Bladder cancer is one of the most common urological malignancies, with 5-year survival rates below 40% in advanced cases. Oncologic immunotherapy has become a popular approach to treating cancer and programmed death ligand 1 (PDL1), programmed death ligand 2 (PDL2), intercellular adhesion molecule 2 (ICAM2) and 4-1BB ligand (4-1BBL) are key costimulatory molecules in oncologic immunotherapy. Previous research has shown plant phytochemicals can act as immunomodulators by regulating costimulatory functions to increase T-cell activation and thus to inhibit malignant proliferation. However, the role of Aloe vera in the growth of bladder cancer and in the expression of these key costimulatory molecules has not been elucidated yet. This study is designed to investigate if Aloe vera could have a role in the growth of bladder cancer and if it has any effect on the expression of these key costimulatory molecules in bladder cancer.

Cisplatin resistance remains a major obstacle in advanced gastric cancer (GC). This study aimed to identify key molecular determinants of cisplatin resistance, with a focus on interferon-stimulated genes (ISGs), and to systematically investigate the functional role of interferon-stimulated gene 15 (ISG15) in mediating chemoresistance.

Cervical cancer remains a significant global challenge, necessitating novel therapeutic strategies beyond conventional radiotherapy and chemotherapy. The anticancer potential of natural compounds has recently garnered increased recognition. This study aimed to expand this knowledge by exploring the molecular mechanisms by which spinach extract (SE) influences the growth and survival of HeLa cervical cancer cells.

Poly I:C-induced maternal immune activation(MIA) during gestation increases the risk of schizophrenia-like behaviors in the offspring. However, the molecular mechanism of poly I:C MIA-induced schizophrenia-like behaviors in the offspring is not well clarified. Available evidence showed that patients with schizophrenia have higher IL-6 levels in the blood and cerebrospinal fluid, which is correlated with psychotic and cognitive impairments. Previous findings suggest a key role for IL-6 in poly I:C MIA-induced schizophrenia-like abnormal behaviors. In the present study, we found that prenatal poly I:C exposure at gestational day (GD) 9 increased the expression of IL-6 and IL-6Rα and led to impaired prepulse inhibition (PPI) and recognition memory in adolescent and adult offspring. We also found that the expression and phosphorylation of IKKα/β, NF-κB, JAK2, and STAT3, the upstream and downstream signal molecules of IL-6, were increased in adolescent and adult offspring of poly I:C-treated mothers at GD 9. The increases in the expression of IL-6, IL-6Rα, IKKα/β, NF-κB, JAK2, and STAT3 and the impairments in PPI and recognition memory were alleviated by IL-6 blockade. These results suggest that IL-6 may be a potential mediator between NF-κB and JAK/STAT cross-talk, thereby contributing to poly I:C MIA-induced impairments in PPI and recognition memory in offspring. Our findings show that blocking of IL-6 could ameliorate prenatal poly I:C exposure-induced schizophrenia-like impairments in adolescent and adult offspring. Our study provides additional insight that targeting IL-6 is a potential strategy for treating poly I:C MIA-induced schizophrenia-like behaviors and behavioral deficits in schizophrenia.

Endocytosis of the epidermal growth factor receptor (EGFR) is considered a key regulator of the receptor signaling activity. However, the molecular mechanisms underlying EGFR endocytosis are incompletely understood. Although ligand-induced ubiquitination of EGFR is known to promote its endocytic trafficking, the importance of EGFR ubiquitination in clathrin-mediated endocytosis, the primary physiological route of EGFR internalization, remains debated, and the relative contributions of ubiquitination-dependent and -independent mechanisms are not defined. Hence, we used NX-1013, a small-molecule inhibitor of the Casitas B-lineage lymphoma-b (CBLB) E3 ubiquitin ligase, to dissect the role of EGFR ubiquitination in its endocytic trafficking and signaling. Strikingly, brief treatment with NX-1013 completely abolished EGF-induced EGFR ubiquitination, demonstrating that this process is exclusively mediated by the closely related CBLB and CBL ligases. NX-1013 inhibited clathrin-mediated internalization of activated EGFR by 60 to 70%. The remaining, ubiquitination-independent internalization required EGFR kinase activity, was highly clathrin-dependent, and was significantly impaired by depletion of the AP-2 clathrin adaptor complex. Interestingly, inhibition of CBLs and EGFR endocytosis by NX-1013 did not affect major downstream signaling pathways in human oral squamous cell carcinoma cells, with the exception of Rac1 activation and EGFR-dependent cell migration, both of which were suppressed.

Controlling the proliferation and immune evasion of cancer cells can lead to effective strategies for cancer treatment. Thymoquinone, a bioactive compound derived from Nigella sativa exhibits a potent anti-tumor activity. It can be used as a therapeutic approach because it stabilizes the G-quadruplex structure in the promoter regions of oncogenes. This study aims to investigate the effects of thymoquinone on CD55, an inhibitor of the complement system, and CD114, which is involved in cancer cell proliferation. Real-time PCR and Western blot were conducted to verify the expression of CD55 and CD114 in patients' tumor samples, HMEC cells, MCF-7 cells, and MCF7-cancer stem cells (MCF7-CSCs). MCF-7 cells were treated with thymoquinone, and their biological behavior was evaluated using proliferation, migration, and wound-healing assays. The result indicated that CD55 and CD114 were induced among the patient's samples. The same result is followed by MCF-7 cells and MCF7-CSCs. Treatment of MCF-7 and MCF7-CSCs with thymoquinone effectively downregulated CD55 and CD114 and suppressed the stemness markers Sox2 and Nanog. Promoter analysis revealed the putative G-quadruplex sequences in the CD55 and CD114 genes. Thymoquinone binds to them at the CD55 and CD114 promoters, thereby limiting mRNA expression. Additionally, the inhibition of their expression reduced cell movement and growth, as verified by biological assays. In summary, treating breast cancer cells with thymoquinone could stabilize the G-quadruplex structure on the promoter regions of CD55 and CD114 and hinder their mRNA expression. Therefore, restoring immune recognition and inhibition of proliferation. Hence, thymoquinone could be a potent target for breast cancer therapeutics.

This study aimed to compare in vivo cerebral gadolinium (Gd3+) accumulation, associated unfolded protein response (UPR), and oxidative stress parameters in rats after exposure to gadolinium-based contrast agents (GBCAs).

Retained placenta (RP) is a significant postpartum complication in dairy cows. Although abnormal estradiol (E2) levels are implicated, the underlying cellular mechanisms remain poorly defined. Through RNA-seq analysis of postpartum blood from cows with or without RP, we identified Serum and Glucocorticoid-regulated Kinase 1 (SGK1) as a differentially expressed gene candidate. Analysis of fetal cotyledonary tissues revealed that SGK1 expression was significantly elevated in these tissues, concomitant with markers of suppressed apoptosis, increased levels of tight junction proteins, and an inhibited epithelial-mesenchymal transition (EMT) phenotype. To explore a potential mechanistic link between E2 and these cellular alterations, we investigated the E2-SGK1 axis in bovine endometrial epithelial cells in vitro. E2 treatment upregulated SGK1 expression, reduced apoptosis, increased tight junction protein levels, and suppressed EMT. Conversely, SGK1 knockdown induced apoptosis, disrupted tight junctions, and impaired EMT. Notably, E2 could not rescue the apoptosis and EMT alterations in SGK1-knockdown cells, indicating that SGK1 is a critical mediator of these E2 effects in this cellular model. Based on these initial correlative findings in tissues, combined with the subsequent mechanistic experiments in cells, we propose a novel model whereby dysregulation of the E2- SGK1 axis could contribute to RP pathogenesis by stabilizing the placental interface. Our findings provide the first experimental evidence linking SGK1 to RP and establish a foundation for future in vivo validation.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies and characterized by pronounced heterogeneity and widespread dysregulation of microRNAs (miRNAs) that influence epithelial-to-mesenchymal transition (EMT) and metastasis. Tumor-derived extracellular vesicles (tEVs) further contribute to TNBC progression by transporting oncogenic cargo that can enhance pro-inflammatory signaling. The synthetic SMRwt peptide has been suggested to modulate oncogenic pathways; however, its effects on EV miRNA composition and inflammatory transcript profiles in TNBC remain unclear. Here, we investigated whether SMRwt alters tEV-associated miRNAs and cytokine transcript signatures relevant to EMT and inflammasome-linked pathways. Extracellular vesicles were isolated from SMR-treated and untreated MDA-MB-231 cells, followed by nanoparticle tracking analysis and small RNA sequencing. SMRwt treatment enriched 11 tumor-suppressive miRNAs (including Let-7a-5p, Let-7b-5p, miR-24-3p, miR-26b-5p, miR-92a-3p, miR-93-5p, and miR-496) previously associated with the regulation of proliferation, EMT, migration, and metastasis. We also observed modest, non-significant decreases (1.01-1.27-fold) in oncogenic miR-1200, miR-374a-5p, and miR-937-3p, which have been implicated in the progression of breast, lung, and bone malignancies. Complementary transcriptomic profiling using the NanoString nCounter Breast Cancer 360 Gene Expression Panel (NanoString Technologies, Inc., Seattle, CA, USA) demonstrated reduced expression of inflammasome-associated cytokines in TNBC cells relative to non-tumorigenic controls, including a log2 fold change of -1.15 for IL 1β (MDA-MB-231 vs. MCF10A). These transcript-level changes suggest potential modulation. Additionally, SMRwt suppresses ASC-mediated caspase-1 activation and reduces IL-1β secretion, thereby inhibiting NLRP3 inflammasome signaling. Therefore, we infer that SMRwt simultaneously restores tumor-suppressive miRNA networks and suppresses inflammasome-driven inflammation, supporting its potential as a dual-target therapeutic strategy for TNBC.

Inflammation is widely viewed as a driver of hepatocellular carcinoma (HCC), yet inflammatory signaling also reshapes hepatic xenobiotic metabolism. Here, we established transgenic (Tg) IKKβΔhep mice (Tg-IKKβΔhep), which combine hepatocyte-specific IKKβ deletion with liver expression of a nuclear, kinase-inactive IKKβ mutant (NLS-IKKβKN). Tg-IKKβΔhep mice developed spontaneous chronic hepatitis and progressive fibrosis but were strikingly resistant to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, with markedly reduced tumor multiplicity and total tumor burden. Despite persistent inflammatory injury, DEN-triggered oxidative DNA damage and p53 activation were markedly attenuated, compatible with reduced tumor initiation. Transcriptomic and biochemical analyses revealed broad repression of xenobiotic-metabolizing cytochrome P450 genes, including the pericentral enzyme CYP2E1, accompanied by reduced CYP2E1 protein abundance. This was associated with impaired HNF4α-PXR-CAR transcriptional output and reduced HNF4α occupancy at target promoters. Acute TNFα or IL-1β exposure recapitulated this repression, in part through reduced PGC-1α expression and decreased RNA polymerase II recruitment to target promoters. In parallel, pericentral xenobiotic metabolism was blunted, a change that could plausibly diminish DEN bioactivation and genotoxic stress. Together, these findings support a "metabolic gatekeeping" model in which chronic inflammation can constrain chemical hepatocarcinogenesis by attenuating carcinogen-metabolizing capacity.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of 13.3%. First-line treatment relies on two chemotherapy regimens, FOLFIRINOX (FOLFNX) or gemcitabine plus nab-paclitaxel (GEMPAC). However, direct clinical comparisons between these regimens have yielded inconsistent results across survival and toxicity endpoints, and the molecular basis of heterogeneous treatment responses remains poorly defined. To investigate regimen-specific tumor-cell-intrinsic mechanisms, we performed quantitative proteomic profiling of a primary PDAC-derived MIA PaCa-2 cell line following treatment with FOLFNX or GEMPAC. Differentially expressed proteins were analyzed using Gene Ontology, KEGG, and Ingenuity Pathway Analysis to define pathway-level alterations, and findings were contextualized using TCGA transcriptomic data. Proteomic analyses revealed that FOLFNX and GEMPAC engage in distinct cytotoxic programs. FOLFNX predominantly suppressed ribosome biogenesis and mitochondrial translation, consistent with sustained metabolic and biosynthetic stress, whereas GEMPAC preferentially disrupted mitotic cytokinesis and phosphatidylinositol phosphate biosynthesis, consistent with mitotic failure. Integration with TCGA data showed that FOLFNX-altered proteins aligned with favorable prognostic expression signatures, whereas GEMPAC-associated proteins were enriched among adverse profiles, reflecting engagement of distinct tumor-intrinsic programs. Together, these findings provide mechanistic insight into differential chemotherapy responses and establish a foundation for proteomics-based biomarkers to guide personalized chemotherapy selection in PDAC.

Src phosphorylation (activation) is associated with the proliferation and survival of numerous human cancer cells. The role of Src phosphorylation and expression, as well as its pharmacological inhibition by PP1, a Src inhibitor, in the growth of oral squamous cell carcinoma (OSCC), remain unclear. The present study explored whether Src is expressed and phosphorylated in HSC‑3 human oral cancer cells and whether PP1 treatment affects the proliferation of these cells. Src was found to be highly expressed and phosphorylated in HSC‑3 human oral cancer cells. Notably, treatment with PP1 at 10 µM significantly reduced cell proliferation and induced apoptosis, evidenced by DNA fragmentation, caspase‑9 and ‑8 activation, and poly(ADP‑ribose) polymerase cleavage. Mechanistically, PP1 not only inhibited Src phosphorylation but also disrupted a broad network of oncogenic pathways, including EGFR, JAK2, STAT‑3, PKB and ERK‑1/2 in HSC‑3 cells. Furthermore, PP1 induced markers of ER stress and inhibited protein translation, as shown by increased eIF‑2α phosphorylation and decreased S6 phosphorylation. The critical role of Src was confirmed by pharmacological inhibition and further validated when small interfering RNA‑mediated knockdown mimicked the anti‑proliferative effects of PP1. Importantly, these potent anticancer effects were conserved in another OSCC cell line (YD‑10B) and, were validated in vivo, where PP1 suppressed tumor growth in a zebrafish xenograft model. Collectively, these findings suggest that PP1 exerts strong anticancer effects on human oral cancer by simultaneously inhibiting Src activity and disrupting a network of associated oncogenic pathways (EGFR, STAT‑3, PKB and ERK‑1/2).

Bladder cancer is a challenging disease with high recurrence rates and limited treatment options. Studies have highlighted the role of ferroptosis, an iron‑dependent cell death mechanism, in cancer progression and treatment. In the present study, the regulatory mechanisms of polyphyllin II (PPII) on ferroptosis in bladder cancer cells were investigated. Cell viability and colony formation assays demonstrated that PPII effectively inhibited the proliferation of bladder cancer cells. RNA sequencing analysis revealed differentially expressed genes upon PPII treatment, with Cluster 6 exhibiting dose‑dependent expression changes. Gene Ontology and pathway enrichment analyses revealed enrichment of ferroptosis‑related pathways. PPII treatment markedly increased reactive oxygen species (ROS) levels and promoted Fe²+ accumulation in bladder cancer cells. Additionally, PPII downregulated the expression of glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis. These findings indicate that PPII promotes ferroptosis in bladder cancer cells through the modulation of ROS levels and GPX4 activity. Further investigations into the molecular mechanisms and potential combination therapies are warranted.

Drug therapy serves a key role in the treatment of cervical cancer, which is one of the most common types of solid tumor in female patients. Therefore, it is important to seek more effective and less toxic therapies. Protein arginine methyltransferase 5 (PRMT5) is a key oncogenic target in cervical cancer, providing a rational basis for the development of targeted therapeutic agents. MS4322 is a highly selective proteolysis targeting chimera degrader specifically targeting PRMT5. Therefore, the present study aimed to investigate the therapeutic potential of MS4322 against cervical cancer and the underlying molecular mechanisms. The effects of MS4322 on human cervical HeLa cells were investigated by Cell Counting Kit‑8, clone formation, wound healing and Transwell assay, flow cytometry, immunofluorescence staining, immunohistochemistry and small interfering RNA assay. PRMT5 expression was upregulated in cervical cancer tissue, and functional analyses confirmed that PRMT5 promoted the proliferation of cervical cancer cells. MS4322 significantly decreased PRMT5 mRNA expression, as well as the proliferation, migration, invasion and clone formation ability of HeLa cells, leading to cell cycle arrest in G0/G1 phase and inducing apoptosis. Mechanistically, MS4322 downregulated the expression of PRMT5, β‑catenin, Wnt‑3a, and c‑myc, while upregulating GSK‑3β, thereby inactivating the Wnt/β‑catenin pathway. These findings indicated that MS4322 exerted anti‑tumor effects via regulating the PRMT5/Wnt/β‑catenin pathway and may serve as a promising candidate agent for cervical cancer treatment.

Covalently closed circular DNA (cccDNA) represents the central obstacle to achieving a functional cure for chronic hepatitis B virus (HBV) infection. Poly6, a peptide encoded within the HBV genome, was investigated for antiviral efficacy in hepatocyte-derived cell lines, hydrodynamic injection models, and HBV transgenic mice. Poly6 administration markedly decreased cccDNA, pregenomic RNA, and viral DNA without detectable cytotoxicity. Poly6 also showed synergistic antiviral effects with entecavir. Mechanistic analyzes demonstrated that Poly6 initiates parallel upstream events: mitochondrial stress resulting in oxidized mtDNA release and activation of the STING-IRF3 pathway, and induction of IFI16, a nuclear DNA sensor implicated in interferon regulation. Both signals converged on robust type I interferon (IFN-I) production. The IFN-I response subsequently promoted expression of canonical ISGs, including iNOS, which generated nitric oxide to disrupt nucleocapsid assembly. Concurrently, IFI16, whose abundance was further increased by interferon signaling, amplified IFN-I production and imposed epigenetic silencing of cccDNA through Sp1 sequestration and histone hypoacetylation. Chromatin immunoprecipitation confirmed reduced acetylation of H3K27, H4K5, and H4K12 on cccDNA minichromosomes. These results delineate a unified IFN-I-centered cascade in which Poly6 coordinates complementary antiviral activities, supporting its translational potential as a therapeutic candidate for durable HBV control.

The tumor suppressor protein p53 orchestrates cellular responses to stress by regulating the transcription of target genes involved in processes such as cell cycle control, DNA damage repair and apoptosis. The protein kinase DYRK1B, known to promote cancer cell survival and contribute to DNA damage repair, is overexpressed in various tumor types. Here, we demonstrate that expression of DYRK1B - but not its closely related paralog DYRK1A - is upregulated by cytostatic drugs (Actinomycin D, Doxorubicin) in multiple cancer cell lines. This induction required functional p53 and was mediated by p53-dependent activation of the transcription factor RFX7. Furthermore, we show that DYRK1B physically interacts with RFX7 and counteracts its activation by p53, thereby establishing a negative feedback loop that attenuates RFX7-dependent gene expression. This inhibitory effect of DYRK1B was strictly dependent on its catalytic activity and could be blocked by using small-molecule DYRK1 inhibitors. In conclusion, our study identifies DYRK1B as an indirect p53 target that suppresses p53-mediated activation of RFX7. These findings suggest that pharmacological inhibition of DYRK1B may represent a therapeutic strategy to enhance RFX7 tumor suppressor function.

Bisphenol S (BPS) is ubiquitously used as a substitute for Bisphenol A (BPA) in various consumer and industrial products. However, recent evidence has shown its detrimental effects on human health. Moreover, toxicological data regarding its cyto-genotoxic potential remains underreported. This study evaluated the BPS induced dose dependent cytotoxicity, DNA damage and DNA repair related gene expression in Madin-Darby Bovine Kidney (MBDK) cell line. In MTT (3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, a significant reduction in cell viability was observed as the concentrations of BPS increased, with 50% of viability noted at 120 µM following 24 hrs exposure. Cyto-genotoxic effects were assessed using alkaline comet and micronucleus assays. A dose-dependent increase in DNA damage and micronucleus frequency was observed, especially above 120 µM dose concentration of BPS (P ≤ 0.05). The gene expression analysis through quantitative real time PCR (qRT-PCR) revealed upregulated expression rates of 8-Oxoguanine DNA Glycosylase 1 (OGG1) and hypoxanthine phosphoribosyltransferase 1(HPRT 1), particularly at 240 µM of BPS (P ≤ 0.05). This upregulation suggests the activation of oxidative DNA repair and nucleotide salvage pathways as triggered responses to genotoxic stress. The results of this study raise serious concerns regarding the cyto-genotoxic safety of BPS, thereby warranting the urgent need to reassess its safety profile and regulate its widespread use.

Colorectal cancer (CRC) is the most prevalent digestive system malignancy worldwide. The development of targeted therapeutics specifically effective for CRC is currently in dire need. Preclinical studies showed that CDK4/6 inhibitor palbociclib suppressed the growth of CRC, but whether this effect is durable is unclear. In this study, we aimed to evaluate the roles of palbociclib-induced senescence and find a new strategy to maximize its effectiveness in CRC treatment. Animal and cellular experiments revealed that palbociclib-induced senescence and the senescence-associated secretory phenotype (SASP) caused drug resistance, anti-apoptosis, PD-L1 upregulation and inhibition of CD8+ T cells' function. Using CRISPR/Cas9 screening, we identified MCL1 as a senolytic target to eliminate palbociclib-induced senescent CRC cells in the presence of palbociclib. Mechanically, palbociclib-induced senescent cells upregulated ZHX2 and its transcriptional target MCL1, rendered their resistance to apoptosis and T cell-mediated cytotoxicity, whereases combining palbociclib with MCL1 inhibitor markedly induced apoptosis in senescent cells by activating both extrinsic and intrinsic apoptotic pathways. Lastly, we proposed a seno-therapy consisting of a palbociclib pre-treatment plus a combination treatment of palbociclib and MCL1 inhibitor and found it effectively inhibited tumor growth and improved the survival of CRC xenografted mice. Besides its senolytic effect, seno-therapy also reduced PD-L1-positive cells and enhancing the cytotoxic functions of CD8+ T cells. In conclusion, co-targeting CDK4/6 and MCL1 efficiently eliminates palbociclib-induced senescent CRC cells and offers a promising CDK4/6 inhibitor-based strategy for CRC treatment, ensuring prolonged tumor suppression and reducing the risk of progression or recurrence.

Cancer progression involves coordinated regulation of oncogenes and tumor suppressors. This study explores the interplay of ENOX2 (ecto-NADH oxidase disulfide-thiol exchanger 2), MMP2 (matrix metalloproteinase-2), and regulatory genes Ras Association Domain Family Member 1, Isoform A (RASSF1A), WAP Four-Disulfide Core Domain Protein 10A (WFDC10A), and Methyltransferase-Like Protein 7A (METTL7A) across multiple cancer cell lines, and evaluates the anticancer potential of repurposed mebendazole.

Cell division cycle 20 homolog (CDC20), a critical substrate-recruiting subunit of the anaphase-promoting complex/cyclosome (APC/C), binds to APC/C to form the active APC/C-CDC20 complex, which regulates the degradation of key cell cycle substrates to ensure accurate and timely mitotic progression. Accumulating evidence demonstrates that CDC20 functions as an oncogenic factor, with its overexpression observed in various malignancies. Its dysregulation is closely associated with tumor initiation, progression, drug resistance, and poor clinical outcomes, underscoring its potential as a therapeutic target in anti-cancer strategies. In this review, we describe the biological functions of CDC20 in cancers, discuss its role and underlying mechanisms in solid tumors and hematological malignancies, and elucidate currently reported CDC20-targeted inhibitors along with their clinical benefits and challenges. By emphasizing the oncogenic significance of CDC20, we propose that the development of specific, safe, and potent CDC20 inhibitors could provide a promising therapeutic approach for cancer patients exhibiting CDC20 overexpression.