P53 Protein Levels Research Articles

Single and combined effect of chrysin and N-acetylcysteine against deltamethrin exposure in rats.

Effects of chrysin and N-acetylcysteine on deltamethrin exposure in rats were investigated. Eighty male Wistar Albino rats, weighing between 150 and 200g and aged 2-3 months, were used and evenly allocated into eight groups. The control group of rats received a corn oil vehicle. Chrysin (50mg/kg.bw), N-acetylcysteine (50mg/kg.bw), a combination of chrysin and N-acetylcysteine, deltamethrin (10mg/kg.bw), deltamethrin combined with chrysin, deltamethrin combined with N-acetylcysteine, and a combination of deltamethrin, chrysin, and N-acetylcysteine were administered via oral gavage for a duration of 21 days. Tissue (liver, kidney, brain, testis, heart, lung) and blood of oxidative stress markers (MDA, NO, GSH, SOD, CAT, GSH-Px, GR, GST, G6PD), hepatic caspase 3, 9 and p53 protein levels, biochemical parameters (glucose, triglyceride, cholesterol, BUN, creatinine, uric acid, total protein, albumin, LDH, AST, ALT, ALP, PChE activities/levels), as well as rat body/organ weights and plasma/liver deltamethrin concentrations. The administration of chrysin and N-acetylcysteine independently did not alter the assessed parameters. Significant differences were observed in most parameters assessed in the deltamethrin-alone group compared to the control group, whereas the parameter values in the groups treated with chrysin, NAC, or their combination with deltamethrin were similar to those of the control.

FLT3 inhibitors induce p53 instability, driven by STAT5/MDM2/p53 competitive interactions in acute myeloid leukemia.

FLT3 mutations are present in one third of patients with Acute myeloid leukemia (AML) and stand as an attractive therapeutic target. Although FLT3 inhibitors demonstrate clinical efficacy, the drug resistance remains challenging attributed to multiple mechanisms. In this study, we found that tyrosine kinase inhibitors (TKIs) targeting FLT3 prompt p53 degradation in AML cells with FLT3-ITD through ubiquitination. STAT5 phosphorylation facilitates its nuclear localization, leading to competitive interactions among STAT5, MDM2, and p53. TKIs blocked STAT5 nuclear entry, amplifying MDM2/p53 binding and subsequent p53 degradation. Additionally, STAT5 overexpression inhibited MDM2-mediated p53 ubiquitination, whereas knock-down of STAT5 destabilizes p53. Co-administration of MDM2 inhibitors stabilizes p53 ubiquitination induced by TKIs, enhancing pro-apoptotic effects on AML cells. Moreover, in mice engrafted with AML cells, gilteritinib treatment results in decreased p53 protein levels and the transcriptional repression of downstream genes in leukemia cells, which are mitigated by the co-administration of MDM2 inhibitors. In conclusion, our study shows that FLT3 TKIs impede STAT5 nuclear translocation, strengthening p53/MDM2 interaction and consequent p53 degradation. This finding reveals a novel mechanism of TKIs resistance and indicates a combination of MDM2 inhibitors with TKIs for AML therapy, offering new insights into effective treatment strategies.

Quercetin Suppresses Glioma Stem Cells via Activating p16-INK4 Gene Expression through Epigenetic Regulation.

Our study aimed to explore the effects of quercetin on glioma stem cells in patients with brain tumors. Human glioblastoma cell line, U373MG, or glioma stem cell lines, were treated with quercetin. Cell viability was determined by using the cell counting kit 8 assays. Cell apoptosis was determined by using the Annexin-V reagent. Western blotting and qPCR were used to detect the protein and mRNA levels of cyclindependent kinase inhibitor 2A (p16INK4a). Chromatin immunoprecipitation analysis was used to determine the enrichment of H3K27me3 on the p16-INK4 locus with or without quercetin. Treatment with quercetin inhibited cell viability and induced cell apoptosis in U373MG cells. Moreover, treatment with quercetin inhibited the cell viability of four glioma stem cell lines (G3, G10, G15, and G17) from brain tumor samples at high concentrations while having no obvious effects for the other two glioma stem cell lines (G9 and G21). Treatment with quercetin increased the mRNA and protein levels of p16- INK4 in glioma stem cell lines. The study of the underlying mechanism revealed that treatment with quercetin reduced H3K27me3 (an epigenetic modification to the DNA packaging protein histone H3) levels at the p16-INK4 locus. In conclusion, quercetin inhibits glioma cell growth by activating p16-INK4 gene expression through epigenetic regulation.

M6A Demethylase FTO-Mediated Upregulation of BAP1 Induces Neuronal Ferroptosis via the p53/SLC7A11 Axis in the MPP+/MPTP-Induced Parkinson's Disease Model.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the involvement of ferroptosis in its pathological mechanism. In this study, the effects and mechanism of BRCA1-associated protein 1 (BAP1) on neuronal ferroptosis in PD were evaluated. Methods: A PD mouse model was constructed by injecting mice with MPTP. Nissl staining, immunohistochemistry, immunofluorescence, and Prussian blue staining evaluated histopathology and iron distribution. The PD cell model was constructed by subjecting SK-N-SH cells to MPP+. The m6A level of BAP1 was assessed by MeRIP. mRNA levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, and SLC7A11 were evaluated utilizing RT-qPCR. Protein levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, SLC7A11, and p53 were measured by Western blot. Cell viability was assessed using CCK-8 assay, and TUNEL was used for assessing apoptosis. The levels of MDA, GSH, SOD, and Fe2+ were also measured. The interactions among molecules were verified using RIP assay, dual luciferase reporter assay, and ChIP assay. Results: SK-N-SH cells treated with MPP+ showed a decrease in overall m6A levels of BAP1. FTO facilitated m6A demethylation of BAP1, leading to an increased level of expression of BAP1. m6A-binding protein, YTHDF2 recognized and decayed methylated mRNA of BAP1, leading to the reduced BAP1 stability. The FTO/BAP1 axis promoted MPP+-induced ferroptosis by suppressing SLC7A11. BAP1, in collaboration with p53, reduced the level of expression of SLC7A11. Knocking down BAP1 mitigated ferroptosis in an MPTP mouse model. Conclusion: m6A-mediated modification of BAP1 regulates neuronal ferroptosis by cooperating with p53 to decrease the level of SLC7A11. Thus, BAP1 may be a potential therapeutic target for PD treatment.

Inhibition of ASIC1a reduces ferroptosis in rheumatoid arthritis articular chondrocytes via the p53/NRF2/SLC7A11 pathway.

The activation of acid-sensing ion channel 1a (ASIC1a) in response to extracellular acidification leads to an increase in extracellular calcium influx, thereby exacerbating the degeneration of articular chondrocytes in rheumatoid arthritis (RA). It has been suggested that the inhibition of extracellular calcium influx could potentially impede chondrocyte ferroptosis. The cystine transporter, solute carrier family 7 member 11 (SLC7A11), is recognized as a key regulator of ferroptosis. Recent studies suggest that the tumor suppressor gene p53 facilitates the induction of ferroptosis by suppressing the upregulation of SLC7A11. This process is mediated by the nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor integral to the maintenance of cellular redox homeostasis and the regulation of inflammatory responses. This study aims to investigate the role of ASIC1a in the ferroptosis of RA chondrocytes and to determine the involvement of the p53/NRF2/SLC7A11 pathway in its underlying mechanism. Invitro experiments revealed that acidosis induces ferroptosis and reduces the expression of NRF2 and SLC7A11 in chondrocytes. Moreover, acidification significantly increased p53 protein levels in chondrocytes. Pifithrin-α (PFN-α), a p53 inhibitor, mitigated acidosis-induced ferroptosis and restored the diminished expression of NRF2 and SLC7A11. Furthermore, PcTx-1, an ASIC1a inhibitor, inhibited acidification-induced ferroptosis, enhanced the protein levels of SLC7A11 and NRF2, and reduced p53 expression. Invivo experiments demonstrated that the ASIC1a-specific inhibitor PcTx-1 ameliorated histopathological characteristics of ankle joints in collagen-induced arthritis (CIA) mice, decreased p53 expression, and enhanced NRF2 and SLC7A11 expression in chondrocytes. These findings suggest that ASIC1a inhibition may mitigate acidification-induced ferroptosis in articular chondrocytes in RA, potentially via the p53/NRF2/SLC7A11 pathway.

Tianxiangdan (TXD) alleviates myocardial ischemia reperfusion-induced ferroptosis through the activation of estrogen receptor alpha (ERα).

Tianxiangdan (TXD), a traditional Chinese herbal remedy, demonstrates efficacy in mitigating myocardial ischemia-reperfusion (I/R)-induced damage. This study employed network pharmacology to evaluate the therapeutic targets and mechanisms of TXD in treating I/R. High-performance liquid chromatography-mass spectrometry (HPLC-MS) identified 86 compounds in TXD. Network pharmacological analysis predicted potential target genes and their modes of action. Cardiac function, ischaemic ST changes, lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, myocardial fiber, and infarct size were assessed using in vivo and in vitro I/R injury models. Estrogen receptor alpha (ERα) protein expression and estradiol (E2) levels were measured to confirm TXD's impact on estrogen levels and ERα expression. To examine if TXD reduces I/R injury through ERα, an AZD group (300 nmol·L-1 AZD9496 and 15% TXD serum) was compared to a TXD group (15% TXD serum). The study hypothesized that TXD upregulates the ERα-mediated iron metamorphosis pathway. I/R injury-induced ferroptosis was identified using a Fer-1 group (1.0 μmol·L-1 Fer-1 and 15% TXD serum) to elucidate the potential association between ferroptosis and ERα proteins. A DCFH-DA probe detected reactive oxygen species (ROS) and Fe2+, while Western blotting assessed target protein expression. Both in vitro and in vivo experiments demonstrated that TXD attenuated I/R injury by reducing elevated ST-segment levels, improving cardiac injury biomarkers (LDH, MDA, and SOD), alleviating pathological features, and preventing I/R-induced loss of cell viability in vitro. The effects and mechanisms of TXD on I/R injury-associated ferroptosis were investigated using I/R-induced H9c2 cells. The TXD group showed significantly decreased ROS and Fe2+ levels, while the AZ group (treated with AZD9496) exhibited increased levels. The TXD group demonstrated enhanced expression of ERα and glutathione peroxidase 4 (GPX4), with reduced levels of P53 protein and ferritin-heavy polypeptide 1 (FTH1). The AZ group exhibited contrasting effects on these expression levels. The literature indicated a novel connection between ERα and ferroptosis. TXD activates the ERα signaling pathway, promoting protection against I/R-induced myocardial cell ferroptosis. This study provides evidence supporting TXD use for myocardial ischemia treatment, particularly in older female patients who may benefit from its therapeutic outcomes.

Evaluation of a Novel PLGA-HA-Based Drug Delivery System Targeting the cell cycle and PI3K/AKT/mTOR Pathway in HCT116 Colorectal Carcinoma Cells with Differing P53 Statuses

Colorectal carcinoma (CRC) is a very important health problem all over the world, and the P53 gene plays an important role in tumor development and in treatment response. The strategy of developing novel DDS that could target specific tumor pathways is one of the most promising approaches to improve therapeutic efficacy. The aim of this study was to evaluate the performance of a newly synthesized PLGA-HA-based DDS encapsulating the mTOR inhibitor Dactolisib on HCT116 CRC cells with differing P53 statuses; P53 positive and P53 negative. The previously synthesized and characterized DDS was tested on HCT-116 P53 positive and negative cell lines. Assessments included: cell cycle distribution analysis by flow cytometry; gene expression profiling of key components of the PI3K/AKT/mTOR pathway by using qPCR, and proteomic via Western blotting. DDS induced a differential effect on the cell cycle progress, which arrested the cell cycle at the G0/G1 phase in a statistically significant way in P53 positive cells, while in P53 negative cells, it resulted in an increase in the S phase. The gene expression analysis revealed downregulation of PIK3CA, AKT1, and MTOR in both cell lines; however, the inhibition seemed more potent in P53-positive cells. The proteomic analysis confirmed reduced p-AKT and p-mTOR with increased levels of P53 protein in P53-positive cells. The new PLGA-HA-based DDS exhibits promising anti-cancer activity against CRC cells, which have different influences related to P53 status. These observations suggest an application for personalized cancer therapy, particularly in the case of tumors with functional P53.

Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide (H2S)-donor hybrid PDE10A inhibitor called COS-2080 with a well-defined mechanism of H2S-releasing action. It exhibited highly potent inhibitory activity against PDE10A and excellent PDE subfamily selectivity. Moreover, COS-2080 demonstrated significant antifibrotic effects by inhibiting cell proliferation and mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation called COS-2080-DPI has been developed using the ultrasonic spray freeze drying (USFD) technique, demonstrating significant antifibrotic efficacy in mice with bleomycin-induced PF at a dosage approximately 600 times lower than pirfenidone. This remarkable antifibrotic efficacy of COS-2080 on TGF-β1-induced FMT could be primarily attributed to its inhibition of the Smad2/Smad3 phosphorylation. Moreover, COS-2080 effectively attenuated fibrosis in MRC-5 cells by activating the cAMP/protein kinase A (PKA)/CREB pathway and potentially increasing levels of p53 protein. Our findings suggest that effective inhibition of PDE10A potentially confers a protective effect on FMT in PF by impeding TGF-β signaling and activating the cAMP/PKA/CREB/p53 axis.

The Impact of SRSF1 -Mediated Alternative Splicing of RBBP6 on the Proliferation of Multiple Myeloma Cells

To investigate the effect of different isoforms of RBBP6 on the proliferation of multiple myeloma (MM) cells after alternative splicing mediated by splicing factor SRSF1 . RT-PCR was used to detect the expression levels of RBBP6 mRNA splicing isoforms regulated by SRSF1 . The GEO database was used to analyze the changes of RBBP6 isoform 1 in the progression of plasma cell disease, and survival analysis was used to evaluate the value of this gene in the prognosis of MM patients. in vitro loss-of-function and gain-of-function experiments were conducted by transfecting control siRNA, RBBP6 isoform 1 siRNA, empty vector (EV), OE-RBBP6 isoform 3 into MM.1S cells, then the expression levels of RBBP6 isoform 1 and RBBP6 isoform 3 were detected by real-time PCR and Western blot. CCK-8 assay was performed to detect the cell proliferation ability. Knockdown of SRSF1 increased the expression of RBBP6 isoform 3 and decreased the expression of RBBP6 isoform 1. RBBP6 isoform 1 was closely related to the progression of plasma cell disease, and the high expression of RBBP6 isoform 1 was associated with poor prognosis in patients with MM. Downregulation of RBBP6 isoform 1 expression and overexpression of RBBP6 isoform 3 both reduced the proliferation ability of MM cells. And after downregulating the expression of RBBP6 isoform 1, the level of p53 protein in MM cells was significantly increased (P < 0.05). In MM, splicing factor SRSF1 can cause alternative splicing abnormalities in RBBP6 . The RBBP6 isoform 1 promotes MM cell proliferation, while the RBBP6 isoform 3 inhibits MM cell proliferation, and the mechanism may be related to regulating the p53 pathway.

Expression of p53 in human adipose tissue correlates positively with FAS and BMI.

Activation of Fas (CD95) in adipocytes inhibits browning and may contribute to body weight gain in mice. Moreover, Fas expression in white adipose tissue (WAT) correlates positively with body mass index (BMI) in humans. However, molecular pathways involved in the inhibitory effect of Fas on energy metabolism remain incompletely understood. Herein, we report that protein levels of the tumor suppressor p53 were reduced in primary white adipocytes of adipocyte-specific Fas-knockout mice. Moreover, Fas ligand (FasL) treatment increased p53 concentrations in cultured adipocytes and decreased mitochondrial oxygen consumption in control but not in p53-depleted cells, indicating that Fas activation reduces energy expenditure in a p53-dependent manner. In line, in differentiated human mesenchymal stem cells and WAT derived from different anatomical depots, FAS expression was positively associated with p53. Furthermore, p53 expression in human subcutaneous and visceral WAT correlated positively with BMI, whereas its expression in visceral WAT was inversely associated with insulin sensitivity (as assessed by hyperinsulinemic-euglycemic clamp). Taken together, our data suggest that Fas regulates p53 expression in adipocytes, and may thereby affect body weight gain and insulin sensitivity.

Verbascum gimgimense an Endemic Turkish Plant: Evaluation of In Vitro Anticancer, Antioxidant, Enzyme Inhibitory Activities, and Phytochemical Profile.

The Verbascum genus has gained significant attention in the pharmaceutical field, particularly in recent years, due to its valuable medicinal properties, which are well-recognized in complementary and alternative medicine. Certain species within this genus contain essential compounds and exhibit a wide range of therapeutic activities. In this study, the ethanolic extract of Verbascum gimgimense (VG) was analyzed for its cytotoxic, apoptotic, antioxidant, and enzyme inhibitory properties, as well as its phenolic and lipophilic compounds. The phenolic compounds in the extract were identified using Exactive Plus Orbitrap HPLC-HRMS, while the lipophilic components were characterized by GC-MS analysis. The Neutral Red Uptake (NRU) cell viability assay and colony formation assay were performed to assess the antiproliferative and anti-colony survival effects of VG on the A549 human lung adenocarcinoma cell line. Additionally, a wound healing assay measured cell migration, and the apoptotic process was evaluated using Caspase-3 ELISA and acridine orange/ethidium bromide staining. Protein expression levels were determined by western blot analysis. DPPH, ABTS FRAP, and CUPRAC assays were used to determine free radical scavenging, reducing power, and metal chelating activities, respectively. VG was rich in dominant phenolic components, including benzoic acid (6.809 mg/g extract), phloretic acid (1.279 mg/g extract), luteolin 7-rutinoside (2.799 mg/g extract), luteoloside (3.300 mg/g extract), kuromanine (3.456 mg/g extract), and rutin hydrate (2.015 mg/g extract). Major fatty acids identified in VG included palmitic acid (17.3%), stearic acid (2.99%), linoleic acid (9.44%), and α-linolenic acid (26.48%). VG treatment significantly reduced colony formation ability, decreased wound closure, and increased both apoptotic cell count and caspase-3 activity compared to the control group. Protein levels of c-PARP, p53, and p21 were substantially elevated compared to controls. In addition to its strong free radical scavenging, reducing power and metal chelating activity, VG exhibited strong inhibitory effects on α-amylase, α-glucosidase, AChE, BChE, and tyrosinase. Our study demonstrates that VG possesses antiproliferative, apoptotic, antioxidant, and enzyme-inhibitory properties. V. gimgimense emerges as a promising natural antioxidant source with potentially significant regulatory effects on key enzymes and proteins, which could contribute to managing various human diseases and inspire the development of novel therapeutic strategies.

Expression of senescence-related CD161 promotes extranodal NK/T cell lymphoma by affecting T cell phenotype and cell cycle

PurposeThe intention of this work is to probe the role of senescence-related gene CD161 in extranodal NK/T cell lymphoma (ENKTL).MethodsThis study used H2O2 to establish three distinct in vitro oxidative stress aging models (NKL, SNT-8, and YT). Western blotting was employed to assess the levels of two iconic aging proteins, MMP1 and P53, and flow cytometry was utilized to investigate cell cycle and the expressions of CD4, CD8, and CD161. Cell viability was evaluated via the CCK-8 assay. The transcriptome analysis assessed the differential gene expression between the control and aging group of NKL. In vivo, we established a BALB/c mice aging tumor model. After 15 days, the mice were euthanized to harvest tumors. ELISA was employed to measure aging indicators in the mouse tissues. Flow cytometry was utilized to assess the levels of CD4, CD8, and CD161 in tumor samples. Hematoxylin-eosin (HE) staining was performed to evaluate the structure and cellular morphology of the tumor tissue.ResultsIn the NKL, SNT-8 and YT aging models, the levels of MMP1 and P53 proteins were significantly increased. Flow cytometry results indicated that all three cell types exhibited marked arrest in the G1 phase. Compared with the control group, the expressions of CD4 and CD161 in the aging group were significantly increased, while the expression of CD8 was decreased. Transcriptome analysis revealed 2,843 differentially expressed genes (DEGs) between the control and aging groups, with 2,060 up-regulated and 783 down-regulated genes identified. Following CD161 knockdown, cell viability of three cell types in the aging group was significantly reduced compared to the control group. The G1 phase of the cells was significantly interrupted. The expressions of CD4 and CD161 were significantly increased, and the expression of CD8 was decreased. However, in the aging + si-CD161 group, a partial alleviation of oxidative stress was observed with a reduction in CD161 expression levels. Animal experiments demonstrated that knockout of CD161 can inhibit tumor progression and partially mitigate oxidative stress.ConclusionsCD161 may inhibit ENKTL tumor development by regulating cell cycle and T-cell phenotype.

High p53 Protein Level Is a Negative Prognostic Marker for Pancreatic Adenocarcinoma.

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.

Rehabilitation of N, N′-methylenebisacrylamide-induced DNA destruction in the testis of adult rats by adipose-derived mesenchymal stem cells and conditional medium

Rehabilitation of N, N′-methylenebisacrylamide-induced DNA destruction in the testis of adult rats by adipose-derived mesenchymal stem cells and conditional medium

Caspase-9 and p53 Protein Levels in Cancer Patients after Different Anesthesia Techniques

The aim of this study was to investigate the changes in caspase-9 and p53 levels as biomarkers of pro- and anti-apoptotic pathways in the early postoperative period in patients who underwent lung surgery for malig-nant tumors under different types of multimodal or inhalation-intravenous anesthesia. Material and Methods. A single-center prospective study of 22 patients aged 45–64 years was conducted at the Omsk Clinical Oncology Early Treatment and Prevention Center from January to April 2020. The participants were divided into two groups. Group 1 patients received multimodal anesthesia, which included sympathetic nerve block and prolonged epidural analgesia in the postoperative period. Group 2 patients received inhalational and intravenous anesthesia followed by systemic morphine analgesia. Serum caspase-9 and p53 protein levels were measured at four time points: before anesthesia, one, twelve, and twenty-four hours after surgery. Statistical hypotheses were tested using nonparametric (rank) analysis methods. Friedman's ANOVA was used to compare multiple time points, while the Wilcoxon test was used to compare variables between two time points in dependent samples. The Mann-Whitney test was used to assess differences between groups in independent samples. P-values &lt; 0.05 were considered statistically significant. Results are expressed as median ± half interquartile range (Me ± (LQ – UQ) / 2). Results. At time point 2, caspase-9 levels were significantly higher in group 2 patients than in group 1 (P = 0.045). There were no significant differences between the groups at any other time points. Conclusion. The lack of a significant difference in serum levels of caspase-9 and p53 protein at most time points between the groups demonstrates the efficacy of the anesthesia and analgesia methods used. Mean-while, a significantly higher level of caspase-9 one hour after surgery demonstrates a greater susceptibility of patients without sympathetic blockade to activation of the apoptotic cell death program.

Curcumin-Etoposide Synergy: Unveiling the Molecular Mechanisms of Enhanced Apoptosis and Chemoresistance Attenuation in Breast Cancer.

Combining natural compounds with chemotherapeutic agents has emerged as a promising approach for cancer treatment. Curcumin (Cur), a natural polyphenol, is known for its anti-cancer properties, including the ability to induce apoptosis and arrest cell cycle progression. This study aimed to evaluate the effects of Cur and etoposide (ETO), both individually and in combination, on the induction of apoptosis in breast cancer (BC) cell lines. The impact of Cur and ETO on cell proliferation was assessed using MTT viability assays. Apoptosis induction by these drugs was evaluated through Annexin V flow cytometry and caspase-3 and caspase-9 activity assays. Quantitative real-time PCR was employed to measure Bax and Bcl-2 gene expression levels. Western blotting was conducted to determine protein levels of p53, p21, Bax, and Bcl-2. A non-significant dose of ETO was selected based on MTT assay results and combined with 75 µM of Cur. Curcumin enhanced ETO's pro-apoptotic effect by increasing caspase activities. The combination of Cur and ETO significantly reduced Bcl-2 gene expression while upregulating Bax expression. Furthermore, treatment with this combination elevated the protein levels of p53, p21, and Bax, compared to ETO or Cur alone, while significantly decreasing Bcl-2 protein levels. Cur has the potential to amplify ETO-induced apoptosis in BC cells. This combination may offer a promising therapeutic approach for BC.

Trastuzumab Potentiates Antitumor Activity of Thiopyrano[2,3-d]Thiazole Derivative in AGS Gastric Cancer Cells.

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.

Short Peptides Protect Fibroblast-Derived Induced Neurons from Age-Related Changes.

Neurons become more vulnerable to stress factors with age, which leads to increased oxidative DNA damage, decreased activity of mitochondria and lysosomes, increased levels of p16, decreased LaminB1 proteins, and the depletion of the dendritic tree. These changes are exacerbated in vulnerable neuronal populations during the development of neurodegenerative diseases. Glu-Asp-Arg (EDR) and Lys-Glu-Asp (KED), and Ala-Glu-Asp-Gly (AEDG) peptides have previously demonstrated neuroprotective effects in various models of Alzheimer's disease. In this study, we investigated the influence of EDR, KED, and AEDG peptides on the aging of fibroblast-derived induced neurons. We used a new in vitro cellular model of human neuronal aging based on the transdifferentiation of aged dermal fibroblasts from elderly donors into induced cortical neurons. All peptides promote the arborization of the dendritic tree, increasing both the number of primary processes and the total length of dendrites. Tripeptides have no effect on the activity of mitochondria and lysosomes and the level of p16 protein in induced neurons. EDR peptide reduces oxidative DNA damage in induced neurons derived from elderly donor fibroblasts. Short peptides partially protect induced neurons from age-related changes and stimulate dendritogenesis in neurons. They can be recommended for use as neuroprotective agents.

Curcumin-loaded emulsome nanoparticles induces apoptosis through p53 signaling pathway in pancreatic cancer cell line PANC-1

Pancreatic cancer is a global health problem with a poor prognosis, limited treatment options and low survival rates of patients. Thus, the exploration of novel treatment approaches is crucial. Curcumin shows promise in pancreatic cancer. Curcumin has anticancer properties promoting apoptosis through the p53 pathway. However, adverse effects and low bioavailability are curcumin's main drawbacks and its delivery by nanoparticles could improve its effectiveness as a treatment option. Curcumin-loaded emulsome nanoparticles (CurEm) have shown promise in colorectal, hepatocellular, and prostate cancers. This study aims to evaluate the anticancer potential of CurEm in pancreatic cancer cell line PANC-1. The cytotoxic effects of CurEm on PANC-1 cells show cytotoxicity in dose and time-dependent manner. The selected dose 30μM CurEm resulted spheroidal morphology in PANC-1 cells and colony forming and scratch assay conducted demonstrated significant growth inhibition and decrease in migration ability, respectively. Cell cycle analysis shows that CurEm induces G2/M arrest in PANC-1 cells. CurEm-treated PANC-1 cells showed a significant increase in p53 and Caspase 3 genes, while a significant decrease in Bcl-2 genes compared to untreated group. Western blot results showed parallel results to qPCR analysis for Bcl-2 protein levels. Interestingly, we saw low p53 protein levels in CurEm-treated PANC-1 cells. These findings shed light on the potential of CurEm as an effective and stable therapeutic approach for pancreatic cancer.

Dendrosomal Curcumin Showed Cytotoxic Effects on Breast Cancer Cell Line by Inducing Mitochondrial Apoptosis Pathway and Cell Division Arrest.

Mutations in the p53 gene have been linked to the initiation and progression of breast cancer, as well as resistance to chemotherapy. Therefore, the development of novel treatment approaches is essential to combat this disease. This study aimed to evaluate the effects of dendrosomal curcumin (DNC) on the breast cancer cell line MDA-MB231. MDA-MB231 cells were treated with 20 μM DNC, and the apoptosis rate and cell proliferation cycles were assessed using flow cytometry. Additionally, after RNA extraction and cDNA synthesis, the expression levels of Lnc-DANCR, EZH2, Noxa, bcl-2, bax, PUMA, p21, and p53 genes were analyzed using RT-PCR. Protein expression levels of P53, P21, Bcl-2, and Bax were evaluated through western blotting. Dendrosomal curcumin induced apoptosis in MDA-MB231 cells and caused cell cycle arrest at the SubG1 phase. Dendrosomal curcumin treatment downregulated Lnc-DANCR, EZH2, bcl-2, and p53 gene expression, while upregulating bax, Noxa, PUMA, and p21 gene expression in a time-dependent manner. Bax and P21 protein levels were significantly upregulated following DNC treatment, whereas Bcl-2 and P53 protein levels were downregulated in DNC-treated breast cancer cells. In summary, dendrosomal nanocurcumin demonstrated potent anti-tumor effects against breast cancer cells, suggesting its potential as a therapeutic agent in breast cancer treatment.