Primary hepatic pleomorphic liposarcoma: Case report and literature review / Liposarcoma pleomorfo hepático primario: presentación de un caso y revisión bibliográfica

Primary hepatic liposarcoma is an extremely rare malignant tumour derived from adipocytes and is part of the group of mesenchymal tumours. We present the case of a 43-year-old Hispanic male patient with a pleomorphic hepatic liposarcoma and absence of MDM2 gene amplification. Two years and six months after surgery, the patient is asymptomatic. The present case is the first report of this entity with positive immunohistochemical testing for p16, p53, S100, vimentin and absence of MDM2 gene amplification. (AU)

El liposarcoma hepático primario es un tumor maligno extremadamente raro, derivado de adipocitos, y forma parte del grupo de tumores mesenquimales. Presentamos el caso de un paciente masculino de 43 años con diagnóstico de liposarcoma hepático pleomorfo con ausencia de amplificación del gen MDM2. Dos años y 6 meses después de la cirugía el paciente se encuentra asintomático. El presente caso es el primer informe de esta entidad con estudio inmunohistoquímico positivo para p16, p53, S100, vimentina y ausencia de amplificación del gen MDM2. (AU)

Clinicopathological importance of Bcl-2 and p53 in postmenopausal triple-negative breast carcinoma and association with age.

Appropriate biomarkers are required to predict the clinical outcome of triple-negative breast cancer (TNBC). In this study, we focused on the clinical importance of two representative tumor-associated proteins, Bcl-2 and p53. Bcl-2 expression is usually related to estrogen receptor expression and a favorable outcome in breast cancer. TNBC has been reported to show a high frequency of p53 positivity suggesting TP53 mutations. The expressions of Bcl-2 and p53 were immunohistochemically examined in TNBC involving two age groups of postmenopausal women (≥75 y/o, n = 75; 55-64 y/o, n = 47), who underwent surgery without neoadjuvant therapy. We examined their associations with each other, or with clinicopathological factors including the outcome. Bcl-2 expression was inversely correlated with androgen receptor, apocrine morphology, and p53 expressions, and was an independent predictor of a poor outcome in total or in younger women. p53 positivity was associated with a more favorable outcome than p53 negativity in the younger group. In combined analyzes, none of the twenty Bcl-2-negative/p53-positive cases in the younger group exhibited recurrence, resulting in the independent favorable predictive value of Bcl-2-negative/p53-positive. The anti-apoptotic nature of Bcl-2 may be apparent in TNBC. The excellent outcome of Bcl-2-negative/p53-positive cases in the younger group warrants further combined investigation of Bcl-2/p53 in TNBC.

Aflatoxin B1-exposed hepatocyte-derived extracellular vesicles: Initiating hepatic stellate cell-mediated liver fibrosis through a p53-Parkin-dependent mitophagy pathway.

Environmental aflatoxin B1 (AFB1) exposure has been proposed to contribute to hepatocellular carcinoma by promoting liver fibrosis, but the potential mechanisms remain to be further elucidated. Extracellular vesicles (EVs) were recognized as crucial traffickers for hepatic intercellular communication and play a vital role in the pathological process of liver fibrosis. The AFB1-exposed hepatocyte-derived EVs (AFB1-EVs) were extracted, and the functional effects of AFB1-EVs on the activation of hepatic stellate cells (HSCs) were explored to investigate the molecular mechanism of AFB1 exposure-induced liver fibrogenesis. Our results revealed that an environment-level AFB1 exposure induced liver fibrosis via HSCs activation in mice, while the AFB1-EVs mediated hepatotoxicity and liver fibrogenesis in vitro and in vivo. AFB1 exposure in vitro increased PINK1/Parkin-dependent mitophagy in hepatocytes, where upregulated transcription of the PARK2 gene via p53 nuclear translocation and mitochondrial recruitment of Parkin, and promoted AFB1-EVs-mediated mitochondria-trafficking communication between hepatocytes and HSCs. The knockdown of Parkin in HepaRG cells reversed HSCs activation by blocking the mitophagy-related AFB1-EVs trafficking. This study further revealed that the hepatic fibrogenesis of AFB1 exposure was rescued by genetic intervention with siPARK2 or p53's Pifithrin-α (PFTα) inhibitors. Furthermore, AFB1-EVs-induced HSCs activation was relieved by GW4869 pharmaceutic inhibition of EVs secretion. These results revealed a novel mechanism that AFB1 exposure-induced p53-Parkin signal axis regulated mitophagy-dependent hepatocyte-derived EVs to mediate the mitochondria-trafficking intercellular communication between hepatocytes and HSCs in the local hepatotoxic microenvironment to promote the activated HSCs-associated liver fibrogenesis. Our study provided insight into p53-Parkin-dependent pathway regulation and promised an advanced strategy targeting intervention to EVs-mediated mitochondria trafficking for preventing xenobiotics-induced liver fibrosis.

Disrupting the interaction between a p53 gain-of-function mutant and the transcriptional co-activator PC4 reverses drug resistance in cancer cells.

PC4 is a chromatin-associated protein and transcriptional coactivator whose role in gene regulation by wild-type p53 is now well known. Little is known about the roles of PC4 in tumor cells bearing mutant p53 genes. We show that PC4 associates with one of the tumor-associated gain-of-function p53 mutants, R273H. This association drives its recruitment to two promoters, UBE2C and MDR1, known to be responsible for imparting aggressive growth and resistance to many drugs. Here, we introduced a peptide that disrupts the PC4-R273Hp53 interaction to tumor cells bearing the R273HTP53 gene, which led to a lowering of MDR1 expression and abrogation of drug resistance in a mutant-specific manner. The results suggest that the PC4-R273Hp53 interaction may be a promising target for reducing proliferation and drug resistance in tumors.

HPV infection and its correlation with p53 and Bcl-2 among pregnant mothers and their infants.

The investigation of perinatal transmission of HPV is vital for early screening of cervical/oral cancers. Here, transmission of HPV from the pregnant women to their infants was studied. p53 and Bcl-2 expressions and their correlations with HPV infection were examined. HPV infection was detected in the cervical and oral swabs of 135 mother-baby pairs employing both PCR and HC-II methods. 1 year follow-up with an interim visit at 3 months for mothers and 6 months for babies was performed. Immunocytochemistry of p53 and Bcl-2 using the streptavidin-biotin peroxidase method was performed. Prevalence of HPV infection in the mothers was 28.14%, (38/135) and 30.37% (41/135) determined by the PCR and HC-II methods respectively. HPV 16 and/or 18 was identified in 81.57% (31/38) and 82.92% (34/41) of the HPV + women estimated by PCR and HC-II methods respectively. Prevalence rate of HPV 16 among the HPV + pregnant women was 63.15% (24/38) and 65.85% (27/41) determined by PCR and HC-II methods respectively. The frequency of perinatal transmission was 21.05% (8/38) and 21.95% (9/41) determined by PCR and HC-II methods respectively at birth. The HPV + infants in the follow up study cleared the infection within 6 weeks. An abnormal nuclear expression of p53 and cytoplasmic expression of Bcl-2 were observed in the HPV + mother-baby pairs. Cesarean section did not protect the infants against perinatal HPV transmission. The detection of p53 and Bcl-2 proteins in the HPV + mother-baby pairs suggests that these biomarkers may be important in the early screening of oral/cervix cancers in positive cases.

Prognostic Value of ATRX and p53 Status in High-Grade Glioma Patients in Morocco.

INTRODUCTION: Glioblastoma and astrocytoma, grade 4, are the most common and aggressive brain tumors. Several biomarkers, such as the isocitrate dehydrogenase mutation (IDH-1), alpha-thalassemia/mental retardation, and the X-linked mutation (ATRX), enable more accurate glioma classification and facilitate patient management. This study aimed to determine the prognostic value of clinical and molecular factors (IDH, TP53, and ATRX mutations). We also studied the relationship between these molecular markers and the overall survival (OS) of 126 patients with grade 4 glioblastoma/astrocytoma. METHODS: The immunohistochemical study was conducted using antibodies namely, IDH1, R132H, p53, and ATRX. Statistical tests were used to investigate factors that might influence overall survival using IBM SPSS Statistics, version 25.0 (IBM Corp., Armonk, NY). RESULTS: The median age at diagnosis was 51.5 years. Patients with a Karnofsky performance score (KPS) <70 presented less favorable survival outcomes compared to those with a KPS ≥70. The median OS for patients was found to be 11.17 months. Expression of IDH1 R132H was found in 13.5% of patients, p53 overexpression was identified in 55.6% of cases, and loss of ATRX expression was detected in 11.9%. The group of patients with IDH mutant/ATRX mutant/p53 wild-type had the best prognosis (OS = 27.393 months; p = 0.015). Our results were in line with previous studies. CONCLUSION: The clinical value of IDH and ATRX mutations in prognostic assessment was confirmed (p ≤0.05). The overexpression of p53 had no significant impact on OS (p = 0.726). Therefore, p53 alone cannot predict survival in glioblastoma patients. Based on the results, these biomarkers may be a potential therapeutic target to prolong patient survival, hence the need for further investigations.

Exploring Solitary Fibrous Tumors at a Tertiary Cancer Center: Clinicopathological and Immunomorphologic Profile.

Background Solitary fibrous tumor (SFT) is a distinct fibroblastic tumor that can occur at any anatomical site and can manifest a variety of histopathological features. NAB2-STAT6 gene fusion has recently emerged as a sensitive and specific molecular marker and its surrogate on immunohistochemistry, STAT6 has also displayed considerable efficacy. Nevertheless, its histologic diversity can result in diagnostic challenges, especially when classic features are not apparent. Methods A retrospective study was conducted at a tertiary cancer centre in North India over 3 years to document the clinicopathologic and immunomorphologic profile of SFTs. Immunohistochemical analysis of BCOR and p53 were gauged additionally and patients were stratified according to Modified Demicco and Salas criteria for risk of metastasis. Results Sixteen patients of SFT were identified, affecting middle-aged men and women equally. Though lung/pleura are known to be involved commonly, SFT affects other sites such as the kidney, brain, buccal mucosa, liver, and penis as well. The majority endured localized disease while a lesser number suffered locoregional/distant spread. Two patients revealed features of a malignant profile. Risk stratification according to the Modified Demicco and Salas criteria evinced comparable results. No discernible relationship however was highlighted between the immunohistochemical expression of BCOR, p53, and any significant SFT parameter. Conclusion Although SFTs are very rare substantially benign mesenchymal neoplasms, pathologists must be conversant with their histological diversity and be vigilant of their malignant attributes. The worth of STAT6 immunohistochemistry for precise diagnosis and long-term studies for delineating clinical behavior cannot be overemphasized.

Proteasome inhibition paradoxically degrades gain-of-function mutant p53 R273H in NSCLC and could have therapeutic implications.

Lung cancer is the leading cause of cancer mortality. Despite therapeutic advances in recent years, new treatment strategies are needed to improve outcomes of lung cancer patients. Mutant p53 is prevalent in lung cancers and drives several hallmarks of cancer through a gain-of-function oncogenic program, and often predicts a poorer prognosis. The oncogenicity of mutant p53 is related to its stability and accumulation in cells by evading degradation by the proteasome. Therefore, destabilization of mutant p53 has been sought as a therapeutic strategy, but so far without clinical success. In this study, we report that proteasome inhibition results in degradation of mutant p53 in non-small cell lung cancer (NSCLC) cell lines bearing the R273H mutant protein and show evidence that this was mediated by hsp70. NSCLC cell lines with the mutant R273H allele demonstrated increased susceptibility and apoptosis to proteasome inhibitors. These data suggest that proteasome inhibitors could have therapeutic implications in some subsets of TP53 mutated NSCLC.

MicroRNA-298 determines the radio-resistance of colorectal cancer cells by directly targeting human dual-specificity tyrosine(Y)-regulated kinase 1A.

BACKGROUND: Radiotherapy stands as a promising therapeutic modality for colorectal cancer (CRC); yet, the formidable challenge posed by radio-resistance significantly undermines its efficacy in achieving CRC remission. AIM: To elucidate the role played by microRNA-298 (miR-298) in CRC radio-resistance. METHODS: To establish a radio-resistant CRC cell line, HT-29 cells underwent exposure to 5 gray ionizing radiation that was followed by a 7-d recovery period. The quantification of miR-298 levels within CRC cells was conducted through quantitative RT-PCR, and protein expression determination was realized through Western blotting. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and proliferation by clonogenic assay. Radio-induced apoptosis was discerned through flow cytometry analysis. RESULTS: We observed a marked upregulation of miR-298 in radio-resistant CRC cells. MiR-298 emerged as a key determinant of cell survival following radiation exposure, as its overexpression led to a notable reduction in radiation-induced apoptosis. Intriguingly, miR-298 expression exhibited a strong correlation with CRC cell viability. Further investigation unveiled human dual-specificity tyrosine(Y)-regulated kinase 1A (DYRK1A) as miR-298's direct target. CONCLUSION: Taken together, our findings underline the role played by miR-298 in bolstering radio-resistance in CRC cells by means of DYRK1A downregulation, thereby positioning miR-298 as a promising candidate for mitigating radio-resistance in CRC.

Resection of supratentorial high-grade gliomas availing of neuronavigation matched intraoperative ultrasound and Fluorescein: How far is it safe to push the resection?

Background: High-Grade Gliomas are the most common primary brain malignancies and despite the multimodal treatment, and the increasing amount of adjuvant treatment options the overall prognosis remains dismal. The present investigation aims to analyze the safety profile of the use of intraoperative ultrasounds (Io-US) in a homogeneous and matched cohort of patients suffering from High-grade gliomas (HGG) operated on with or without the aid of Io-US and Fluorescein in specific relation to the incidence of neurological and functional status sequelae. Methods and materials: A retrospective analysis was performed on 74 patients affected by HGG. 22 patients were treated with Io-US matched with neuronavigational system (Group A); 15 patients were treated both with the use of Io-US and Fluorescein matched with neuronavigational system (Group B); 37 patients were treated with the use of the neuronavigational system only (Group C). Primary endpoints were the extent of resection and functional outcome (measured with Karnofski Performance Status). Results: Significative differences were observed in terms of a higher extent of resection in Group B. In a multivariate analysis, this data appears to be independent of the location (eloquent/non-eloquent) of the lesion and from its histology. Regarding functional outcomes, no differences were detected between the two groups. Conclusions: The present study is the first that analyzes the simultaneous use of Io-US and Fluorescein, and the results demonstrate that these two instruments together could improve the extent of resection in HGG while ensuring good outcomes in terms of functional status.

Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules.

This study discusses the synthesis and use of a new library of spirooxindole-benzimidazole compounds as inhibitors of the signal transducer and activator of p53, a protein involved in regulating cell growth and cancer prevention. The text includes the scientific details of the [3 + 2] cycloaddition (32CA) reaction between azomethine ylide 7a and ethylene 3a within the framework of Molecular Electron Density Theory. The mechanism of the 32CA reaction proceeds through a two-stage one-step process, with emphasis on the highly asynchronous transition state structure. The anti-cancer properties of the synthesized compounds, particularly 6a and 6d, were evaluated. The inhibitory effects of these compounds on the growth of tumor cells (MDA-MB 231 and PC-3) were quantified using IC50 values. This study highlights activation of the p53 pathway by compounds 6a and 6d, leading to upregulation of p53 expression and downregulation of cyclin D and NF-κB in treated cells. Additionally, we explored the binding affinity of spirooxindole analogs, particularly compound 6d, to MDM2, a protein involved in regulation of p53. The binding mode and position of compound 6d were compared with those of a co-crystallized standard ligand, suggesting its potential as a lead compound for further preclinical research.

Probing the Effects of Retinoblastoma Binding Protein 6 (RBBP6) Knockdown on the Sensitivity of Cisplatin in Cervical Cancer Cells.

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

Important molecular mechanisms in ferroptosis.

Ferroptosis is a type of cell death that is caused by the oxidation of lipids and is dependent on the presence of iron. It was first characterized by Brent R. Stockwell in 2012, and since then, research in the field of ferroptosis has rapidly expanded. The process of ferroptosis-induced cell death is genetically, biochemically, and morphologically distinct from other forms of cellular death, such as apoptosis, necroptosis, and non-programmed cell death. Extensive research has been devoted to comprehending the intricate process of ferroptosis and the various factors that contribute to it. While the majority of these studies have focused on examining the effects of lipid metabolism and mitochondria on ferroptosis, recent findings have highlighted the significant involvement of signaling pathways and associated proteins, including Nrf2, P53, and YAP/TAZ, in this process. This review provides a concise summary of the crucial signaling pathways associated with ferroptosis based on relevant studies. It also elaborates on the drugs that have been employed in recent years to treat ferroptosis-related diseases by targeting the relevant signaling pathways. The established and potential therapeutic targets for ferroptosis-related diseases, such as cancer and ischemic heart disease, are systematically addressed.

Using Apparent Diffusion Coefficient (ADC) of Endometrial Cancer MRI to Determine P53 Molecular Subtypes.

BACKGROUND: Endometrial Cancer (EC) is a highly heterogeneous cancer comprising both histological and molecular subtypes. Using a non-invasive modality method to trigger these subtypes as early as possible can aid clinicians in establishing individualized treatment. PURPOSE: The study aimed to clarify the value of the Apparent Diffusion Coefficient (ADC) of EC MRI in determining molecular subtypes. MATERIAL AND METHODS: We retrospectively recruited 109 patients with pathologically proven EC (78 endometrioid cancers and 31 non-endometrioid cancers) with available molecular classification from a tertiary centre. MRI was prospectively performed a month prior to surgery; images were blindly interpreted by two experienced radiologists with consensus reading. The ADC value was measured by an experienced radiologist on the commercially available processing workstation. Interoperator measurement consistency was calculated. RESULTS: Our sample comprised 17 PLOE, 32 MSI-H, 31 NSMP, and 29 P53abn ECs. Clinical information did not differ significantly among the groups. The maximum diameter and volume of the lesions differed among the groups. The ADC value in the maximal area (ADCarea) or region of interest (ROI, ADCroi) in the P53abn group was higher than that in the other groups (894.0 ±12.6 and 817.5 ± 83.3 x10-6 mm2/s). The ADC mean values were significantly different between the P53abn group and the other groups (P = 0.000). The nomogram showed the highest discriminative ability to distinguish P53abn EC from other types (AUC: 0.859). CONCLUSION: Our results have suggested the quantitative MR characteristics (ADC values) derived from preoperative EC MRI to provide useful information in preoperatively determining P53abn cancer.

Evaluation of histological and ultrastructural changes provoked by prenatal tramadol on postnatal cortical cerebellar neuronal development in rats: possible implication of Ki67, GFAP and MicroRNA-7/P53 signalling trajectories.

Tramadol is a novel centrally acting analgesic. Despite, its implementation during pregnancy may impair neuronal survival and synaptic development in neonatal cerebella. The current investigation assessed the histological and ultrastructural alterations in postnatal cortical cerebellar neuronal development induced by prenatal tramadol. 30 offsprings were divided to control group I: fifteen pups born to mothers given saline from D10 till D21 of gestation. Tramadol-treated group II: fifteen pups born to mothers received tramadol HCL (50 mg/kg/day) from D10 till D21 of gestation. Pups were categorized into three subgroups (a, b, and c) and offered for sacrifice on the seventh, fourteenth and twenty-first post-natal days. Light microscopic examination revealed the overcrowding and signs of red degeneration affecting purkinje cell layer. Neurodegenerative signs of both purkinje and granule cell neurons were also confirmed by TEM in form of chromatin condensation, dilated Golgi channels, disrupted endoplasmic reticulum, marked infolding of the nuclear envelope and decrease in granule cell precursors. In addition, the astrocytic processes and terminal nerve axons appeared with different degrees of demyelination and decreased number of oligodendrocytes and degenerated mitochondria. Furthermore, group II exhibited an increase in P53 immune expression. The area percentage of apoptotic cells detected by TUNEL assay was significantly increased. Besides to the significant decrease of Ki67 immunoreactivity in the stem neuronal cell progenitors. Quantitative PCR results showed a significant decline in micro RNA7 gene expression in tramadol treated groups resulting in affection of multiple target genes in P53 signaling pathways, improper cortical size and defect in neuronal development.

Effect of N-acetylcysteine on hair follicle changes in mouse model of cyclophosphamide-induced alopecia: histological and biochemical study.

Chemotherapy-induced alopecia (CIA) represents one of the most severe side effects of chemotherapy, which forces some patients to reject cancer treatment. The exact pathophysiological mechanisms of CIA are not clearly understood, which makes it difficult to discover efficient preventive or therapeutic procedures for this adverse effect. N-acetylcysteine (NAC) has a strong antioxidant activity as it stimulates glutathione synthesis and acts as an oxygen radical scavenger. The current study tried to investigate the efficacy of NAC in preserving biochemical parameters and hair follicle structure against cyclophosphamide (CYP) administration. In total, 40 adult female C57BL/6 mice were induced to enter anagen by depilation (day 0) and divided into four groups: group I (control), group II (CYP) received a single dose of CYP [150 mg/kg body weight (B.W.)/intraperitoneal injection (IP)] at day 9, group III (CYP & NAC) received a single dose of CYP at day 9 as well as NAC (500 mg/kg B.W./day/IP) from day 6-16, and group IV (NAC) received NAC from day 6-16. CYP administration in group II induced an increase in malondialdehyde (MDA), decrease in superoxide dismutase (SOD), histological hair follicle dystrophy, disruption of follicular melanogenesis, overexpression of p53, and loss of ki67 immunoreactivity. NAC coadministration in group III reversed CYP-induced alterations in the biochemical parameters and preserved hair follicle structure, typical follicular melanin distribution as well as normal pattern of p53 and ki67 expression. These findings indicated that NAC could be used as an efficient and safe therapeutic option for hair loss induced by chemotherapy.

IRG1/Itaconate inhibits proliferation and promotes apoptosis of CD69+CD103+CD8+ tissue-resident memory T cells in autoimmune hepatitis by regulating the JAK3/STAT3/P53 signalling pathway.

To investigate the protective role of immune response gene 1 (IRG1) and exogenous itaconate in autoimmune hepatitis (AIH) and elucidate the underlying mechanisms. Wild-type and IRG1-/- AIH mouse models were established, and samples of liver tissue and ocular blood were collected from each group of mice to assess the effects of IRG1/itaconate on the expression of pro- and anti-inflammatory cytokines. The levels of liver enzymes and related inflammatory factors were determined using enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR). Liver histomorphology was detected through hematoxylin and eosin staining and then scored for liver injury, and the infiltration levels of tissue-resident memory T (TRM) cells and related molecules in the liver tissue were detected through immunofluorescence staining in vitro. RNA sequencing and gene enrichment analysis were conducted to identify the corresponding molecules and pathways, and lentiviral transfection was used to generate TRM cell lines with IRG1, Jak3, Stat3, and p53 knockdown. Real-time quantitative PCR and western blot were performed to detect the expression levels of relevant mRNAs and proteins in the liver tissue and cells. The percentage of apoptotic cells was determined using flow cytometry. IRG1/itaconate effectively reduced the release of pro-inflammatory cytokines and the pathological damage to liver tissue, thereby maintaining normal liver function. At the same time, IRG1/itaconate inhibited the JAK3/STAT3 signaling pathway, regulated the expression of related downstream proteins, and inhibited the proliferation and promoted the apoptosis of CD69+CD103+CD8+ TRM cells. For the first time, P53 was found to act as a downstream molecule of the JAK3/STAT3 pathway and was regulated by IRG1/itaconate to promote the apoptosis of CD8+ TRM cells. IRG1/itaconate can alleviate concanavalin A-induced autoimmune hepatitis in mice by inhibiting the proliferation and promoting the apoptosis of CD69+CD103+CD8+ TRM cells via the JAK3/STAT3/P53 pathway.

Research progress on the role of p53 in pulmonary arterial hypertension.

PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by increased pulmonary vascular resistance and pulmonary arterial pressure. At present, the definitive pathology of PAH has not been elucidated and its effective treatment remains lacking. Despite PAHs having multiple pathogeneses, the cancer-like characteristics of cells have been considered the main reason for PAH progression. RECENT FINDINGS: p53 protein, an important tumor suppressor, regulates a multitude of gene expressions to maintain normal cellular functions and suppress the progression of malignant tumors. Recently, p53 has been found to exert multiple biological effects on cardiovascular diseases. Since PAH shares similar metabolic features with cancer cells, the regulatory roles of p53 in PAH are mainly the induction of cell cycle, inhibition of cell proliferation, and promotion of apoptosis. SUMMARY: This paper summarized the advanced findings on the molecular mechanisms and regulatory functions of p53 in PAH, aiming to reveal the potential therapeutic targets for PAH.

An arresten-derived anti-angiogenic peptide triggers apoptotic cell death in endothelial cells.

BACKGROUND: In recent years, anti-angiogenic peptides have received considerable attention as candidates for cancer treatment. Arresten is an angiogenesis inhibitor that cleaves from the α1 chain of type IV collagen and stimulates apoptosis in endothelial cells. We have recently indicated that a peptide corresponding to the amino acid 78 to 86 of arresten, so-called Ars, prevented the migration and tube formation of HUVECs and the colon carcinoma growth in mice significantly. The current study aimed to determine whether induction of apoptotic cell death in endothelial cells is one of the biochemical mechanisms of this anti-angiogenic peptide. METHODS AND RESULTS: This hypothesis was assessed using the MTT assay, cell cycle analysis, Annexin V-FITC/PI staining, BCL2, CASP8, CASP9, p53, and CDKN2A gene expression studies as well as evaluating apoptosis in tumor tissues by TUNEL assay. Results demonstrated that 40 µM of Ars significantly stimulated 46.2% of early and late apoptosis in HUVECs compared to 13.6% in the untreated cells and did not significantly alter the cell cycle distribution. Moreover, BCL2 and CASP8 were down-regulated, while CASP9 and p53 were up-regulated in endothelial cells. CDKN2A gene expression, the regulator of G1 cell cycle arrest, was not significantly altered. CONCLUSIONS: It might be suggested that Ars induced apoptosis in endothelial cells through the mitochondrial pathway and had no effect on the cell cycle. Besides, Ars induced apoptosis significantly in vivo. However, further studies are required to confirm the detailed molecular mechanism of Ars, this peptide has the potential to be optimized for clinical translations.

Eukaryotic Initiation Factor 3C Can Affect the Proliferation and Invasion of Ovarian Cancer by Regulating the p53 Signalling Pathway.

BACKGROUND: Eukaryotic Initiation Factor 3C (EIF3C) represents a pivotal translational initiation factor in eukaryotes and has been shown to facilitate the progression of various neoplasms. However, its mechanistic role in ovarian cancer remains elusive. METHODS: In this research, the expression of EIF3C in ovarian cancer tissues was investigated using immunohistochemistry. In addition, the assessments were made on changes in cellular proliferation, invasion, and apoptotic abilities by reducing the expression of EIF3C in ovarian cancer cells. By utilizing microarray analysis, a comparison was performed between the downregulated EIF3C group and the control group of ovarian cancer cells, revealing the genes that were expressed differently. Furthermore, the signalling pathways associated with cellular proliferation were validated. The functional role of EIF3C in vivo was investigated using a xenograft tumour model. RESULTS: The immunohistochemical analysis showed that elevated levels of EIF3C are linked to a negative prognosis in patients with ovarian cancer. Suppression of EIF3C greatly hindered the growth and spread of SK-OV-3 and HO-8910 cells while enhancing cellular programmed cell death. Following KEGG and GSEA enrichment analyses of differentially expressed genes, the p53 signalling pathway was found to be associated with EIF3C. Suppression of EIF3C resulted in the upregulation of the p53 signalling pathway, leading to the inhibition of cell proliferation and invasion and the promotion of apoptosis. In vivo experiments demonstrated that EIF3C knockdown suppressed the growth of subcutaneous tumours in nude mice. CONCLUSION: There is a correlation between overexpression of EIF3C in tumour tissues of ovarian cancer patients and this is associated with a poorer prognosis. By influencing the p53 signaling pathway, EIF3C facilitates the growth and infiltration of cells in ovarian cancer.