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PMC12842104
At least three separate experiments, each containing three replicates, were performed.
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PMC12842104
HMECs showed reduction in cell viability starting at 125 µg/mL concentration using E. bicolor xylene extract.
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PMC12842104
Therefore, the rest of the experiments were set up to use 62.5 µg/mL concentration to determine the antiproliferative mechanisms.
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PMC12842104
The 50% inhibitory concentration (IC50) was estimated using the GraphPad Prism 9.4 software as described before .
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PMC12842104
The IncuCyte live cell imaging system (Sartorius, Ann Arbor, MI, USA) was used to observe and capture photos at 4 h intervals of morphological changes of treated cells for several days.
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PMC12842104
Cells were seeded into a 96-well plate (10,000 cells/well) and exposed to 62.5 µg/mL of E. bicolor xylene extract, before being placed into the IncuCyte .
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PMC12842104
Cell apoptosis was assessed with the Click-iT™ Plus TUNEL assay kit (ThermoFisher Scientific, Waltham, MA, USA) as reported previously .
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PMC12842104
Cells were treated with E. bicolor xylene extract at a concentration of 62.5 µg/mL for 24 h before proceeding with the TUNEL assays.
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PMC12842104
Cells were pretreated with 10 µM of the TRPV1 antagonist capsazepine (Abcam, USA) for 30 min as previously described before being treated with E. bicolor xylene extract (62.5 µg/mL) and cell viability measured using MTS assays.
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PMC12842104
Three independent experiments were conducted.
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PMC12842104
Cells were pretreated with 1 µM of the calcium chelator BAPTA-AM (Abcam, San Francisco, CA, USA), as previously described , and then treated with E. bicolor xylene extract (62.5 µg/mL) before MTS assays for cell viability were performed.
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PMC12842104
Three independent experiments were conducted.
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PMC12842104
The cytoplasmic calcium dynamics as the result of TRPV1 activation were observed using Fura2-AM staining.
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PMC12842104
T47D and MDA-MB-231 cells were seeded into a 6-well plate and cultured overnight.
[ { "end": 4, "label": "CellLine", "start": 0, "text": "T47D" }, { "end": 19, "label": "CellLine", "start": 9, "text": "MDA-MB-231" } ]
PMC12842104
After 24 h, cells were loaded with 5 μM of Fura2-AM for 30 min .
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PMC12842104
Following E. bicolor xylene treatment, the cytosolic Ca signal was monitored continuously for 20 min using a LionHeart FX microscope (Agilent, Santa Clara, CA, USA).
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PMC12842104
The intracellular ROS levels were determined using cell-permeant reagent 2’,7’-dichlorofluorescin diacetate (DCFDA) according to the manufacturer’s instructions (Abcam).
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PMC12842104
Tert-butyl hydroperoxide (TBHP; 250 μM) was used as positive control.
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PMC12842104
The fluorescence intensity values at each time point were calculated as the ratio of the value at a specific t-time point to the value at point zero time (t-time point/t0); t0 = first measurement.
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PMC12842104
Briefly, cells were plated in FBS-supplemented medium without phenol red onto 96-well plates.
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PMC12842104
After 24 h, the cells were washed once with 1× buffer provided in the kit, then the cells were incubated with 10 μM of DCFDA for 30 min at 37 °C, protected from light.
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PMC12842104
Following incubation, the wells were washed with PBS, and treated with E. bicolor xylene extract.
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PMC12842104
ROS production was determined immediately by measuring the formation of fluorescent dichlorofluorescein (DCF), using a Synergy microplate reader (Agilent, Winooski, VT, USA), at 485 nm excitation and 535 nm emission.
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PMC12842104
Measurements were taken every 60 min for six hours.
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PMC12842104
Three independent experiments were conducted.
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PMC12842104
Cells were pretreated with NAC (5 mM) for 1 h followed by treatment with or without E. bicolor xylene extract for another 72 h, and cell viability was measured using MTS assay.
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PMC12842104
Three independent experiments were conducted.
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PMC12842104
ER-targeted low-affinity GCaMP6-210 variant, a fluorescent reporter for ER calcium signaling, was used to observe endoplasmic reticulum (ER) Ca dynamics.
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PMC12842104
T47D cells were seeded into a 24-well plate at 10.4 × 10 cells in 500 µL phenol red free growth medium.
[ { "end": 4, "label": "CellLine", "start": 0, "text": "T47D" } ]
PMC12842104
After 24 h, cells were transfected with the GCaMP6-210 variant using Invitrogen™ Lipofectamine™ 3000 Transfection Reagent (Thermofisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions.
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PMC12842104
Twelve hours after incubation, immediately after E. bicolor xylene extract treatment (62.5 µg/mL), calcium influx was observed with the LionHeart FX microscope.
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PMC12842104
The mitochondrial calcium dynamics were observed using Rhod2-AM (Abcam, USA) as previously described .
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PMC12842104
Cells simultaneously loaded with 5 μM of Rhod2-AM, and 10 μM of MitoTracker Green (ThermoFisher Scientific, Waltham, MA, USA) were treated with E. bicolor xylene extracts (62.5 µg/mL) and fluorescence signals were monitored for 10 min with the LionHeart FX microscope.
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PMC12842104
Cells treated with E. bicolor xylene extract (62.5 µg/mL) for 24 h and incubated at 37 °C for 24 h. Detection of caspase 3 activation with the CellEvent™ Caspase-3/7 Green ReadyProbes™ reagent (ThermoFisher Scientific, Waltham, MA, USA) was performed as described before .
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PMC12842104
As previously reported , Western blotting was carried out with a few changes.
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PMC12842104
Proapoptotic and anti-apoptotic proteins were examined using total cellular protein.
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PMC12842104
Preparation of cell lysates, estimation of total protein concentrations, SDS-PAGE, transfers onto polyvinylidene difluoride (PVDF) membranes (BioRad, Hercules, CA, USA), and probing with antibodies follow the procedure described before .
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PMC12842104
Antibodies used were as follows: anti-beta actin, anti-caspase 9, anti-caspase 8, anti-CHOP, anti-ATF4, anti-FAS, anti-PERK (mouse monoclonal antibody conjugated with HRP; 1:1000, v/v) (Santa Cruz Biotechnology, Dallas, TX, USA), anti-AKT, anti-pAKT (mouse monoclonal antibody conjugated with Alexa 488; 1:1000, v/v) (Santa Cruz Biotechnology, USA).
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PMC12842104
Membranes were washed with Tris-buffered saline containing 0.1% (v/v) Tween 20 (TBST), incubated with enhanced chemiluminescence substrate solution (BioRad, USA), according to the manufacturer’s instructions, and visualized with a ChemiDoc system.
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PMC12842104
For anti-Bcl-2, anti-BAX (rabbit monoclonal antibody; 1:1000, v/v) (Abcam, USA), anti-pPERK, anti-PI3K, anti-XBP1s (rabbit monoclonal antibody; 1:1000, v/v) (Cell Signaling Technology, Danvers, MA, USA), following the overnight incubation, the membranes were incubated with the secondary antibody (Goat Anti-Rabbit IgG H&L, Alexa Fluor 488; 1:500 v/v) (Thermofisher scientific, Waltham, MA, USA) for five minutes each after being rinsed three times in Tris-buffered saline containing 0.1% (v/v) Tween 20 (TBST) for 1 h. Means and standard errors of at least three experiments were calculated.
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PMC12842104
One-way ANOVA was performed, followed by Tukey’s post hoc test to determine significant differences among the means for the antiproliferative (MTS) assays and fold expression analysis of Western blot (to compare DMSO control and E. bicolor xylene extract treatment) using GraphPad Prism 9.4.
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PMC12842104
A p-value < 0.05 was considered statistically significant.
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PMC12842104
Unpaired Welch’s t-test, to compare treated to DMSO control set, was used for TUNEL assays.
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PMC12842104
A two-way ANOVA was performed, followed by the Dunnett test to determine significant differences among the means of Western blot fold expression (to compare DMSO control, E. bicolor xylene extract, and capsaicin treatment).
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PMC12842104
ImageJ 1.5p software, (https://imagej.net/ij/download.html, accessed on 11 November 2023) was used to determine fold protein expression on Western blots.
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PMC12842104
Our study presents for the first time the ROS-mediated antiproliferative activity of E. bicolor xylene extract in T47D cells and TRPV1-dependent antiproliferative activity in MDA-MB-231 cells and their mechanisms of action.
[ { "end": 118, "label": "CellLine", "start": 114, "text": "T47D" }, { "end": 185, "label": "CellLine", "start": 175, "text": "MDA-MB-231" } ]
PMC12842104
E. bicolor xylene extract generates high ROS levels in T47D cells and triggers several apoptotic pathways.
[ { "end": 59, "label": "CellLine", "start": 55, "text": "T47D" } ]
PMC12842104
In contrast, E. bicolor xylene extract activates TRPV1 and induces mitochondrial and endoplasmic reticulum stress-mediated apoptotic pathways in MDA-MB-231 cells.
[ { "end": 155, "label": "CellLine", "start": 145, "text": "MDA-MB-231" } ]
PMC12842104
In addition, E. bicolor xylene extract downregulates the PI3K/AKT signaling pathway in both T47D and MDA-MB-231 cells.
[ { "end": 96, "label": "CellLine", "start": 92, "text": "T47D" }, { "end": 111, "label": "CellLine", "start": 101, "text": "MDA-MB-231" } ]
PMC12842104
Our findings suggest that E. bicolor biochemicals could be used to design cancer cell type-specific therapeutics.
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PMC12514566
Epstein–Barr virus-associated gastric carcinoma (EBVaGC), a distinct subtype of gastric cancer, accounts for approximately 10 % of all gastric cancer cases.
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PMC12514566
2-deoxyglucose (2-DG), a glycolysis inhibitor, has emerged as a crucial tool in cancer therapy.
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PMC12514566
However, the differential effects of 2-DG on EBVaGC and EBV-negative gastric carcinoma (EBVnGC) are not yet fully understood.
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PMC12514566
In this study, we demonstrated that 2-DG inhibited the proliferation of both AGS and AGS-EBV cells, with AGS-EBV cells exhibiting greater sensitivity, particularly under hypoxic conditions.
[ { "end": 80, "label": "CellLine", "start": 77, "text": "AGS" }, { "end": 92, "label": "CellLine", "start": 85, "text": "AGS-EBV" }, { "end": 112, "label": "CellLine", "start": 105, "text": "AGS-EBV" } ]
PMC12514566
Furthermore, EBV infection was found to upregulate glycolytic gene expression in AGS-EBV cells, particularly under hypoxic conditions, through HIF-1α-dependent mechanisms.
[ { "end": 88, "label": "CellLine", "start": 81, "text": "AGS-EBV" } ]
PMC12514566
Notably, 2-DG also inhibited EBV lytic reactivation in AGS-EBV cells under hypoxic conditions.
[ { "end": 62, "label": "CellLine", "start": 55, "text": "AGS-EBV" } ]
PMC12514566
These findings provide valuable insights into the molecular mechanisms of EBV-mediated metabolic reprogramming and highlight the potential of 2-DG as a therapeutic agent for EBVaGC.Epstein–Barr virus (EBV) infects over 90 % of the global population and is a well-established contributor to various human malignancies.
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PMC12514566
Among EBV-related cancers, EBV-associated gastric carcinoma (EBVaGC) is the most prevalent subtype, with an estimated 75,000 to 90,000 new cases diagnosed worldwide each year.
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PMC12514566
Representing approximately 5–10 % of all gastric cancers, EBVaGC is recognized as an independent subtype with distinct clinical, pathological, and molecular characteristics.2, 3, 4 The gold standard for its diagnosis is the detection of EBV-encoded small RNAs (EBERs) through in situ hybridization (ISH).
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PMC12514566
EBERs-ISH results consistently show that both cancer cells and adjacent dysplastic epithelial cells in EBVaGC are EBERs-positive, while surrounding normal gastric mucosal epithelial cells and lymphocytes are EBERs-negative, strongly suggesting that EBV infection precedes malignant transformation.
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PMC12514566
In EBVaGC, EBV typically maintains a non-classical latent type I infection stage, primarily expressing viral products such as EBNA1, EBERs, ebv-miR-BARTs, and ebv-circRNAs, with LMP2A detectable in approximately 50 % of cases.7, 8, 9 These viral factors play crucial roles in maintaining latency and contributing to oncogenesis.
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PMC12514566
Metabolic reprogramming is a well-established hallmark of cancer, where cells often adopt glycolysis as their primary energy source, even in the presence of sufficient oxygen, a phenomenon known as the "Warburg effect".
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PMC12514566
While glycolysis is less efficient at producing ATP than oxidative phosphorylation, its enhanced glycolytic rate in tumor cells provides key metabolites necessary for rapid cell growth and division.
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PMC12514566
This metabolic shift is particularly evident in solid tumors, including gastric cancer, where hypoxic microenvironments frequently develop due to uncontrolled tumor growth outcompeting vascular oxygen supply and aberrant neovascularization.
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PMC12514566
The cellular adaptation to hypoxia is largely orchestrated by hypoxia-inducible factors (HIFs), particularly HIF-1α and HIF-2α.
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PMC12514566
In gastric cancer, studies utilizing gas chromatography-mass spectrometry (GC/MS) have identified significant increases in key glycolytic metabolites, such as fumarate and α-ketoglutarate, in tumor tissues compared to healthy controls.
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PMC12514566
Other studies have reported elevated serum levels of metabolites like 3-hydroxypropionic acid and pyruvate in gastric cancer patients, further emphasizing the critical role of glycolysis in gastric cancer progression.
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PMC12514566
Given the heavy reliance of cancer cells on glycolysis, targeting metabolic pathways, particularly glycolysis, has emerged as an attractive therapeutic strategy.
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PMC12514566
However, the metabolic characteristics of EBVaGC in comparison to EBVnGC, particularly with respect to glycolysis, remain poorly understood.
[ { "end": 48, "label": "CellLine", "start": 42, "text": "EBVaGC" }, { "end": 72, "label": "CellLine", "start": 66, "text": "EBVnGC" } ]
PMC12514566
While some studies have highlighted glycolytic alterations in gastric cancer, it is unclear whether EBVaGC exhibits distinct metabolic features or differences in glycolysis and its response to glycolysis inhibitors.
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PMC12514566
Investigating these differences could provide valuable insights into precision metabolic therapies tailored to EBVaGC, offering potential new strategies for the treatment of this challenging subtype of gastric cancer.
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PMC12514566
In this study, we explored the effects of 2-DG on AGS and AGS-EBV cells, discovering that AGS-EBV cells exhibited greater sensitivity to 2-DG, particularly under hypoxic conditions.
[ { "end": 53, "label": "CellLine", "start": 50, "text": "AGS" }, { "end": 65, "label": "CellLine", "start": 58, "text": "AGS-EBV" }, { "end": 97, "label": "CellLine", "start": 90, "text": "AGS-EBV" } ]
PMC12514566
EBV infection enhanced glycolytic gene expression in AGS-EBV cells through a HIF-1α-dependent mechanism.
[ { "end": 60, "label": "CellLine", "start": 53, "text": "AGS-EBV" } ]
PMC12514566
Furthermore, treatment with 2-DG significantly reduced EBV lytic reactivation in EBVaGC cells under hypoxic conditions.
[ { "end": 87, "label": "CellLine", "start": 81, "text": "EBVaGC" } ]
PMC12514566
Our findings provide new insights into EBV-mediated metabolic reprogramming and underscore the potential of 2-DG as a promising therapeutic approach for EBVaGC.
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PMC12514566
The gastric carcinoma cell lines AGS and SNU719 are cultured in RPMI-1640 medium with 10 % FBS.
[ { "end": 36, "label": "CellLine", "start": 33, "text": "AGS" }, { "end": 47, "label": "CellLine", "start": 41, "text": "SNU719" } ]
PMC12514566
Akata-EBV-GFP is an Akata Burkitt lymphoma cell line that carries a GFP-tagged Akata bacterial artificial chromosome (BAC) and is cultured in RPMI-1640 medium with 10 % fetal bovine serum (FBS) (Gibco, Carlsbad, CA, USA).
[ { "end": 25, "label": "CellLine", "start": 20, "text": "Akata" }, { "end": 47, "label": "CellLine", "start": 26, "text": "Burkitt lymphoma cell" } ]
PMC12514566
The GFP fluorescein gene, introduced via recombinant EBV, is integrated into the open reading frame of the lytic gene BXLF1.
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PMC12514566
For EBV production, Akata-EBV-GFP cells were treated with 0.5 % (v/v) goat anti-human IgG for 8 h to induce the transition of EBV from the latent phase to the lytic cycle.
[ { "end": 33, "label": "CellLine", "start": 20, "text": "Akata-EBV-GFP" } ]
PMC12514566
Afterward, the medium was replaced with fresh medium containing 5 % FBS, and the cells were co-cultured with AGS cells that had been pre-treated with basic medium for 24 h. The culture flask was gently shaken every 4 h to ensure adequate contact between the Akata-EBV-GFP cells and AGS cells.
[ { "end": 112, "label": "CellLine", "start": 109, "text": "AGS" }, { "end": 271, "label": "CellLine", "start": 258, "text": "Akata-EBV-GFP" }, { "end": 285, "label": "CellLine", "start": 282, "text": "AGS" } ]
PMC12514566
The medium was partially changed every 24 h, and finally, the Akata cells were thoroughly washed.
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PMC12514566
The cells were then maintained in culture medium containing 700 μg/mL G418 (Sangon Biotech, Chengdu, China).
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PMC12514566
Briefly, 1 × 10^5 indicated cells were seeded in a 6-well plate and treated with either 0 or 5 mM 2-DG under normoxic (21 % O2) or hypoxic (1 % O2) conditions for 48 h. Following the treatment, cells were collected and stained with 0.4 % Trypan Blue (1:9 ratio) for 5 min.
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PMC12514566
Viable cells were then counted using a hemocytometer.
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PMC12514566
For RNA interference experiments, siRNAs targeting HIF1-α and HIF2-α were synthesized by RiboBio (Guangzhou, China).
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PMC12514566
Transfections were performed using Lipo3000 (Invitrogen, Life Technologies, Carlsbad, CA, USA) according to the manufacturer's instructions.
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PMC12514566
Here is the sequence: siHIF-1α: CCAGCAACTTGAGGAAGTA; siHIF-2α: GGCCCTCATTTGAGTCCTA.
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PMC12514566
Total RNA was isolated from the cells according to the AG RNAex Pro Reagent manual (AG, Changsha, China).
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PMC12514566
The extracted RNA was then reverse transcribed using the Evo M-MLV RT Kit with gDNA Clean (AG), following the manufacturer's protocol.
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PMC12514566
The RT-qPCR was carried out on the LightCycler 480 (Roche, Basel, Switzerland) using the SYBR Green Premix Pro Taq HS qPCR Kit (AG) in accordance with the manufacturer's guidelines.
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PMC12514566
Each sample was analyzed in three biological replicates, with each biological replicate including three technical replicates for robustness and accuracy.
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PMC12514566
The RT-qPCR data were evaluated using the relative quantification method (2), with ACTB as the internal reference for normalization.
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PMC12514566
Primer sequences: ACTB-F: CACCATTGGCAATGAGCGGTTC.
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PMC12514566
ACTB-R: AGGTCTTTGCGGATGTCCACGT.
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PMC12514566
HIF1α-F: TATGAGCCAGAAGAACTTTTAGGC.
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PMC12514566
HIF1α-R: CACCTCTTTTGGCAAGCATCCTG.
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PMC12514566
GLUT1-F: TTGCAGGCTTCTCCAACTGGAC.
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PMC12514566
GLUT1-R: CAGAACCAGGAGCACAGTGAAG.
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PMC12514566
HK2-F: GAGTTTGACCTGGATGTGGTTGC.
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PMC12514566
HK2-R: CCTCCATGTAGCAGGCATTGCT.
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