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The occurrence and progression of traumatic brain injury involve a complex process. The pathophysiological mechanisms triggered by neuronal damage include various forms of programmed cell death, including ferroptosis. We observed upregulation of TNFAIP3 in mice after traumatic brain injury. Overexpression of TNFAIP3 inhibits HT-22 proliferation and cell viability through ferroptosis. Mechanistically, TNFAIP3 interacts with the HMOX1 protein and promotes its stability through the deubiquitination pathway. Additionally, TNFAIP3 can enhance lipoperoxidation, mitochondrial damage, and neuronal cell death by promoting ACSL3 degradation via NEDD4-mediated ubiquitination. Mice injected with AAV-shTNFAIP3 exhibited reduced neuronal degeneration and improved motor and cognitive function following cortical impact injury. In conclusion, our findings demonstrate that TNFAIP3 deficiency inhibits neuronal cell ferroptosis and ameliorates cognitive impairment caused by traumatic brain injury and demonstrate its potential applicability in the treatment of traumatic brain injury. [Display omitted] • Brain injury boosts TNFAIP3, affecting neurons via ferroptosis. • TNFAIP3 alters HMOX1 stability through deubiquitination. • It promotes ACSL3 degradation, enhancing lipoperoxidation, mitochondrial damage, and neuronal death via NEDD4. [ABSTRACT FROM AUTHOR]

Cervical cancer (CC) is a significant global health issue and remains one of the leading causes of cancer-related mortality in women. Radiotherapy is a crucial treatment modality for CC; however, tumor heterogeneity and resistance to radiotherapy often result in suboptimal outcomes for some patients, including recurrence and metastasis. Periostin (POSTN), a matricellular protein within the tumor microenvironment, has been implicated in the promotion of tumor progression and treatment resistance, particularly through mechanisms such as epithelial-mesenchymal transition (EMT). Despite this, the role of POSTN in radiotherapy resistance in CC patients remains underexplored. Therefore, in this study, we investigated the prognostic significance of POSTN expression in CC patients undergoing radical radiotherapy and explored potential mechanisms underlying radiotherapy resistance. We analyzed data from 92 CC patients in The Cancer Genome Atlas (TCGA) and 153 patients from our institution, assessing POSTN expression levels through mRNA analysis and immunohistochemistry (IHC). Our findings revealed that high POSTN expression was significantly associated with advanced tumor stages, poorer radiotherapy outcomes, and worse overall survival (OS). Additionally, multivariate Cox regression analysis identified POSTN as an independent prognostic factor for CC patients undergoing radical radiotherapy. A prognostic nomogram integrating POSTN expression and clinicopathological features demonstrated superior predictive accuracy for OS. Drug sensitivity analysis suggested that high POSTN expression may be linked to resistance to multiple chemotherapeutic agents. Furthermore, weighted correlation network analysis (WGCNA) and gene set enrichment analysis (GSEA) identified EMT as a top enriched pathway in patients with high POSTN expression, suggesting it may play a critical role in radiotherapy resistance. Subsequently, in vitro experiments confirmed that POSTN knockdown significantly inhibited HeLa cell proliferation, invasion, and enhanced radiosensitivity, while promoting apoptosis. These findings indicate that high POSTN expression is a risk factor for poor prognosis in CC patients undergoing radical radiotherapy, and targeting POSTN may improve radiotherapy efficacy by reducing tumor proliferation and resistance. [ABSTRACT FROM AUTHOR]

Phosphodiesterase 4D interacting protein (PDE4DIP) is a Golgi/centrosome-associated protein that plays critical roles in the regulation of microtubule dynamics and maintenance of the Golgi structure. However, its biological role in human cancer remains largely unknown. In this study, we showed that PDE4DIP is overexpressed in human non-small cell lung cancer (NSCLC) tissues and that upregulated PDE4DIP expression is associated with poor prognosis in patients with lung cancer. We demonstrated that PDE4DIP knockdown inhibits NSCLC cell proliferation in vitro and tumorigenicity in vivo. We further demonstrated that PDE4DIP knockdown triggers apoptosis and cell cycle arrest in NSCLC cells by activating the Protein kinase A (PKA) /CREB signalling pathway. PDE4DIP coordinates with A-kinase anchoring proteins 9 (AKAP9) to enhance the Golgi localization and stability of PKA RIIα. Depletion of PDE4DIP mislocalizes PKA RIIα from the Golgi and leads to its degradation, thereby compromising its negative regulatory effect on PKA signalling. Overall, our findings provide novel insights into the roles of the PDE4DIP-AKAP9 complex in regulating PKA signalling and NSCLC growth and highlight PDE4DIP as a promising therapeutic target for NSCLC. Mechanistic exploration of PDE4DIP in the progression of non-small cell lung cancer (NSCLC) demonstrates that PDE4DIP coordinates with AKAP9 to promotes NSCLC growth via regulating PKA/CREB signaling pathway. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most lethal primary tumor of the central nervous system, with its resistance to treatment posing significant challenges. This study aims to develop a comprehensive prognostic model to identify biomarkers associated with temozolomide (TMZ) resistance. We employed a multifaceted approach, combining differential expression and univariate Cox regression analyses to screen for TMZ resistance-related differentially expressed genes (TMZR-RDEGs) in GBM. Using LASSO Cox analysis, we selected 12 TMZR-RDEGs to construct a risk score model, which was evaluated for performance through survival analysis, time-dependent ROC, and stratified analyses. Functional enrichment and mutation analyses were conducted to explore the underlying mechanisms of the risk score and its relationship with immune cell infiltration levels in GBM. The prognostic risk score model, based on the 12 TMZR-RDEGs, demonstrated high efficacy in predicting GBM patient outcomes and emerged as an independent predictive factor. Additionally, we focused on the molecule TSPAN13, whose role in GBM is not well understood. We assessed cell proliferation, migration, and invasion capabilities through in vitro assays (including CCK-8, Edu, wound healing, and transwell assays) and quantitatively analyzed TSPAN13 expression levels in clinical glioma samples using tissue microarray immunohistochemistry. The impact of TSPAN13 on TMZ resistance in GBM cells was validated through in vitro experiments and a mouse orthotopic xenograft model. Notably, TSPAN13 was upregulated in GBM and correlated with poorer patient prognosis. Knockdown of TSPAN13 inhibited GBM cell proliferation, migration, and invasion, and enhanced sensitivity to TMZ treatment. This study provides a valuable prognostic tool for GBM and identifies TSPAN13 as a critical target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Myocardial dysfunction is a crucial determinant of the development of heart failure in salt‐sensitive hypertension. Ferroptosis, a programmed iron‐dependent cell death, has been increasingly recognised as an important contributor to the pathophysiology of various cardiovascular diseases. This study aims to investigate the role and underlying mechanism of ferroptosis in high‐salt (HS)‐induced myocardial damage. Our results reveal that HS stimulation inhibited cell proliferation and promoted apoptosis in cardiomyocyte HL‐1 cells in a dose‐dependent manner. Ferroptotic features were observed in HS‐induced HL‐1 cells, including ferric iron accumulation, decreased glutathione levels, increased oxidative stress levels, upregulation of ferroptosis marker proteins PTGS2, 4HNE and FTH1 and downregulation of GPX4, all of which were reversed by treatment with the ferroptosis suppressor Fer‐1. Furthermore, the administration of Fer‐1 ameliorated HS‐induced ferroptosis and myocardial damage in salt‐sensitive Dahl SS rats. Additionally, we found that a HS diet suppressed the SIRT1/Nrf2 signalling pathway activation in our in vivo experiments. Activation of SIRT1/Nrf2 signalling by SIRT1 overexpression significantly attenuated ferroptosis in HS‐induced HL‐1 cells. In conclusion, our findings demonstrate that HS levels induce myocardial injury by promoting ferroptosis via the deactivation of the SIRT1/Nrf2 signalling pathway, highlighting the potential for therapeutic targeting of ferroptosis for hypertension‐related cardiovascular disorders. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs play an important role in regulating lung adenocarcinoma (LUAD). Bioinformatics analysis identified circ_0015278 as differentially expressed in LUAD. However, the biological mechanism of circ_0015278 in LUAD has not been fully clarified, especially in ferroptosis. Materials and Methods: Bioinformatics analysis was employed to explore the downstream mechanisms of Circ_0015278, subsequently confirmed by luciferase reporter assays. The impact of Circ_0015278 on cell proliferation, migration, invasion, and ferroptosis was investigated through a loss-of-function experiment. A xenotransplantation mouse model elucidated the effect of Circ_0015278 on tumour growth. Results: Circ_0015278 exhibited downregulation in LUAD. It inhibited cell proliferation, migration, and invasion while promoting ferroptosis by interacting with miR-1228 to regulate P53 expression through a competitive endogenous RNA mechanism. Moreover, circ_0015278 suppressed tumour growth in mice. Conclusions: Circ_0015278 was identified as a novel factor promoting ferroptosis in LUAD. Furthermore, it suppressed the malignant progression of LUAD through the miR-1228/P53 axis. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the regulatory effects of long non-coding RNA-ANRIL on CDKN2A in the cell cycle of Kasumi-1 cells and elucidate the underlying molecular mechanisms. Methods: ANRIL and CDKN2A expression levels were quantified using RT-qPCR in peripheral blood samples from acute myeloid leukemia (AML) patients. CDKN2A knockdown efficiency was validated via RT-qPCR, and cell cycle distribution was analyzed using flow cytometry. Cell proliferation assays were conducted with CCK-8 following palbociclib treatment and CDKN2A downregulation. RNA immunoprecipitation (RIP) identified potential ANRIL-associated targets, while western blotting assessed the expression levels of GSK3β/β-catenin/cyclin D1 signaling components and related proteins. Results: ANRIL and CDKN2A were markedly overexpressed in AML patient samples. Knockdown of ANRIL and CDKN2A led to G1 phase arrest accompanied by reduced CDK2/4/6 and cyclin D1 protein levels, while ANRIL upregulation induced the opposite effect. Palbociclib treatment for 24 h and 48 h elevated the G1 phase cell population and suppressed CDK2/4/6 and cyclin D1 protein expression, demonstrating its ability to counteract ANRIL-driven cell cycle progression. Downregulation of ANRIL and CDKN2A also suppressed the GSK3β/β-catenin signaling pathway, reducing cyclin D1 expression, whereas ANRIL upregulation reactivated this axis. Co-transfection experiments showed that simultaneous cyclin D1 suppression and ANRIL overexpression attenuated ANRIL's stimulatory effects on cell cycle progression. RIP analysis confirmed a physical interaction between ANRIL and CDKN2A. Furthermore, CDKN2A downregulation inhibited cell proliferation and reversed GSK3β/β-catenin/cyclin D1 pathway activation mediated by ANRIL upregulation. Conclusion: ANRIL facilitates Kasumi-1 cell survival by modulating CDKN2A to activate the GSK3β/β-catenin/cyclin D1 signaling pathway. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma(HCC) has a high mortality and morbidity rate and seriously jeopardizes human life. Chemicals and chemotherapeutic agents have been experiencing problems such as side effects and drug resistance in the treatment of HCC, which cannot meet the needs of clinical treatment. Therefore, finding novel low-toxicity and high-efficiency anti-hepatocellular carcinoma drugs and exploring their mechanisms of action have become the current problems to be solved in the treatment of HCC. Several studies have reported anticancer effects of inotodiol. This study focuses on the anticancer effect of inotodiol in HCC cells and its molecular mechanism, aiming to explore its anticancer effect in depth. The CCK8 assay was utilized to assess cell viability, the scratch assay was utilized to detect migration ability, the clone formation assay was utilized to detect clonogenic ability, and flow cytometry was utilized to analyze apoptosis and cell cycle. Animal experiments was utilized to verify the inhibitory effect of inotodiol on HCC. Meanwhile, western blotting was utilized to detect proteins associated with apoptosis, cell cycle and MAPK/ERK pathway. These results showed that inotodiol has the ability to promote apoptosis, as well as inhibit the ability of cell proliferation, migration, and clonogenic ability. The cell cycle was arrested in G1 phase, when the expression of CDK2, CDK4, CDK6 and Cyclin D were inhibited. In addition, inotodiol showed to induce apoptosis, characterized by an increase in Bax expression, a decrease in Bcl-2, Bcl-XL and MCL1 expression, the initiation of cleaved PARP1 and cleaved caspase 3, and inhibition of the MAPK/ERK pathway. Animal studies demonstrated that inotodiol possessed the ability to suppress tumor growth in nude mice models, at the same time, there was no significant impact on the body weight and organs of the mice. In conclusion, the findings presented herein compellingly suggest that inotodiol may serve as a promising candidate for the treatment of hepatocellular carcinoma (HCC). [ABSTRACT FROM AUTHOR]

Introduction: Pyrogallol is a catechin compound, as an active ingredient extracted from Emblica officinalis, has antiproliferative and antiapoptotic effects on some of the human cancer cells. Cisplatin is known as an effective chemotherapeutic agent against cancer by inducing DNA damage and apoptosis. However, the effect of pyrogallol alone and in combination with cisplatin on proliferation and apoptosis of ovarian cancer has not yet been reported. Methods: In the present study, ovarian carcinoma cell line A2780 was cultivated, and the anticancer properties of pyrogallol and cisplatin determined by cell treatment of the two drugs separately and combination. Cell viability and apoptosis rate was investigated by MTT assay and flow cytometry. The effects of the compounds in inhibiting colony formation and migration were measured by colony formation and scratch methods. Results: The results of the present study revealed that pyrogallol significantly inhibited the proliferation of A2780 cells in a dose-dependent manner. The combination treatment of pyrogallol and cisplatin exhibited a prominent inhibitory effect on the growth, colony formation and migration, and increased the induction of apoptosis up to 2.5 times compared to single treatments. Also, the qPCR results showed a significant increase in the expression of miR-15a and a decrease in the expression of miRNA target genes under treatment with the drugs both separately and in their combination. Conclusion: This study suggests that the combination treatment of pyrogallol and cisplatin significantly increases the death of ovarian cancer cells by inducing apoptosis. Therefore, it can boost the efficacy of chemotherapy and reduce its side effects. It is hoped that the findings of the present study can provide a new perspective for pyrogallol as a therapeutic agent in the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Reduced expression of thyroid hormone receptors (TRs) has been observed in various human malignancies, though its predictive value in hepatocellular carcinoma (HCC) remains uncertain. Objective: To explore the predictive value of TRs in patients with hepatocellular carcinoma. Design: The design was bioinformatic analysis combined with experimental study. Methods: This study utilized Kaplan-Meier analysis of TR expression profiles from The Cancer Genome Atlas (TCGA). Expression levels of TRs in HCC and immune single cells were assessed using datasets from the Gene Expression Omnibus (GEO) and TCGA, analyzed with R software. Cox and logistic regression analyses were also conducted. Functional assays, including wound healing, CCK-8, and Transwell migration assays, were employed to investigate the role of the THRB gene. Results: Kaplan-Meier analysis revealed that low THRB expression was significantly associated with reduced overall survival (OS), 5-year OS and disease-specific survival (DSS) in HCC patients (P < 0.05), while no significant association was found with THRA expression. Both Cox regression and logistic regression identified low THRB expression as an independent risk factor for HCC. THRB expression was significantly downregulated in tumor tissues compared to non-tumorous tissues in 3 GEO datasets and the TCGA profile. Functional assays confirmed that THRB inhibited HCC cell proliferation and migration. Additionally, single-cell RNA sequencing revealed that THRB was primarily expressed in CD16+ monocytes within tumor tissues and was associated with a poor OS rate. Conclusion: Reduced THRB expression, but not THRA, was correlated with decreased OS in HCC patients. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer with a high metastatic rate and high mortality rate. The molecular mechanism of ccRCC development, however, needs further study. Aurora kinase B (AURKB) functions as an important oncogene in various tumors; therefore, in the present study, we aimed to explore the mechanism by which AURKB affects ccRCC development. Methods: We performed bioinformatics analysis, CCK-8 assay, RNA sequencing, RT-PCR and Western blot to analyze the function and mechanism of AURKB in ccRCC. Results: TIMER2.0 showed that AURKB was overexpressed in Kidney Renal Clear Cell Carcinoma (KIRC), the UALCAN database showed the survival rate of KIRC patients with different expression levels of AURKB and different gender indicated in the same gender, high AURKB expression predicts lower survival rate. Silencing of AURKB expression inhibits the proliferation of ccRCC cells. RNA-seq data suggested that AURKB is involved in fatty acid metabolism. Silencing of AURKB inhibited the expression of fatty acid synthase (FASN). FASN is a key gene involved in fatty acid metabolism. TIMER2.0 showed that FASN is upregulated in KIRC. Silencing of FASN inhibited the proliferation of ccRCC cells. Conclusions: AURKB induces the proliferation of ccRCC cells by regulating fatty acid metabolism. [ABSTRACT FROM AUTHOR]

The Warburg effect, characterized by the shift toward aerobic glycolysis, is closely associated with the onset and advancement of tumors, including multiple myeloma (MM). Nevertheless, the specific regulatory mechanisms of glycolysis in MM and its functional role remain unclear. In this study, we identified that growth differentiation factor 15 (GDF15) is a glycolytic regulator, and GDF15 is highly expressed in MM cells and patient samples. Through gain-of-function and loss-of-function experiments, we demonstrated that GDF15 promotes MM cell proliferation and inhibits apoptosis. Moreover, GDF15 enhances Warburg-like metabolism in MM cells, as evidenced by increased glucose uptake, lactate production, and extracellular acidification rate, while reducing oxidative phosphorylation. Importantly, the tumor-promoting effects of GDF15 in MM cells are fermentation-dependent. Mechanistically, GDF15 was found to promote the expression of key glycolytic genes, particularly the glucose transporter GLUT1, through the activation of the TGFβ signaling pathway. Pharmacological inhibition of the TGFβ signaling pathway effectively abrogated the oncogenic activities of GDF15 in MM cells, including cell proliferation, apoptosis, and fermentation. In vivo experiments using a subcutaneous xenotransplanted tumor model confirmed that GDF15 knockdown led to a significant reduction in tumor growth, while GDF15 overexpression promoted tumor growth. Overall, our study provides insights into the molecular mechanisms underlying MM pathogenesis and highlights the potential of targeting GDF15-TGFβ signaling -glycolysis axis as a therapeutic approach for future therapeutic interventions in MM. [ABSTRACT FROM AUTHOR]

Introduction: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors in oral and maxillofacial region. The development of new chemotherapy agents and new drug combinations may improve patient survival and quality of life, but both surgery and radiotherapy have significant functional side effects and drug resistance, ultimately resulting in a 5-year survival rate of no more than 60% for OSCC patients. Studies have shown that Brucea javanica oil (BJO) extracts have anti-cancer effects against a variety of cancers, but little research has been reported on OSCC. Methods: CCK8, Colony formation, Scratch test and Transwell invasion assays were applied to determine the effects of BJO on the proliferation, migration, and invasion ability of OSCC cells in vitro. MTFR2 knockdown (shRNA) and overexpression (cDNA) OSCC cells were constructed to evaluate the effect of MTFR2 on the proliferation and invasion of OSCC cells. The nude mouse model of subcutaneous xenograft tumor was used to evaluate the effect of BJO on OSCC cells in vivo. PCR, western blot and immunohistochemistry were used to verify the expression of MTFR2, glycolysis markers and related pathway molecules after BJO treatment. Results: In vivo experiments using nude mice with xenografted OSCC cells and in vitro experiments with OSCC cell lines demonstrated that BJO treatment significantly inhibited the proliferation, migration, and invasiveness of OSCC cells. WB and PCR proved that BJO could effectively reduce the expression levels of MTFR2 and SOD2/H2O2 related signal transduction pathways. At the same time, the expression of oxidative phosphorylation markers increased, the expression of glycolytic markers decreased, and glycolysis-mediated decomposition of reactive oxygen species decreased, and H2O2 and oxygen levels decreased.In addition, when MTFR2 expression increased or decreased, SOD2/H2O2 expression also increased or decreased. Discussion: In this study, we concluded through in vitro and in vivo experiments that BJO may affect the SOD2/H2O2 signaling pathway by down-regulating MTFR2-mediated aerobic glycolysis, thereby inhibiting cell proliferation, Migration, and Invasion. The elucidation of this mechanism helps us to understand the molecular mechanism ofinhibiting OSCC invasion and metastasis by BJO, which has important clinical value or improving the survival rate of OSCC patients. [ABSTRACT FROM AUTHOR]

Background: Metastasis is a leading cause of cancer-related death in castration-resistant prostate cancer (CRPC) patients. Circular RNAs (circRNAs) have emerged as key regulators of the metastasis of various cancers. However, the functional effects and regulatory mechanisms of circRNAs in metastatic CRPC (mCRPC) remain largely unknown. Methods: The expression of circBNC2 in prostate cancer (PCa), CRPC and neuroendocrine prostate cancer (NEPC) tissues was analyzed through bioinformatics analysis. Functional assays, including cell proliferation, migration, invasion and ferroptosis, were conducted in vitro and in vivo. The interactions between circBNC2, miR-4298, and ACSL6 were explored via luciferase reporter assays, RNA immunoprecipitation, and western blotting analysis. In addition, for the first time in PCa, we developed novel nanobowls (NBs) loaded with docetaxel (DTX) and circBNC2 (Dc-NBs) and evaluated the antitumor efficacy of Dc-NBs in a photothermal therapy (PTT) strategy. Results: We identified a novel tumor-suppressive circRNA, circBNC2, in human PCa, CRPC and NEPC samples via bioinformatic analysis. CircBNC2 expression was significantly downregulated in PCa tissues and PCa cell lines. Functional assays demonstrated that circBNC2 inhibited PCa cell proliferation and migration both in vitro and in vivo. Mechanistically, circBNC2 acted as a sponge for miR-4298, and ACSL6 was identified as a direct target of the circBNC2/miR-4298 axis. Moreover, we demonstrated that ACSL6 is essential for mediating circBNC2-regulated ferroptosis in PCa cells. More importantly, we demonstrated the nanodelivery of Dc-NBs, which exhibited significant antitumor effects in both subcutaneous and metastatic PCa models. Conclusion: This study revealed the tumor-suppressive role of circBNC2 in mCRPC by driving ferroptosis via the circBNC2/miR-4298/ACSL6 axis. Additionally, we developed an efficient and safe PTT strategy based on a nanodelivery system that codelivers circBNC2 and DTX, highlighting its potential as a novel therapeutic approach for mCRPC. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer (BC) is the most prevalent malignant tumor in women, with triple-negative breast cancer (TNBC) showing the poorest prognosis among all subtypes. Glycosylation is increasingly recognized as a critical biomarker in the tumor microenvironment, particularly in BC. However, the glycosylation-related genes associated with TNBC have not yet been defined. Additionally, their characteristics and relationship with prognosis have not been deeply investigated. Methods: Transcriptomic analyses were used to identify a glycosylation-related signature (GRS) associated with TNBC prognosis. A machine learning-based prediction model was constructed and validated across multiple independent datasets. The model's predictive capability was extended to evaluate the prognosis of TNBC individuals, tumor immune microenvironment and immunotherapy response. LMAN1L (Lectin, Mannose Binding 1 Like) was identified as a novel prognostic marker in TNBC, and its biological effects were validated through experimental assays. Results: The GRS showed significant prognostic relevance for TNBC patients. The risk model effectively predicted molecular features, including immune cell infiltration and potential responses to immunotherapy. Experimental validation confirmed LMAN1L as a novel glycosylation-related prognostic gene, with low expression significantly inhibiting TNBC cell proliferation and migration. Discussion: Our GRS risk model demonstrates robust predictive capability for TNBC prognosis and immunotherapy response. This model offers a promising strategy for personalized treatment and improved clinical outcomes in TNBC. [ABSTRACT FROM AUTHOR]

The role of the dynein light chain Tctex-type 3 (DYNLT3) protein in the biological behavior of cervical cancer and its relative molecular mechanisms were investigated. Immunohistochemical staining was used to detect DYNLT3 protein expression in cervical cancer tissues. Cell proliferation and apoptosis rates and invasiveness and migratory capacities were determined by CCK-8 assays, BrdU staining assays and colony formation assays, fluorescence activated cell sorting (FACS), wound healing assays, and Transwell invasion assays of cervical cancer cells after DYNLT3 modulation. The expression levels of Wnt signaling pathway- and EMT-related proteins were examined by Western blotting. Furthermore, the effects of DYNLT3 on the tumorigenicity and metastasis of cervical cancer in nude mice were analyzed by performing immunohistochemistry, and we found that the expression level of the DYNLT3 protein was higher in human normal cervical tissues than in cervical cancer tissues. Overexpression of DYNLT3 obviously attenuated the proliferation, migration and invasion of CaSki and SiHa cells, and promoted cell apoptosis. Upregulation of DYNLT3 expression markedly decreased the expression of Wnt signaling pathway-related proteins (Dvl2, Dvl3, p-LRP6, Wnt3a, Wnt5a/b, Naked1, Naked2, β-catenin and C-Myc) and EMT-related proteins (N-cadherin, SOX2, OCT4, vimentin and Snail), and increased the expression of E-cadherin and Axin1. However, the opposite results were observed after down-regulation of DYNLT3 expression. Up-regulation of DYNLT3 expression significantly inhibited tumor growth in a nude mouse model, while downregulation of DYNLT3 showed the opposite results. In addition, the major metastatic site of cervical cancer cells in mice was the lung, and downregulation of DYNLT3 expression increased cancer metastasis in vivo. DYNLT3 exerted inhibitory effects on cervical cancer by inhibiting cell proliferation, migration and invasion, promoting cell apoptosis in vitro , and inhibiting tumor growth and metastasis in vivo , possibly by suppressing the Wnt signaling pathway and the EMT. [ABSTRACT FROM AUTHOR]

Introduction: Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer to treat. While previous studies have demonstrated that ginsenoside Rh2 induces apoptosis in TNBC cells, the specific molecular targets and underlying mechanisms remain poorly understood. This study aims to uncover the molecular mechanisms through which ginsenoside Rh2 regulates apoptosis and proliferation in TNBC, offering new insights into its therapeutic potential. Methods: Network analysis and transcriptome sequencing were utilized to explore the potential mechanisms of ginsenoside Rh2 in treating TNBC. In vivo imaging and immunohistochemistry were employed to examine the effects of ginsenoside Rh2 in a TNBC mouse model. Functional assays were conducted to assess the impact of ginsenoside Rh2 on TNBC cell behavior. Additionally, ELISA, Western blot, and quantitative real-time PCR were used to further investigate the mechanisms of ginsenoside Rh2-induced apoptosis in TNBC cells. Results: Through network analysis, 47 common targets were identified, and Gene Ontology (GO) enrichment analysis suggested that ginsenoside Rh2 may exert therapeutic effects in TNBC by influencing apoptosis, cell proliferation, and protein kinase activity. Both transcriptomic analysis and network analysis revealed the JAK/STAT signaling pathway as a key mechanism. Ginsenoside Rh2 inhibited tumor growth in TNBC mice and reduced the expression of IL- 6, IL-6R, STAT3, Bcl-2, and Bcl-xL in tumor tissues. The ability of ginsenoside Rh2 to inhibit TNBC cell proliferation was further confirmed by attenuating the activation of the IL-6/JAK2/STAT3 apoptosis pathway and reducing the expression of protein kinases AMPK-α1 and PKA-Cα. Conclusion: Based on network analysis and experimental validation, our findings demonstrate that ginsenoside Rh2 regulates TNBC proliferation and apoptosis through suppression of the IL-6/JAK2/STAT3 pathway, both in vitro and in vivo. This comprehensive approach represents a significant advancement in understanding the therapeutic potential of ginsenoside Rh2 in treating TNBC. [ABSTRACT FROM AUTHOR]

This study explores the influence of miR-21 and its interaction with the target gene Neurotrophin-3 (NTF3) in cervical cancer (CC). We employed bioinformatics tools, including DIANA, Targetscan, miRDB, and miRDIP, to predict the target genes of miR-21. Immunohistochemistry, RT-qPCR, and Western blotting were performed to quantify the expression levels of miR-21-5p and NTF3 in cervical cancer cells. Additionally, a dual luciferase reporter assay was conducted to examine the specific relationship between miR-21-5P and NTF3. We assessed cell behavior through various tests, including cell viability, scratch wound assays, colony formation, cell invasion experiments, and flow cytometry assays. The dual luciferase reporter assay confirmed that NTF3 is a direct target of miR-21. Overexpression of NTF3 inhibited cell proliferation and migration, while promoting apoptosis, as demonstrated by flow cytometry. Transcriptome sequencing and enrichment analyses (KEGG and GO) revealed NTF3's involvement in key oncogenic pathways, including PI3K-AKT, MAPK, and calcium signaling. This study underscores the critical role of miR-21 in regulating the proliferation, migration, and apoptosis of cervical cancer cells by targeting NTF3. [ABSTRACT FROM AUTHOR]

Numerous emerging chemotherapeutic agents incorporate N-heterocyclic fragments in their structures, with the quinoline skeleton being particularly significant. Our recent works have focused on glycoconjugates of 8-hydroxyquinoline (8-HQ), which demonstrated enhanced bioavailability and solubility compared to their parent compounds, although they fell short in selectivity. In this study, our objective was to improve the selectivity of glycoconjugates by replacing the oxygen atom with nitrogen by substituting the 8-HQ moiety with 8-aminoquinoline (8-AQ). The 8-AQ derivatives were functionalized through the amino group and linked to sugar derivatives (D-glucose or D-galactose) that were modified with an azide, alkylazide, or propargyl group at the anomeric position by copper(I)-catalyzed 1,3-dipolar azido-alkyne cycloaddition (CuAAC). The resulting glycoconjugates, as well as their potential metabolites, were evaluated for their ability to inhibit the proliferation of cancer cell lines (including HCT 116 and MCF-7) and a healthy cell line (NHDF-Neo). Two of the synthesized glycoconjugates (17 and 18) demonstrated higher cytotoxicity than their oxygen-containing counterparts and showed improved selectivity for cancer cells, thus enhancing their anticancer potential. Furthermore, it was found that glycoconjugates exhibited greater cytotoxicity in comparison to their potential metabolites. [ABSTRACT FROM AUTHOR]

Mebendazole (MBZ), a benzimidazole anthelmintic and cytoskeleton-disrupting compound, exhibits antitumor properties; however, its action on ovarian cancer (OC) is not clearly understood. This study evaluates the effect of MBZ on OC cell lines OVCAR3 and OAW42, focusing on cell proliferation, migration, invasion, and cancer stemness. The underlying mechanisms, including cytoskeletal disruption, epithelial–mesenchymal transition (EMT), and signaling pathways, were explored. MBZ inhibited OVCAR3 and OAW42 cell proliferation in a dose- and time-dependent manner. Additionally, MBZ significantly impedes migration, spheroid invasion, colony formation, and stemness. In addition, it reduced actin polymerization and down-regulated CSC markers (e.g., CD24, CD44, EpCAM). Moreover, MBZ suppressed MMP-9 activity and inhibited the EMT marker as judged by decreased N-Cadherin and Vimentin and increased E-Cadherin. Furthermore, MBZ induced G2/M cell cycle arrest by modulating Cyclin B1, CDC25C, and WEE1. Also, it triggered apoptosis by disrupting mitochondrial membrane potential. Mechanistic studies revealed a significant downregulation of Girdin, an Akt modulator, along with reduced p-Akt, p-IKKα/β, and p-NF-κB, indicating MBZ's novel mechanism of action through the Girdin-mediated Akt/IKKα/β/NF-κB signaling axis. Thus, by targeting Girdin, MBZ presents a promising repurposed therapeutic strategy to inhibit cancer cell proliferation and metastasis in ovarian cancer. [ABSTRACT FROM AUTHOR]

AbstractGastric cancer (GC) is a malignant tumor with high morbidity and mortality rates worldwide. This study aimed to investigate the effects and mechanisms of action of didymin, a dietary flavonoid glycoside, on GC treatment. Human GC cell lines Hs-746T and AGS were used to assess the effects of didymin on cell viability, cell proliferation, and cell cycle. The results showed that didymin decreased the proliferative capacity of GC cells and blocked cell cycle. Didymin decreased wound healing, invasion, and migration capacities of GC cells. Mitochondrial reactive oxygen species (ROS) levels and mitochondrial membrane potentials were reduced in cells treated with didymin. Network pharmacology analysis revealed that the therapeutic effects of didymin on AGS cells were related to the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In vivo mouse xenograft studies confirmed that didymin treatment decreased tumor cell proliferation, cell cycle protein levels, and Akt phosphorylation. The present study demonstrated that didymin regulates mitochondrial function and the PI3K/Akt pathway to inhibit cell proliferation and induce apoptosis in GC cells in vitro and in vivo. Therefore, didymin is a promising drug for the treatment of GC. [ABSTRACT FROM AUTHOR]

Deapioplatycodin D (DPD) is a triterpenoid saponin natural compound isolated from the Chinese herb Platycodon grandiflorum that has antiviral and antitumor properties. This study aimed to investigate the effects of DPD on glioblastoma (GBM) cells and to determine its intrinsic mechanism of action. Using a CCK8 assay, it was found that DPD significantly inhibited the growth of GBM cells. DPD-treated GBM cells contained swollen and degenerated mitochondria with empty vesicular bilayer membrane-like autophagic vesicle structures in the periphery of the mitochondria under transmission electron microscopy. DPD activated autophagy in GBM cells and induced a blockage of autophagic flux in the late stage. Transcriptomics identified differences in mitophagy-related genes, and analysis of the levels of the corresponding proteins indicated that mitophagy in GBM cells was induced mainly through BNIP3L. Increased expression of BNIP3L disrupts the Bcl-2-Beclin-1 complex, thereby releasing Beclin-1 and activating autophagy. Autophagy was inhibited after silencing of BNIP3L and overexpression of Bcl-2 in GBM cells, and the growth inhibitory effect of DPD was significantly reduced. This result demonstrated that DPD induces mitophagy in GBM cells through BNIP3L. Finally, activation of incomplete mitophagy in GBM cells by DPD through BNIP3L in vivo was demonstrated by establishing a mouse subcutaneous xenograft tumor model. In this study, in vitro and in vivo experiments established that DPD inhibited GBM cell growth by inducing BNIP3L-mediated incomplete mitophagy, which provides an experimental basis for studying new treatments of GBM. [ABSTRACT FROM AUTHOR]

Caesalpinia sappan L. has exhibited various pharmacological effects, yet its anticancer activities against colorectal cancer (CRC) and underlying molecular mechanisms remain unclear. This study investigated the anticancer properties of an ethanol extract of C. sappan L. (CSE) against CRC cells, focusing on the identification of bioactive compounds and their mechanisms of action. A network pharmacology analysis was conducted to identify potential CRC targets and bioactive compounds of CSE, using LC-MS for compound identification. The anticancer effects of CSE were then validated through in vitro and in vivo models of CRC. The network pharmacological approach identified 87 overlapping genes between CSE targets and CRC-related genes, with protein–protein interaction analysis highlighting 33 key target genes. CSE inhibited cell proliferation in human CRC cell lines, including HCT 116, KM12SM, HT-29, and COLO 205, and induced apoptosis via caspase 3/7 activation. Western blot analyses confirmed the modulation of critical signaling pathways, including STAT3, AKT, and mitogen-activated protein kinases. Furthermore, CSE significantly suppressed tumor growth in MC38 CRC-bearing mice. These findings suggest that CSE possesses substantial potential as a natural anticancer agent for CRC treatment, highlighting the need for further exploration in therapeutic development. [ABSTRACT FROM AUTHOR]

In this study, firstly chitin was reacted with chloracetyl chloride to synthesize the macroinitiator chitinchloroacetate (Ch.ClAc). Then, graft copolymers of methacrylamide (MAM), diacetone acrylamide (DAAM), N-(4-nitrophenyl)acrylamide (NPA), and 2-hydroxyethyl methacrylate (HEMA) monomers were synthesized by atom transfer radical polymerization (ATRP). All of the polymers were characterized by FTIR spectra and elemental analysis. According to the elemental analysis results, the mole percent (y) of the macro initiator was found to be 17.39%. The thermal stability of all the polymers (chitin, Ch.ClAc and its graft copolymers) was determined by thermogravimetric analysis (TGA) method and the highest thermal stability was observed in the ungrafted raw chitin. DPPH• scavenging activity and antitumor activity of all polymers were then investigated. Ch.ClAc was found to be the polymer that inhibited the proliferation of tumor cells more than chitin and graft copolymers. It was observed that the antitumor (L1210 cell lines) effect increased with increasing time and concentration in all polymers. [ABSTRACT FROM AUTHOR]

AbstractPurposeMaterials and methodsResultsConclusionsBreast cancer ranks as the most prevalent cancer in women, characterized by heightened fatty acid synthesis and glycolytic activity. Fatty acid synthase (FASN) is prominently expressed in breast cancer cells, regulating fatty acid synthesis, thereby enhancing tumor growth and migration, and leading to radioresistance. This study aims to investigate how FASN inhibition affects cell proliferation, migration, and radioresistance in breast cancer, as well as the mechanisms involved.We used lentiviruses carrying shFASN to create FASN-knockdown cell lines called MCF-7-shFASN and MDA-MB-231-shFASN. We conducted Western blot analysis to determine the expression levels of FASN and other proteins of interest. Furthermore, we evaluated cellular glucose uptake and migration using the 18F-FDG assay, wound healing, and transwell assays. We also employed the MTT assay to assess the short-term survival of the negative control and FASN-knockdown cells after irradiation.FASN knockdown led to a decrease in the expressions of proteins related to fatty acid synthesis and glycolysis in both MCF-7-shFASN and MDA-MB-231-shFASN cells when compared to their counterparts. Moreover, reduced 18F-FDG uptake and lactate production were also detected after FASN knockdown. FASN knockdown inhibited cell proliferation and survival by downregulating the AKT, ERK, and AMPK pathways and promoted apoptosis by increasing the BAX/p-Bcl-2 ratio. In addition, FASN knockdown impaired cell migration while enhancing radiosensitivity.FASN knockdown disrupts fatty acid synthesis and glycolysis, inhibits cell proliferation and induces apoptosis. The increased radiosensitivity after FASN inhibition suggests that it could potentially complement radiotherapy in treating breast cancer. [ABSTRACT FROM AUTHOR]

Melanoma is a highly malignant and serious form of skin cancer. In addition to the standard treatments, complementary approaches, including phytotherapy, are also used to alleviate symptoms and improve patient well-being. This study aims to investigate the anticancer effects of Gypsophila eriocalyx (GE), an endemic species from Türkiye, on melanoma cells. We set out to determine the efficacy of GE in inhibiting melanoma cell proliferation, migration, and growth, and to explore its underlying mechanisms.We examined the impact of GE on the proliferation of two melanoma cell lines, Malme-3M and SK-MEL-28, and assessed its developmental toxicity in zebrafish embryos. Next, we evaluated GE’s influence on colony formation and wound healing in melanoma cells, as well as its ability to induce apoptosis and affect the TGF-β/Smad signaling pathway, by measuring pathway reporter activity and target gene expression.GE inhibited cell proliferation in melanoma cell lines at concentrations 104 to 488 times lower than those required for normal non-malignant L929 fibroblast cells. In zebrafish embryos, GE demonstrated developmental toxicity only at concentrations above 50 μg/mL. GE treatment significantly impaired the colony formation and wound healing abilities of melanoma cells, indicating reduced proliferation and migration. Moreover, GE induced apoptosis in melanoma cells and inhibited the TGF-β/Smad signaling pathway, as evidenced by decreased pathway reporter activity and target gene expression.This study highlights the potential of GE as a novel therapeutic agent in melanoma treatment by demonstrating its ability to inhibit tumor growth and progression. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma-associated herpesvirus (KSHV) infection can cause a variety of tumors and is one of the leading causes of death in acquired immune deficiency syndrome (AIDS) patients. As a small molecule antiviral drug, ganciclovir (GCV) can be used for anti-KSHV treatment. However, GCV has non-specific action and toxic side effects in vivo, and how to make it safer and more effective against KSHV is still a great challenge. By encapsulating GCV into metal–organic skeleton material zeolitic imidazolate framework-8 (ZIF-8) and further modification of hyaluronic acid (HA), the nanomedical delivery system of GCV (HA/GCV@ZIF-8) has been developed for efficient GCV delivery and targeted anti-KSHV treatment. The modification of HA leads to the targeted binding of the nanocomplex with the overexpressed CD44 receptors in tumor cell membranes, resulting in the increased accumulation and cellular uptake of GCV. Exploiting the decomposition property of ZIF-8 under acidic conditions, the nanocomplex exhibits pH-responsive drug release in slightly acidic tumor environment. In addition, HA/GCV@ZIF-8 not only suppresses expression of KSHV pathogenic genes with less drug dose, but also inhibits the ability of cell proliferation and migration. In vivo anti-tumor results showed that HA/GCV@ZIF-8 accumulated in tumor cells and effectively inhibited tumor growth. The results open a gate for the targeted anti-KSHV treatment. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer (PC) is a highly aggressive malignancy with a poor prognosis due to its late-stage diagnosis and limited treatment options. Objectives: This study aimed to elucidate the molecular mechanisms underlying PC progression and identify potential molecular targets for its diagnosis and treatment. Methods: DAZAP1 expression in PC tissues, normal tissues and cell lines was assessed using immunohistochemistry (IHC), reverse transcription–quantitative polymerase chain reaction (RT–qPCR) and western blotting. DAZAP1 knockdown was achieved through plasmid transfection, and its effects on ferroptosis and PC progression were evaluated using RT–qPCR, western blotting, CCK-8 assays, EdU staining, Fe2+ content measurement, reactive oxygen species (ROS) detection, wound healing and Transwell migration assays. Results: DAZAP1 expression was significantly upregulated in PC tissues and cell lines compared to normal counterparts. DAZAP1 knockdown suppressed PC cell proliferation and induced ferroptosis, while ferroptosis inhibition reversed these effects, enhancing PC cell proliferation and metastasis. Conclusions: DAZAP1 suppression promotes ferroptosis, thereby inhibiting PC cell proliferation and metastasis. These findings suggest that DAZAP1 is a potential therapeutic target for PC. Highlights: DAZAP1 facilitates the proliferation and metastasis of pancreatic cancer; Downregulation of DAZAP1 in pancreatic cancer promotes ferroptosis; DAZAP1 regulates pancreatic cancer proliferation and metastasis through ferroptosis; DAZAP1 has therapeutic potential in pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate effect of rapamycin on proliferation of human chronic lymphoblastic leukemia tumor cell MEC-1 in vitro. Methods: Human γδT cells were cultured and expanded in vitro. Human γδT cells percentage was detected by flow cytometry on the 10th day. γδT cells were treated with different concentrations of rapamycin (0，50，100 and 200 nmol/L). After 48 h of intervention, IL-17, IL-12, IFN-γ and TNF-α contents secreted by γδT cells were determined by ELISA, and AKT/mTOR protein expression was detected by Western blot. Supernatant of γδT was collected and co-cultured with MEC-1 indirectly. Co-cultured experi‐ mental was divided into DMSO group, rapamycin group，γδT group, rapamycin treated γδT group and control group. Survival rate of MEC-1 cells in each group was determined by CCK-8 after 48 h of culture. Results: IL-12, IFN-γ and TNF-α levels secreted by γδT cells were the highest when rapamycin was 100 nmol/L, which was significantly higher than other groups (P<0.05). When rapamycin was 50 nmol/L, IL-17 secretion level of γδT cells was the highest, and IL-17 level secreted by γδT cells gradually decreased with increase of rapamycin concentration. Survival rates of MEC-1 cells in supernatant of DMSO group, rapamycin group, rapamycin treated γδT cell group and γδT cell group were (93.48±2.52) %， (71.44±4.31) %, (83.93±1.54) % and (57.97±2.47) %, whose differences were statistically significant compared with control group (P<0.05). Compared with control group, mTOR protein level of γδT cells was decreased in all rapamycin treated groups. Protein expressions of upstream AKT, pAKT and downstream specific transcription factor 4EBP-1 were decreased with increase of rapamycin concentration (P<0.05). Conclusion: There is a dose-effect relationship between rapamycin concentration and IL-17, IL-12, IFN-γ, TNF-α secretions by γδT cells. Rapamycin and γδT cells can inhibit proliferation of MEC-1 cells, and 100 nmol/L rapamycin can enhance inhibitory effect of γδT cells on proliferation of MEC-1 cells. Rapa‐ mycin can weaken AKT pathway on γδT cells, and rapamycin combined with γδT cells plays a positive role in anti-tumor application of leukemia. [ABSTRACT FROM AUTHOR]

Bladder cancer is notorious for its high recurrence and costly treatment burden, prompting a search for novel therapeutic targets. Our study focuses on HSPB6, a small heat shock protein whose reduced expression in bladder cancer suggests a role in tumor biology. Using an integrative approach of bioinformatics, RNA sequencing, and cell-based assays, we show that HSPB6 upregulation inhibits cancer cell proliferation and metastasis while promoting apoptosis. Moreover, TCF7L1-mediated upregulation of HSPB6 leads to suppression of the PI3K/AKT/mTOR signaling pathway, a key driver of cancer progression. These results position HSPB6 as a compelling target for bladder cancer therapy, and its regulatory role in the PI3K/AKT/mTOR axis underscores its therapeutic potential. Our findings pave the way for future investigations into HSPB6-centered treatment strategies. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is the most common malignant tumor of the digestive tract. However, the molecular pathogenesis is not well understood. Through bioinformatic analysis and analyzing clinical tissue samples, we found that E2F1 and E2F7 as well as their potential downstream target MYBL2 were all upregulated in GC tissues and that their expressions correlated with patient prognosis. While knockdown of E2F1 or MYBL2 inhibited cell proliferation and promoted apoptosis, knockdown of E2F7 promoted cell proliferation but had no effects on apoptosis. Chromatin immunoprecipitation and dual luciferase reporter assays demonstrated that MYBL2 was transcriptionally activated and repressed by E2F1 and E2F7, respectively. Importantly, in vitro and ex vivo experiments demonstrated that the effects of E2F1 and E2F7 on GC cell proliferation were significantly attenuated by reversely modulating MYBL2 expression, indicating that MYBL2 is a direct and functionally relevant target of E2F1 and E2F7 in GC cells. Furthermore, the effects of E2F1 and E2F7 on GC cell proliferation through transcriptional regulation of MYBL2 can be mediated by the PI3K/AKT signaling pathway. Interestingly, we found differential nucleocytoplasmic distribution of E2F7 in GC cells with functional relevance. Taken together, our data suggest that targeted therapies of GC may be achieved from three different angles, E2F1, E2F7, and MYBL2 themselves, E2F1/E2F7 expression balance, and E2F7 nuclear localization. [ABSTRACT FROM AUTHOR]

The different spatiotemporal distribution of progenitor and neurogenic capacities permits that brain regions engage asynchronously in neurogenesis. In the hindbrain, rhombomere progenitor cells contribute to neurons during the first neurogenic phase, whereas boundary cells participate later. To analyze what maintains boundary cells as non-neurogenic progenitors, we addressed the role of Her9, a zebrafish Hes1-related protein. her9 expression is temporarily sustained in boundary cells independently of Notch at early embryonic stages, while they are non-neurogenic progenitors. Complementary functional approaches show that Her9 inhibits the onset of Notch signaling and the neurogenic program, keeping boundary cells as progenitors. Multicolor clonal analysis combined with genetic perturbations reveal that Her9 expands boundary progenitors by promoting symmetric proliferative and preventing neurogenic cell divisions. Her9 also regulates the proliferation of boundary cells by inhibiting the cell cycle arrest gene cdkn1ca and interplaying with Cyclin D1. Moreover, her9 is enriched in hindbrain radial glial cells at late embryonic stages independently of Notch. Together these data demonstrate that Her9 maintains the stemness properties of hindbrain boundary progenitors and late radial glial cells, ensuring the different temporal distribution of neurogenic capacities within the hindbrain. [ABSTRACT FROM AUTHOR]

Curcumin, a bioactive compound derived from the rhizome of Curcuma longa L., has garnered significant attention for its potent anticancer properties. Despite its promising therapeutic potential, its poor bioavailability, rapid metabolism, and low water solubility hinder curcumin's clinical application. Nanotechnology offers a viable solution to these challenges by enabling the development of curcumin-based nanoparticles (CNPs) that enhance its bioavailability and therapeutic efficacy. This review provides a comprehensive overview of the recent advancements in the design and synthesis of CNPs for cancer therapy. We discuss various NP formulations, including polymeric, lipid-based, and inorganic nanoparticles, highlighting their role in improving curcumin's pharmacokinetic and pharmacodynamic profiles. The mechanisms by which CNPs exert anticancer effects, such as inducing apoptosis, inhibiting cell proliferation, and modulating signaling pathways, are explored in details. Furthermore, we examine the preclinical and clinical studies that have demonstrated the efficacy of CNPs in treating different types of tumors, including breast, colorectal, and pancreatic cancers. Finally, the review addresses the current challenges and future perspectives in the clinical translation of CNPs, emphasizing the need for further research to optimize their design for targeted delivery and to enhance their therapeutic outcomes. By synthesizing the latest research, this review underscores the potential of CNPs as a promising avenue for advancing cancer therapy. [ABSTRACT FROM AUTHOR]

Cells meticulously regulate free calcium ion (Ca2+) concentrations, with the endoplasmic reticulum (ER) being crucial for Ca2+ homeostasis. Disruptions in ER Ca2+ balance can contribute to various diseases, including cancer. Although considerable research has focused on the direct mechanisms of ER Ca2+ regulation, the role of microRNAs (miRNAs) in this process remains underexplored. Mainly using data from a CRISPR-based genomic screening previously conducted in our laboratory, we identified 33 candidate miRNAs that may regulate ER Ca2+ levels. From these, 10 miRNAs were found to significantly lower basal ER Ca2+ levels. RNA sequencing analysis indicated that these miRNAs downregulate the tumor suppressor tumor protein p53 (TP53)-inducible protein 11 gene (TP53I11), which is a key regulator of ER Ca2+ levels. Functional assays confirmed that TP53I11 influences ER Ca2+ levels and affects cancer cell proliferation. Additionally, the chemotherapeutic agent doxorubicin (DOX) was shown to upregulate TP53I11 and enhance ER Ca2+ accumulation. These findings elucidate the central role of TP53I11 in miRNA-mediated regulation of ER Ca2+ homeostasis and suggest potential therapeutic strategies targeting ER Ca2+ upregulation for cancer intervention. [ABSTRACT FROM AUTHOR]

Microplastics, defined as plastic fragments smaller than 5 mm, degrade from larger pollutants, with nanoscale microplastic particles presenting significant biological interactions. This study investigates the toxic effects of polystyrene nanoplastics (PS-NPs) on juvenile mice, which were exposed through lactation milk and drinking water at concentrations of 0.01 mg/mL, 0.1 mg/mL, and 1 mg/mL. The results show that PS-NP exposure during lactation and juvenile periods caused delayed weight gain and impaired organ development, particularly in the liver and kidneys, without causing functional abnormalities or toxic injuries. The primary toxicity of PS-NPs was observed in the intestinal tract, including shortened villi, disrupted tight junctions, inhibited epithelial cell proliferation, and oxidative stress responses. These findings highlight the importance of evaluating the developmental toxicity of nanoplastics at environmentally relevant doses. [ABSTRACT FROM AUTHOR]

Erythroleukemia, a complex myeloproliferative disorder presenting as acute or chronic, is characterized by aberrant proliferation and differentiation of erythroid cells. Although nootkatone, a sesquiterpene derived from grapefruit peel and Alaska yellow cedar, has shown anticancer activity predominantly in solid tumors, its effects in erythroleukemia remain unexplored. This study aimed to investigate the impact of nootkatone and its derivatives on erythroleukemia. Our results demonstrate that the nootkatone derivative nootkatone-(E)-2-iodobenzoyl hydrazone (N2) significantly inhibited erythroleukemia cell proliferation in a concentration- and time-dependent manner. More importantly, N2 induced megakaryocytic differentiation, as evidenced by significant morphological changes, and upregulation of megakaryocytic markers CD41 and CD61. In vivo, N2 treatment led to a marked increase in platelet counts and megakaryocytic cell counts. Mechanistically, N2 activated a crosstalk between the JAK2/STAT3 and PKCδ/MAPK signaling pathways, enhancing transcriptional regulation of key factors like GATA1 and FOS. Network pharmacology and experimental validation confirmed that N2 targeted JAK2, and knockdown of JAK2 abolished N2-induced megakaryocytic differentiation, underscoring JAK2's critical role in erythroleukemia differentiation. In conclusion, N2 shows great promise as a differentiation therapy for erythroleukemia, offering a novel approach by targeting JAK2-mediated signaling pathways to induce megakaryocytic differentiation. [ABSTRACT FROM AUTHOR]

Disrupted neonatal lung alveologenesis often leads to bronchopulmonary dysplasia (BPD), the most common chronic lung disease in children. The inhibition of type 2 alveolar (AT2) cell proliferation plays an important role in the arrest of alveologenesis. However, the mechanism of AT2 cell proliferation retardation in BPD is still not fully elucidated. The purpose of the present study was to explore the effects of cyclin G1 (CCNG1) on AT2 cell proliferation in hyperoxia-induced lung injury in neonatal mice. Our findings revealed that hyperoxia significantly reduced the proportion of AT2 cells in the lungs of neonatal mice and coincided with an upregulation of CCNG1 expression. Notably, this upregulation of CCNG1 was accompanied by an increase in Wnt signaling. We observed colocalization of CCNG1 and Wnt3a within AT2 cells in the hyperoxia group. Further analysis showed that inhibiting CCNG1 expression regressed the expression of Wnt signaling and enhanced cell proliferation. These results suggest that CCNG1 plays a pivotal role in suppressing AT2 cell proliferation, at least partly by counteracting the effects of Wnt signaling to modulate AT2 cell growth in the BPD model. Our findings contribute to a better understanding of the mechanisms underlying BPD. [ABSTRACT FROM AUTHOR]

Ophiocordyceps gracilis (O. gracilis) , the same genus as Ophiocordyceps sinensis , has been used as an edible medicinal fungus for many years. However, the active ingredients of O. gracilis polysaccharides remain relatively unknown. To address this, a 310.1 kDa novel polysaccharide (PDP-1a) was isolated from O. gracilis. The structural characteristics of PDP-1a were determined by different spectroscopy analyses, revealing that PDP-1a was α-glucan homologs with →4)-α-Glc p (1→ as the main chain. Furthermore, PDP-1a inhibited tumor cell proliferation, particularly in the A549 cell line, with a cell death mechanism involving cell cycle blockage, mitochondrial membrane potential reduction, and increased reactive oxygen species, thereby leading to apoptosis. Importantly, PDP-1a promotes antitumor cytokine secretion and enhances macrophage phagocytosis concentration-dependently. These findings provide a theoretical foundation for the use of O. gracilis and emphasize the potential application of PDP-1a in antitumor immunomodulatory therapy. [Display omitted] • A novel polysaccharide (PDP-1a) was extracted from Ophiocordyceps gracilis. • PDP-1a was identified as an α-D-glucan containing →4)-α-Glc p (1→ in the backbone. • PDP-1a selectively inhibited lung cancer in vitro. • PDP-1a enhanced the phagocytosis and cytokine secretion of macrophages. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to reveal the role of nuclear poly(A) binding protein 1 (PABPN1) in the proliferation of preadipocytes, and to reveal the relationship between PABPN1 and cAMP response element (CRE)-binding protein (CREB) in the regulation of preadipocyte proliferation. Methods: Vectors overexpressing and siRNAs against PABPN1/CREB were transiently transfected into both porcine preadipocytes and mouse 3T3-L1 cells. Preadipocyte proliferation was measured with cell counting kit-8, 5-ethynyl-2'-deoxyuridine, real-time quantitative polymerase chain reaction, Western blotting, and flow cytometry analyses. Additionally, the transcriptional regulation of CREB on PABPN1 were analyzed with dual-luciferase reporter gene and electrophoretic mobility shift assay. Results: Overexpression of PABPN1 inhibits, and knockdown of PABPN1 promotes, the proliferation of both porcine preadipocytes and 3T3-L1 cell lines. PABPN1 overexpression increased, while knockdown decreased, the cell population in the G0/G1 phase. These indicates that PABPN1 repressed preadipocyte proliferation by inhibiting cell cycle progress. Additionally, it was revealed that CREB regulated the expression of PABPN1 through binding to the promoter and that CREB inhibited preadipocyte proliferation by repressed cell cycle progress. Furthermore, we showed that PABPN1 functions as a downstream gene of CREB to regulate the proliferation of preadipocytes. Conclusion: PABPN1 inhibits preadipocyte proliferation by suppressing the cell cycle. We also found that CREB could promote PABPN1 expression by binding to a motif in the promoter. Further analysis confirmed that PABPN1 functions as a downstream gene of CREB to regulate the proliferation of preadipocytes. These results suggest that the CREB/ PABPN1 axis plays a role in the regulation of preadipocyte proliferation, which will contribute to further revealing the mechanism of fat accumulation. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) poses a significant global health burden, being the third most prevalent cancer and the second most significant contributor to cancer-related deaths worldwide. Preventive strategies are crucial to combat this rising incidence. 6-shogaol, derived from ginger, has shown promise in preventing and treating various cancers. This study investigated the preventive effects of 6-shogaol on azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CRC in mice. Forty male BALB/c mice were randomly divided into control, 6-shogaol, AOM + DSS, and 6-shogaol + AOM + DSS. Mice in the control group received corn oil for 16 weeks, while those in the 6-Shogaol group were administered 20 mg/kg of 6-shogaol for 16 weeks. The AOM + DSS group received a single intraperitoneal dose (ip) of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The 6-shogaol + AOM + DSS group received both 6-shogaol for 16 weeks and a single ip of 10 mg/kg of AOM, followed by three cycles of 2.5% DSS in drinking water. The AOM + DSS-treated mice exhibited reduced food consumption, colon weight, and colon length, along with increased tumor formation. Co-administration of 6-shogaol effectively reversed these changes, inhibiting CRC development. Histopathological analysis revealed protective effects of 6-shogaol against colonic insults and modulation of inflammatory responses. 6-shogaol significantly reduced Carcinoembryonic antigen and Kiel 67 levels, indicating inhibition of tumor cell proliferation. Mechanistically, 6-shogaol promoted apoptosis by upregulating protein 53 and caspase-3 expression, and it effectively restored the balance of the Wingless-related integration site signaling pathway by regulating β-catenin and adenomatous polyposis coli levels. Moreover, 6-shogaol demonstrated anti-inflammatory effects, reducing myeloperoxidase, Tumor necrosis factor alpha, and cyclooxygenase-2 levels in AOM/DSS-treated mice. Additionally, 6-shogaol restored redox homeostasis by reducing lipid peroxidation and nitrosative stress and enhancing antioxidant enzyme activities. The findings suggest that 6-shogaol inhibits cell proliferation, induces apoptosis, regulates Wnt signaling, suppresses inflammation, and restores redox homeostasis, providing comprehensive insights into its potential therapeutic benefits for CRC. [ABSTRACT FROM AUTHOR]

This study aims to explore the role of 1-deoxynojirimycin (DNJ) in high glucose-induced β-cells and to further explore the molecular mechanism of DNJ effect on β-cells through network pharmacology. In the study, high glucose treatment of mouse INS-1 cells inhibited cell proliferation and insulin secretion, decreased the expression of Bcl-2 protein and Ins1 and Ins2 genes, promoted apoptosis, and increased cleaved caspase-3 and cleaved caspase-9 expression levels as well as intracellular reactive oxygen species production. DNJ treatment significantly restored the dysfunction of INS-1 cells induced by high glucose, and DNJ showed no toxicity to normal INS-1 cells. Silencing CEBPA promoted, while overexpression of CEBPA relieved the dysfunction of pancreatic β-cells induced by high glucose. DNJ treatment partially restored the pancreatic β-cell dysfunction caused by silencing CEBPA. In conclusion, DNJ can inhibit high glucose-induced pancreatic β-cell dysfunction by promoting the expression of CEBPA. [ABSTRACT FROM AUTHOR]

• Based on the previous studies, the feasibility and effectiveness of hydroxyapatite-coated magnesium in ophthalmology were further explained from the molecular biological level. Hydroxyapatite-coated magnesium extract inhibited TGF-β1-induced cell proliferation and migration without cytotoxicity, and suppressed the activation of the Smad-signaling pathway induced by TGF-β1 by reducing the phosphorylation levels of Smad2 and Smad3. • In vivo, hydroxyapatite-coated magnesium significantly improved bleb survival rate and maintained a lower intraocular pressure, which illustrates the effectiveness of hydroxyapatite-coated magnesium in the animal ophthalmological filtration surgery model. Given the alarmingly increasing rates of glaucoma worldwide and the lack of satisfactory treatments, there is a dire need to explore more feasible treatment options. Magnesium (Mg) is an essential element in maintaining the functional and structural integrity of vital ocular tissues, but Mg and its alloys are rarely mentioned in ophthalmic applications. Our previous research found that hydroxyapatite-coated Mg (Mg@HA) shows the best biocompatibility and bioactivity, and exhibits the effect of inhibiting fibrosis after filtration surgery in the rabbit model, which is expected to be a promising material for glaucoma drainage device. In this study, we further demonstrated the anti-fibrosis effect of Mg@HA from the molecular signal level and the efficacy of implantation in the rabbit filtration surgery model. In vitro experiments showed the surface modification of Mg affects the adhesion behavior and the reorganization of cytoskeleton of Human Western blot analysis and immunofluorescence found that Mg@HA regulates the adhesion and motility of human Tenon's capsule fibroblasts mainly by down-regulating the phosphorylation of Smad2 and Smad3 in the canonical transforming growth factor-beta (TGF - β) signaling pathway. By observing and recording the condition of filtering blebs and intraocular pressure after surgery, the effectiveness of Mg@HA applied in the rabbit filtration surgery model was further evaluated. In conclusion, the application of hydroxyapatite-coated Mg in the eye has good biocompatibility and has the potential to resist postoperative glaucoma filtration fibrosis, which may be mediated by the regulation of the TGFβ/Smad signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Naringenin, a flavonoid compound found in citrus fruits, possesses valuable anticancer properties. However, its potential application in cancer treatment is limited by poor bioavailability and pharmacokinetics at tumor sites. To address this, Naringenin nanoparticles (NARNPs) were prepared using the emulsion diffusion technique and their anticancer effects were investigated in HepG2 cells. Methods: The particle size of NARNPs was determined by transmission electron microscopy and scanning electron microscopy analysis. NARNP is characterized by Fourier transform infrared spectroscopy and X-ray diffraction. Study the cytotoxic effects of various doses of naringenin, NARNPs and DOX on HepG2 and WI38 cell lines after 24 h and 48 h using the MTT assay. Flow cytometric analysis was used to study the apoptotic cells. The study also examined the expression of apoptotic proteins (p53) and autophagy-related genes ATG5, LC3 after treatment with naringenin, NARNPs, doxorubicin, and their combinations in HepG2 cells. Results: The particle size of NARNPs was determined by transmission electron microscopy and scanning electron microscopy analysis, showing mean diameters of 54.96 ± 18.6 nm and 31.79 ± 6.8 nm, respectively. Fourier transform infrared spectroscopy confirmed successful conjugation between naringenin and NARNPs. NARNPs were in an amorphous state that was determined by X-ray diffraction. The IC50 values were determined as 22.32 µg/ml for naringenin, 1.6 µg/ml for NARNPs and 0.46 µg/ml for doxorubicin. Flow cytometric analysis showed that NARNPs induced late apoptosis in 56.1% of HepG2 cells and had no cytotoxic effect on WI38 cells with 97% viable cells after 48 h of incubation. NARNPs induced cell cycle arrest in the Go/G1 and G2/M phases in HepG2 cells. The results showed increased expression of ATG5, LC3, and p53 in HepG2 cells treated with IC50 concentrations after 48 h of incubation. NARNPs enhanced the cytotoxic effect of doxorubicin in HepG2 cells but decreased the cytotoxic effect of doxorubicin in WI38 cells. Conclusions: The study demonstrated that NARNPs effectively inhibit cell proliferation and induce apoptosis in human hepatocellular carcinoma cells. Importantly, NARNPs showed no cytotoxic effects on normal cells, indicating their potential as a promising therapy for hepatocarcinogenesis. Combining NARNPs with chemotherapy drugs could present a novel approach for treating human cancers. [ABSTRACT FROM AUTHOR]

Goldenberry and purple passion fruit contain bioactive compounds (BCs) that can prevent gastrointestinal cancers; hydrogel beads can protect and control their release in the gastrointestinal tract. This study aimed to develop an encapsulating material for fruit hydrogel beads (FHBs) to increase their bioaccessibility and to assess antiproliferative effects. A blend of goldenberry–purple passion fruit was encapsulated using ionic gelation and electrospraying. Through a mixture experimental design with sodium alginate (SA), hydroxypropylmethylcellulose (HPMC) and arabic gum (AG) as components, the following response variables were optimized: polyphenol bioaccessibility and encapsulation efficiency. Polyphenols and antioxidant activity were quantified before and after digestion. Antiproliferative effect was evaluated on Caco-2 colon cancer cells. Variations in formulation proportions had a significant effect (p < 0.05) on most responses. An SA-AG mixture in a 0.75:0.25 ratio maximized polyphenol bioaccessibility to 213.17 ± 19.57% and encapsulation efficiency to 89.46 ± 6.64%. Polyphenols and antioxidant activity were lower in FHBs than in the fruit blend (F). Both F and FHBs inhibited tumor cell proliferation by 17% and 25%, respectively. In conclusion, encapsulating BCs in hydrogel beads with SA-AG can enhance the effectiveness of polyphenols in food applications by improving their bioaccessibility and showing a more pronounced effect in inhibiting tumor cell proliferation. [ABSTRACT FROM AUTHOR]

Background/Aim: Breast cancer stem cells (BCSCs) are a subpopulation of tumor cells that play a role in therapeutic resistance. In this study, we demonstrated that sertaconazole, an antifungal agent, displayed a potent inhibition on cancer stem cells (CSCs) and investigated the mechanism of action involved in its anti-BCSC effect. Materials and Methods: The effect of sertaconazole on BCSCs was investigated using a mammosphere formation assay, a colony formation assay, and a cell migration assay. In addition, CD44high/CD24low and ALDEFLOR analyses, an apoptosis assay, quantitative real-time PCR, western blotting, an electrophoretic mobility shift assay, and a cytokine profiling assay were performed. Results: Sertaconazole inhibited cell proliferation, colony formation, cell migration, mammosphere formation, and mammosphere proliferation. It also induced apoptosis of breast cancer cells. It decreased the subpopulation of CD44high/CD24low and aldehyde dehydrogenase-expressing cells. It also reduced the DNA binding of Stat3 and nuclear protein expression levels of phosphorylated Stat3. Furthermore, it reduced the IL-8 mRNA levels of the mammosphere. Conclusion: Sertaconazole can inhibit the Stat3 and IL-8 signaling pathways and induce CSC death. Thus, sertaconazole might be a potential inhibitor of BCSCs. [ABSTRACT FROM AUTHOR]

Background: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and aggressive cancer with a poor prognosis and limited treatment options. Current chemotherapy regimens are predominantly platinum-based; however, the development of platinum resistance during treatment significantly worsens patient outcomes. Everolimus, an mTOR inhibitor, has been widely used in combination cancer therapies and has successfully enhanced the efficacy of platinum-based treatments. Method: In this study, we investigated the combined effects of everolimus and cisplatin on SCCOHT through both in vitro and in vivo experiments, complemented by RNA sequencing (RNA-seq) analyses to further elucidate the therapeutic impact. Result: Our findings revealed that everolimus significantly inhibits the proliferation of SCCOHT cells, induces cell cycle arrest, and accelerates apoptosis. When combined with cisplatin, everolimus notably enhances the therapeutic efficacy without increasing the toxicity typically associated with platinum-based drugs. RNA-seq analysis uncovered alterations in the expression of apoptosis-related genes, suggesting that the underlying mechanism involves autophagy regulation. Conclusions: Despite the current challenges in treating SCCOHT and the suboptimal efficacy of platinum-based therapies, the addition of everolimus significantly suppresses tumor growth. This indicates that everolimus enhances cisplatin efficacy by disrupting survival-promoting signaling cascades and inducing cell cycle arrest. Furthermore, it points to potential biomarkers for predicting therapeutic response. [ABSTRACT FROM AUTHOR]

Although pituitary tumors (PTs) are mostly benign, some PTs are characterized by low surgical resection rates, high recurrence rates, and poor response to conventional treatments and profoundly affect patients' quality of life. Everolimus (EVE) is the only FDA-approved mTOR inhibitor, which can be used for oral treatment. It effectively inhibits tumor cell proliferation and angiogenesis. It has been administered for various neuroendocrine tumors of the digestive tract, lungs, and pancreas. EVE not only suppresses the growth and proliferation of APT cells but also enhances their sensitivity to radiotherapy and chemotherapy. This review introduces the role of the PI3K/AKT/mTOR pathway in the development of APTs, comprehensively explores the current status of preclinical and clinical research of EVE in APTs, and discusses the blood-brain barrier permeability and safety of EVE. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) ranks as the second leading cause of cancer-related mortality among men. Long non-coding RNAs (lncRNAs) are known to play a regulatory role in the development of various human cancers. LncRNA MAFG-divergent transcript (MAFG-DT) was reported to play a crucial role in tumor progression of multiple human cancers, such as pancreatic cancer, colorectal cancer, bladder cancer, and gastric cancer. Nevertheless, the specific function of MAFG-DT in the context of bone metastasis in PCa remains inadequately understood. Methods: The expression level of MAFG-DT was analyzed in published datasets and further confirmed in clinical samples and cell lines by RT-qPCR and in situ hybridization assays. Additionally, we further examined the effect of MAFG-DT on cell proliferation, migration, invasion and bone metastasis through CCK8, EdU, colony formation, transwell assays and bone metastasis model with intracardiac injection. Subsequently, the specific mechanism of MAFG-DT in PCa was investigated by RIP, ChIP, bioinformatic analysis and luciferase reporter assays. Results: We found that MAFG-DT expression was significantly upregulated in PCa tissues exhibiting bone metastasis. Elevated levels of MAFG-DT expression were found to be positively associated with poor prognostic outcomes in PCa patients. Functionally, the knockdown of MAFG-DT resulted in a pronounced inhibition of cellular proliferation, migration, invasion, and bone metastasis. Moreover, it was demonstrated that MAFG-DT enhanced the expression of FZD4 and FZD5 mRNAs by sequestering miR-24-3p, thereby activating the Wnt/β-catenin signaling pathway. Additionally, the transcription factor MAFG was found to transcriptionally activate MAFG-DT in PCa. Conclusion: This study confirms the oncogenic role of MAFG/MAFG-DT/miR-24-3p/Wnt/β-catenin in PCa, which suggests that MAFG-DT could serve as a potential therapeutic target for PCa. [ABSTRACT FROM AUTHOR]

The correction notice addresses errors in figures and supplementary material in the original article titled "Phosphoglycerate dehydrogenase promotes pancreatic cancer development by interacting with eIF4A1 and eIF4E." The corrected figures and data are provided in the notice, ensuring the accuracy of the research findings. The correction does not impact the overall conclusions of the article, maintaining the integrity of the study on pancreatic cancer development. [Extracted from the article]

Background: The insulin-like growth factor 1 receptor (IGF-1R) and the thyrotropin receptor (TSH-R) are expressed on orbital cells and thyrocytes. These receptors are targeted in autoimmune-induced thyroid eye disease (TED). Effective therapeutic treatment of TED inhibits activation of the IGF-1R/TSH-R complex. Methods: The inhibitory effect on cell proliferation of a small molecule targeting IGF-1R phosphorylation (Linsitinib) was investigated in an IGF-1R expressing cell line and a Chinese Hamster Ovary (CHO) cell line overexpressing TSH-R. An IGF-1R monoclonal antibody antagonist, Teprotumumab served as control. Both cell lines were plated in a 96-well format and treated with both compounds for 24 hours. After addition of tetrazolium, absorbance was measured. The apoptosis marker caspase-3/7 activity was measured. The half-maximal inhibitory concentration (IC50) of TSH-R-Ab induced stimulation (stimulatory monoclonal antibody, mAb, M22) of the TSH-R cell line was evaluated with a cell-based bioassay for blocking TSH-R-Ab. Cells were treated with ten rising concentrations of either Linsitinib, Linsitinib + Metformin, Teprotumumab, or a blocking TSH-R mAb (K1-70). Results: Linsitinib strongly inhibited the proliferation of both cell lines at several concentrations: 31,612.5 ng/mL (IGF-1R cell line -78%, P=0.0031, TSH-R cell line -75%, P=0.0059), and at 63,225 ng/mL (IGF-1R cell line -73%, P=0.0073, TSH-R cell line -73%, P=0.0108). Linsitinib induced apoptosis of both cell lines, both morphologically confirmed and with an increased caspase-3/7 activity at concentrations of 31,612.5 ng/mL (IGF-1R cell line P=0.0158, TSH-R cell line P=0.0048) and 63,225 ng/mL (IGF-1R cell line P=0.0005, TSH-R cell line P=0.0020). Linsitinib markedly inhibited proliferation of the IGF-1R cell line at all concentrations compared to Teprotumumab (P=0.0286). Teprotumumab inhibition was significant only at 15,806.25 ng/mL with the TSH-R cell line (-15%, P=0.0396). In addition, in the TSH-R-Ab blocking bioassay, Linsitinib and the tested compounds demonstrated strong inhibition across all ten dilutions (100%). Conclusions: Linsitinib effectively induces apoptosis and inhibits proliferation of both IGF-1R and TSH-R expressing target cells, therefore demonstrating its therapeutic potential to block the reported crosstalk of the two mediators in autoimmune TED. [ABSTRACT FROM AUTHOR]