis, and multivariate Cox regression analysis. The median RS was used to classify high-risk (HR) and low-risk (LR) groups. ResultsA predicted unfavorable outcome of GC was observed when the ratio of activated CD4 T cells to Tregs was less than 1. Our proposed RS was utilized for prognostic risk categorization in ten distinct independent cohorts (TCGA-STAD, n = 371; GSE84437, n = 433; GSE26253, n = 432; GSE13861, n = 65; GSE15459, n = 192; GSE26899, n = 93; GSE26901, n = 109; GSE28541, n = 40; GSE34942, n = 56; GSE62254, n = 300) and exhibited exceptional precision. In terms of tumor microenvironment (TME) and treatment strategies, compared to the LR group, the HR group was characterized by a higher infiltration levels of stromal cells, Tregs, macrophages, Tfh, mast cells, and NK cells, inclined to activated CD4 T cells/Tregs <1, and exhibited insensitivity to immunotherapy and multiple chemotherapy drugs. In relation to the potential molecular mechanism, the excessive activation of oncogenic pathways such as MAPK, hedgehog, WNT, calcium, and TGF-β signaling pathways may accelerate the malignant progression of GC by stimulating angiogenesis, promoting EMT, and altering ECM. Conversely, the overactivation of the P53 pathway is likely to inhibit tumor proliferation by regulating the cell cycle. ConclusionThe immune-metabolism signature associated with the ratio of activated CD4 T cells and Tregs could be used to assess prognosis, TME, and treatment strategies in GC patients.

Protective effect of secretory APE1/Ref-1 on doxorubicin-induced cardiotoxicity via suppression of ROS and p53 pathway.

The clinical application of doxorubicin (DOX), a potent anthracycline anticancer drug that effectively treats various malignancies, is limited by its side effects, such as cardiomyopathy. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that can be secreted and is a promising target for the reduction of DOX-induced inflammation and oxidative stress. We aimed to investigate the protective role of secretory APE1/Ref-1 against DOX-induced cardiac injury. Designated adenoviral preprotrypsin-leading sequence APE1/Ref-1 (Ad-PPTLS-APE1/Ref-1) was used to overexpress secretory APE1/Ref-1 and assess its role in preventing DOX-induced cardiomyopathy in vitro. Our findings revealed that exposure to secretory APE1/Ref-1 significantly decreased N-terminal pro-B-type natriuretic peptide levels in DOX-treated H9C2 cells. In addition, secretory APE1/Ref-1 reduced the severity of cardiomyocyte injury and apoptosis in both in vitro and in vivo DOX-induced cardiotoxicity models. The observed cardioprotective effects of secretory APE1/Ref-1 were mediated via inhibition of the p53 signalling pathway and enhancement of cell viability through attenuation of oxidative stress in DOX-treated cardiomyocytes. Our study provides evidence that secretory APE1/Ref-1 has the potential to inhibit DOX-induced cardiac toxicity by inhibiting oxidative stress and p53 related apoptosis both in vitro and in vivo. These findings suggest that secretory APE1/Ref-1 supplementation is a promising strategy to attenuate DOX-induced cardiomyocyte damage in a preclinical model. Further clinical investigations are essential to validate the therapeutic efficacy and safety of the intervention in human subjects.