Resistant Cells Research Articles

MicroRNA-505-5p/-3p Regulates the Proliferation, Invasion, Apoptosis, and Temozolomide Resistance in Mesenchymal Glioma Stem Cells by Targeting AUF1.

Mesenchymal glioma stem cells (MES-GSCs) are a major subtype of GSCs that reside within glioma tissues and contribute to metastasis, therapy resistance, and glioma recurrence. However, the precise molecular mechanisms governing MES-GSC functions remain elusive. Our findings revealed that expression levels of miR-505-5p/-3p are elevated in MES-GSCs compared with those in proneural (PN)-GSCs, glioma cell lines, and normal brain tissue and that miR-505-5p/-3p expression levels are decreased in differentiated MES-GSCs. We assumed that miR-505-5p/-3p would play distinctive roles in MES-GSCs and performed loss-of-function experiments targeting miR-505-5p/-3p. Knockdown of miR-505-5p/-3p increased proliferation and promoted differentiation in MES-GSCs while suppressing invasion, temozolomide resistance, and enhancing apoptosis in MES-GSCs. Mechanistically, miR-505-5p/-3p directly targets the 3' UTR of AUF1, leading to its repression in MES-GSCs. Notably, AUF1 expression levels were significantly lower in MES-GSCs compared with those in PN-GSCs, glioma cell lines, and normal brain tissues. Co-inhibition of AUF1 expression with miR-505-5p/-3p knockdown ameliorated the observed cellular phenotypes caused by miR-505-5p/-3p knockdown in MES-GSCs. These results suggest that miR-505-5p/-3p exerts MES-GSC-specific roles in regulating proliferation, differentiation, invasion, apoptosis, and temozolomide resistance by repressing AUF1 expression.

Construction of a Carbon Monoxide-Releasing Bioactive Hydrogel Coating on the Magnesium Alloy Surface for Better Corrosion Resistance, Anticoagulant Properties, and Endothelial Cell Growth

In this study, we first fabricated a crosslinked hydrogel coating by polymerizing methacryloyloxyethyl sulfonyl betaine and acrylamide (SBMA) on the magnesium (Mg) alloy surface employing ultraviolet (UV) polymerization. Bivalirudin and CO-releasing molecules (CORM-401) were further grafted onto the hydrogel coating surface to acquire a multifunctional biocompatible coating capable of releasing CO to augment corrosion-resisting properties and biocompatibility. The findings verified that the bioactive hydrogel coating significantly increased the corrosion potential and reduced the corrosion current, thereby improving the anticorrosion performance. Meanwhile, owing to the excellent hydrophilicity, the antifouling performance of the hydrogel coating, and the excellent anticoagulant performance of bivalirudin, the hydrogel coating significantly reduced the fibrinogen adsorption, platelet adhesion and activation, and hemolysis occurrence, displaying excellent ability to inhibit blood clotting. Moreover, endothelial cell (EC) experimental results demonstrated that the hydrogel coating could significantly promote EC growth, displaying great potential to induce re-endothelialization after implantation. Specifically, in the presence of cysteine capable of catalyzing CO release, the anticoagulant performance and ability to promote EC growth were further improved significantly. Therefore, the study offers an effective strategy to prepare a hydrogel coating capable of releasing CO to improve the corrosion-resisting performance and biocompatibility of Mg alloys, which is anticipated to be applied in the surface modification of Mg alloy intravascular stents.

Cytotoxic Effects of Plant Secondary Metabolites and Naturally Occurring Bioactive Peptides on Breast Cancer Model Systems: Molecular Mechanisms

Breast cancer is the second leading cause of death among women, and the number of mortal cases in diagnosed patients is constantly increasing. The search for new plant compounds with antitumor effects is very important because of the side effects of conventional therapy and the development of drug resistance in cancer cells. The use of plant substances in medicine has been well known for centuries, but the exact mechanism of their action is far from being elucidated. The molecular mechanisms of cytotoxicity exerted by secondary metabolites and bioactive peptides of plant origin on breast cancer cell lines are the subject of this review.

Targeting ketone body metabolism in mitigating gemcitabine resistance.

Chemotherapy is often combined with surgery for muscle invasive and non-muscle invasive bladder cancer. However, 70% of the patients recur within 5 years. Metabolic reprogramming is an emerging hallmark in cancer chemoresistance. Here, we report a gemcitabine resistance mechanism which promotes cancer reprogramming via the metabolic enzyme, OXCT1. This mitochondrial enzyme, responsible for the rate-limiting step in β-hydroxybutyrate (βHB) catabolism, was elevated in muscle invasive disease and in chemo-resistant bladder cancer patients. Resistant orthotopic tumors presented an OXCT1-dependent rise in mitochondrial oxygen consumption rate, ATP, and nucleotide biosynthesis. In resistant bladder cancer, knocking out OXCT1 restored gemcitabine sensitivity, and administering the non-metabolizable βHB, enantiomer (S-βHB) only partially restored gemcitabine sensitivity. Suggesting an extra-metabolic role for OXCT1, multi-omics analysis of gemcitabine sensitive and resistant cells revealed an OXCT1-dependent signature with the transcriptional repressor, OVOL1, as a master regulator of epithelial differentiation. The elevation of OVOL1 target genes was associated with its cytoplasmic translocation and poor prognosis in a chemotherapy-treated BCa patient cohort. The knockout of OXCT1 restored OVOL1 transcriptional repressive activity by its nuclear translocation. Orthotopic mouse models of bladder cancer supported OXCT1 as a mediator of gemcitabine sensitivity through ketone metabolism and regulating cancer stem cell differentiation.

DLK1 Is Associated with Stemness Phenotype in Medullary Thyroid Carcinoma Cell Lines

Medullary thyroid carcinoma (MTC) is a rare and aggressive tumor, often requiring systemic treatment in advanced or metastatic stages, where drug resistance presents a significant challenge. Given the role of cancer stem cells (CSCs) in cancer recurrence and drug resistance, we aimed to identify CSC subpopulations within two MTC cell lines harboring pathogenic variants in the two most common MEN2-associated codons. We analyzed 15 stemness-associated markers, along with well-established thyroid stem cell markers (CD133, CD44, and ALDH1), a novel candidate (DLK1), and multidrug resistance proteins (MRP1 and MRP3). The ability to efflux the fluorescent dye Hoechst 3342 and form spheroids, representing CSC behavior, was also assessed. MZ-CRC-1 cells (p.M918T) displayed higher expressions of canonical markers, DLK1, and MRP proteins than TT cells (p.C634W). MZ-CRC-1 cells also formed more spheroids and showed less dye accumulation (p < 0.0001). Finally, we observed that DLK1+ cells (those expressing DLK1) in both cell lines exhibited significantly higher levels of stemness markers compared to DLK1− cells (those lacking DLK1 expression). These findings underscore DLK1’s role in enhancing the stemness phenotype, providing valuable insights into MTC progression and resistance and suggesting potential therapeutic implications.

ZNF480 Accelerates Chemotherapy Resistance in Breast Cancer by Competing With TRIM28 and Stabilizing LSD1 to Upregulate the AKT-GSK3β-Snail Pathway.

Zinc finger protein 480 (ZNF480) may interact with lysine-specific demethylase 1 (LSD1), which is highly expressed in many malignant tumors; however, ZNF480 expression has not previously been investigated in breast cancer. Therefore, we explored the expression and molecular mechanisms of ZNF480 in breast cancer. According to public databases and immunohistochemical staining analysis, ZNF480 is highly expressed in the tissue of patients with breast cancer, and ZNF480 expression is positively correlated with advanced TNM stage (p = 0.036), lymph node metastasis (p = 0.012), and poor prognosis (p = 0.005). ZNF480 overexpression enhances breast cancer cell proliferation, migration, and stemness by activating AKT-GSK3β-Snail signaling both in vitro and in vivo. Moreover, ZNF480 binds to LSD1 through its KRAB domain, thereby activating AKT signaling. Mass spectrometry and co-immunoprecipitation revealed that ZNF480 abrogates ubiquitination degradation and subsequently stabilizes LSD1 through competitive binding with TRIM28. Ipragliflozin was identified as a small-molecule inhibitor of ZNF480 and LSD1 interaction that may block breast cancer progression. Moreover, ZNF480 expression was significantly higher in treatment-resistant patients than in treatment-sensitive patients. Thus, ipragliflozin may neutralize neoadjuvant chemotherapy resistance induced by ZNF480 overexpression. Overall, elevated ZNF480 expression is positively associated with poor patient outcomes. Mechanistically, ZNF480 accelerates proliferation and neoadjuvant chemotherapy resistance in breast cancer cells via the AKT-GSK3β-Snail pathway by interacting with and stabilizing LSD1 in a competitive manner within TRIM28. This research has implications for developing targeted drugs against chemotherapy resistance in breast cancer.

Androgen Receptor Mediates Dopamine Agonist Resistance by Regulating Intracellular Reactive Oxygen Species in Prolactin-Secreting Pituitary Adenoma.

Aims: Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. Results: Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both in vitro and invivo. Mechanistically, we demonstrated that intracellular reactive oxygen species (ROS) function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. Conclusion and Innovation: We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. Antioxid. Redox Signal. 00, 000-000.

Photothermally Reinforced Nanozyme Remodeling Tumor Microenvironment of Redox and Metabolic Homeostasis to Enhance Ferroptosis in Tumor Therapy.

The acidity and high GSH level in the tumor microenvironment (TME) greatly limit the antitumor activity of nanozymes. Thus, enhancing nanozymes' activity is fundamentally challenging in tumor therapy. Although the combination of photothermal therapy (PTT) and nanozymes can enhance the catalytic activity, cancer cells will overexpress heat shock proteins (HSPs) at high temperature, aggravating the heat resistance of tumor cells, which in turn compromises the outcome of chemodynamic therapy. Herein, we propose an iron-doped metal-organic framework nanozyme (IB@Fe-ZIF8@PDFA) that can be activated under the weak acidity and high level of GSH, demonstrating the activities of GSH oxidation (GSH-OXD), peroxidase (POD), and NADH oxidase (NADH-OXD). Under laser irradiation, it displays photothermal-enhanced multienzyme activities to simultaneously eliminate tumors and inhibit tumor metastasis. While consuming endogenous GSH, IB@Fe-ZIF8@PDFA promotes the decomposition of H2O2 into ·OH, enhancing ferroptosis in tumor cells. Surprisingly, IB@Fe-ZIF8@PDFA nanozyme can oxide NADH and subsequently limit the ATP supply, reducing the expression of HSPs and significantly weakening the heat resistance of tumor cells during PTT. Meanwhile, H2O2 is generated during this procedure, which can endogenously replenish the consumed H2O2. Thus, this IB@Fe-ZIF8@PDFA nanozyme constitutes a self-cascading platform to consume GSH and NADH, endogenously replenish the H2O2 and continuously generate ·OH to facilitate ferroptosis by disrupting the redox and metabolic homeostasis in tumor cells, achieving tumor elimination and tumor metastasis inhibition.

Retraction: SH2 Modified STAT1 Induces HLA-I Expression and Improves IFN-γ Signaling in IFN-α Resistant HCV Replicon Cells.

Retraction: SH2 Modified STAT1 Induces HLA-I Expression and Improves IFN-γ Signaling in IFN-α Resistant HCV Replicon Cells.

STUB1 suppresses paclitaxel resistance in ovarian cancer through mediating HOXB3 ubiquitination to inhibit PARK7 expression

Paclitaxel (PTX) is a first-line drug for ovarian cancer (OC) treatment. However, the regulatory mechanism of STUB1 on ferroptosis and PTX resistance in OC remains unclear. Genes and proteins levels were evaluated by RT-qPCR, western blot and IHC. Cell viability and proliferation were measured by CCK-8 and clone formation. The changes of mitochondrial morphology were observed under a transmission electron microscope (TEM). Reactive oxygen species (ROS), iron, malondialdehyde (MDA) and glutathione (GSH) were measured using suitable kits. The interactions among STUB1, HOXB3 and PARK7 were validated using Co-IP, and dual luciferase reporter assay. Our study found that STUB1 was decreased and PARK7 was increased in tumor tissue, especially from chemotherapy resistant ovarian cancer tissue and resistant OC cells. STUB1 overexpression or PARK7 silencing suppressed cell growth and promoted ferroptosis in PTX-resistant OC cells, which was reversed by HOXB3 overexpression. Mechanistically, STUB1 mediated ubiquitination of HOXB3 to inhibit HOXB3 expression, and HOXB3 promoted the transcription of PARK7 by binding to the promoter region of PARK7. Furthermore, STUB1 overexpression or PARK7 silencing suppressed tumor formation in nude mice. In short, STUB1 promoted ferroptosis through regulating HOXB3/PARK7 axis, thereby suppressing chemotherapy resistance in OC.

Knockdown of Inhibin Beta A Reversed the Epithelial Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance and Enhanced the Therapeutic Effect of Radiotherapy in Non-Small Cell Lung Cancer.

Lung cancer is a malignant tumor with the highest mortality rate worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately half of all lung cancer cases. Inhibin beta A (INHBA) is a ligand of the transforming growth factor-beta superfamily. This study aimed to analyze the function of INHBA in NSCLC resistance cells. Gene Expression Omnibus and The Cancer Genome Atlas databases were used to identify differentially expressed genes (DEGs) in NSCLC resistance cells and patients. DEGs were further analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. A colony formation assay was performed to determine cell growth. Cell migration and invasion were tested by Transwell assay. Epithelial-mesenchymal transition (EMT)-related genes were analyzed using qRT-PCR and Western blot analysis. Using bioinformatics tools, INHBA was demonstrated to be overexpressed in NSCLC resistant cells and patients. Gefitinib treatment affected NSCLC resistant cells. Additionally, INHBA silencing or X-ray treatment suppressed the growth and metastasis of NSCLC resistant cells. Moreover, the combined application of INHBA silencing and X-ray treatment enhances the therapeutic effects. Moreover, EMT has been confirmed to occur in NSCLC resistant cell lines. Both INHBA silencing and X-ray treatment inhibited EMT development. This study demonstrated that INHBA silencing ameliorates EGFR-TKI resistance and enhances the therapeutic effect of radiotherapy in NSCLC.

USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer.

The chromatin-remodeling enzyme SMARCA5 plays a key role in DNA-templated events including transcription, DNA replication, and DNA repair. Loss of function of the SMARCA5 can cause neurodevelopmental disorder and Williams syndrome. However, the molecular mechanism underlying the regulation of SMARCA5 in prostate cancer remains largely elusive. Here, we report that the deubiquitinating enzyme USP3 directly interacts with SMARCA5 and removes K63-linked polyubiquitination of SMARCA5 to maintain its stability, which promotes DNA damage repair and chemotherapy resistance. Depletion of USP3 or SMARCA5 promoted PCa cells sensitive to docetaxel and overexpression of USP3 restored the cells resistance to docetaxel treatment in SMARCA5 silenced cells in vitro and vivo. Clinically, USP3 was significantly up-regulated in prostate cancer tissues and positively associated with SMARCA5 expression. Collectively, our findings uncover a novel molecular mechanism for the USP3-SMARCA5 axis in regulating DSB repair with an important role in chemotherapy response in human prostate cancers, highlighting that targeting USP3-SMARCA5 axis could be a valuable strategy to treat USP3/SMARCA5-overexpressing chemotherapy-resistant patients and improve drug treatment.

IGF2BP3-dependent N6-methyladenosine modification of USP49 promotes carboplatin resistance in retinoblastoma by enhancing autophagy via regulating the stabilization of SIRT1.

Retinoblastoma (RB) poses significant challenges in clinical management due to the emergence of resistance to conventional chemotherapeutic agents, particularly carboplatin (CBP). In this study, we investigated the molecular mechanisms underlying CBP resistance in RB, with a focus on the role of autophagy and the influence of ubiquitin-specific peptidase 49 (USP49). We observed upregulation of USP49 in RB tissues and cell lines, correlating with disease progression. Functional assays revealed that USP49 promoted aggressive proliferation and conferred CBP resistance in RB cells. Furthermore, USP49 accelerated tumor growth and induced CBP resistance in vivo. Mechanistically, we found that USP49 facilitated CBP resistance by promoting autophagy activation. In addition, we identified insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3)-mediated N6-methyladenosine (m6A) modification of USP49 as a regulatory mechanism, wherein IGF2BP3 upregulated USP49 expression in an m6A-dependent manner. Moreover, USP49 stabilized SIRT1, a protein associated with CBP resistance and autophagy, by inhibiting its ubiquitination and degradation. Rescue experiments confirmed the pivotal role of SIRT1 in USP49-mediated CBP resistance. Our findings delineate a novel molecular network involving USP49-mediated autophagy in promoting CBP resistance in RB, offering potential targets for therapeutic intervention to enhance treatment efficacy and improve outcomes for RB patients.

YAP regulates HER3 signaling-driven adaptive resistance to RET inhibitors in RET-aberrant cancer.

Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKIs). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells. Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-RTK antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET-fusion-positive lung cancer were analyzed for pre-treatment YAP expression and correlated with treatment outcomes. In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/TEAD inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pre-treatment YAP expression in clinical specimens obtained from patients with RET-fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes. The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.

Knockout of Caspase-1 Disrupts Pyroptosis and Protects Photoreceptor Cells from Photochemical Damage

Retinal photochemical damage (RPD) plays a significant role in the development of various ocular diseases, with Caspase-1 being a key contributor. This study investigates the protective effects of Caspase-1 gene-mediated pyroptosis against RPD. Differentially expressed genes (DEGs) associated with RPD were identified through the analysis of two expression profiles from the GEO database. Correlation analysis was used to pinpoint pyroptosis-related genes (PRGs) linked to RPD. A Caspase-1 knockout 661W cell line was generated via CRISPR-Cas9 gene editing, and single-cell colonies were screened and purified. Validation of knockout cells was performed through RT-qPCR, gene sequencing, and Western blot analysis. Comparative assays on cell proliferation, intracellular reactive oxygen species (ROS), and cytotoxicity were conducted between wild-type and Caspase-1 knockout cells under light exposure. Further RT-qPCR and Western blot experiments examined changes in the mRNA and protein levels of key pyroptosis pathway components. Significant alterations in Caspase-1 expression were observed among PRGs. Homozygous Caspase-1 knockout cell lines were confirmed through RT-qPCR, genomic PCR product sequencing, and Western blot analysis. Compared to wild-type 661W cells, Caspase-1 knockout cells exhibited higher viability and proliferation rates after 24 hours of light exposure, alongside reduced LDH release. The expression of downstream pyroptosis factors at both the mRNA and protein levels was markedly decreased in the knockout group. CRISPR/Cas9-mediated Caspase-1 knockout enhanced the resistance of 661W cells to photochemical damage, suggesting that Caspase-1 may serve as a potential therapeutic target for RPD-related diseases.

The Mechanism of Action of Exosomes Derived from Glioblastoma Cells.

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor characterized by rapid growth, invasive behavior, and resistance to conventional therapies, such as surgery, radiotherapy, and chemotherapy. Despite these interventions, patient survival remains poor due to the tumor's ability to recur and adapt to treatments. The function of GBM-derived exosomes (GBM-exosomes) as essential mediators in tumor growth has drawn attention in recent years. These small extracellular vesicles are involved in the transfer of a variety of molecules, including cytokines, miRNAs, proteins, and DNA, facilitating intercellular communication that promotes GBM cell proliferation, angiogenesis, immune evasion, and resistance to therapies. This review aims to provide an in- -depth examination of the mechanisms through which GBM-exosomes contribute to these pathological processes, as well as to discuss the current methodologies for isolating and characterizing GBM exosomes. Additionally, we explore the potential of exosomes as biomarkers for diagnosis and prognosis and as novel therapeutic targets in the fight against GBM. By improving our understanding of GBM-exosomes, we can pave the way for the development of more effective, personalized treatment strategies that may improve patient outcomes and quality of life.

Targeting the SPC25/RIOK1/MYH9 Axis to Overcome Tumor Stemness and Platinum Resistance in Epithelial Ovarian Cancer.

In epithelial ovarian cancer (EOC), platinum resistance, potentially mediated by cancer stem cells (CSCs), often leads to relapse and treatment failure. Here, the role of spindle pole body component 25 (SPC25) as a key determinant promoting stemness and platinum resistance in EOC cells, with its expression being correlated with adverse clinical outcomes is delineated. Mechanistically, SPC25 acts as a scaffolding platform, orchestrating the assembly of an SPC25/RIOK1/MYH9 trimeric complex, triggering RIOK1-mediated phosphorylation of MYH9 at Ser1943. This prompts MYH9 to disengage from the cytoskeleton, augmenting its nuclear accumulation, thus potentiating CTNNB1 transcription and subsequent activation of Wnt/β-catenin signaling. CBP1, a competitive inhibitory peptide, can disrupt the formation of the aforementioned trimeric complex, diminishing the activity of the SPC25/RIOK1/MYH9 axis-mediated Wnt/β-catenin signaling, and thus attenuate CSC phenotypes, thereby enhancing platinum efficacy in vitro, in vivo, and in patient-derived organoids. Therefore, targeting the SPC25/RIOK1/MYH9 axis, which mediates the maintenance of stemness and platinum resistance in EOC cells, may enhance platinum sensitivity and increase survival in patients with EOC.

Dual surface-bulk aluminum modification in a-Al2O3@Na3VAl(PO4)3 sodium-ion batteries cathode to boost high voltage utilization and electrolyte protection

Amorphous alumina (a-Al2O3)-coated Na3VAl(PO4)3 samples are prepared by a low-cost, easily scalable, and environmentally friendly sol-gel process. X-ray diffraction reveals no significant structural changes after deposition. The presence of the amorphous carbon conductive and a-Al2O3 phases will be respectively confirmed in the light of Raman and NMR spectroscopies. Electron microscopy evidences the presence of alumina particles deposited on the substrate. Ex-situ XRD shows the reversible structural changes while sodium is inserted. Ex-situ XPS reveals the effective participation of V5+/V4+/V3+ species during the electrochemical reaction, while the formation of aluminum oxyfluorides justifies the efficient HF removal that prevents electrode degradation.Electrochemical tests will validate this proposal. Thus, rate capability essays indicate that 1–3 % a-Al2O3 coating enhances capacity at high rates, with coated samples exhibiting a fast sodium migration and lower cell resistance at both the beginning and conclusion of cycling tests. It is supported by evaluating the kinetic response showing their high capacitive contributions and diffusion coefficients, especially in the 2 % a-Al2O3 coated sample. Eventually, these findings are corroborated by the good capacity retention of the 2 % coated sample during prolonged cycling at both room and low temperatures.

Composition of four polyphenol fractions extracted from partridge tea and their mechanisms on ameliorate insulin resistance in HepG2 cells

Partridge tea is a plant used as a speciality tea drink in Hainan Province, China. The aim of this study was to isolate polyphenols from partridge tea, investigate their main constituent compositions and ameliorative effects on insulin resistance in insulin resistant HepG2 (IR-HepG2) cells. PTP was obtained from partridge tea, then PTP-1, PTP-2 and PTP-3 were obtained after further purification. The polyphenol contents of PTP, PTP-1, PTP-2, PTP-3 were determined to be 15.9%, 51.4%, 42.51% and 22.74%, respectively. PTP and PTP-1 had similar compositions, and the contents of the main components of PTP-1 was higher than that of PTP. Structural compositions and contents of PTP-2 and PTP-3 differ significantly. Further analysis indicated that PTP failed to have significant hypoglycaemic activity, while other three polyphenols regulated the fat metabolism disorders caused by insulin resistance, thus improving the body’s utilization of blood glucose. In addition, the three polyphenols reversed the damage caused by insulin resistance in IR-HepG2 cells by up-regulating the activities of HK (200 μg/mL PTP-1: 2.8414 mol/min/mL) and PK (200 μg/mL PTP-1: 10.7204 U/L), increasing the activity of SOD and CAT and decreasing the level of MDA. The mRNA results showed that PTP-1, PTP-2 and PTP-3 could achieve hypoglycaemic efficacy in the body by regulating the IRS-1/PI3K/AKT signal pathway. In summary, our results suggested that the polyphenols of partridge tea could be a promising natural source for preventing and treating hyperglycemia.

Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRASG12C inhibitor resistant tumors

The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.