Ursolic acid (UA) and rosmarinic acid (RA) are secondary metabolites obtained from Mesona procumbens Hemsl. and exhibit potent antitumor properties. Using Gd3(Sc,Al)2Ga3O12:Cr3+ near-infrared phosphor-converted light-emitting diodes (NIR pc-LEDs), this study optimized UA and RA production by 16 and 48%, respectively. Liposomal encapsulation generated a nanoscale delivery system (RA/UA@LP, 290 +/- 14 nm), improving their dispersity and establishing a nanoliposomal platform with in vitro BBB-crossing potential for brain-targeted delivery. Experiments revealed that in vitro, RA/UA@LP reduced U87MG glioblastoma cell viability to 49%, with no toxicity in SVGp12 cells. In vivo analysis using a heterotopic glioblastoma model (subcutaneous transplantation) showed that RA/UA@LP decreased tumor fluorescence radiance by 78% after 5 weeks, outperforming nonencapsulated RA/UA by 71%. This model facilitates noninvasive tumor monitoring while maintaining clinical relevance. The integration of NIR pc-LEDs and nanocarrier technology enhances therapeutic compound production and efficacy, advancing agriculture and oncology.

Sterol regulatory element-binding proteins (SREBPs) are master regulators of cholesterol and lipid biosynthesis - pathways increasingly linked to cancer progression. Statins, which inhibit HMG-CoA reductase to lower cholesterol, have shown potential in reducing cancer recurrence. However, their efficacy in lung cancer remains uncertain, and predictive biomarkers for statin responsiveness are still lacking. We examined the relationship between cholesterol biosynthesis and estrogen receptor alpha (ERα) signaling and assessed the therapeutic potential of targeting this axis in lung cancer models. Overexpression of farnesyl-diphosphate farnesyltransferase 1 (FDFT1), also known as squalene synthase (SQS), significantly increased the IC50 of lovastatin in lung cancer cell lines, indicating a role in mediating statin resistance. Gene expression profiling revealed enrichment of estrogen receptor alpha (ERα) signaling in SQS-overexpressing cells. Immunohistochemical analysis of 125 NSCLC patient samples showed a positive correlation between SQS and ERα protein expression, and their co-expression was significantly associated with poorer disease-free survival. Mechanistically, SQS upregulated ERα at the protein level via cholesterol replenishment, without altering ESR1 mRNA levels, suggesting a post-transcriptional regulatory mechanism. SQS promotes statin resistance in lung cancer by stabilizing ERα through cholesterol replenishment. Its co-expression with ERα predicts poor prognosis, highlighting the SQS–ERα axis as a potential therapeutic target and biomarker for stratifying patients likely to benefit from statin–antiestrogen combination therapy.

Oncogene-induced senescence (OIS) is regarded a tumor suppressive mechanism in normal cells. Accumulated evidences, however, demonstrate that OIS would play a role in cancer promotion through the secretion of senescence associated secretory phenotypes (SASP). The underlying mechanisms remain to be addressed. In this study, we found that c-Myc oncogene could induce senescence in human diploid lung fibroblasts and non-small cell lung cancer cells (NSCLC) without concomitant emergence of apoptosis. c-Myc-induced senescence (cMIS) caused morphological enlargement, increased F-actin and nuclear G-actin that generally detected in senescent cells. These events were found to be associated with increased expression of cofilin-1, an actin-binding protein required for actin dynamics. Transfection of c-Myc could induce cofilin-1, but transfection of truncated Myc-Nick mutant and inhibition of c-Myc reduced cofilin-1 expression. Additionally, knockdown of cofilin-1 could suppress cMIS. The chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assay showed that the endogenous c-Myc mainly bound to two out of three predicted E-boxes located in middle and proximity to the transcription initiation site of the CFL1 promoter. Interestingly, ectopic expression of c-Myc bound to all E-boxes, especially the distal one. Furthermore, the conditioned medium (CM) collected from cells with cMIS could enhance the proliferation and migration of other NSCLC cells, whereas that obtained from cofilin-1 silencing cells with forced expression of c-Myc diminished these capacities. The c-Myc transactivated cofilin-1 could also be triggered by H2O2 through the middle E-box. Surprisingly, a physical interaction between c-Myc and cofilin-1 was detected, and H2O2 increased this effect. Clinically, high expression of both c-Myc and CFL1 genes correlated to worse survival rates among NSCLC patients, especially those with the adenocarcinoma subtype. Taken together, the c-Myc-cofilin-1 regulatory axis would explain the mechanism of OIS promoted cancer progression, and it may be a potent target for design of treatments.

Background Although focal adhesion kinase (FAK) inhibition shows promise in lung cancer therapy, emerging evidence suggests it may promote cellular dormancy and drug resistance through transcriptional regulation. We investigated the therapeutic efficacy and drug resistance inhibition mechanisms of FAK inhibitor VS-4718 in lung cancer. Methods Using an orthotopic syngeneic LLC1 mouse model, we evaluated the effects of VS-4718 (50 mg/kg/day) on tumor progression, survival, and molecular mechanisms. Comprehensive analyses included histological examination, immunohistochemistry, Western blotting, and clinical tissue validation from TKI-treated patients. Results VS-4718 demonstrated significant anti-tumor efficacy, reducing tumor burden by 60%, decreasing surface nodules, and improving overall survival (p < 0.01). Mechanistically, FAK inhibition induced cell cycle arrest through spatially heterogeneous p27 upregulation at tumor margins while suppressing Cyclin A1 expression. Unexpectedly, VS-4718 controlled COUP-TF1/β-catenin interactions, leading to reciprocal protein regulation. Critically, region-specific analysis revealed selective COUP-TF1 upregulation in bronchiolar areas, indicating anatomically-restricted dormancy pathway activation. Clinical validation in TKI-treated patient samples confirmed variable COUP-TF1 expression patterns, supporting its potential as a therapeutic resistance biomarker. Conclusions VS-4718 achieved significant therapeutic benefits through coordinated regulation of cell cycle and transcriptional networks. However, concurrent induction of COUP-TF1-mediated dormancy pathways, particularly in bronchiolar niches, may promote the formation of therapy-resistant cell populations. These findings reveal a fundamental paradox in FAK-targeted therapy and suggest that monotherapy may be insufficient for complete tumor eradication. Our

Magnetic Resonance Imaging (MRI) is a non-invasive technique that provides high-resolution tissue imaging, making it a potential tool for hepatocellular carcinoma (HCC) imaging diagnosis. However, effective visualization of HCC-related molecular changes requires advanced nanoscale contrast agents with surface modifications for specific biomarker binding. Iron-platinum nanoparticles (FePt NPs) are widely used for T2-weighted MRI contrast but are rapidly degraded by macrophages, limiting their accumulation and signal enhancement in vivo. To address this issue, metal-organic frameworks (MOFs) can encapsulate FePt NPs to improve stability and imaging contrast. Additionally, red blood cell membrane (RBC-m) coating enhances tumor tissue accumulation, enabling real-time tracking and diagnosis of HCC. Initial studies have demonstrated the effectiveness of this technology in HCC imaging diagnosis, contributing to disease monitoring and treatment evaluation. With further optimization, these nanocomposite probes have the potential to enhance MRI-based HCC diagnostics, bridging molecular biology and clinical imaging to advance personalized medicine.

Breast cancer (BC) is a global health challenge, with approximately 75 % of cases classified as estrogen receptor alpha (ER-α)-positive luminal subtype. Although hormone therapies such as tamoxifen have improved outcomes, a subset of ER-α-positive BC patients develop resistance, resulting in early metastasis. Our research shows that ER-α loss is more frequent in distant metastases and is associated with poorer survival. We investigated the role of ER-α expression in BC progression, metastasis, and recurrence using comprehensive in vitro and in vivo models. Low ER-α expression in primary tumors was associated with increased metastasis and recurrence in ER-α-positive BC. Luminal BC cells with low ER-α expression exhibited increased invasiveness, whereas ER-α overexpression in triple-negative BC cells suppressed metastatic behavior. Mechanistically, ER-α downregulation promoted epithelial-mesenchymal transition (EMT) and upregulated MMP9 expression in BC cells. These findings suggest that ER-α loss facilitates BC metastasis through the EMT process. Relatively low ER-α expression may serve as a potential prognostic indicator in ER-positive luminal BC. These results have potential implications for predicting outcomes in ER-positive BC and highlight the importance of personalized treatment strategies.

X-linked inhibitor of apoptosis (XIAP) inhibits caspases 3, 7, and 9, thereby preventing cell apoptosis. Endogenous Second mitochondria-derived activator of caspase (Smac) competes out the binding of caspases with XIAP and causes apoptosis, so that Smac mimetics are under clinical trials for anti-cancer chemotherapy. We demonstrated by selectively alkylating caspase 7 (CASP7) to release the active CASP7 for killing the drug-resistant cancer cells with accumulated XIAP:CASP7 resulted from caspase-3 down-regulation (CASP3/DR). However, finding a reversible inhibitor of the protein-protein interaction (PPI) poses a significant challenge. Here, we identified a reversible XIAP:CASP7 inhibitor, 643943, through a multiple-mode virtual screening strategy. In vitro experiments revealed that 643943 bound to CASP7, released the linker-BIR2 domain of XIAP, and activated the caspase. Removing an essential hydroxyl group on 643943 or replacing the OH-interacting Asp93 on CASP7 caused loss of 643943 cytotoxicity, revealing the binding mode. This compound thus selectively killed MCF-7 and other CASP3/DR triple-negative breast cancer cell lines, but not the cancer and normal cell lines expressing higher levels of CASP3 in vitro and in vivo. Moreover, 643943 overcame chemoresistance via down-regulating β-catenin and its associated ABC transporters in paclitaxel-resistant MCF-7 cells. Our studies not only serve as a proof-of-concept for using XIAP:CASP7 as a drug target, but also provide the first reversible XIAP:CASP7 inhibitor for cancer therapy of CASP3/DR malignancies.

In the original publication [...].

The intricate involvement of the histaminergic system, encompassing histamine and histamine receptors, in the progression of diverse neoplasias has attracted considerable scrutiny. Histamine receptor H1 (HRH1) was reported to be overexpressed in several cancer types, but its specific functional implications in oral squamous cell carcinoma (OSCC) predominantly remain unexplored. Our findings indicate that dysregulated high levels of HRH1 were correlated with lymph node (LN) metastasis and poor prognoses in OSCC patients. We identified a disintegrin and metalloprotease 9 (ADAM9) as a critical downstream target of HRH1, promoting protumorigenic and prometastatic characteristics both in vitro and in vivo. Molecular investigations revealed that the cyclic increase in the HRH1-ADAM9-Snail/Slug axis promoted progression of the epithelial-to-mesenchymal transition (EMT). Clinical analyses demonstrated significant correlations of HRH1 expression with ADAM9 and with EMT-related markers, with elevated ADAM9 also associated with LN metastasis in OSCC patients. Regarding therapeutic aspects, we discovered that activated STAT3 acts as a compensatory pathway for the long-term HRH1 signaling blockade in OSCC cells. Combining inhibition of HRH1 and STAT3 using their respective inhibitors or short hairpin (sh)RNAs enhanced the tumor-suppressive effects compared to HRH1 inhibition/depletion alone in OSCC cells and a xenograft model. In summary, HRH1 has emerged as a valuable biomarker for predicting OSCC progression, and combined targeting of HRH1 and STAT3 may represent a promising strategy for preventing OSCC progression.

Near-infrared (NIR) applications have attracted researchers' attention in recent years. Particularly in noninvasive treatment, NIR photons can activate the receptor in mitochondria and modulate through multiple pathways. As a safe and low-cost light source, a light-emitting diode (LED) opens new possibilities for NIR photobiomodulation (PBM). In this study, 770 and 810 nm LEDs are used as light sources to alleviate the symptoms of Alzheimer's Disease. The penetration ability of NIR-LEDs is verified in ex vivo and in vivo experiments and by simulated energy distribution with the Monte Carlo method. Mitochondrial abnormalities are associated with the progression and worsening of Alzheimer's disease, which fail to mitigate the appearance of abnormal plaques and neurofibrillary tangles in the brain. This research utilizes PBM to activate mitochondria, aiming to reduce the excessive accumulation of amyloid beta. Furthermore, behavioral pattern and staining assessments were conducted to evaluate the amyloid beta aggregation in APP/PS1 mice. After one and two-stage treatments, the improvement in animal behavior can be observed at 45 % and 72 %, respectively. Amyloid-beta aggregates also present a significant reduction (similar to 63 %-87 %) in the brain imaging system. The safety of NIR-LEDs is confirmed by cell viability with SH-SY5Y cells. NIR-LED not only makes the light source more accessible but also provides adjuvant therapeutic effects and safety under PBM treatment.

In the original publication [...].

Estrogen receptor-positive (ER⁺) breast cancer is commonly treated with hormone therapy; however, these tumors frequently develop drug resistance and exhibit poor responses to radiotherapy. To investigate the molecular basis of therapy resistance, we explored the role of estrogen receptor alpha (ESR1) in modulating sensitivity to oxidative and radiation stress. Through integrative analysis of publicly available datasets, we identified ESR1 as a key molecular marker associated not only with breast cancer classification but also with radiosensitivity. In ER⁺ breast cancer cell lines, higher endogenous ESR1 expression correlated with increased resistance to ionizing radiation. Functional studies using ESR1 overexpression and knockdown models revealed that depletion of ESR1 sensitized cells to radiation-induced DNA damage, impaired DNA repair efficiency, and reduced clonogenic survival. Notably, we found that the ESR1–SQSTM1 (p62) interaction impairs autophagic flux, contributing to treatment resistance. Mechanistically, ESR1 translocates to the cytoplasm and binds to SQSTM1, thereby disrupting autophagosome maturation. Furthermore, estradiol enhances ESR1 phosphorylation and its affinity for SQSTM1, reinforcing this inhibitory effect on autophagy and promoting resistance to radiation. Our findings uncover a previously unrecognized ESR1–SQSTM1 axis that governs autophagy and redox response in ER⁺ breast cancer. Targeting this pathway may restore sensitivity to radiotherapy and offer a new therapeutic strategy. Assessment of ESR1 expression and autophagy activity may serve as predictive biomarkers for treatment response in ER⁺ breast cancer patients.

Oral squamous cell carcinoma (OSCC) is an immune-cold tumor characterized by an immunosuppressive microenvironment with low cytotoxic activity to eliminate tumor cells. Tumor escape is one of the initial steps in cancer development. Understanding the underlying mechanisms of cancer escape can help researchers develop new treatment strategies. In this study, we prove the oral oncogenic miR-762 can suppress T-cell recruitment and cytotoxic activation in the tumor microenvironment (TME) through horizontal transmission from OSCC cells to adaptive immune T cells. Public database analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine the prognosis and expression of miR-762 in OSCC. T-cell activation by flow cytometry, qRT-PCR, IL-12 secretion, and T-cell recruitment and cytotoxicity abilities were conducted in the miR-762 manipulation T-cell and OSCC-T-cell co-culture system. A luciferase reporter and CXCR3 protein expression were also carried out to validate the direct interaction between CXCR3 and microRNA (miR)-762. This horizontal transmission of miR-762 directly suppresses CXCR3 expression in T cells, inhibiting CXCR3-induced T-cell migration and downstream T-cell cytotoxic activity by disrupting AKT activation. Additionally, miR-762 transmission suppressed T-cell activation marker expression, T-cell proliferation, IL-12 secretion, and T-cell cytotoxicity. In conclusion, our findings reveal a novel miR-762/CXCR3 axis that regulates the immunosuppressive microenvironment in OSCC and may be a potential RNA-targeted therapeutic approach to restore the anti-tumor immune response in OSCC treatment.

Oral squamous cell carcinoma (OSCC) remains a formidable challenge due to its high recurrence rates and poor prognosis. This study focuses on miR-876, a microRNA significantly associated with OSCC recurrence and clinical outcomes. Analysis of miRNA expression profiles from recurrent OSCC patients revealed that miR-876-5p is markedly upregulated in recurrent tumor tissues and the high expression of miR-876-5p correlates with reduced disease-free and overall survival. Functional assays demonstrated that miR-876 enhances OSCC cell growth, migration, and stemness, contributing to chemoresistance. Mechanistically, miR-876-5p directly targets SOCS4, leading to increased STAT3 activation and subsequent upregulation of PD-L1, which facilitates immune evasion. Additionally, exposure to the tobacco-specific carcinogen NNK was found to induce miR-876 expression and STAT3 activation, implicating environmental factors in miR-876 regulation and promote cancer recurrent. These findings identify the miR-876-5p-SOCS4-STAT3 axis as a critical pathway in OSCC progression, highlighting miR-876-5p as a potential biomarker and therapeutic target to improve treatment outcomes in OSCC patients.

Background Cholangiocarcinoma is a challenging malignancy with limited responses to conventional therapies, particularly immune checkpoint inhibitor therapy. Tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) are key components of the tumor microenvironment (TME) and have been implicated in the immune response to cancer. However, the role and difference of TLSs and TILs in patients with cholangiocarcinoma remains unclear. This study elucidates their contributions to the TME.Methods We examined 16 tumor samples from a single-arm, phase II trial of nivolumab plus modified gemcitabine and S-1 and various datasets. Immunohistochemistry and RNA sequencing were employed to assess TLSs and TILs presence and activity. Differential gene expression and signature of immune cell composition were examined by GeoMx Digital Spatial Profiler and Cancer Transcriptome Altas analysis.Results TLS-positive (N=7) patients demonstrated significantly better immunotherapy outcomes compared with TLS-negative (N=9) patients, including higher objective response rates (71% vs 0%) and disease control rates (100% vs 67%). The presence of TLSs correlated with improved progression-free and overall survival (p=0.03). TLSs were associated with “inflamed” tumors characterized by substantial immune infiltration, particularly involving T and B cells. Gene expression analyses identified significant upregulation of B cell-related genes in TLSs. Additionally, TLSs exhibited higher properties of memory B cells and myeloid dendritic cells but lower levels of innate immune cells compared with TILs. T cells within TLSs showed elevated expression of precursor-exhausted-related genes and lower cytotoxicity signature. Furthermore, TILs in TLS-positive tumors had higher levels of exhaustion signatures compared with TILs in TLS-negative tumors. Clinical data corroborated these findings, with higher PD-L1 and LAG-3 expression in TLS-positive tumors.Conclusion Our findings revealed that TILs in TLS-positive tumors have more exhausted T cell signature and PD-1 and LAG-3 protein expression in CCA which support our clinical finding. TLSs can predict favorable immunotherapy responses in patients with cholangiocarcinoma, highlighting their potential as a biomarker and therapeutic target to enhance treatment efficacy.

K-homology-type splicing regulatory protein (KSRP) is an RNA-binding protein involved in mRNA decay and translational repression through recognition of adenine–uracil-rich elements. Although KSRP regulates approximately 16

Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell cytoskeleton and vesicle transport. However, it is not yet clear how the Rab family contributes to cancer progression by participating in EMT. By analysing various in silico datasets, we identified a statistically significant increase in RAB31 expression in the oxaliplatin-resistant group compared to that in the parental or other chemotherapy drug groups. Our findings highlight RAB31's powerful effect on colorectal cancer cell lines when compared with other family members. In a study that analysed multiple online meta-databases, RAB31 RNA levels were continually detected in colorectal tissue arrays. Additionally, RAB31 protein levels were correlated with various clinical parameters in clinical databases and were associated with negative prognoses for patients. RAB31 expression levels in all three probes were calculated using a computer algorithm and were found to be positively correlated with EMT scores. The expression of the epithelial-type marker CDH1 was suppressed in RAB31 overexpression models, whereas the expression of the mesenchymal-type markers SNAI1 and SNAI2 increased. Notably, RAB31-induced EMT and drug resistance are dependent on extracellular vesicle (EV) secretion. Interactome analysis confirmed that RAB31/AGR2 axis-mediated exocytosis was responsible for maintaining colorectal cell resistance to oxaliplatin. Our study concluded that RAB31 alters the sensitivity of oxaliplatin, a supplementary chemotherapy approach, and is an independent prognostic factor that can be used in the treatment of colorectal cancer.

To date, all-inorganic lead halide perovskite quantum dots have emerged as promising materials for photonic, optoelectronic devices, and biological applications, especially in solar cells, raising numerous concerns about their biosafety. Most of the studies related to the toxicity of perovskite quantum dots (PeQDs) have focused on the potential risks of hybrid perovskites by using zebrafish or human cells. So far, the neurotoxic effects and fundamental mechanisms of PeQDs remain unknown. Herein, a comprehensive methodology is designed to investigate the neurotoxicity of PeQDs by using Caenorhabditis elegans as a model organism. The results show that the accumulation of PeQDs mainly focuses on the alimentary system and head region. Acute exposure to PeQDs results in a decrease in locomotor behaviors and pharyngeal pumping, whereas chronic exposure to PeQDs causes brood decline and shortens lifespan. In addition, some abnormal issues occur in the uterus during reproduction assays, such as vulva protrusion, impaired eggs left in the vulva, and egg hatching inside the mother. Excessive reactive oxygen species formation is also observed. The neurotoxicity of PeQDs is explained by gene expression. This study provides a complete insight into the neurotoxicity of PeQD and encourages the development of novel nontoxic PeQDs.

Breast cancer is a malignant tumor with a high mortality rate among women. Therefore, it is necessary to develop novel therapies to effectively treat this disease. In this study, iron selenide nanorods (FeSe2 NRs) were designed for use in magnetic hyperthermic, photothermal, and chemodynamic therapy (MHT/PTT/CDT) for breast cancer. To illustrate their efficacy, FeSe2 NRs were modified with the chemotherapeutic agent methotrexate (MTX). MTX-modified FeSe2 (FeSe2-MTX) exhibited excellent controlled drug release properties. Fe2+ released from FeSe2 NRs induced the release of •OH from H2O2 via a Fenton/Fenton-like reaction, enhancing the efficacy of CDT. Under alternating magnetic field (AMF) stimulation and 808 nm laser irradiation, FeSe2-MTX exerted potent hyperthermic and photothermal effects by suppressing tumor growth in a breast cancer nude mouse model. In addition, FeSe2 NRs can be used for magnetic resonance imaging in vivo by incorporating their superparamagnetic characteristics into a single nanomaterial. Overall, we presented a novel technique for the precise delivery of functional nanosystems to tumors that can enhance the efficacy of breast cancer treatment.

BACKGROUND AND PURPOSE:Our previous study reported that fructose intake increased systemic blood pressure and reduced nitric oxide (NO) in the nucleus tractus solitarius (NTS) due to oxidative stress and neuroinflammation. However, it remains unclear how reactive oxygen species (ROS) reduce NO and how this process impacts neuroinflammation in the NTS. This study aimed at investigating the effect of ROS on acetylation of high mobility group box 1 protein (HMGB1) in the NTS of fructose-induced hypertensive rats. EXPERIMENTAL APPROACH:Male Wistar-Kyoto (WKY) rats were fed with 10% fructose water to elevate blood pressure. Thereafter, CLI-095 and glycyrrhizic acid (GA) treatments were delivered for up to 2 weeks (1 mg·12 μL-1·day-1, by intracerebroventricular injection) to reduce the negative effects of toll-like receptor 4 (TLR4) and HMGB1 activation. KEY RESULTS:Two weeks of CLI-095 and GA treatment reduced systemic blood pressure and significantly preserved neuronal and endothelial nitric oxide synthase (nNOS and eNOS) availability against the inflammatory insults of fructose consumption. Both CLI-095 and GA halted the interaction of acetylated HMGB1 and TLR4. Two weeks of CLI-095 and GA treatment markedly reduced NTS inflammation (pro-inflammatory cytokines and microglial activation) and lowered serum norepinephrine levels. CONCLUSION AND IMPLICATIONS:Our data reveal novel pharmacological properties for CLI-095 and GA, which improved blood pressure and inflammatory conditions by decreasing the interaction of acetylated HMGB1 with TLR4. These findings challenge the commonly accepted dogma that essential hypertension is specifically mediated by neuroinflammation due to acetylated HMGB1 coupling to TLR4. LINKED ARTICLES:This article is part of a themed issue Recent Innovations in Targeting Redox Biology for Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.1/issuetoc.