ODF3B affects the proliferation and apoptosis of glioma via the JAK/STAT pathway.

The pathogenesis of glioma has remained unclear. In this study, it was found that high expression of the outer dense fibers of sperm tail 3B (ODF3B) in gliomas was positively correlated with the grade of glioma. The higher the grade, the worse the prognosis. ODF3B is closely related to the growth and apoptosis of glioma. In terms of mechanism, ODF3B was found to affect the proliferation and apoptosis of glioma through the JAK1 and JAK2/STAT3 pathways. ODF3B was also found to affect the growth and apoptosis of glioma in vivo. We conclude that ODF3B affects glioma proliferation and apoptosis via the JAK/STAT pathway and is a potential therapeutic target.

Bergaptol inhibits glioma cell proliferation and induces apoptosis via STAT3/Bcl-2 pathway.

Glioblastoma (GBM) is the most common primary malignant brain tumour and lacks therapeutic options with significant effects. The aberrant activation of STAT3 is a critical factor in glioma progression via activating multiple signalling pathways that promote glioma. Among them, the antiapoptotic gene Bcl-2 could be upregulated by p-STAT3, which is an important reason for the continuous proliferation of glioma. We previously reported that bergaptol, a natural furanocoumarin widely found in citrus products, exerts antineuroinflammatory effects by inhibiting the overactivation of STAT3. Here, we aimed to evaluate whether bergaptol could promote glioma apoptosis by inhibiting the STAT3/Bcl-2 pathway. This study found that bergaptol inhibited the proliferation and migration of GBM cell lines (U87 and A172) and promoted apoptosis in vitro. We also found that bergaptol significantly inhibited the STAT3/Bcl-2 pathway in GBM cells. U87 cells were implanted intracranially into nude mice to establish a glioma model, and glioma-bearing mice were treated with bergaptol (40 mg/kg). Bergaptol treatment significantly inhibited glioma growth and prolonged the glioma-bearing mice's survival time. In addition, bergaptol administration also significantly inhibited the STAT3/Bcl-2 pathway of tumour tissue in vivo. Overall, we found that bergaptol could effectively play an antiglioma role by inhibiting STAT3/Bcl-2 pathway, suggesting the potential efficacy of bergaptol in treating glioma.

Near-Field Terahertz Morphological Reconstruction Nanoscopy for Subsurface Imaging of Protein Layers.

Protein layers formed on solid surfaces have important applications in various fields. High-resolution characterization of the morphological structures of protein forms in the process of developing protein layers has significant implications for the control of the layer's quality as well as for the evaluation of the layer's performance. However, it remains challenging to precisely characterize all possible morphological structures of protein in various forms, including individuals, networks, and layers involved in the formation of protein layers with currently available methods. Here, we report a terahertz (THz) morphological reconstruction nanoscopy (THz-MRN), which can reveal the nanoscale three-dimensional structural information on a protein sample from its THz near-field image by exploiting an extended finite dipole model for a thin sample. THz-MRN allows for both surface imaging and subsurface imaging with a vertical resolution of ∼0.5 nm, enabling the characterization of various forms of proteins at the single-molecule level. We demonstrate the imaging and morphological reconstruction of single immunoglobulin G (IgG) molecules, their networks, a monolayer, and a heterogeneous double layer comprising an IgG monolayer and a horseradish peroxidase-conjugated anti-IgG layer. The established THz-MRN presents a useful approach for the label-free and nondestructive study of the formation of protein layers.

Integrated metabolomics revealed the photothermal therapy of melanoma by Mo2C nanosheets: toward rehabilitated homeostasis in metabolome combined lipidome.

Melanoma, the most aggressive and life-threatening form of skin cancer, lacks innovative therapeutic approaches and deeper bioinformation. In this study, we developed a photothermal therapy (PTT) based on Mo2C nanosheets to eliminate melanoma while utilizing integrated metabolomics to investigate the metabolic shift of metabolome combined lipidome during PTT at the molecular level. Our results demonstrated that 1 mg ml-1 Mo2C nanosheets could efficiently convert laser energy into heat with a strong and stable photothermal effect (74 ± 0.9 °C within 7 cycles). Furthermore, Mo2C-based PTT led to a rapid decrease in melanoma volume (from 3.299 to 0 cm2) on the sixth day, indicating the effective elimination of melanoma. Subsequent integrated metabolomics analysis revealed significant changes in aqueous metabolites (including organic acids, amino acids, fatty acids, and amines) and lipid classes (including phospholipids, lysophospholipids, and sphingolipids), suggesting that melanoma caused substantial fluctuations in both metabolome and lipidome, while Mo2C-based PTT helped improve amino acid metabolism-related biological events (such as tryptophan metabolism) impaired by melanoma. These findings suggest that Mo2C nanosheets hold significant potential as an effective therapeutic agent for skin tumors, such as melanoma. Moreover, through exploring multidimensional bioinformation, integrated metabolomics technology provides novel insights for studying the metabolic effects of tumors, monitoring the correction of metabolic abnormalities by Mo2C nanosheet therapy, and evaluating the therapeutic effect on tumors.

A sensitive coumarin fluorescence sensor designed for isoprene detection and imaging research in plants.

The release of isoprene by plants is considered to be an adaptation to the environment. Herein, a highly selective coumarin fluorescent probe (DMIC) was designed for detecting isoprene. When isoprene came into contact with the maleimide of DMIC, an electrophilic addition process took place. The powerful push-pull effect of DMIC was disrupted. Simultaneously, intramolecular charge transfer was initiated. This enabled DMIC to achieve rapid detection of isoprene within 5 min. Furthermore, excellent linearity was observed in the concentration range of 1-560 ppm (R2 = 0.996). A limit of detection is 1.6 ppm. DMIC was applied to in vitro studies of plant release of liberated isoprene. By monitoring the release of isoprene from different tree species throughout the day, the dynamics of isoprene release from plants throughout the day have been successfully revealed. In addition, the release of isoprene varied considerably among different tree species. In particular, the biocompatibility of DMIC allowed for the in vivo detection of isoprene using fluorescence imaging. The results successfully revealed the dynamics of isoprene release in plants under stress. The amount of isoprene that a plant produced increased with the severity of the stress it experienced. This suggested that the level of isoprene content in plants could be used as a preliminary indicator of the physiological health status of plants. This research demonstrates great potential for clarifying signal transduction in biological systems. It provided ideas for further understanding the biology of isoprene.

Rational Biomimetic Construction of Lignin-based Carbon Nanozyme for Identification of Uric Acid in Human Urine.

Nanozymes have made remarkable progress in the field of sensing assays by replacing native enzyme functions. However, it is still a challenge to rationally design active centers from molecular structure to enhance the catalytic performance and develop low-cost nanozymes. In this work, guided by the catalytic site of horseradish peroxidase (HRP), iron source and histidine were coupled to the main chain of aminated sodium lignosulfonate (SL) through the self-assembly biomimetic strategy to construct His-SL-Fe with peroxidase activity. The inherent functional groups and basic framework of aminated SL provide a robust environment and promote the formation of active sites. His-SL-Fe shows excellent robustness over multiple test cycles and has a strong affinity for the substrate compared to HRP. His-SL-Fe had been effectively integrated in the sensing system for catalytic detection of uric acid (UA) to achieve accurate recognition of UA in the range of 0.5-100 µM with the limit of detection as low as 0.18 µM. The recovery of human urine samples is in the range of 96.8%-106.1 % and the error is within 4 %. This work not only provides a new approach for the directed design of high-performance nanozymes, but also demonstrates promising ideas for the refined application of biomass resources.

Embedding Atomically Dispersed Manganese/Gadolinium Dual Sites in Oxygen Vacancy-Enriched Biodegradable Bimetallic Silicate Nanoplatform for Potentiating Catalytic Therapy.

Due to their atomically dispersed active centers, single-atom nanozymes (SAzymes) have unparalleled advantages in cancer catalytic therapy. Here, loaded with chlorin e6 (Ce6), a hydrothermally mass-produced bimetallic silicate-based nanoplatforms with atomically dispersed manganese/gadolinium (Mn/Gd) dual sites and oxygen vacancies (OVs) (PMnSA GMSNs-V@Ce6) is constructed for tumor glutathione (GSH)-triggered chemodynamic therapy (CDT) and O2 -alleviated photodynamic therapy. The band gaps of silica are significantly reduced from 2.78 to 1.88 eV by doping with metal ions, which enables it to be excited by a 650 nm laser to produce electron-hole pairs, thereby facilitating the generation of reactive oxygen species. The Gd sites can modulate the local electrons of the atom-catalyzed Mn sites, which contribute to the generation of superoxide and hydroxyl radicals (• OH). Tumor GSH-triggered Mn2+ release can convert endogenous H2 O2 to • OH and realize GSH-depletion-enhanced CDT. Significantly, the hydrothermally generated OVs can not only capture Mn and Gd atoms to form atomic sites but also can elongate and weaken the O-O bonds of H2 O2 , thereby improving the efficacy of Fenton reactions. The degraded Mn2+ /Gd3+ ions can be used as tumor-specific magnetic resonance imaging contrast agents. All the experimental results demonstrate the great potential of PMnSA GMSNs-V@Ce6 as cancer theranostic agent.

MicroRNA-124 conducts neuroprotective effect via inhibiting AK4/ATF3 after subarachnoid hemorrhage.

Spontaneous subarachnoid hemorrhage (SAH) accounts for approximately 5% of all cases of stroke. SAH is correlated with elevated rates of mortality and disability. Despite significant advancements in comprehending the pathogenesis and surgical management, efficacious clinical interventions remain restricted, and the prognosis is yet to be enhanced. MicroRNAs play a crucial role in various pathological processes in organisms. Revealing these regulatory processes is conducive to the development of new treatment methods. MicroRNA-124 is highly expressed in the nervous system and has significant research value for SAH. This study aims to explore the role of miR-124 in the early post-SAH period on neural function and verify whether it is involved in the pathological and physiological processes of SAH. In this study, we used methods such as comparing the expression levels of miR-124 in cerebrospinal fluid, establishing a rat SAH model, and a mouse embryonic primary neuron hemoglobin stimulation model to verify the downstream proteins of miR-124 in SAH. Through transfection techniques, we adjusted the expression of this small RNA in Vitro and in Vivo models using miR-124 inhibitor and mimic in the primary neuron hemoglobin stimulation model and rat SAH model, and observed the phenotype. Finally, by consulting the literature and verifying in Vivo and in Vitro methods, AK4 and downstream molecule ATF3 were identified as downstream targets of miR-124.

Dual-functionalization of fluorescent carbon dots via cyclodextrin and aminosilane for visual detection of ß-glucuronidase and bioimaging.

A sensitive method for the detection of ß-glucuronidase was established using functionalized carbon dots (ß-CD-SiCDs) as fluorescent probes. The ß-CD-SiCDs were found to be obtained through in situ autopolymerization by mixing the solutions of methyldopa, mono-6-ethylenediamine-ß-cyclodextrin and N-(ß-aminoethyl)-γ-aminopropyltrimethoxysilane at room temperature. The method has the characteristics of low energy consumption, simple and rapid. ß-CD-SiCDs exhibited green fluorescence at 515 nm emission with a quantum yield of 7.9 %. 4-nitrophenyl-ß-D-glucuronide was introduced as a substrate for ß-glucuronidase to generate p-nitrophenol. Subsequently, p-nitrophenol self-assembled with ß-CD-SiCDs through host-guest recognition to form a stable inclusion complex, resulting in the fluorescence quenching of ß-CD-SiCDs. The linear range of ß-CD-SiCDs for detecting ß-glucuronidase activity was 0.5-60 U L-1 with a detection limit of 0.14 U L-1. For on-site detection, gel reagents were prepared by a simple method and the images were visualized and quantified by taking advantage of smartphones, avoiding the use of large instrumentation. The constructed fluorescence sensing platform has the benefits of easy operation and time saving, and has been successfully used for the detection of ß-glucuronidase activity in serum and cell imaging.

The Necessity or Not of Additional Endovascular Therapy to Medical Therapy for Symptomatic Intracranial Artery Stenosis: Insights from 30-Day and 1-Year Results.

BACKGROUND: The optimal treatment between endovascular therapy and medical treatment for symptomatic intracranial artery stenosis is still unclear. This study aimed to compare the safety and efficacy of 2 treatments based on the results from currently published randomized controlled trials (RCTs). METHODS: PubMed, Cochrane Library, EMBASE, and Web of Science were used for searching the RCTs evaluating the addition of endovascular therapy to medical therapy for treating symptomatic intracranial artery stenosis from the inception of these databases to September 30, 2022. P < 0.05 was considered statistically significant. All analyses were performed using STATA version 12.0. RESULTS: A total of 4 RCTs were involved in the current study, including 989 participants. In the 30-day results, the data showed that compared with the medical therapy alone group, the additional endovascular therapy group was associated with a higher risk of death or stroke (relative risk (RR): 2.857; 95% confidence interval (CI): 1.756-4.648; P < 0.001), ipsilateral stroke (RR: 3.525; 95% CI: 1.969-6.310; P < 0.001), death (risk differences (RD): 0.01; 95% CI: 0.004-0.03; P = 0.015), hemorrhagic stroke (RD: 0.03; 95% CI: 0.01-0.06; P < 0.001), and ischemic stroke (RR: 2.221; 95% CI: 1.279-3.858; P = 0.005). In the 1-year results, the additional endovascular therapy group was related to a greater incidence of ipsilateral stroke (RR, 2.247; 95% CI, 1.492-3.383; P < 0.001) and ischemic stroke (RR: 2.092; 95% CI: 1.270-3.445; P = 0.004). CONCLUSIONS: Given that the medical treatment alone was related to a lower risk of stroke and death in the short-term and long-term compared with endovascular therapy combined with medical therapy. Based on this evidence, these findings do not support the addition of endovascular therapy to medical therapy for treating patients with symptomatic intracranial stenosis.

Ratiometric luminescent sensor based on BSA-coated gold/silver nanoclusters for the selective determination and spatiotemporal imaging of gallic acid in plants.

A new fluorescence sensing strategy has been developed. Four bimetallic nanoclusters, gold/silver, gold/copper, gold/molybdenum and gold/cobalt, were prepared using bovine serum albumin (BSA) as a reducing and stabilizing agent. The fluorescence properties of four nanoclusters were explored by solid-state UV and XPS. The gold/silver nanoclusters (BSA-Au/Ag NCs) with the best ratiometric fluorescence properties for gallic acid (GA) in plants were selected to realize the sensitive detection of GA. GA affected the conformation of BSA, thereby disrupting the luminescent environment of the nanoclusters, resulting in a pronounced fluorescence quenching at 566 nm. The ratiometric fluorescence signal (I566/I453) was used for trace detection of GA in plants. It has a wide response range of 1.25-40.0 µM and a low detection limit of 45.27 nM. GA was detected at 19.49 µM in the plant extract, and the spiked recoveries ranged from 96.09 to 104.6%. In addition, due to the non-toxic and biocompatible properties of BSA, BSA-Au/Ag NCs have also been validated for fluorescence imaging of plant tissues. It realized the comparison of GA content in different parts of plants and the difference of GA content in plants after abiotic stress. Therefore, the developed strategy offers potential application for the analytical study of active substances in plants.

Enhancing brain entry and therapeutic activity of chimeric antigen receptor T cells with intra-arterial NEO100 in a mouse model of CNS lymphoma.

OBJECTIVE: Malignancies of the CNS are difficult to treat because the blood-brain barrier (BBB) prevents most therapeutics from reaching the intracranial lesions at sufficiently high concentrations. This also applies to chimeric antigen receptor (CAR) T cells, for which systemic delivery is inferior to direct intratumoral or intraventricular injection of the cells. The authors previously reported on a novel approach to safely and reversibly open the BBB of mice by applying intra-arterial (IA) injections of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol. The authors hypothesized that this method would enable enhanced brain entry and therapeutic activity of intravenously delivered CAR T cells, which the authors tested in a mouse model of CNS lymphoma. METHODS: Human Raji lymphoma cells were implanted into the brains of immune-deficient mice. After tumor uptake was confirmed with bioluminescent imaging, 0.3% NEO100 was injected intra-arterially, which was followed by intravenous (IV) delivery of CD19-targeted CAR T cells. After this single intervention, tumor growth was monitored with imaging, long-term survival of mice was recorded, and select mice were euthanized to analyze the distribution of CAR T cells in brain tissue. RESULTS: Intravenously injected CAR T cells could be readily detected in brain tumor areas after IA injection of NEO100 but not after IA injection of the vehicle (without NEO100). Although all untreated control animals died within 3 weeks, all mice that received IA NEO100 followed by IV CAR T cells survived and thrived for 200 days, when the experiment was terminated. Of the mice that received IV CAR T cells without prior IA NEO100, 3 died within 3 weeks and 2 survived long-term. CONCLUSIONS: BBB opening by IA NEO100 facilitates brain entry of intravenously delivered CD19 CAR T cells. The long-term survival of all mice with CNS lymphoma, along with the disappearance of the tumor as determined with imaging, suggests that this one-time therapeutic intervention was curative. BBB opening by IA NEO100 may offer a novel option to increase brain access by CAR T cells.

Protein Disulfide Isomerase A2 Is Correlated with Immune Infiltrates and Is a Novel Prognostic Biomarker in Glioma Patients.

OBJECTIVE: Protein disulfide isomerase A2 (PDIA2), a member of the protein disulfide isomerase family, plays a key role in the folding of nascent proteins in the endoplasmic reticulum by forming disulfide bonds, together with enzymes such as thiol isomerase, oxidase, and reductase. This study investigated the clinical significance and potential functions of PDIA2 in glioma. METHODS: The expression of PDIA2 in gliomas was explored using The Cancer Genome Atlas and Gene Expression Omnibus databases. We analyzed the clinical characteristics of glioma patients and the prognostic and diagnostic value of PDIA2 expression. Kaplan-Meier and Cox regression analyses were used to examine the effect of PDIA2 expression on overall survival, progression-free interval, and disease-specific survival. Furthermore, we performed Gene Set Enrichment Analysis and immune infiltration analysis to investigate the functions of PDIA2. PDIA2 mRNA and protein expression was evaluated in cell lines and glioma tissues. RESULTS: PDIA2 was expressed at low levels in glioma patients. Kaplan-Meier survival analysis showed that glioma patients with low PDIA2 levels had a worse prognosis than those with high PDIA2 levels. Receiver operating characteristic curve analysis indicated the diagnostic and prognostic ability of PDIA2 (area under the curve = 0.918). Pathways associated with PD1, PI3K/AKT, cancer immunotherapy via PD1 blockade, Fceri-mediated NF-kB activation, FOXM1, and DNA repair were enriched in glioma patients with low levels of PDIA2. PDIA2 expression levels were negatively correlated with immune cell infiltrate levels. CONCLUSION: PDIA2 levels are significantly downregulated in glioma. PDIA2 expression may be a potential biomarker for the diagnosis and prognosis of glioma patients.

Long non-coding RNA MIR17HG impedes FOSL2-mediated transcription activation of HIC1 to maintain a pro-inflammatory phenotype of microglia during intracerebral haemorrhage.

Activation and polarization of microglia play decisive roles in the progression of intracerebral haemorrhage (ICH), and lactate exposure correlates with microglia polarization. This study explores molecules influencing lactate production and microglia phenotype alteration following ICH. A murine model of ICH was induced by intracerebral injection of collagenase. The mice experienced autonomous neurological function recovery, haematoma resolution and rapid lactate production, along with a gradual increase in angiogenesis activity, neuronal recovery and an M1-to-M2 phenotype change of microglia. Galloflavin, a lactate dehydrogenase antagonist, suppressed this phenotype change and the functional recovery in mice. FOS like 2 (FOSL2) was significantly upregulated in the brain tissues from day 7 post-ICH. Overexpression of FOSL2 induced an M1-to-M2 phenotype shift in microglia and accelerated lactate production in vivo and in haemoglobin-treated microglia in vitro. Long non-coding RNA MIR17HG impeded FOSL2-mediated transcription activation of hypermethylated in cancer 1 (HIC1). MIR17HG overexpression induced pro-inflammatory activation of microglia in mice, which was blocked by further HIC1 overexpression. Overall, this study demonstrates that MIR17HG maintains a pro-inflammatory phenotype of microglia during ICH progression by negating FOSL2-mediated transcription activation of HIC1. Specific inhibition of MIR17HG or upregulation of FOSL2 or HIC1 may favour inflammation inhibition and haematoma resolution in ICH.

RUNX1 predicts poor prognosis and correlates with tumor progression in clear cell renal carcinoma.

BACKGROUND: Runt-related transcription factor 1 (RUNX1), also called acute myeloid leukaemia 1, is a member of RUNX family of transcription factors. This family is composed of evolutionarily conserved transcription factors that function as critical lineage determinants in various tissues, however its function in cancer development and clinical significance in RCC are still unknown. METHODS: We used paraffin-embedded tumor tissues from 100 patients and fresh-harvested and paired adjacent normal renal tissues from 15 RCC patients who underwent primary surgical resection in Xijing Hospital between 2018 and 2022. The expression level of RUNX1 was evaluated by immunohistochemistry and Western Blot. RUNX1 promoted tumor cells proliferation, migration and invasion were verified by CCK-8, wound-healing and transwell assays. Finally, we constructed a xenografts model of the 786-O cell lines to observe the effect of RUNX1 on tumorigenesis in vivo. RESULTS: TCGA database showed higher RUNX1 expression levels in KIRC (kidney renal clear cell carcinoma). In overall survival analysis, RCC patients with higher RUNX1 expression level would have a shorter survival period than those with lower expression. Similarly, immunohistochemical results of our cohort also showed that RUNX1 was over-expression in cancer tissues than in corresponding non-cancer tissues. We also proved this result at protein level by western-blot. Meanwhile, prognostic and OS analyses of our cohort showed that the RUNX1 expression level was an individual prognostic factor in RCC patients. CCK-8, wound-healing and transwell assays proved that the overexpression of RUNX1 in Caki-1 cells promoted the proliferation, migration and invasion of the cells. Knocking down RUNX1 in 786-O cells inhibited the proliferation, migration and invasion of cells. The experimental results of xenografts model in nude mice showed that the knockdown of RUNX1 in 786-O cells slowed down the growth of tumor. CONCLUSION: RUNX1 is a poor prognostic factor of clear cell renal carcinoma, which may provide a novel therapeutic target for ccRCC.

High PGAP3 expression is associated with lymph node metastasis and low CD8+T cell in patients with HER2+ breast cancer.

BACKGROUND: Breast cancer (BC) stands as the most prevalent malignancy among women and ranks as the second most frequently diagnosed cancer globally among newly identified cases. Post-GPI attachment to proteins factor 3（PGAP3）was reported to involve in lipid remodeling. However, its specific role in breast cancer remains inadequately elucidated. Consequently, the principal objective of this study was to investigate the clinical significance of PGAP3 in breast cancer. METHODS: We conducted an extensive analysis using both public databases and our own sample cohort to assess the role of PGAP3 in breast cancer. Immunohistochemistry was employed to assess PGAP3 expression, immune markers, and the co-expression of PGAP3 with key susceptibility genes. Data analysis was performed using the R programming language. RESULTS: Our findings revealed that PGAP3 is significantly overexpressed in breast cancer, particularly in human epidermal growth factor 2 positive (HER2 +) breast cancer cases (p < 0.001). Co-expression analyses demonstrated a significant correlation between PGAP3 and susceptibility genes associated with breast cancer, including BRCA1, BRCA2, PALB2, ATM, CHEK2, RAD51C, and RAD51D (p < 0.05). Logistic regression analysis identified PGAP3 as a significant predictor of estrogen receptor (ER), progesterone receptor (PR), HER2, and lymph node metastasis status (p < 0.01). Furthermore, higher PGAP3 expression was associated with decreased infiltration of CD8 + T cells in breast cancer samples. CONCLUSION: Our study sheds light on the clinical significance of PGAP3 in breast cancer. PGAP3 is not only overexpressed in breast cancer but also correlates with key susceptibility genes, lymph node metastasis, and CD8 + T cell infiltration. These findings provide valuable insights into the potential role of PGAP3 as a biomarker in breast cancer and may contribute to our understanding of the disease's pathogenesis.

Terahertz label-free detection of nicotine-induced neural cell changes and the underlying mechanisms.

Nicotine exposure can lead to neurological impairments and brain tumors, and a label-free and nondestructive detection technique is urgently required by the scientific community to assess the effects of nicotine on neural cells. Herein, a terahertz (THz) time-domain attenuated total reflection (TD-ATR) spectroscopy approach is reported, by which the effects of nicotine on normal and cancerous neural cells, i.e., HEB and U87 cells, are successfully investigated in a label/stain-free and nondestructive manner. The obtained THz absorption coefficients of HEB cells exposed to low-dose nicotine and high-dose nicotine are smaller and larger, respectively, than the untreated cells. In contrast, the THz absorption coefficients of U87 cells treated by nicotine are always smaller than the untreated cells. The THz absorption coefficients can be well related to the proliferation properties (cell number and compositional changes) and morphological changes of neural cells, by which different types of neural cells are differentiated and the viabilities of neural cells treated by nicotine are reliably assessed. Collectively, this work sheds new insights on the effects of nicotine on neural cells, and provides a useful tool (THz TD-ATR spectroscopy) for the study of chemical-cell interactions.

Ribosomal S6 protein kinase 4 promotes resistance to EZH2 inhibitors in glioblastoma.

Glioblastoma (GBM) is a highly malignant type of brain tumor with limited treatment options. Recent research has focused on epigenetic regulatory factors, such as Enhancer of Zeste Homolog 2 (EZH2), which plays a role in gene expression through epigenetic modifications. EZH2 inhibitors have been developed as potential therapeutic agents for GBM, but resistance to these inhibitors remains a considerable challenge. This study aimed to investigate the role of ribosomal S6 protein kinase 4 (RSK4) in GBM and its association with resistance to EZH2 inhibitors. We first induced drug resistance in primary GBM cell lines by treatment with an EZH2 inhibitor and observed increases in the expression of stemness markers associated with glioblastoma stem cells (GSCs) in the drug-resistant cells. We also found high expression of RSK4 in GBM patient samples and identified the correlation of high RSK4 expression with poor prognosis and GSC marker expression. Further experiments showed that knocking down RSK4 in drug-resistant GBM cells restored their sensitivity to EZH2 inhibitors and decreased the expression of GSC markers, thus reducing their self-renewal capacity. From a mechanistic perspective, we discovered that RSK4 directly phosphorylates EZH2, activating the EZH2/STAT3 pathway and promoting resistance to EZH2 inhibitors in GBM. We also found that combining EZH2 inhibitors with an RSK4 inhibitor called BI-D1870 had better inhibitory effects on GBM occurrence and progression in both in vitro and in vivo experiments. In conclusion, this study demonstrates that RSK4 enhances cancer stemness and mediates resistance to EZH2 inhibitors in GBM. Combination treatment with EZH2 inhibitors and RSK4 inhibitors is a promising potential therapeutic strategy for GBM. Collectively, our results strongly demonstrate that RSK4 regulates the EZH2/STAT3 pathway to promote GSC maintenance and EZH2i resistance in a PRC2-independent manner, indicating that RSK4 is a promising therapeutic target for GBM.