A ketogenic diet can revert acquired resistance to immunotherapy in prostate cancer through β-hydroxybutyrate-mediated inhibition of histone deacetylases
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ABSTRACT:
PROVIDER: PRJNA851379 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19796040.fastq.gz | Fastqsanger.gz | |||
| SRR19796041.fastq.gz | Fastqsanger.gz | |||
| SRR19796042.fastq.gz | Fastqsanger.gz | |||
| SRR19796043.fastq.gz | Fastqsanger.gz | |||
| SRR19796044.fastq.gz | Fastqsanger.gz |
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Project description:Prostate cancer is the second leading cause of cancer deaths in men in the US. In the past decade, immune checkpoint blockade (ICB) drugs targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have revolutionized the field of cancer therapeutics, but the objective response rate in prostate cancers is in the low single digits. A major complicating issue is that immunotherapies can have significant adverse effects, so there is a clinical need for novel combinatorial strategies that do not involve additional or compounding adverse effects. We developed a model system of advanced prostate cancer that has acquired resistance to ICB therapy. The PD-1 resistant sublines showed strong downregulation of the mouse major histocompatibility complex (MHC-I), which was reversed by treating cells with either the pan-histone deacetylase (HDAC) inhibitor Vorinostat or β-hydroxybutyrate. When mice bearing these ICB resistant tumor are treated with either Vorinostat, with a cyclical ketogenic diet (CKD), or with a 1,3-butanediol diet (BD), tumors are resensitized to ICB therapy. We analyzed changes in the tumor immune microenvironment and showed that this effect is driven by a shift in monocyte differentiation, changing from M2 polarized immunosuppressive macrophages into iNOS+ dendritic cells instead. This differentiation is dependent on an ICB-induced increase in CD40L+ CD8+ T-cells in the tumor immune microenvironment. Our results indicate a novel mechanism in which a ketogenic diet can be used to increase therapeutic efficacy of ICB therapy.
2024-02-13 | GSE206561 | GEO
Project description:Suppression of colorectal cancer by ketogenic diet and beta-hydroxybutyrate
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Project description:Rationale: Sepsis patients suffer from severe metabolic and immunologic dysfunction that may be amplified by standard carbohydrate-based nutritional regimes. We therefore hypothesize that a ketogenic diet improves sepsis treatment. Objectives: We investigated the safety and feasibility of a ketogenic diet in sepsis patients. Methods: We conducted a monocentric open-labeled randomized controlled trial (DRKS00017710) enrolling adult sepsis patients randomly assigned to either ketogenic or standard high-carbohydrate diet for 14 days with follow-up until day 30. The primary outcome measure was β-hydroxybutyrate serum concentration on day 14. Secondary outcomes included safety, clinical and immunological changes. Measurements and Main Results: 40 critically ill septic patients were assigned to the study groups. Increase in β-hydroxybutyrate concentrations from baseline to day 14 was markedly greater under ketogenic diet (1.2 ±0.9) compared to controls (-0.3 ±0.4); estimated mean difference 1.4 (95%-CI 1.0-1.8; p<0.0001). During ketogenic diet, no patient required insulin treatment beyond day 4, whereas 35% to 60% of control patients did (p=0.0095). Metabolic side effects were not observed under ketogenic diet. Ventilation-free (IRR 1.7; 95%-CI: 1.5 to 2.1; p<0.0001), vasopressor-free (IRR 1.7; 95%-CI: 1.5 to 2.0; p<0.0001), dialysis-free (IRR 1.5; 95%-CI: 1.3 to 1.8; p<0.0001), and ICU-free days (IRR 1.7; 95%-CI: 1.4 to 2.1; p<0.0001) significantly increased in patients under ketogenic diet. There was no difference in 30-day mortality. Analyses indicated favorable changes towards immune homeostasis. Conclusions: Ketogenic diet is a feasible and safe nutritional regimen in septic patients promoting recovery from sepsis-related organ dysfunction and could become a new tool in modern treatment concepts.
2024-06-13 | PXD046061 | Pride
Project description:The ketone body β-hydroxybutyrate (BHB) is produced during dietary restriction, fasting, and exercise. A ketogenic diet (KD) results in long-term production of BHB outside of these contexts. We sought to determine a protein-matched, non-obese ketogenic diet (KD) would affect the longevity and healthspan of C57BL/6 male mice. We find that feeding KD every-other-week to prevent obesity (cyclic KD) reduces mid-life mortality but does not affect maximum lifespan. Similar feeding of a non-ketogenic high-fat/low-carbohydrate (HF) diet may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite measures of healthspan. RNAseq gene expression analysis identifies down-regulation of insulin, TOR, and fatty acid synthesis pathways as possible longevity mechanisms common to KD and HF. However, up-regulation of fasting-related PPARα target genes is unique to KD, consistent across tissues, and preserved in old age, suggesting a mechanism for an incremental benefit from KD. In all, we show that a non-obese ketogenic diet improves survival, memory, and healthspan into old age. These gene expression studies were carried out on 12 month-old male C56BL/6 mice from the NIA Aged Rodent Colony, habituated to AIN-93M control diet and then either maintained on this diet or switched for one week to a 75% kcal fat non-ketogenic high-fat diet or a 90% kcal fat ketogenic diet (all diets with 10% kcal from carbohydrates). Tissues were harvested in the middle of the nighttime feeding period (MN-3am).
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Project description:Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus, and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granular cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed upon exogenous administration of beta-hydroxybutyrate. These data suggests that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders. We used microarrays to query global gene expression changes in the hippocampus of wild type and Kmt2d+/βGeo (Kabuki syndrome model) mice on a regular diet to identify specific gene expression abnormalities in the hippocampus of the Kabuki syndrome mouse model.
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Project description:The ketogenic diet has long been used to treat epilepsy, but its mechanism is not yet clearly understood. To explore the potential mechanism, the changes in gene expression induced by the ketogenic diet in the rat kainic acid (KA) epilepsy model were analyzed. Two-condition experiment, Normal diet-fed rat brain vs. Ketogenic diet-fed rat brain. Duplicate per array
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Project description:Specific pathogen free wild-type C57Bl/6 male mice fed ketogenic diet (Bio-Serv AIN-76-A) for 4 weeks Keywords: RNA Expression Array Hearts from 12 week-old mice that were maintained on a standard polysacchardide-rich chow until the age of 8 weeks, at which time they were switched to a ketogenic diet (ad libitum) and maintained for 4 additional weeks prior to collection of tissues
2010-06-16 | E-GEOD-21368 | biostudies-arrayexpress
Project description:The experiment was carried out in triplicates in untreated, etomoxir treated and etomoxir plus beta-hydroxybutyrate (3HB) treated conditions. MES83 (Glioma-derived Mesenchymal stem cells) were either untreated or treated with 40uM of etomoxir alone or in combination with 0.5mM of beta-hydroxybutyrate for 48 hrs. The cells were collected and total RNA was extracted and the library was prepared according to the manufacturer protocol.
2020-03-31 | E-MTAB-8017 | biostudies-arrayexpress
Project description:The ketogenic diet has long been used to treat epilepsy, but its mechanism is not yet clearly understood. To explore the potential mechanism, the changes in gene expression induced by the ketogenic diet in the rat kainic acid (KA) epilepsy model were analyzed.
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Project description:Mice on two different ketogenic diets induce p53 and cellular senescence in multiple organs, including heart and kidney. This is mediated through inactivation of MDM2 by caspase-2 cleavage, leading to p53 accumulation and induction of p21. Ketogenic diet also induced pAMPK, suggesting that persistent activation leads to p53-dependent senescence.
2024-04-12 | GSE233831 | GEO