Irisin mitigates diabetic cardiac damage and is associated with improved redox status and reduced p53/VCAM-1 mRNA expression in STZ-treated rats.

Xin Jia congrong tusizi decoction reverses ferroptosis in granulosa cells to rescue ovarian function decline via p53/Nrf2/SLC7A11/GPX4 signaling pathway.

Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth muscle cells (MASMCs) with oleic acid (OA)-induced lipotoxic senescence were treated with BA (30 μM). Transcriptomic analysis and functional assays were conducted. In vivo, ApoE-/- mice fed a high-fat diet received oral BA (25 mg/kg/day) for 14 weeks. OA-induced lipotoxic senescence was associated with overactivation of peroxisome proliferator-activated receptor alpha (PPAR-α)/fatty acid oxidation (FAO) signaling, which was attenuated by BA intervention. Molecular docking suggested that BA binds to the Arg226 site of PPAR-α, which was further supported by surface plasmon resonance analysis. BA significantly reduced OA-induced expression of P16, P21, and P53 (p < 0.05), inhibited reactive oxygen species generation, and improved mitochondrial function, indicating pronounced antisenescence effects of BA. Moreover, PPAR-α overexpression reversed these protective effects. In ApoE-/- mice, BA intervention reduced vascular pulse wave velocity (2.7 ± 0.32 vs. 3.3 ± 0.45 m/s, p < 0.05) and intima-media thickness (0.114 ± 0.012 vs. 0.137 ± 0.018 mm, p < 0.05). BA attenuates MASMC lipotoxic senescence and aortic metabolism-associated vascular aging by inhibiting PPAR-α/carnitine palmitoyl transferase 1A-mediated FAO, suggesting a potential metabolic-targeted strategy for preventing lipid-associated vascular aging.

Iodine-125 (125I) seed has effectively treated cholangiocarcinoma (CCA) in previous research. Ferroptosis, a new form of programmed cell death, is linked to cancers including CCA. However, the relationship between 125I seed and ferroptosis in CCA requires further investigation. Five pairs of CCA and adjacent normal tissue were collected, CCA tissues then were subjected to 125I seed brachytherapy. The optimal 125I seed dose for irradiating RBE cells was determined using the CCK-8 assay, and the cells were treated with ferroptosis inhibitors or MG132. RNF216 expression was modulated by short interfering RNA (siRNA) or overexpression plasmid. Cell viability, proliferation, and apoptosis were evaluated by CCK-8, EdU assays, TUNEL staining, and flow cytometric analysis. Intracellular Fe²⁺ levels, Lipid reactive oxygen species (ROS) and the GSH/GSSG ratio were detected by an iron assay kit, C11-BODIPY 581/591 and the EZ-Glutathione Assay Kit, respectively. The expression of RNF216, p53, SLC7A11 and GPX4 were analyzed by RT-qPCR and Western Blot. Ubiquitination of p53 by RNF216 was verified through ubiquitination immunoprecipitation. In CCA cell and tissues, 125I seed induced ferroptosis and reduced RNF216 expression. Additionally, 125I seed inhibited cell viability and proliferation but promoted apoptosis, and these trends were reversed by RNF216 overexpression or ferroptosis inhibitors. RNF216 was a key regulator of 125I seed-induced ferroptosis. Mechanistically, RNF216 promoted p53 degradation through ubiquitination, leading to upregulated SLC7A11 expression and ultimately inhibiting ferroptosis.125I seed inhibited SLC7A11 expression by preventing RNF216-mediated ubiquitination of p53, ultimately inducing ferroptosis in CCA. This provides crucial molecular evidence for the anticancer effects of 125I seed.

Dibutyl phthalate induces DNA damage and activates ATM-Chk2-p53 signaling to disrupt the prepubertal blood-testis barrier.

Somatic carcinomas with yolk sac tumor differentiation in the female genital tract: clinicopathological and molecular analysis of four cases with a literature review.

Yulin Yangchao formula improves premature ovarian insufficiency by inhibiting granulosa cell apoptosis through the PI3K/AKT/p53 signaling axis.

Wedelolactone alleviates rheumatoid arthritis by gut microbiota-dependent immunomodulation and p53-mediated inhibition of fibroblast-like synoviocytes.

α-KG alleviates mitochondrial dysfunction and attenuates HPDLSCs senescence in periodontitis through LKB1-AMPK activation.

The overall response rate of patients with advanced metastatic melanoma treated with anticancer agents remains poor, and their prognosis is extremely unfavorable. Combination therapy has become a prevalent treatment strategy, but resistance to the key drug dacarbazine (DTIC) contributes significantly to poor outcomes. We focused on programmed cell death 4 (Pdcd4), a tumor suppressor gene, as a potential target for overcoming drug resistance. Recent studies indicate that Pdcd4 expression impacts cell cycle regulation, with its specific function varying with cancer type. To date, detailed mechanisms remain unclear. We established DTIC-resistant mouse melanoma cells and evaluated whether resistance was acquired by measuring the proliferation of those cells. To evaluate the resistance mechanism, we investigated cell cycle regulatory factors using western blotting and flow cytometry. We also examined the relationship between Pdcd4 expression and cell cycle regulation. DTIC-resistant cells showed significantly decreased Pdcd4 protein levels, while expression of Cyclin D1 (a G1 phase regulator) and Cyclin E (involved in S-phase progression) was significantly increased. Expression of p21, a CDK inhibitor, also increased. Flow cytometric analysis revealed that DTIC treatment reduces the S-phase population in non-resistant cells, but not in resistant cells, and Cyclin D1 expression remains elevated in resistant cells even after extended culture in the absence of DTIC. Pdcd4 expression is downregulated in highly malignant DTIC-resistant melanoma cells and the resulting disruption in cell cycle control may contribute to drug resistance. Reactivating Pdcd4 to modulate cell cycle progression may offer a promising approach for overcoming chemotherapy resistance in patients with tumors.

Hepatocellular carcinoma (HCC) is a major health issue, but treatment options are limited. This study investigated the role of CCR4-NOT transcription complex subunit 9 (CNOT9) in the pathogenesis of HCC and its potential as a therapeutic target. Bioinformatics analysis was performed on RNA-seq data from the TCGA and GTEx databases to assess CNOT9 expression and prognostic significance. CNOT9 expression was validated in clinical samples and cell lines using qRT-PCR and Western blot. CNOT9 was knocked down in HCC cell lines, and its effects on proliferation, apoptosis, and cell cycle were investigated using functional assays (CCK-8, EdU, colony formation, and flow cytometry). The underlying molecular mechanisms were explored via RNA-seq and Western blot analysis of the AKT pathway and cell cycle regulators. Xenograft mouse models were used to confirm the oncogenic role of CNOT9 in vivo. CNOT9 mRNA and protein expression were upregulated in HCC patients and associated with poor prognosis. CNOT9 induces abnormal proliferation of HCC cells and G2/M phase cell cycle progression. Knocking down CNOT9 reduces cell proliferation, increases apoptosis, and causes cell arrest at the G2 phase. CNOT9 knockdown activates PTEN to inhibit the AKT pathway and suppresses the expression of cell cycle-related proteins p53, p21, CCNE1 and CDK2. CNOT9-deficient tumors exhibited reduced growth in mice, supporting its pro-oncogenic role. This study first elucidates the molecular mechanism by which CNOT9 drives HCC progression through post-transcriptional regulation of the PTEN/AKT/p53 axis, providing a theoretical basis for precision treatment strategies targeting CNOT9 or the PTEN/AKT/p53 pathway.

Bone morphogenetic protein-2 (BMP-2) regulates cell differentiation and proliferation. However, its role in colorectal cancer (CRC) remains debatable owing to potential oncogenic effects. Here, we investigated the role of BMP-2 in modulating CRC progression, particularly in regulating the Hippo signaling pathway. Exposure to recombinant human BMP-2 (rhBMP-2) resulted in a concentration-dependent decrease in CRC cell proliferation, leading to G1 cell cycle arrest. This effect was associated with the increased expression of p53, p21, and Smad4, while the levels of cyclin D1, cyclin-dependent kinase 4 (CDK4), and CDK6 decreased. Additionally, rhBMP-2 promoted apoptosis by decreasing poly (ADP-ribose) polymerase and caspase-9 expression while increasing their cleaved forms. It also activated the Hippo signaling cascade, enhancing the expression of mammalian sterile 20-like kinase 1/2, Mps One Binder 1 (MOB1), phosphorylated MOB1, and Salvador homolog, along with elevated levels of phosphorylated yes-associated protein (YAP), while concurrently suppressing total YAP expression. This resulted in cytoplasmic sequestration and subsequent degradation of YAP, thereby attenuating the transcription of YAP-responsive genes such as Connective Tissue Growth Factor. Silencing of Ras association domain family member 1 restored the rhBMP-2-induced decrease in cell viability, whereas silencing YAP further reduced the viability of CRC cell lines. Administering rhBMP-2 significantly suppressed tumor expansion in a mouse model of CRC, further supporting its potential as an antitumor agent. Collectively, these results indicate that rhBMP-2 mitigates CRC progression by activating the Hippo signaling pathway and suppressing YAP-mediated oncogenic processes, thereby highlighting its potential as a therapeutic agent that warrants further clinical evaluation.

Xiao Zhen Fang mitigates cutaneous toxicity by inhibiting PANoptosis: Insights from untargeted metabolomics and transcriptomics.

Carcinogenesis is a dynamic, multistep process in which the initiation stage represents a critical and irreversible event that determines cellular fate. Although genetic alterations play a central role in tumor development, dysregulation of intracellular organelles such as the endoplasmic reticulum (ER) has emerged as an important contributor to cancer initiation. In the present study, we aimed to evaluate how modulation of ER stress affects the initiation phase of hepatocarcinogenesis. The initiation-stage hepatocarcinogenic model was developed by administering a single dose of N-nitrosodiethylamine (NDEA) (50 mg/kg b.w, i.p.) to male Wistar rats. To modulate ER activity, the endogenous chaperone inducer 1-(3,4-dihydroxyphenyl)-2-thiocyanatoethanone (BIX) was administered intraperitoneally (0.1 mg/kg body weight) for 2 weeks prior to NDEA treatment. The effect of ER modulation on pro-tumorigenic events was assessed in terms of oxidative DNA damage, expression of inflammatory cytokines, p53, and cellular proliferation. Modulation of UPR by BIX was evaluated based on expression levels of PERK, ATF6, CHOP, and p-PERK/PERK ratio. BIX treatment demonstrated marked attenuation of pro-tumorigenic events as evidenced by significantly decreased levels of 8-OHdG, TNF-α, IL-6, PCNA, and p53, which were upregulated in the NDEA-treated group. Histopathological analysis further confirmed the preservation of hepatic architecture in the BIX-treated group as compared with the NDEA group. In addition, significantly decreased expression of UPR markers in the BIX-treated group, as compared to the NDEA group, confirmed inhibition of UPR activation. Collectively, these findings demonstrated that BIX-mediated ER-stress modulation effectively inhibited the initiation of NDEA-induced hepatocarcinogenesis.

Surgery followed by adjuvant chemoradiation is the standard treatment for glioblastoma multiforme (GBM). Temozolomide (TMZ) is the only first-line chemotherapeutic drug approved by the US Food and Drug Administration for the treatment of GBM. Acquired chemoresistance to TMZ is the primary cause of treatment failure, resulting in recurrence and a poor prognosis. O6-methylguanine DNA methyltransferase (MGMT) overexpression and loss of function mutations targeting mismatch repair (MMR) are the major mechanisms TMZ-resistance found in GBM cells. In this study we developed a new alkylating agent that could overcome TMZ resistance. We designed a new chloroethylnitrosourea analog HJ03, and demonstrated that HJ03 was more potent than TMZ in inhibiting GBM cell lines U251 (MGMT-, MMR+), U87 (MGMT-, MMR-) and T98G (MGMT+, MMR+) as well as colorectal cancer cell line HCT116 (MGMT+, MMR-) with MGMT overexpression or MMR dysfunction. Furthermore, HJ03 exerted a dual synergistic attack effect by inducing DNA damage and ferroptosis in U251, U87 and T98G cells. We showed that HJ03 caused U251 and T98G cells to bearrested in G2/M phase and undergo apoptosis by inducing the formation of DNA adducts and interstrand crosslinks. In U251, U87 and T98G cells, HJ03 promoted extensive ferroptosis by upregulating p53 and ATF3 expression while downregulating SLC7A11, leading to intracellular accumulation of ROS and Fe2+ along with increased MDA levels. Pharmacokinetic study showed that HJ03 crossed the blood-brain barrier more efficiently than TMZ and exhibited lower levels of bone marrow toxicity. In model mice bearing orthotopic CT2A GBM tumors, administration of HJ03 (20 mg/kg, i.g. 5 consecutive days per week for 3 weeks) significantly prolonged the lifespan. Furthermore, HJ03 synergized with radiotherapy and an anti-PD-1 monoclonal antibody to dramatically prolong mouse survival. Thus, HJ03 emerges as a promising novel candidate for GBM treatment, particularly for patients with TMZ-resistant tumors.

BAP1 (BRCA 1-associated protein 1)-inactivated melanocytic tumor (BIMT) is a melanocytic neoplasm characterized histologically by large epithelioid cells and is commonly associated with a conventional nevus component. The defining molecular alteration is inactivation of the BAP1 gene. Initiating mutations in BIMT include BRAF p.V600E, or less commonly RAS mutations and fusions involving RAF1 . In this article, we report a case of BIMT with a BAP1 mutation and a novel PDZRN3::BRAF fusion. Histologic examination revealed an intradermal melanocytic neoplasm with nests and single units of large, atypical epithelioid cells with abundant amphophilic-eosinophilic cytoplasm, well-defined cell borders, large vesicular nuclei, and prominent nucleoli. Frequent binucleated and multinucleated melanocytes were present. There was no associated conventional nevus component. Scattered mitotic activity were identified. No evidence of maturation, necrosis, or lymphovascular or perineural invasion was seen. The lesional cells were immunoreactive for SOX10, Melan A, and HMB45 (focal, minimal, and weak), and were negative for PRAME. There was patchy loss of expression of p16 and complete loss of BAP1 expression. Molecular analysis demonstrated BAP1 mutation and a novel fusion involving PDZRN3::BRAF . Our finding expands our current understanding of the molecular landscape and pathogenesis of BIMT.

Temozolomide (TMZ) is a first-line chemotherapeutic agent for the treatment of glioblastoma (GBM), while a majority of patients do not effectively respond to TMZ owing to the multiple resistance mechanisms. In this study, we found that TMZ treatment substantially increased the exosome secretion from GBM cell line. The secreted exosomes from TMZ-treated C6 cells maintained typical physicochemical properties, with only slight fluctuation in expression profile of surface markers compared to untreated cell-derived exosomes. Further investigation revealed that increased expression of p53 might be the predominant reason to promote exosome secretion, potentially through the upregulation of six-transmembrane epithelial antigen of prostate 3 (STEAP3) expression under stress condition. Moreover, we identified that pre-treatment with TMZ-induced exosomes could reduce the sensitivity of C6 cells to TMZ and considered that exosome secretion may serve as a potent TMZ resistance mechanism via enhancing anti-apoptotic ability of GBM cells towards TMZ exposure. Proteomics analysis revealed a strategic mechanism to resist TMZ-induced apoptosis by upregulating exosomal proteins associated with biogenesis, chemoresistance, and therapeutic adaption. This finding revealed a considerable TMZ resistance mechanism and provided a new inspiration for preventing exosome biogenesis to resensitise TMZ cytotoxicity towards GBM.

Radiopharmaceutical therapy (RPT) represents a critical approach in oncology, nevertheless its efficacy may be limited by tumor resistance mechanisms associated with metabolic reprogramming. Enhancing tumor radiosensitivity remains a major challenge. Engineered bi-functional starvation probes (CRT3LP and CRT4LP) that simultaneously target ecto-CRT and exert L-ASNase activity are explored for disrupting tumor amino acid metabolism. Herein, we systematically evaluate the ability of targeted starvation probes to enhance antitumor efficacy in radioactive iodine (RAI) therapy. In vitro, the probes upregulated p53 expression while downregulating Rev1 and SOD2, thereby impairing ROS scavenging and sensitizing tumor cells to RAI-induced oxidative stress. In vivo, the combination treatment elevated intratumoral ROS levels, increased CD4⁺ and CD8⁺ T cell infiltration, upregulated pro-inflammatory cytokines (IFN-γ and TNF-α), and reduced regulatory T cell populations. Additionally, markers of tumor proliferation (Ki67 and CD31) were suppressed, while apoptotic markers (TUNEL and p21) were increased. Co-administration of the immune checkpoint inhibitor αPD-L1 further improved therapeutic efficacy. These findings suggest that targeted tumor starvation probes boost radiosensitivity and anti-tumor immunity, and this strategy shows improved efficacy in combination with αPD-L1 therapy.

Folate receptor 1 (FOLR1) has recently become a well-accepted therapeutic target in advanced-stage cancers. In this study, the prevalence of FOLR1 expression across all types of gynecologic tumors was investigated and correlated with selected clinicopathologic features. A total of 306 gynecologic tumors from 304 patients were evaluated for FOLR1 expression by immunohistochemistry (IHC). A positive FOLR1 is defined as ≥75% of viable tumor cells with moderate to strong membrane staining. Of 306 tumors, 31 (10.1%) had positive FOLR1 tests; a large majority of these FOLR1-positive tumors were HGSCs (64.5%), followed by uterine serous carcinoma, poorly differentiated/high-grade carcinoma, ovarian endometrioid carcinoma, ovarian mixed carcinoma, ovarian low-grade serous carcinoma, and serous borderline tumor with cribriform and micropapillary features. FOLR1 overexpression correlated with positive PD-L1 expression ( P =0.012), intact mismatch repair protein (MMR) expression ( P =0.024), and positive ER expression ( P =0.040). In endometrial tumors, positive FOLR1 expression was associated with poor histologic grade ( P =0.019), larger tumor size ( P =0.048), mutant p53 expression ( P <0.001), and lower PR expression ( P =0.015). Endometrial tumors with FOLR1 overexpression had a significantly higher rate of TP53 mutations ( P =0.013), while all endometrial tumors with PTEN alterations were negative for FOLR1 ( P =0.037). Overall, FOLR1 overexpression was associated with poor prognostic factors, such as advanced clinical stage, increased recurrence rate, higher pathologic T and N stage, poor histologic grade, larger tumor size, lymphovascular invasion, uterine serosa involvement, and shorter progression-free survival.

Ionising radiation (IR) is a recognised risk factor for cardiovascular disease (CVD), yet the mechanisms linking it to exposure remain incompletely understood. We show that IR drives a pro-atherogenic phenotype in human coronary artery endothelial cells (HCAECs) through the induction of cellular senescence, and that rapamycin attenuates these effects. IR triggered hallmark senescence features, including elevated senescence-associated-β-galactosidase activity, nuclear enlargement, and increased Cyclin dependent kinase inhibitor 1A and p53 expression. Functionally, irradiated HCAECs displayed impaired barrier integrity and heightened monocyte adhesion. Transcriptomic and proteomic profiling revealed broad IR-induced alterations enriched in DNA damage response, cell-cycle arrest, senescence, proteostasis, and immune-related pathways. These findings establish a mechanistic link between radiation-induced endothelial senescence and early atherogenic-associated dysfunction, demonstrating that senescence is a driver of pro-atherogenic phenotypes in HCAECs in vitro. Importantly, mTOR inhibition is identified as a promising strategy to counteract radiation-associated endothelial dysfunction. This work positions senescence as a tractable therapeutic target in radiation-induced vascular injury.