Single-cell sequencing of carfilzomib-associated HSV-1 encephalitis mouse model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE328235 | GEO | 2026/04/21
REPOSITORIES: GEO
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Project description:This study investigates the molecular mechanisms underlying the interaction between Carfilzomib (CFZ) and Herpes Simplex Virus type 1 (HSV-1) infection in microglial cells. Using the BV2 microglial cell line, we performed RNA sequencing to dissect the transcriptional responses under different conditions. Cells were either infected with HSV-1 (MOI=1) for 24 hours or left uninfected, and subsequently treated with 30 nM Carfilzomib (CFZ) or the vehicle control (DMSO) 6 hours post infection.
2026-04-21 | GSE328236 | GEO
Project description:KMS-11 and KMS-34 cells were exposed to stepwise increasing concentrations of carfilzomib over a period of 18 weeks: cells adapted to growth in 4 nM carfilzomib by 4 weeks, in 6 nM in another 6 weeks and in 12 nM after a further 8 weeks. The resulting cell cultures, denoted KMS-11/Cfz and KMS-34/Cfz, respectively, retained resistance to carfilzomib even when tested after removal of selective pressure for approximately 8 weeks. KMS-11/Cfz and KMS-34/Cfz cells were profiled for gene expression after 1 week of growth in the absence of carfilzomib together with parental KMS-11 and KMS-34 cells which had not been selected in the drug (triplicate samples).
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Project description:KMS-11 and KMS-34 cells were exposed to stepwise increasing concentrations of carfilzomib over a period of 18 weeks: cells adapted to growth in 4 nM carfilzomib by 4 weeks, in 6 nM in another 6 weeks and in 12 nM after a further 8 weeks. The resulting cell cultures, denoted KMS-11/Cfz and KMS-34/Cfz, respectively, retained resistance to carfilzomib even when tested after removal of selective pressure for approximately 8 weeks.
2015-07-09 | GSE69078 | GEO
Project description:LP-1 cells were exposed to stepwise increasing concentrations of carfilzomib over a period of 18 weeks: cells adapted to growth in 4 nM carfilzomib by 4 weeks, in 6 nM in another 6 weeks and in 12 nM after a further 8 weeks. The resulting cell culture, denoted LP-1/Cfz, retained resistance to carfilzomib even when tested after removal of selective pressure for approximately 8 weeks.
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Project description:Jurkat cells were treated with either Carfilzomib (CFZ) or DMSO for 1h before Spautin-1 or DMSO as a control were added for 4 h. As an additional condition, Cells were treated only with CFZ for 1h before being harvested. This experiment should show the potential alterations of protein ubiquitination caused by the respective compounds and the effect of CFZ on the ubiquitome after 1 and 5h.
2025-05-31 | PXD062845 | Pride
Project description:Carfilzomib (CFZ) is a proteasome inhibitor commonly used in the treatment of multiple myeloma, but its clinical application is limited due to its cardiotoxicity. The Neiguan acupoint (PC6) stimulation has been reported to effectively improve cardiac function, but its regulatory mechanism remains unclear. The aim of this study was to investigate the effect and underlying mechanism of electroacupuncture (EA) against CFZ-induced cardiotoxicity in C57BL/6 mice. According to our results, EA treatment significantly reversed CFZ-induced ejection fraction and fractional shortening reduction, which showed great potential effect for heart protection. By using RNA-sequencing, we compared the transcriptome profile of heart samples from DMSO control, CFZ injection, and EA treatment mice, and nearly 40,000,000 valid sequence reads aligned with 20,000 genes from six libraries were obtained. A total of 770 differentially expressed genes (DEGs) were identified in the CFZ (vs. Control) group, including 65 up-regulated and 705 down-regulated genes. Meanwhile, 329 DEGs were obtained in the EA (vs. CFZ) group, including 251 up-regulated and 78 down-regulated genes. Our results shed new insights into the regulatory mechanism of EA at PC6 against CFZ-induced cardiotoxicity, which could further provide theoretical basis for clinical EA therapy.
2025-09-01 | GSE243878 | GEO
Project description:Carfilzomib (CFZ) is a cornerstone in the treatment of relapsed multiple myeloma (MM). However, its efficacy is limited by resistance mediated by the overexpression of the ABC-transporter P-glycoprotein (P-gp).The signaling pathways driving emergence of P-gp in MM remain unclear. To investigate this, we generated CFZ-resistant AMO-1/CFZ cells with P-gp overexpression by long-term selection. RNA sequencing of control AMO-1 and AMO-1/CFZ, sorted into two subpopulations P-gp HIGH and P-gp LOW, implicated the Ras/MEK/ERK pathway as the most likely signaling cascade involved in P-gp upregulation. We therefore evaluated two clinically used MAPK pathway inhibitors, cobimetinib and ulixertinib, for their ability to re-sensitize AMO-1/CFZ cells to CFZ. Co-administration at non-toxic concentrations enhanced sensitivity 5-fold with cobimetinib and 17-fold with ulixertinib. Analysis of combined MTT assay results, rhodamine efflux experiments, molecular docking, and western blotting revealed distinct actions. Ulixertinib primarily functions as a potent direct P-gp inhibitor. Conversely, non-toxic concentrations of cobimetinib sensitizes cells by suppressing MAPK signaling, though it also exhibits P-gp inhibition at higher concentrations. Both inhibitors at the IC₅₀ concentration reduced P-gp expression. In conclusion, combining CFZ with MAPK pathway inhibitors like cobimetinib or ulixertinib represents a promising strategy to overcome P-gp-mediated resistance in ММ.
2025-11-23 | GSE310880 | GEO
Project description:Carfilzomib-sensitive (AMO1) and resistant (AMO1-CFZ) MM cells were grown in RPMI-1640 medium supplemented with 10 % FBS and 0.68 mM L-glutamine, in a humidified incubator at 5% CO2 and 37 °C. The AMO1-CFZ medium was additionally added 90 nM CFZ, while the CFZ sensitive AMO1 cells were added vehicle (0.009 % DMSO) only. AMO1-CFZ was either harvested directly or grown for 1 week in CFZ free medium (vehicle only) prior to harvest. AMO1 and carfilzomib-resistant AMO1-CFZ cells were resuspended in 100 µl 1% sodium deoxycholate, 100 mM Tris-HCl pH 8.5, 10 mM tris(2-carboxyethyl)phosphine (TCEP), 40 mM chloroacetamide (CAA), heated at 90 °C for 45 min and sonicated for 10 cycles (30 s ON/30 s OFF) using a Bioruptor pico sonicator. After centrifugation at 16000 × g for 10 min, 50 µg soluble protein from each sample was added 100 µl 0.1M ammonium bicarbonate, 0.5 µg trypsin and digested overnight at 37°C. Peptides were desalted using C18 spin columns, dried in a speedvac centrifuge and resuspended in 0.1% formic acid prior to MS analysis. Label-free quantitatative (LFQ) LC-MS/MS was performed on a timsTOF Pro (Bruker Daltonics) connected to a nanoElute (Bruker Daltonics) HPLC. Peptides were separated over a Bruker PepSep C18 (75 µm × 15 cm) column with running buffers A (0.1 % formic acid) and B (0.1 % formic acid in acetonitrile) using a 100 min gradient from 2 % B to 40 % B. The timsTof instrument was operated in the DDA PASEF mode with 10 PASEF scans per acquisition cycle and accumulation and ramp times of 100 ms each. The ‘target value’ was set to 20000 and dynamic exclusion was activated and set to 0.4 min. The quadrupole isolation width was set to 2 Th for m/z < 700 and 3 Th for m/z > 800.
2024-06-07 | PXD045439 | Pride
Project description:Carfilzomib has a good effect in treating multiple myeloma, but more and more clinical studies have shown that the drug can cause cardiac toxicity during use, but the mechanism of action is unclear. This study aimed to comprehensively elucidate the mechanism of CFZ-induced cardiomyopathy by constructing a C57BL/6 mouse model and combining cell experiments. The research results showed that the hearts of mice treated with CFZ appeared significantly enlarged, and the cardiac function indicators decreased. The serum enzyme LDH, AST, and CK-MB levels significantly increased, suggesting severe myocardial injury. RNA extraction and QPCR detection of the heart showed that the expression of heart hypertrophy and fibrosis markers increased. Meanwhile, histological staining found that there were fewer cardiomyocytes, damaged myofibrils, and cardiac fibrosis. In the cell experiments, CFZ treatment caused the release of more LDH from rat cardiomyocytes and H9C2 cells, increased CASPASE 3/7 activity, abnormal cell morphology, enlarged cell size, myocardial hypertrophy and fibrosis marker gene expression in cardiomyocytes. Through the study of the SUMOYLATION pathway, it was found that CFZ's effects on cardiomyocyte structure and function were related to the expression of SENP genes, especially SENP1, which showed a significant downregulation in cardiomyocytes and mouse heart tissue, and was positively correlated with the levels of cardiac injury marker genes. This study further explored the mechanism of action by specifically altering the expression of SENP1 in cardiomyocytes. The results show that the knockdown of SENP1 in cardiomyocytes leads to more severe myocardial damage after CFZ treatment, suggesting that the expression of SENP1 can potentially affect the cardiotoxicity caused by CFZ. Further, by using silver staining and mass spectrometry to identify the interacting proteins with SENP1 after CFZ treatment, we found that the knockdown of DDX17 had a similar myocardial injury effect as SENP1. Subsequently, through Co-IP, protein stability experiments, and ubiquitination analysis experiments, we determined that SENP1 can maintain the protein stability of DDX17 by inhibiting its SUMO modification, thereby preventing cardiomyocyte injury and apoptosis. We hope to provide a new perspective and potential cardioprotective strategy for clinical use.
2024-08-10 | GSE273971 | GEO
Project description:Bortezomib (BTZ), Carfilzomib (CFZ) and Ixazomib (IXA) are proteasome inhibitors (PI) approved for Multiple Myeloma (MM) treatment. By design, they all target the rate-limiting proteasome beta 5 (B5) subunit. CFZ treatment increases the survival of patients with relapsed/refractory MM compared to BTZ but is associated with heart failure not commonly observed for BTZ. The molecular basis for CFZ-induced cardiotoxicity is poorly understood. We time to investigate the transcriptomic effects of acute proteasome inhibition in the murine heart.
2023-07-01 | E-MTAB-11028 | biostudies-arrayexpress